CN104513252A - Substituted urea derivatives and application thereof in drugs - Google Patents

Substituted urea derivatives and application thereof in drugs Download PDF

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

The invention provides substituted urea derivatives or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutical compositions thereof. The compounds can be used for regulating the activity of FLT3 kinase and inhibiting FLT3-ITD kinase, and besides, can be used for treatment of FLT3 mediated or FLT3-ITD caused diseases.

Description

Substituted urea derivative and the application in medicine thereof
Invention field
The invention belongs to pharmacy field.The invention provides the new substituted urea derivative of a class and composition thereof and be used for the treatment of the purposes of the disease that flt3 mediation or flt3-ITD cause.This compounds is a kind for the treatment of, alleviation or the prevention disease relevant with tyrosine kinase activity or illness, or the new substituted carbamide compounds of the purposes of its one or more symptoms.
Background of invention
Protein kinase (PKs) is the enzyme of the oh group phosphorylation in the tyrosine of catalytic proteins, Serine and threonine residues.Protein kinase, especially receptor protein tyrosine kinase (RTK) race of protein kinase, mainly as growth factor receptors, control important role, such as cell cycle, Growth of Cells, cytodifferentiation and necrocytosis at the signal transduction pathway of many cell functions.The imbalance that receptor protein tyrosine kinase (RPTK) is active or excessive, erratic activity are observed under numerous disease situation, comprise optimum with pernicious Proliferative Disorders, inflammatory conditions, immune system disorder, it is caused by the unsuitable activation of immunity system, can cause such as autoimmune disease.
For the irregular activity of the receptor tyrosine kinase of PDGF acceptor (PDGFR) race, as wherein one example, have been found that it is relevant with various Proliferative Disorders.The gene amplification of PDGFR or rise generation in the patient suffering from neurospongioma or sarcoma (see Kumabe etc., Oncogene, (1992) 7:627-633; Ostman and Heldin Cancer Res. (2001) 80:1-38).A member of PDGFR race, Flt3 (also referred to as Flk-2), play an important role in the propagation and variation of hemopoietic stem cell, the activated mutant of this receptor or overexpression are found 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, and some are expected to the clinical effectiveness (see Levis etc., lnt J Hematol. (2005) 82:100-107) obtaining anti-AML.Flt3 acceptor is also expressed in large quantities of dendritic cell precursor, and stimulates this receptor to cause these precursor cells propagation and differentiation to become dendritic cell (DC).Due to the main initiators that dendritic cell are the cell-mediated immunne responses (comprising spontaneous immunne response) of T-, Flt3 restraining effect lowers the inflammation of DC-mediation and the mechanism of autoimmune response.Research display Flt3 inhibitor C EP-701 can reduce Autoimmune Encephalomyelitis (EAE) experiment effectively, myelin loss (see Whartenby etc., PNAS (2005) 102:16741-16746) in multiple cerebral sclerosis mouse models.High-caliber Flt3 part is found in the patients serum suffering from Langerhans cell histiocytosis and systemic lupus erythematous, this implies further, Flt3 carries out intracellular signaling (see Rolland etc., J Immunol. (2005) 174:3067-3071) in the dendritic cell precursor imbalance of those autoimmune diseases.
It is reported, some suppresses the small molecules of kinases FLT3 can the effective apoptosis of FLT3 kinase mutant in inducible cell line, and can extend and suffer from lifetime of mouse that medullary cell FLT3 suddenlys change (see Levis etc., Blood (2002) 99:3885-3891; Kelly etc., Cancer Cell 1 (2002): 421-432; Weisberg etc., Cancer Cell 1 (2002) 433-443; Yee etc., Blood (2002) 100:2941-2949).
The ITD that FLT3 internal series-connection repeats is activated (flt3-ITD), finds, and be associated with some poor prognosis in the acute myelocytic leukemia people of about 20%.A large amount of experimental datas and clinical data, comprise the shortage of the clinical event of early stage FLT3 inhibitor, makes cancer occur when proving that FLT3-ITD plays, time and the role of the health pathology that cancer is maintained.Reporting, in some patient, have the trend of recurrence especially after the treatment, may be because flt3 kinase mutant (see the .Blood such as Heidel, F. (2006) 107:293 – 300.).There are some researches show, FLT3-ITD inhibitor play a part hinder bring out Incidence mechanism role and in patient AML effective therapeutic goal (see Catherine etc., Nature (2012) 485:260-263).
The sudden change of Flt3 often occurs in AML patient and comprises the other coding region of repetition (ITD) of internal series-connection of film or the tyrosine kinase domain (TKD) of the sudden change of point.FLT3-ITD and FLT3-TKD sudden change causes part independently to spread due to the dimerisation of flt3 acceptor and activity.The ratio of the height variation wild-type allele of FLT3-ITD be grown up and the poor prognosis relevant (see AS Moore etc., Leukemia (2012) 26:1462-1470) of child.
The treatment that investigators are used for cancer for exploitation kinase inhibitor has sizable interest, has wherein had and has reported that urea derivatives can as selectivity Flt3 inhibitor.
Abstract of invention
The invention provides for the substituted carbamide derivative of pharmacological agent and pharmaceutical composition thereof with for regulating Flt3 kinase activity and for suppressing a series of substitute urea compound of FLT3-ITD and being used for the treatment of the purposes of the disease that flt3 mediation or flt3-ITD cause.
On the one hand, the invention provides a kind of compound, it is the shown compound of formula (I) or the steric isomer of the shown compound of formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
Q and W is CH or N independently of one another;
G is-O-,-S (=O) t-,-S-,-C (=O)-or five yuan of inferior heteroaryls;
R is-NR 3r 2, alkoxyl group, alkyl, thiazolinyl, alkynyl, haloalkyl, alkyl-S (=O) t-, alkoxyalkyl, hydroxyalkyl, hydroxy alkoxy base, aminoalkoxy, halogenated alkoxy, alkylamino halogenated alkoxy, alkylaminoalkoxy, alkyloxy-alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkyl oxy, cycloalkyl amino, heterocyclic radical, cycloheteroalkylalkyl, heterocyclic radical alkylamino, heterocyclylalkoxy, heterocyclyloxy base alkoxyl group, heterocyclyloxy base, carbocylic radical oxygen base alkoxyl group, carbocyclylalkoxy, carbocylic radical alkylamino, aryl, arylalkyl, aryloxy alkoxyl group, aryloxy, alkoxy aryl, aryl alkane amino, heteroarylalkyl, heteroaryl, heteroarylalkoxy, heteroarylalkylamino, heteroaryl oxygen base, heteroaryl oxygen base alkoxyl group, condensed-bicyclic base oxygen base, condensed-bicyclic base alkyl, condense assorted bicyclic group alkyl, condense assorted bicyclic group oxygen base, condense assorted bicyclic group amino, condense assorted bicyclic group alkoxyl group, condense assorted bicyclic group alkylamino, condense assorted bicyclic group oxygen base alkoxyl group, condense assorted bicyclic group oxygen base alkylamino, spiral shell is mixed bicyclic group alkyl, spiral shell is mixed bicyclic group alkoxyl group, bridge is mixed bicyclic group alkyl, bridge is mixed bicyclic group oxygen base, bridge is mixed bicyclic group alkoxyl group, bridge is mixed bicyclic group alkylamino, bridge is mixed bicyclic group, spiral shell is mixed bicyclic group or condense assorted bicyclic group,
K is the heteroaryl groups of 5-6 unit; Have 2 heteroatomss in wherein said heteroaryl groups at least, each heteroatoms is O, S, NR independently 4or N;
Each L is amino independently, nitro, C 1-4alkylthio, C 1-6alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 1-4haloalkyl, C 1-4alkylamino, hydroxyl, fluorine, chlorine, bromine, iodine, C 1-4alkyl-C (=O)-NH-, C 1-4alkoxyl group, hydroxyl C 1-4alkyl or cyano group;
E is bicyclic heteroaryl group;
Each R 1be hydrogen independently, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-6alkoxy C 1-6alkyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, C 1-4alkyl-C (=O)-NH-, C 1-4alkoxyl group, hydroxyl C 1-4alkyl or C 1-4alkylthio;
Each R 3and R 2be hydrogen independently, C 1-6alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Each R 4be H, C independently 1-4alkyl, C 3-10cycloalkyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Each d is 1,2,3 or 4 independently;
Each n is 1,2,3 or 4 independently;
Each t is 0,1 or 2 independently;
Each a is 0,1,2,3 or 4 independently;
Wherein, described aryl, bicyclic heteroaryl group, heteroaryl groups ,-(CH 2) n-C (=O)-, alkoxyl group, alkyl-S (=O) t-,-G-(CH 2) n-R, alkoxyalkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, heteroaryl, heterocyclic radical, bridge is mixed bicyclic group, spiral shell is mixed bicyclic group, condense assorted bicyclic group, alkyl, haloalkyl, alkylamino, hydroxy alkoxy base, aminoalkoxy, halogenated alkoxy, thiazolinyl, alkynyl, cycloalkylalkyl, cycloheteroalkylalkyl, alkoxyalkyl, hydroxyalkyl, alkylamino halogenated alkoxy, alkylaminoalkoxy, alkyloxy-alkoxy, cycloalkyl oxy, alkoxy aryl, aryl alkane amino, heteroarylalkoxy, heteroarylalkylamino, heterocyclic radical alkylamino, cycloalkyl oxy, cycloalkyl amino, heterocyclylalkoxy, carbocyclylalkoxy, carbocylic radical alkylamino, aryloxy alkoxyl group, aryloxy, heteroaryl oxygen base, heteroaryl oxygen base alkoxyl group, heterocyclyloxy base alkoxyl group, carbocylic radical oxygen base alkoxyl group, heterocyclyloxy base, condensed-bicyclic base oxygen base, condensed-bicyclic base alkyl, condense assorted bicyclic group alkyl, condense assorted bicyclic group oxygen base, condense assorted bicyclic group amino, condense assorted bicyclic group alkoxyl group, condense assorted bicyclic group alkylamino, condense assorted bicyclic group oxygen base alkoxyl group, condense assorted bicyclic group oxygen base alkylamino, spiral shell is mixed bicyclic group alkyl, spiral shell is mixed bicyclic group alkoxyl group, bridge is mixed bicyclic group alkyl, bridge is mixed bicyclic group oxygen base, bridge is mixed bicyclic group alkoxyl group, bridge is mixed bicyclic group alkylamino, alkyl-C (=O)-NH-, alkylthio and cycloalkyl, can independently by hydrogen, aminoalkyl group, aminoacyl, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, C 1-4alkyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C 1-4alkyl-C (=O)-, C 2-10heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, wherein, described E is one of heteroaryl groups of following subformula formation:
Wherein, X, Y, Z, Z 1, Z 2, Z 3and Z 4be N or CH independently of one another;
T and T 1be-O-,-S-,-NR independently of one another 4-or-CH 2-;
Wherein, the X on described E ring, Y, Z, T, T 1, Z 1, Z 2, Z 3and Z 4there are two for heteroatoms at least simultaneously;
R is-NR 3r 2, C 2-4thiazolinyl, C 2-4alkynyl, C 3-10cycloalkyl, C 3-10cycloalkyl C 1-4alkyl, C 2-10heterocyclic radical C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-6alkoxy C 1-6alkyl, hydroxyl C 1-4alkyl, hydroxyl C 1-4alkoxyl group, amino C 1-4alkoxyl group, halo C 1-4alkoxyl group, C 1-4alkylamino halo C 1-4alkoxyl group, C 1-4alkylamino C 1-4alkoxyl group, C 1-4alkoxy C 1-4alkoxyl group, C 3-10cycloalkyl oxy, C 6-10aryl C 1-4alkoxyl group, C 6-10aryl C 1-4alkylamino, C 1-9heteroaryl C 1-4alkoxyl group, C 1-9heteroaryl C 1-4alkylamino, C 2-10heterocyclic radical C 1-4alkylamino, C 3-10cycloalkyl oxy, C 3-10cycloalkyl amino, C 2-10heterocyclic radical C 1-4alkoxyl group, C 3-10carbocylic radical C 1-4alkoxyl group, C 3-10carbocylic radical C 1-4alkylamino, C 6-10aryloxy C 1-4alkoxyl group, C 6-10aryloxy, C 1-9heteroaryl oxygen base, C 1-9heteroaryl oxygen base C 1-4alkoxyl group, C 2-10heterocyclyloxy base C 1-4alkoxyl group, C 3-10carbocylic radical oxygen base C 1-4alkoxyl group, C 2-10heterocyclyloxy base, C 1-4alkoxyl group, C 1-4alkyl, C 1-4haloalkyl, C 6-10aryl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 1-9heteroaryl,
Or R is following subformula:
Wherein, each X 8, X 9and X 10be N or CH independently;
Each X 1, X 2, X 3, X 4, X 5, X 6and X 7be-CH independently 2-,-O-,-NR 4a-,-S (=O) t-or-S-;
Each q, m, p, r and s are 0,1,2,3 or 4 independently;
Each R 3and R 2be C independently 1-6alkyl, C 3-10cycloalkyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Each R 4be H, C independently 1-4alkyl, C 3-10cycloalkyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Wherein, each subformula representated by described E and each R, all can independently by hydrogen, aminoalkyl group, aminoacyl, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, C 1-4alkyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C 1-4alkyl-C (=O)-, C 2-10heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
In other embodiments, wherein said E is one of heteroaryl groups of following subformula formation:
R is-NR 3r 2, C 2-4thiazolinyl, C 2-4alkynyl, C 2-10heterocyclic radical C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-4alkoxy C 1-4alkyl, hydroxyl C 1-4alkyl, hydroxyl C 1-4alkoxyl group, amino C 1-4alkoxyl group, halo C 1-4alkoxyl group, C 1-4alkylamino halo C 1-4alkoxyl group, C 1-4alkylamino C 1-4alkoxyl group, C 1-4alkoxy C 1-4alkoxyl group, C 1-4alkoxyl group, C 1-4alkyl, C 1-4haloalkyl, C 1-9heteroaryl C 1-6alkyl or
R is following subformula:
Each R 3and R 2be methyl independently, ethyl, n-propyl, sec.-propyl, the tertiary butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Wherein, each subformula representated by described E and each R, all can independently by hydrogen, aminoalkyl group, aminoacyl; fluorine, chlorine, bromine, iodine, trifluoromethyl; chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl; sec.-propyl, dimethylamino, methylamino, diethylamino, ethylamino; hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-; ethyl-C (=O)-, n-propyl-C (=O)-, sec.-propyl-C (=O)-, C 2-10heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, wherein said G is-O-or furylidene.
In some embodiments, wherein said K is one of heteroaryl groups of subformula formation as follows:
Each L is cyclopropyl independently, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6heterocyclylalkyl, amino, cyano group, nitro, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, methyl, ethyl, butyl, n-propyl, sec.-propyl, the tertiary butyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, C 1-4alkyl-C (=O)-NH-, C 1-4alkoxyl group, hydroxyl C 1-4alkyl or C 1-4alkylthio.
In some embodiments, the invention provides a kind of substituted carbamide derivative, it is the steric isomer of compound shown in the compound shown in formula (II) or formula (II), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
Q and W is CH or N independently of one another;
Each R 1be hydrogen independently, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-6alkoxy C 1-6alkyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, C 1-4alkyl-C (=O)-NH-, C 1-4alkoxyl group, hydroxyl C 1-4alkyl or C 1-4alkylthio;
Each L is the tertiary butyl independently;
D is 1;
Each n is 1,2,3 or 4 independently;
Each t is 0,1 or 2 independently;
Each a is 0,1,2,3 or 4 independently;
E is one of heteroaryl groups of following subformula formation:
R is-NR 3r 2, C 2-4thiazolinyl, C 2-4alkynyl, C 2-10heterocyclic radical C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-4alkoxy C 1-4alkyl, hydroxyl C 1-4alkyl, hydroxyl C 1-4alkoxyl group, amino C 1-4alkoxyl group, halo C 1-4alkoxyl group, C 1-4alkylamino halo C 1-4alkoxyl group, C 1-4alkylamino C 1-4alkoxyl group, C 1-4alkoxy C 1-4alkoxyl group, C 1-4alkoxyl group, C 1-4alkyl, C 1-4haloalkyl, C 1-9heteroaryl C 1-6alkyl or R are following subformula:
Each R 3and R 2be methyl independently, ethyl, propyl group, sec.-propyl, the tertiary butyl, amyl group, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Wherein, each subformula representated by described E and each R, all can independently by hydrogen, aminoalkyl group, aminoacyl; fluorine, chlorine, bromine, iodine, trifluoromethyl; chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl; sec.-propyl, dimethylamino, methylamino, diethylamino, ethylamino; hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-; ethyl-C (=O)-, n-propyl-C (=O)-, sec.-propyl-C (=O)-, C 2-10heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, the invention provides a kind of substituted carbamide derivative, it is the steric isomer of compound shown in the compound shown in formula (III) or formula (III), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein, X, Y, Z, Z 1, Z 2, Z 3and Z 4be N or CH independently of one another;
Wherein, described X, Y, Z, Z 1, Z 2, Z 3and Z 4there are two for heteroatoms at least simultaneously;
Described R 1, a, n and R have implication as described in the present invention.
On the other hand, present invention also offers a kind of pharmaceutical composition, this pharmaceutical composition comprises compound of the present invention.
In some embodiments, pharmaceutical composition of the present invention, it further comprises pharmaceutically acceptable carrier, vehicle, thinner, at least one in assistant agent and vehicle.
In some embodiments, pharmaceutical composition of the present invention, it further comprises additional treatment agent, described additional treatment agent is chemotherapeutic agent, antiproliferative, anti-inflammatory reagent, immunosuppressor, immunostimulant, is used for the treatment of atherosclerotic medicine, is used for the treatment of medicine or their combination of pulmonary fibrosis.
In other embodiments, pharmaceutical composition of the present invention, wherein said additional treatment agent is Chlorambucil (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), Procarbazine (procarbazine), methotrexate (methotrexate), Fluracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), gengshengmeisu (dactinomycin), Dx (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogue (gonadorelin analogues), megestrol (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, A Pa is for Buddhist nun (apatinib), Axitinib (axitinib), Velcade (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), rhuMAb-VEGF (bevacizumab), brentuximab vedotin, block appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody (ofatumumab) difficult to understand, Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab) or their combination.
On the other hand, the present invention relates to described compound or pharmaceutical composition is preparing the purposes in medicine, wherein said medicine is used for preventing, processes, alleviates or treat proliferative disease, autoimmune disorders or inflammatory diseases.
In some embodiments, described proliferative disease is acute myeloid leukaemia, chronic myelogenous leukemia, gastrointestinal stromal tumors, acute myelocytic leukemia (AML), the chronic myelogenous leukemia (CML) of sudden change, acute lymphoblastic leukemia (ALL), colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, kidney, brain tumor, neck cancer, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukemia, lymphatic cancer, rheumatism, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinaemia, half molecular disease, monocytic leukemia, primary macroglobulinaemia purpura, Secondary cases benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, non-Hodgkin lymphoma, Sezary syndrome, infectious monocytosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colorectal carcinoma, the rectum cancer, polyposis intestinalis, small cell lung cancer, neuroblastoma, neuroendocrine cell tumour, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterus carcinoma, ovarian cancer, G. cephalantha, malignant tumor of digestive tract, nonsmall-cell lung cancer, cervical cancer, tumor of testis, bladder cancer or myelomatosis.
In some embodiments, described autoimmune disorders is rheumatic arthritis, lupus, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, inflammatory bowel, Crohn's disease or systemic lupus.
In some embodiments, described inflammatory diseases refers to diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, liver cirrhosis, cholecystitis or chronic inflammatory diseases.
In some embodiments, described disease is the disease that FLT3 mediation or FLT3-ITD cause.
On the other hand, the present invention relates to described compound or pharmaceutical composition for preventing, processing, treat or alleviate patient's proliferative disease, the method of autoimmune disorders or inflammatory diseases, its method comprises the effective therapeutic dose having the patient of this infection or disease compound as described in the present invention or pharmaceutical composition of the present invention.
In some embodiments, described disease is the disease that the kinase mediated or FLT3-ITD kinases of FLT3 causes.
On the other hand, the present invention relates to described compound or pharmaceutical composition for preventing, processing, treat or alleviate patient's proliferative disease, autoimmune disorders or inflammatory diseases.
The present invention relates to prevention on the other hand, processes, treats or alleviate patient's proliferative disease, the method for autoimmune disorders or inflammatory diseases, and described method comprises the pharmaceutically acceptable effective dose of use compound of the present invention and carries out administration to patient.
The present invention relates to prevention on the other hand, processes, treats or alleviate patient's proliferative disease, the method of autoimmune disorders or inflammatory diseases, the pharmaceutically acceptable effective dose that described method comprises the pharmaceutical composition of use containing compound of the present invention carries out administration to patient.
The present invention relates to a kind of compound of the present invention of use on the other hand and produces for prevention, process or treatment patient proliferative disease, autoimmune disorders or inflammatory diseases, and the purposes alleviating the medicine of its severity.
Content noted earlier only outlines some aspect of the present invention, but the content being not limited to these aspects and other aspect will do more specifically complete description below.
Detailed description of the invention book
Definition and general terms
The present invention will list the document corresponding to the content specialized determined in detail, and embodiment is all attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinator, and these may be included in existing invention field as claim defines.Those skilled in the art is by many for identification similar or be equal to method described herein and material, and these can be applied in practice of the present invention and go.The present invention is limited to absolutely not the description of method and material.Have a lot of document distinguish with similar material and the present patent application or conflict, comprising but be never limited to the definition of term, the usage of term, the technology of description or the scope controlled as the present patent application.
Unless other aspects of the following definition of application show by the present invention.According to object of the present invention, chemical element according to the periodic table of elements, CAS version and pharmaceutical chemicals handbook, 75, thed, 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry; " Thomas Sorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry; " by Michael B.Smithand Jerry March, John Wiley & Sons, New York:2007, therefore all contents have all merged reference.
As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term.Generally speaking, term " optionally " no matter before whether being positioned at term " replacement ", represent give the one or more hydrogen atoms in structure can replace by concrete substituting group.Unless other aspects show, an optional substituted radical can have a substituting group to replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.Wherein said substituting group can be, but be not limited to: hydrogen, aminoalkyl group, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH-or alkoxyalkyl etc.
The term " alkyl " that the present invention uses comprises the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or side chain, wherein alkyl can independently optionally replace by one or more substituting group described in the invention.Some of them embodiment is, alkyl group contains 1-10 carbon atom, other embodiment is, alkyl group contains 1-8 carbon atom, and other embodiment is, alkyl group contains 1-6 carbon atom, other embodiment is, alkyl group contains 1-4 carbon atom, and other embodiment is, alkyl group contains 1-3 carbon atom.Alkyl group further example comprises, but be not limited to, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 2-methyl-propyl or isobutyl-, 1-methyl-propyl or sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl isophthalic acid-butyl, 2-methyl-1-butene base, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 3-methyl-3-amyl group, 2-methyl-3-amyl group, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, n-heptyl, n-octyl etc.Term " alkyl " and its prefix " alkane " use herein, all comprise the saturated carbon chains of straight chain and side chain.
Term " alkynyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, wherein at least one position is undersaturated condition, namely a C-C is sp triple bond, wherein alkynyl group can independently optionally replace by one or more substituting group described in the invention, concrete example comprises, but be not limited to, ethynyl propargyl etc..
Term " thiazolinyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, and wherein at least one position is undersaturated condition, and namely a C-C is sp 2double bond, wherein thiazolinyl group can independently optionally replace by one or more substituting group described in the invention, comprise the location that group has negation " just " or " E " " Z ", wherein concrete example comprises, but is not limited to, vinyl (-CH=CH 2), allyl group (-CH 2cH=CH 2) etc.
Bivalent hydrocarbon chain that term " alkylidene group " and " alkylidene chain " refer to straight or branched, that be only made up of carbon and hydrogen atom, not containing unsaturated link(age), has 1 to 8 carbon atoms, such as, and methylene radical, ethylidene, propylidene, positive butylidene etc.Alkylidene chain can be connected on the remainder of molecule by any two carbon atoms in chain.
Term " alkenylene " or " alkenylene chain " refer to straight or branched, the unsaturated divalent group that is only made up of carbon and hydrogen atom, there are 1 to 8 carbon atoms, wherein unsaturated link(age) only exists as double bond, and double bond to may reside in chain between any two carbon atoms, such as, vinylidene, propenylene, 2-crotonylidene etc.Alkenylene chain can be connected on the remainder of molecule by two carbon atoms any in chain.
Term " alkynylene " or " sub-alkynes chain " refers to straight or branched, the unsaturated divalent group that is only made up of carbon and hydrogen atom, there are 1 to 8 carbon atoms, wherein unsaturated link(age) only exists with triple bond form, triple bond may reside between any two carbon atoms of carbochain, such as, sub-acetylene, the sub-propine of 1-, 2-Aden alkynes, the sub-pentyne of 1-, the sub-pentyne of 3-etc.This sub-alkynes chain can be connected on the remainder of molecule by two carbon atoms any in chain.
The term " halogen " that the present invention uses, " halogen atom " or " halogen atom " comprises fluorine, chlorine, bromine, iodine.
Term " amino " refers to have formula-NH 2.
Term " alkylamino " or " alkylamino " comprise " N-alkylamino " and " N, N-dialkyl amido ", wherein amino group separately replace by one or two alkyl group, wherein alkyl group has implication as described in the present invention.Some of them embodiment is, alkylamino is one or two C 1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is, alkylamino is C 1-3more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to, N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.
The term " alkoxyl group " used in the present invention, is related to alkyl, defines as the present invention, be connected in main carbochain by Sauerstoffatom.Such embodiment comprises, but is not limited to, methoxyl group, oxyethyl group, propoxy-etc.
Term " alkoxyalkyl " or " alkyloxy-alkoxy ", represent the situation that alkyl or alkoxyl group can be replaced by one or more identical or different alkoxyl group, wherein alkyl and alkoxyl group have implication as described in the present invention.Such embodiment comprises, but is not limited to, methoxy methyl alkyl, (ethoxymethyl) alkyl, methoxy propoxy, methoxymethoxy etc.
Term " alkyl-S (=O) t-", represent-S (=O) t-the situation that can be connected with an alkyl, wherein alkyl has implication as described in the present invention.Wherein, t is 0,1 or 2.Such embodiment comprises, but is not limited to, methyl-S (=O) 2-, ethyl group-S (=O) 2-, propyl-S (=O) 2-, methyl-S (=O)-, ethyl group-S (=O)-, propyl-S (=O)-, methyl-S-, ethyl group-S-, propyl-S-, etc.
Term " alkyl-C (=O)-", represent the situation that acyl group (-C (=O)-) can be connected with an alkyl, wherein alkyl has implication as described in the present invention.Such embodiment comprises, but is not limited to, ethanoyl (CH 3-C (=O)-), propionyl (C 2h 5-C (=O)-) etc.
Term " haloalkyl " or " halogenated alkoxy " represent alkyl or alkoxyl group can by one or more identical or different halogen atom situation about replacing.Wherein alkyl and alkoxy base have implication as described in the present invention, and such example comprises, but is not limited to trifluoromethyl, trifluoromethoxy etc.
Term " alkylamino halogenated alkoxy " represent halogenated alkoxy can by one or more identical or different alkylamino situation about replacing.Wherein alkylamino and halo alkoxy group have implication as described in the present invention, and such example comprises, but are not limited to methylamino-difluoro-methoxy etc.
Term " hydroxyalkyl " or " hydroxy alkoxy base " represent that alkyl or alkoxyl group can be optionally substituted with one or more hydroxyl replaced situation.Wherein alkyl and alkoxy base have implication as described in the present invention, and such example comprises, but is not limited to methylol, 1-hydroxyethyl, hydroxypropyl, 1,2-dihydroxypropyl, hydroxyl methoxyl group, 1-hydroxy ethoxy etc.
Term " aminoalkoxy " or " alkylaminoalkoxy " represent alkoxyl group can by one or more amino or alkylamino situation about replacing.Wherein alkylamino or alkoxy base have implication as described in the present invention, and such example comprises, but is not limited to aminomethoxy, 1-amino ethoxy, methylamino-methoxyl group, ethylamino oxyethyl group etc.
Term " aryl " can be used alone or as " aralkyl ", most of " aralkoxy " or " aryloxy alkyl ", can be monocycle, dicyclo, and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and wherein each member ring systems comprises 3-7 atom.Term " aryl " can exchange with term " aromatic nucleus " and use, as aromatic nucleus can comprise phenyl, and naphthyl and anthracene.And described aryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydrogen, aminoalkyl group, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH-or alkoxyalkyl etc.TV structure and determining, aryl can be monoradical or divalent group (that is, arylidene).
Term " heteroaryl ", " hetero-aromatic ring " be commutative use herein, to can be used alone or as the part of " heteroarylalkyl " or " heteroarylalkoxy ", all refer to monocycle, dicyclo, three rings or tetracyclic ring system, wherein, Bicyclic heteroaromatic rings, three ring hetero-aromatic rings or Fourth Ring heteroaromatic ring systems are with the form Cheng Huan condensed.Wherein, heteroaromatic ring systems is aromaticity, on ring one or more atom independent optionally replace by heteroatoms (heteroatoms is selected from N, O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain picture SO, SO 2, PO, PO 2group).Assorted fragrant system can be connected in main structure thus to form stable compound on any heteroatoms or carbon atom.Assorted fragrant system group can be 3-7 former molecular monocycle, or 7-10 former molecular dicyclo, or 10-15 former molecular three rings.The dicyclo with 7-10 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, and three rings with 10-15 atom can be three rings [5,5,6], [5,7,6] or [6,5,6] system.And described heteroaryl or hetero-aromatic ring can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydrogen, aminoalkyl group, aminoacyl; oxo (=O), fluorine, chlorine, bromine, iodine; hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH-or alkoxyalkyl etc.TV structure and determining, hetero-aromatic ring can be monoradical or divalent group (that is, inferior heteroaryl).
Other embodiment is, assorted fragrant system (comprises heteroaryl, hetero-aromatic ring) comprise following example, but be not limited to these examples: 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methyl-isoxazole-5-base, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, pyrimidine-5-base, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, 1, 3, 4-thiadiazoles-2-base, pyrazinyl, pyrazine-2-base, 1, 3, 5-triazinyl, benzo [d] thiazol-2-yl, imidazo [1, 5-a] pyridine-6-base, benzimidazolyl-, benzoxazolyl, 1, 8-phthalazinyl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl is (as 2-quinolyl, 3-quinolyl, 4-quinoline), tetralyl, benzopyrazoles base, acridyl, benzimidazolyl-, benzindole base, Ben Bing Yi oxazinyl, benzo [4, 6] imidazo [1, 2-a] pyridyl, benzo [d] imidazoles [2, 1-b] thiazolyl, benzofuryl, aphthofurans base, diazosulfide base, benzo thio-phenyl, benzotriazole base, benzo thiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carboline base, carbazyl, cinnoline base, dibenzofuran group, imidazopyridyl, Imidazothiazole base, indazolyl, indolizinyl, indyl, different benzo thienyl, iso-dihydro-indole-group, isoquinolyl, isothiazole alkyl, isothiazolyl, naphthyridinyl, oxazolidinedione base, oxazolidinyl, oxazole pyridyl, oxazolyl, Oxyranyle, embedding two pyridyls of tea, phenanthridinyl, phenanthrolinyl, phenarsazine base, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridyl, pyridopyridine base, quinazolyl, quinoxalinyl, thio-phenyl, triazinyl, 2H-pyrrolo-[3, 4-c] pyridyl, pyrazolo [2 ', 1 ': 2, 3] oxazole also [4, 5-c] pyridyl, imidazo [2 ', 1 ': 2, 3] thiazole also [4, 5-c] pyridyl, imidazo [2 ', 1 ': 2, 3] thiazole also [4, 5-b] pyridyl, imidazo [2 ', 1 ': 2, 3] thiazole also [5, 4-b] pyridyl, pyrazolo [2 ', 1 ': 2, 3] thiazole also [4, 5-b] pyrazinyl, 1H-benzo [4, 5] thieno-[2, 3-d] imidazolyl, 1-methyl isophthalic acid H-benzo [4, 5] thieno-[2, 3-d] imidazolyl, imidazo [2', 1':2, 3] thiazole also [4, 5-b] pyrazinyl, 1H-benzo [f] imidazo [4, 5-b] [1, 4] sulphur azatropylidene base etc.
Term " Bicyclic heteroaromatic rings " " Bicyclic heteroaromatic rings base " is with the form Cheng Huan condensed.Wherein, heteroaromatic ring systems is aromaticity, on ring one or more atom independent optionally replace by heteroatoms (heteroatoms is selected from N, O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain picture SO, SO 2, PO, PO 2group).Assorted fragrant system can be connected in main structure thus to form stable compound on any heteroatoms or carbon atom.Assorted fragrant system is 7-10 former molecular dicyclo, and the dicyclo of 7-10 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system.And described heteroaryl or hetero-aromatic ring can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydrogen, aminoalkyl group, aminoacyl; oxo (=O), fluorine, chlorine, bromine, iodine; hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH-or alkoxyalkyl etc.TV structure and determining, Bicyclic heteroaromatic rings can be monoradical or divalent group (that is, sub-bicyclic heteroaryl).
Other embodiment is, benzo [d] thiazol-2-yl, imidazo [1, 5-a] pyridine-6-base, benzimidazolyl-, benzoxazolyl, 1, 8-phthalazinyl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl is (as 2-quinolyl, 3-quinolyl, 4-quinoline), tetralyl, benzopyrazoles base, benzimidazolyl-, benzindole base, Ben Bing Yi oxazinyl, benzofuryl, aphthofurans base, diazosulfide base, benzo thio-phenyl, benzotriazole base, benzo thiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carboline base, carbazyl, cinnoline base, dibenzofuran group, imidazopyridyl, Imidazothiazole base, indazolyl, indolizinyl, indyl, different benzo thienyl, iso-dihydro-indole-group, isoquinolyl, naphthyridinyl, oxazole pyridyl, embedding two pyridyls of tea, phenanthridinyl, phenanthrolinyl, phenarsazine base, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridyl, pyridopyridine base, quinazolyl, quinoxalinyl etc.
Term " carbocylic radical " or " annular aliphatic ", " carbocyclic ring ", " cycloalkyl " refers to monovalence or multivalence, non-aromatic, the unsaturated ring of saturated or part, and do not comprise heteroatoms, comprising the monocycle of 3-12 carbon atom or two rings of 7-12 carbon atom or three rings.The bicyclic carbocyclic ring with 7-12 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, and the bicyclic carbocyclic ring simultaneously with 9 or 10 atoms can be two rings [5,6] or [6,6] system.TV structure and determining, " carbocylic radical " or " annular aliphatic ", " carbocyclic ring ", " cycloalkyl " can be monoradical or divalent group, namely in certain embodiments of the present invention, can to substitute or as sub-carbocylic radical, cycloalkylidene uses.The example of cyclic aliphatic group comprises further, but is never limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, adamantyl etc.And described " carbocylic radical " or " annular aliphatic ", " carbocyclic ring " can be substituted or non-substituted, and wherein substituting group can be; but be not limited to, hydrogen, aminoalkyl group; aminoacyl, oxo (=O), fluorine; chlorine, bromine, iodine; hydroxyl, amino, carboxyl; alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH-or alkoxyalkyl etc.
Term " heterocyclic radical ", " Heterocyclylalkyl ", " heterocycle ", " assorted alicyclic " or " heterocycle " commutative use herein, all refer to monocycle, dicyclo, three rings or tetracyclic ring system, wherein on ring one or more atom independent optionally replace by heteroatoms, ring can be completely saturated or comprise one or more degree of unsaturation, but is never the fragrant same clan.TV structure and determining, " heterocyclic radical ", " Heterocyclylalkyl ", " heterocycle ", " assorted alicyclic " can be monoradical or divalent group, namely in certain embodiments of the present invention, can substitute or use as sub-heterocyclic radical.Heterocyclic system can be connected in main structure thus to form stable compound on any heteroatoms or carbon atom.One or more ring hydrogen atom independent optionally replace by one or more substituting group described in the invention.Some of them embodiment is, " heterocyclic radical ", " Heterocyclylalkyl ", " heterocycle ", " assorted alicyclic " or " heterocycle " group be 3-7 ring monocycle (1-6 carbon atom be selected from N, O, P, 1-3 the heteroatoms of S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group; In addition, carbon atom can by oxo, formation-C=O-; When described ring is triatomic ring, wherein only have a heteroatoms), or 7-10 former molecular dicyclo (4-9 carbon atom be selected from N, 1-3 the heteroatoms of O, P, S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group).
" heterocyclic radical " can be carbon back or heteroatoms base." heterocyclic radical " equally also comprises heterocyclic group and the saturated or unsaturated ring of part or heterocycle and closes the group formed.The example of heterocycle comprises, but is not limited to, 1,2,3,6-tetrahydro pyridyl, piperidyl, piperazinyl, pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, epoxypropyl, azacycloheptyl, oxepane base, thia suberyl, N-morpholinyl, 2-morpholinyl, morpholinyl, thio-morpholinyl, homopiperazine base, 4-Methoxy-piperidin-1-base, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, pyrroline-1-base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2-indoline base, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxy amyl group, dithiane base, dithiode alkyl, dihydro-thiophene base, 1,2,6-thiadiazine alkane 1,1-dioxy-2-base, six hydrogen-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrryl, 1,1-titanium dioxide thio-morpholinyl, 2,3,3a, 7a-tetrahydrochysene-1H-pseudoindoyl, 1,2,3,4-tetrahydric quinoline group, N-pyridyl urea, dioxolanyl, dihydro pyrazinyl, dihydropyridine base, pyrazoline base, dihydro-pyrimidin base, pyrrolin base, Isosorbide-5-Nitrae-dithiane base, morpholinyl, decahydro indyl, decahydro pseudoindoyl, piperazinyl, piperidyl, pteridyl, and purine radicals.And described heterocyclic radical can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydrogen, aminoalkyl group, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH-or alkoxyalkyl etc.Such as 1-picoline-2 (1H)-one, hexamethylene-2,4-diene ketone group, 2,6-dimethyl-purine base etc.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " represent saturated or undersaturated fused ring system, relate to the bicyclic system of non-aromatic, have at least a ring to be nonaromatic.TV structure and determining, " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " can be unit price or divalent group, namely in certain embodiments of the present invention, can substitute or use as sub-condensed-bicyclic base.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can as the substituting group on it).Each ring in condensed-bicyclic is carbocyclic ring or is that assorted alicyclic, such example comprises, but is not limited to, six hydrogen-furans [3,2-b] furyl, 2,3,3a, 4,7,7a-six hydrogen-1H-indenyl, 7-azabicyclo [2.2.1] heptane base, condensed-bicyclic [3.3.0] octyl, condensed-bicyclic [3.1.0] hexyl, 1,2,3,4,4a, 5,8,8a-octahydro naphthyl, these are included within the system of condensed-bicyclic.And described condensed-bicyclic base can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydrogen, aminoalkyl group, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH-or alkoxyalkyl etc.
Term " condenses assorted bicyclic group " and represents saturated or undersaturated fused ring system, relates to the bicyclic system of non-aromatic, has at least a ring to be nonaromatic.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can as the substituting group on it).TV structure and determining, " condensing assorted bicyclic group " can be unit price or divalent group, namely in certain embodiments of the present invention, can substitute or condense assorted bicyclic group as Asia and use.And at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 former molecular ring, namely comprises 1-6 carbon atom and is selected from N, 1-3 the heteroatoms of O, P, S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group, in addition, carbon atom also can be formed-C=O-by oxo, such example comprises, but be not limited to, six hydrogen-2H-[1, 4] dioxin [2, 3-c] pyrryl, 3-azabicyclo [3.3.0] octyl, 3-methyl-3, 7-diazabicyclo [3.3.0] octyl, 8-azabicyclo [4.3.0] nonyl, 8-azabicyclo [4.3.0] nonane 3-base, 3-azabicyclo [4.3.0] nonane-3-base, 1, 5-dioxy-8-azabicyclo [4.3.0] nonyl, (1R, 6S)-2, 5-dioxy-8-azabicyclo [4.3.0] nonyl, (1R, 6R)-2, 5-dioxy-8-azabicyclo [4.3.0] nonyl, isoindoline base, 1, 2, 3, 4-tetrahydric quinoline group, (1S, 5S)-1-hydroxyl-3-azabicyclo [3.1.0] hexyl, (1R, 5S)-1-hydroxyl-3-azabicyclo [3.1.0] hexyl, (1R, 5S)-1-N, N-dimethylamino-3-azabicyclo [3.1.0] hexyl, (1S, 5R, 6R)-1-methyl-6-alcohol-3-azabicyclo [3.2.0] heptane base, 3-nitrogen-7-oxabicyclo [3.3.0] octyl, 3, 7-diazabicyclo [3.3.0] octyl, 2, 6-diazabicyclo [3.3.0] octyl, 3-ethyl-3, 7-diazabicyclo [3.3.0] octyl, 2, 7-diazabicyclo [3.3.0] octyl, 7-ethanoyl-2, 7-diazabicyclo [3.3.0] octyl, 2, 8-diazabicyclo [4.3.0] nonyl, 2-methyl-2, 8-diazabicyclo [4.3.0] nonyl, 3-oxygen-8-azabicyclo [4.3.0] nonyl, 2-oxygen-8-azabicyclo [4.3.0] nonyl, 2, 8-phenodiazine-5-oxabicyclo [4.3.0] nonyl, (1S, 6R)-2-methyl-2, 8-phenodiazine-5-oxabicyclo [4.3.0] nonyl, 3-ethyl-3, 9-diazabicyclo [4.3.0] nonyl, 4, 9-diazabicyclo [4.3.0] nonyl, 2, 9-diazabicyclo [4.3.0] nonyl, 3-methyl-3, 9-diazabicyclo [4.3.0] nonyl, 3-ethyl-3, 7-diazabicyclo [4.3.0] nonyl, 3-methyl-3, 7-diazabicyclo [4.3.0] nonyl, 2-ethyl-2, 8-diazabicyclo [4.3.0] nonyl, 3-oxo-2, 4, 8-tri-azabicyclo [4.3.0] nonyl, 3-oxo-4-oxygen-2, 8-diazabicyclo [4.3.0] nonyl, 3-oxo-2, 8-diazabicyclo [4.3.0] nonyl, 3, 8-diazabicyclo [4.3.0] nonyl, 8-methyl-2, 8-diazabicyclo [4.3.0] nonyl, 3, 7-diazabicyclo [4.3.0] nonyl, 3, 9-diazabicyclo [4.3.0] nonyl, 3-oxygen-8-azabicyclo [4.3.0] nonyl, 3-sulphur-8-azabicyclo [4.3.0] nonyl, 9-methyl-3, 9-diazabicyclo [4.3.0] nonyl, 7-methyl-3, 7-diazabicyclo [4.3.0] nonyl, 9-ethyl-3, 9-diazabicyclo [4.3.0] nonyl, 7-ethyl-3, 7-diazabicyclo [4.3.0] nonyl, 8-ethyl-2, 8-diazabicyclo [4.3.0] nonyl, 5, 6-dihydro-4H-pyrrolo-[3, 4-c] isoxazolyl, 3-ethyl-[1, 2, 4] triazole [4, 3-a] and piperidyl, [1, 2, 4] triazole [4, 3-a] and piperidyl, 3-methyl-isoxzzole also [4, 3-c] piperidyl, 3-methyl-5, 6-dihydro-4H-pyrrolo-[3, 4-c] isoxazolyl, 2-methyl-4, 5, 6, 7-tetrahydrochysene-1H-imidazo [4, 5-c] pyridyl, 2-methyl-4, 5, 6, 7-tetrahydrochysene oxazole also [4, 5-c] pyridyl, 2-methyl-4, 5, 6, 7-tetrahydrochysene-1H-thiazole also [4, 5-c] pyridyl, isoxzzole also [4, 3-c] piperidyl, 4, 5, 6, 7-tetrahydrochysene isoxzzole also [3, 4-c] pyridyl, [1, 2, 4] triazole also [4, 3-a] piperazinyl, 3-trifluoromethyl-[1, 2, 4] triazole also [4, 3-a] piperazinyl, 3-methyl-[1, 2, 4] triazole also [4, 3-a] piperazinyl, 2-oxo-3-oxygen-8-azabicyclo [4.3.0] nonyl, 1, 3-dimethyl-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [4, 3-c] pyridin-2-yl-, 2-oxygen-7-azabicyclo [4.4.0] decyl, 1, 5-dioxy-9-azabicyclo [4.4.0] decyl, 2, 3-dimethyl-4, 5, 6, 7-tetrahydrochysene-2H-pyrazolo [4, 3-c] pyridin-2-yl-, 3-azabicyclo [4.4.0] decyl, 5-benzyl-2-oxygen-5, 8-diazabicyclo [4.3.0] nonyl, 2, 7-diaza decahydro naphthyl or 2-oxygen-8-azabicyclo [4.4.0] decyl etc.And described in condense assorted bicyclic group can be substituted or non-substituted, wherein substituting group can be, but is not limited to, hydrogen, aminoalkyl group, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH-or alkoxyalkyl etc.
Term " bridge bicyclic group " represents saturated or undersaturated bridged-ring system, relates to the bicyclic system of non-aromatic.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or hetero-aromatic ring (but aromatic series can as the substituting group on it).Wherein each member ring systems comprises 3-7 atom, and such example comprises, but is not limited to, dicyclo [2.2.1] heptane base, 2-methyl-assorted two rings [2.2.1] heptane base etc.And described bridge bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydrogen, aminoalkyl group, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH-or alkoxyalkyl etc.
Term " bridge mix bicyclic group " represents saturated or undersaturated bridged-ring system, relates to the bicyclic system of non-aromatic.TV structure and determining, " bridge mix bicyclic group " can be monoradical or divalent group, namely in certain embodiments of the present invention, can substitute or use as sub-bridge bicyclic group of mixing.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can as the substituting group on it).And at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 atom, namely comprises 1-6 carbon atom and is selected from N, 1-3 the heteroatoms of O, P, S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group, in addition, carbon atom also can be formed-C=O-by oxo; Such example comprises, but be not limited to 2-oxygen-5-azabicyclo [2.2.1] heptane base, 2-sulfo--5-azabicyclo [2.2.1] heptane base, 2-oxo-5-azabicyclo [2.2.1] heptane base, 2,5-diazabicylo [2.2.1] heptane base, 2-methyl-2,5-diazabicylo [2.2.1] heptane base etc.And described bridge is mixed, bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydrogen, aminoalkyl group, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH-or alkoxyalkyl etc.
Term " cycloalkylalkyl " refers to that alkyl is by one or more cycloalkyl substituted, and wherein, alkyl and group of naphthene base have implication as described in the present invention, and wherein embodiment may be, but not limited to, Cvclopropvlmethvl, cyclohexyl methyl, cyclohexyl-ethyl etc.
Term " cycloheteroalkylalkyl " refers to that alkyl is replaced by one or more heterocyclic radical, and wherein, alkyl and heterocyclyl groups have implication as described in the present invention, and wherein embodiment may be, but not limited to, ring propoxy methyl, morpholinyl methyl, piperidinoethyl etc.
Term " cycloalkyl oxy " or " carbocylic radical oxygen base " comprise cycloalkyl or the carbocylic radical of optional replacement, as defined herein, be connected on Sauerstoffatom, and be connected with all the other molecules by Sauerstoffatom, such example comprises, but is not limited to cyclopropyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base, the cyclopropyl oxygen base etc. that hydroxyl replaces.
Term " cycloalkyl amino " represent amino group replace by one or two group of naphthene base, wherein cycloalkyl has implication as described in the present invention, such example comprises, but be not limited to cyclopropylamino, clopentylamino, Cyclohexylamino, the cyclopropylamino that hydroxyl replaces, dicyclohexyl is amino, and Bicyclopropyl is amino.
Term " alkoxy aryl " represent alkoxy base replace by one or more aryl, wherein aryl and alkoxyl group have implication of the present invention, and such example comprises, but be not limited to, Phenylmethoxy, phenyl ethoxy, p-methylphenyl methoxyl group, phenyl-propoxy etc.
Term " aryl alkane amino " represent alkylamino radicals replace by one or more aromatic yl group, wherein aryl and alkoxyl group have implication of the present invention, and such example comprises, but be not limited to, phenyl methylamino-, phenylethylamino, phenylpropylamino, p-methylphenyl methylamino-etc.
Term " heteroarylalkoxy " represent alkoxy base replace by one or more heteroaryl, wherein heteroaryl and alkoxyl group have implication of the present invention, such example comprises, but be not limited to, pyridine-2-ylmethoxy, thiazol-2-yl oxyethyl group, imidazoles-2-base oxethyl, pyrimidine-2-base propoxy-, pyrimidine-2-base methoxyl group etc.
Term " heteroarylalkylamino " comprises heteroarylalkyl group and is connected on other groups by nitrogen-atoms, wherein heteroarylalkyl has implication as described in the present invention, such example comprises, but be not limited to, pyridine-2-base methylamino-, thiazol-2-yl ethylamino, imidazoles-2-base ethylamino, pyrimidine-2-base third is amino, pyrimidine-2-base methylamino-etc.
Term " heterocyclylalkoxy " comprises the alkoxyl group that heterocyclic radical replaces, and wherein Sauerstoffatom is connected with the rest part of molecule; Term " heterocyclic radical alkylamino " comprises the alkylamino that heterocyclic radical replaces, and wherein nitrogen-atoms is connected with the rest part of molecule.Wherein heterocyclic radical, alkoxyl group and alkylamino have implication as described in the present invention, and such example comprises, but is not limited to, morpholine-4-base oxethyl, piperazine-4-base oxethyl, piperidin-4-yl ethylamino etc.
Term " cycloalkyl alkoxy ", or " carbocyclylalkoxy " represent alkoxy base by one or more group of naphthene base or carbocylic radical group replace, wherein group of naphthene base or carbocylic radical group and alkoxy base have implication as described in the present invention, and such example comprises, but is not limited to, cyclo propyl methoxy, cyclopropylethoxy, cyclopentyl oxyethyl group, cyclohexylethoxy radical, cyclohexyl methoxy, cyclopropyl propoxy-etc.
Term " amino-n-cycloalkyl " or " carbocylic radical alkylamino " represent alkylamino radicals by one or more group of naphthene base or carbocylic radical group replace, wherein group of naphthene base or carbocylic radical group and alkylamino radicals have implication as described in the present invention, such example comprises, but be not limited to, cyclopropyl methylamino-, cyclopropyl ethylamino, cyclopentyl ethylamino, cyclohexyl ethylamino, cyclohexyl-methyl-amino, cyclopropyl propylamino etc.
Term " aryloxy alkoxyl group " represent alkoxyl group replace by one or more aryloxy group, wherein alkoxyl group and aryloxy group have implication as described in the present invention, and such example comprises, but be not limited to, phenoxy group methoxyl group, phenoxy group, Phenoxypropoxy etc.
Term " heteroaryl oxygen base alkoxyl group " represent alkoxyl group replace by one or more heteroaryl oxygen base group, wherein alkoxyl group and heteroaryl oxygen base group have implication as described in the present invention, such example comprises, but be not limited to, pyridyl Oxymethoxy, pyrimidyl oxygen base oxethyl, thiazolyl oxygen base propoxy-etc.
Term " aryloxy " or " aryloxy " comprise the optional aryl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein aromatic yl group has implication as described in the present invention, and such example comprises, but be not limited to, phenoxy group, tolyloxy, second phenoxy group etc.
Term " heteroaryl oxygen base " comprises the optional heteroaryl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein heteroaryl groups has implication as described in the present invention, such example comprises, but be not limited to, pyridine-2-oxygen base, thiazole-2-oxygen base, imidazoles-2-oxygen base, pyrimidine-2-oxygen base etc.
Term " heterocyclyloxy base alkoxyl group " represent alkoxyl group replace by one or more heterocyclyloxy base group, wherein alkoxyl group and heterocyclyloxy base group have implication as described in the present invention, such example comprises, but be not limited to, pyrroles-2-Oxymethoxy, pyrroles-3-oxygen base oxethyl, piperidines-2-oxygen base oxethyl, piperidines-3-oxygen base oxethyl, piperazine-2-Oxymethoxy, piperidines-4-oxygen base oxethyl etc.
Term " carbocylic radical oxygen base alkoxyl group " represent alkoxyl group replace by one or more carbocylic radical oxygen base group, wherein alkoxyl group and carbocylic radical oxygen base group have implication as described in the present invention, such example comprises, but be not limited to, cyclopropyl Oxymethoxy, cyclopropyl oxygen base oxethyl, cyclopentyloxy oxyethyl group, cyclohexyl oxygen base oxethyl, cyclohexenyl-3-oxygen base oxethyl etc.
Term " heterocyclyloxy base " comprises the optional heterocyclic radical replaced, as defined herein, be connected on Sauerstoffatom, wherein Sauerstoffatom is connected with the rest part of molecule, such example comprises, but be not limited to, pyrroles-2-oxygen base, pyrroles-3-oxygen base, piperidines-2-oxygen base, piperidines-3-oxygen base, piperazine-2-oxygen base, piperidines-4-oxygen base etc.
Term " condensed-bicyclic base oxygen base " comprises the optional condensed-bicyclic base replaced, and defines, be connected on Sauerstoffatom as the present invention, and be connected with molecule rest part by Sauerstoffatom, such example comprises, but is not limited to, 1,2,3,4,4a, 5,8,8a-octahydro naphthyl oxygen base, condensed-bicyclic [3.3.0] octane-2-oxygen base, condensed-bicyclic [3.1.0] hexane-2-oxygen base etc.
Term " condense assorted bicyclic group oxygen base " and comprise optional replace condense assorted bicyclic group, define as the present invention, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, such example comprises, but is not limited to, six hydrogen-furo [3,2-b] furans-2-base oxygen base, 7-azabicyclo [2.3.0] heptane-2-base oxygen base, 7-azabicyclo [2.3.0] heptane-4-base oxygen base etc.
Term " condensed-bicyclic base amino " represent amino group replace by one or two condensed-bicyclic base, wherein condensed-bicyclic base has implication as described in the present invention, and such example comprises, but is not limited to, 1,2,3,4,4a, 5,8,8a-octahydro naphthyl-amino, two (1,2,3,4,4a, 5,8,8a-octahydro naphthyl) amino, condensed-bicyclic [3.3.0] octyl is amino, and condensed-bicyclic [3.1.0] hexyl is amino.
Term " condense assorted bicyclic group amino " represent amino group by one or two condense assorted bicyclic group replace, wherein condense assorted bicyclic group and there is implication as described in the present invention, such example comprises, but be not limited to, six hydrogen-furo [3,2-b] furans-2-base amino, 7-azabicyclo [2.3.0] heptane-2-base is amino, and 7-azabicyclo [2.3.0] heptane-4-base is amino.
Term " condensed-bicyclic base alkylamino " represent alkylamino radicals replace by one or two condensed-bicyclic base, wherein condensed-bicyclic base has implication as described in the present invention, and such example comprises, but is not limited to, 1,2,3,4,4a, 5,8,8a-octahydro napthylmethylamino, two (1,2,3,4,4a, 5,8,8a-octahydro naphthyl) methylamino-, condensed-bicyclic [3.3.0] octyl methylamino-, condensed-bicyclic [3.1.0] hexyl methylamino-etc.
Term " condense assorted bicyclic group alkylamino " and represent alkylamino radicals by one or two condense assorted bicyclic group replace, wherein condense assorted bicyclic group and there is implication as described in the present invention, such example comprises, but be not limited to, six hydrogen-furo [3,2-b] furans-2-base methylamino-, 7-azabicyclo [2.3.0] heptane-2-base methylamino-, 7-azabicyclo [2.3.0] heptane-4-base methylamino-etc.
Term " condensed-bicyclic base alkoxyl group " represent alkoxyl group replace by one or more condensed-bicyclic base group, wherein alkoxyl group and condensed-bicyclic base have implication as described in the present invention, and such example comprises, but is not limited to, 1,2,3,4,4a, 5,8,8a-octahydro naphthylmethoxy, 1,2,3,4,4a, 5,8,8a-octahydro naphthyl oxyethyl group, condensed-bicyclic [3.3.0] octane-oxyethyl group, condensed-bicyclic [3.1.0] hexane-propoxy-etc.
Term " condense assorted bicyclic group alkoxyl group " and represent alkoxyl group by one or more condense assorted bicyclic group group replace, wherein alkoxyl group and condense assorted bicyclic group there is implication as described in the present invention, such example comprises, but be not limited to, six hydrogen-furo [3, 2-b] furans-2-base propoxy-, 7-azabicyclo [2.2.1] heptane-2-base oxethyl, 7-azabicyclo [2.3.0] heptane-4-base propoxy-, six hydrogen-furo [3, 2-b] furans-2-base oxethyl, 7-azabicyclo [2.3.0] heptane-2-base propoxy-, 7-azabicyclo [2.3.0] heptane-4-base oxethyl etc.
Term " condensed-bicyclic base alkyl " represent alkyl replace by one or more condensed-bicyclic base group, wherein alkyl and condensed-bicyclic base have implication as described in the present invention, and such example comprises, but is not limited to, 1,2,3,4,4a, 5,8,8a-octahydro naphthyl methyl, 1,2,3,4,4a, 5,8,8a-octahydro naphtylethyl group, condensed-bicyclic [3.3.0] octane-ethyl, condensed-bicyclic [3.1.0] hexane-propyl group etc.
Term " condense assorted bicyclic group alkyl " and represent alkyl by one or more condense assorted bicyclic group group replace, wherein alkyl and condense assorted bicyclic group there is implication as described in the present invention, such example comprises, but be not limited to, six hydrogen-furo [3, 2-b] furans-2-base propyl group, 7-azabicyclo [2.2.1] heptane-2-base ethyl, 7-azabicyclo [2.3.0] heptane-4-base propyl group, six hydrogen-furo [3, 2-b] furans-2-base ethyl, 7-azabicyclo [2.3.0] heptane-2-base propyl group, 7-azabicyclo [2.3.0] heptane-4-base ethyl etc.
Term " condense assorted bicyclic group oxygen base alkoxyl group " and represent alkoxyl group by one or more condense assorted bicyclic group oxygen base group replace, wherein alkoxyl group and condense assorted bicyclic group oxygen base there is implication as described in the present invention, such example comprises, but be not limited to, six hydrogen-furo [3, 2-b] furans-2-base oxygen base propoxy-, 7-azabicyclo [2.2.1] heptane-2-base oxygen base oxethyl, 7-azabicyclo [2.3.0] heptane-4-base oxygen base propoxy-, six hydrogen-furo [3, 2-b] furans-2-base oxygen base oxethyl, 7-azabicyclo [2.3.0] heptane-2-base oxygen base propoxy-, 7-azabicyclo [2.3.0] heptane-4-base oxygen base oxethyl etc.
Term " condense assorted bicyclic group oxygen base alkylamino " and represent alkylamino by one or more condense assorted bicyclic group oxygen base group replace, wherein alkylamino and condense assorted bicyclic group oxygen base there is implication as described in the present invention, such example comprises, but be not limited to, six hydrogen-furo [3, 2-b] furans-2-base oxygen base third amino, 7-azabicyclo [2.2.1] heptane-2-base oxygen base ethylamino, 7-azabicyclo [2.3.0] heptane-4-base oxygen base third is amino, six hydrogen-furo [3, 2-b] furans-2-base oxygen base ethylamino, 7-azabicyclo [2.3.0] heptane-2-base oxygen base third is amino, 7-azabicyclo [2.3.0] heptane-4-base oxygen base ethylamino etc.
Term " bridge mix bicyclic group alkoxyl group " represent alkoxy base by one or more bridge mix bicyclic group replace, mix bicyclic group and alkoxy base of its jackshaft has implication as described in the present invention, such example comprises, but be not limited to, 2-oxygen-5-azabicyclo [2.2.1] heptane ylmethoxy, 2,5-diazabicylo [2.2.1] heptane base oxethyl, 2-methyl-2,5-diazabicylo [2.2.1] heptane base propoxy-etc.
Term " bridge mix bicyclic group alkyl " represent alkyl group by one or more bridge mix bicyclic group replace, mix bicyclic group and alkyl group of its jackshaft has implication as described in the present invention, such example comprises, but be not limited to, 2-oxygen-5-azabicyclo [2.2.1] heptane ylmethyl, 2,5-diazabicylo [2.2.1] heptane base ethyl, 2-methyl-2,5-diazabicylo [2.2.1] heptane base propyl group etc.
Term " bridge mix bicyclic group alkylamino " represent alkylamino radicals by one or more bridge mix bicyclic group replace, mix bicyclic group and alkylamino radicals of its jackshaft has implication as described in the present invention, such example comprises, but be not limited to, 2-oxygen-5-azabicyclo [2.2.1] heptane base methylamino-, 2,5-diazabicylo [2.2.1] heptane base ethylamino, 2-methyl-2,5-diazabicylo [2.2.1] heptane base third amino etc.
Term " bridge mix bicyclic group oxygen base " comprises the optional bridge replaced and to mix bicyclic group, define as the present invention, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, such example comprises, but is not limited to, 2-methyl-2,5-diazabicylo [2.2.1] alkyl oxy in heptan, 2,5-diazabicylo [2.2.1] alkyl oxy in heptan etc.
Term " arylalkyl " represent alkyl group replace by one or more aromatic yl group, wherein alkyl group and aromatic yl group have implication as described in the present invention, and such example comprises, but is not limited to styroyl, phenmethyl, to methylphenylethyl etc.
Term " heteroarylalkyl " represent alkyl group replace by one or more heteroaryl groups, wherein alkyl group and heteroaryl groups have implication as described in the present invention, such example comprises, but be not limited to, pyridine-2-ethyl, thiazole-2-methyl, imidazoles-2-ethyl, pyrimidine-2-propyl group etc.
Term " alkylthio " comprises C 1-10the alkyl of straight or branched is connected on the sulphur atom of divalence, and wherein alkyl group has implication as described in the present invention.Some of them embodiment is, alkylthio is more rudimentary C 1-3alkylthio, such example comprises, but is not limited to, methylthio group (CH 3s-), ethylmercapto group etc.
Term " aminoacyl " refers to-C (=O) NH 2.
Term " alkyl-C (=O) NH-" comprises C 1-10the alkyl of straight or branched is connected on-C (=O) NH-, and wherein alkyl group has implication as described in the present invention.Such example comprises, but is not limited to, acetamido (CH 3c (=O) NH-), propionamido-(C 2h 5c (=O) NH-) etc.
Term " volution base ", " volution ", " spiral shell bicyclic group ", " spiral shell dicyclo " represents that a ring originates from ring-type carbon special on another ring.Such as, as described below, a saturated bridged-ring system (ring B and B') is called as " condensed-bicyclic ", otherwise ring A and ring B shares a carbon atom in two saturated member ring systems, be then called as " volution ".Each ring inside volution is carbocyclic ring or is assorted alicyclic.Such example comprises, but be not limited to, 4-azaspiro [2.4] heptane-5-base, 4-oxaspiro [2.4] heptane-5-base, 5-azaspiro [2.4] heptane-5-base, spiral shell [2.4] heptane base, spiral shell [4.4] nonyl, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base etc.And described spiral shell bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydrogen, aminoalkyl group, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH-or alkoxyalkyl etc.
Term " spiral shell mix bicyclic group " represents that a ring originates from ring-type carbon special on another ring.Such as, as described above, a saturated bridged-ring system (ring B and B') is called as " condensed-bicyclic ", otherwise ring A and ring B shares a carbon atom in two saturated member ring systems, be then called as " volution ".And at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 atom, namely comprises 1-6 carbon atom and is selected from N, 1-3 the heteroatoms of O, P, S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group, such example comprises, but be not limited to 4-azaspiro [2.4] heptane base, 4-oxaspiro [2.4] heptane base, 5-azaspiro [2.4] heptane base, 7-hydroxyl-5-azaspiro [2.4] heptane base, 2-azaspiro [4.5] decyl, 2-azepine spiroheptane base, 2-azaspiro [4.4] nonyl, 2-methyl-2, 6-diaza spiro [4.5] decyl, 3-azaspiro [5.4] decyl, 2-methyl-2-azepine spiroheptane base, 2-oxygen-6-azepine spiroheptane base, 2, 6-diaza spiroheptane base, 2-sulphur-6-azepine spiroheptane base 2-monoxide, 2-sulphur-6-azepine spiroheptane base 2, 2-dioxide etc.And described spiral shell is mixed, bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydrogen, aminoalkyl group, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH-or alkoxyalkyl etc.
Term " spiral shell mix bicyclic group alkoxyl group " represent alkoxy base by one or more spiral shell mix bicyclic group replace, wherein mix bicyclic group and alkoxy base of spiral shell has implication as described in the present invention, such example comprises, but be not limited to, 4-azaspiro [2.4] heptane-5-ylmethoxy, 4-azaspiro [2.4] heptane-2-base oxethyl, 4-oxaspiro [2.4] heptane-5-base oxethyl, 5-azaspiro [2.4] heptane-5-base propoxy-etc.
Term " spiral shell mix bicyclic group alkyl " represent alkyl group by one or more spiral shell mix bicyclic group replace, wherein mix bicyclic group and alkyl group of spiral shell has implication as described in the present invention, such example comprises, but be not limited to, 4-azaspiro [2.4] heptane-5-ylmethyl, 4-azaspiro [2.4] heptane-2-base ethyl, 4-oxaspiro [2.4] heptane-5-base ethyl, 5-azaspiro [2.4] heptane-5-base propyl group etc.
" antiproliferative " refers to that metabolic antagonist (such as, 5-fluoro-uridylic, methotrexate, fludarabine), anti-microtubule agent (such as, Vinca alkaloids is as vincristine(VCR), vincaleucoblastine, Taxan is taxol such as, polyenoid taxol), alkylating reagent (such as endoxan, melphalan, carmustine, nitrosourea is as two chlorethylnitrosourea and hydroxyurea), platinum reagent (such as cis-platinum, NSC-241240, Oxalipratin, JM-216, Cl-973), anthracyclines (such as doxrubicin, zhengdingmeisu), antitumor antibiotics (such as mitomycin, jaundice element, Zorubicin, zhengdingmeisu), topoisomerase inhibitors (such as etoposide, camptothecine), anti-angiogenic agent (such as and Bevacizumab) or any cytotoxic agent (Emcyt phosphoric acid salt, PM), hormone or hormone agonist, antagonist, partial agonist agent or topical antagonist, kinase inhibitor and radiation therapy.
As described in the present invention, substituent R is connected to by a key member ring systems that the ring at center is formed and represents substituent R and can replace in any desirable generation or any rational position on ring.Such as, formula a represents any position that may be substituted on A ring or B ring and all can be replaced by R, such as formula b, and formula c, formula d, formula e, formula f, formula g, and shown in formula h.
As described in the present invention, substituting group (R) nbe connected to by a key member ring systems that the ring at center is formed to represent n substituent R and can replace any commutable position on ring.Such as, formula i represents any position that may be substituted on A ring or B ring and all can be replaced by n R.
As described in the invention, ring C has two tie points can be connected with molecule rest part, such as, shown in j, expression both can be E end also can be that E ' end is connected with the rest part of molecule, and namely the mode of connection at two ends can be exchanged.
As described in the present invention, attachment point can be connected with molecule rest part any attachable position on ring.Such as, formula k represents any position that may be connected on A ring or B ring and all can be used as the point of connection.
As described in the present invention, attachment point can be connected with molecule rest part any attachable position on ring, and the two ends simultaneously connected can exchange.Such as, formula m represents any position that may be connected on ring and all can be used as the point of connection, and the two ends of tie point can exchange simultaneously.
In addition, it should be noted that, unless otherwise explicitly pointed out, the describing mode that adopts in the whole text in this article " each ... with ... be independently ", " ... with ... be independently of one another " and " ... with ... be separately " can exchange; should be interpreted broadly, it both can refer in different group, did not affect mutually; also can represent in identical group between concrete option expressed between same-sign, did not affect mutually between concrete option expressed between same-sign.Such as, structural formula q and structural formula s each Z between the two 1concrete option mutually between unaffected, meanwhile, in same structure formula, such as formula q, the concrete option of multiple G is unaffected each other; Or such as formula s, multiple R 9concrete option mutually between unaffected.
The definition of neutral body chemistry of the present invention and the usual reference of the use of convention are with Publication about Document: S.P.Parker, Ed., McGraw-Hill Dictionaryof Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley & Sons, Inc., New York, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore there is different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, enantiomer, atropisomer, and their mixture, as racemic mixture, constitutes a part of the present invention.A lot of organic compound all exists with optical active forms, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for the symbol naming compound plane polarized light to rotate, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause not having stereoselectivity or stereospecificity in chemical reaction process.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
Term " tautomer " or " tautomeric form " represent that the isomers of different-energy can be transformed mutually by lower energy barrier.Such example comprises, but is not limited to, and proton tautomer (i.e. prototropy isomer) comprises the change by proton shifting, the isomerization of such as keto-enol and imine-enamine.Valence tautomer comprises the restructuring change of some bonding electronss.
" hydrate " of the present invention refers to compound or its salt provided by the present invention, and it also comprises chemical quantity or the non-chemically water that combined by non-covalent intermolecular forces of equivalent, also can say be solvent molecule to be the associated complex that water is formed.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.
" ester " of the present invention refers to that formula (I), formula (II) or formula (III) compound containing hydroxyl can hydrolyzable esters in organizer.Such ester is that such as in human or animal body, hydrolysis produces the pharmaceutically acceptable ester of parent alcohol.In formula (I) containing hydroxyl, formula (II) or formula (III) chemical combination object, the group of hydrolyzable ester comprises; but be not limited to; phosphate, acetoxymethoxy, 2; 2-dimethylpropionyloxymethoxy; alkyloyl, benzoyl, benzene first and second acyl group; alkoxy carbonyl, dialkyl carbamoyl and N-(di-alkyaminoethyl group)-N-alkyl-carbamoyl etc.
" oxynitride " of the present invention refers to when compound is containing several amine functional group, 1 or the nitrogen-atoms oxidation being greater than 1 can be formed N-oxide compound.The particular example of N-oxide compound is the N-oxide compound of tertiary amine or the N-oxide compound of nitrogen heterocyclic ring nitrogen-atoms.Available oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) process corresponding amine and form N-oxide compound (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).Especially, N-oxide compound can be prepared (Syn.Comm.1977,7,509-514) by the method for L.W.Deady, wherein such as in inert solvent such as methylene dichloride, amine compound and m-chloroperoxybenzoic acid (MCPBA) is reacted.
Can be there is multiple different geometrical isomer and tautomer in compound, described formula (I), formula (II) or formula (III) compound comprise this type of forms all.For avoiding feeling uncertain, when compound to exist with one of several geometrical isomer or tautomer and only specifically describe or display is a kind of time, obviously other forms all are included in formula (I), formula (II) or formula (III).
Term used in the present invention " prodrug ", represents a compound and is converted into formula (I), formula (II) or the compound shown in formula (III) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug 1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as NovelDelivery Systems, Vol.14of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers inDrug 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 other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
The various pharmacy acceptable salt forms of the compounds of this invention are all useful.Term " pharmacy acceptable salt " refers to that those salt forms are apparent for pharmaceutical chemistry man, and namely they are substantially nontoxic and can provide required pharmacokinetic property, palatability, absorption, distribution, metabolism or excretion.Other factors, more practical in nature, also very important for selection, these are: easy, productive rate, stability, the water absorbability of raw-material cost, crystallization and the mobility of result bulk drug.Simply, pharmaceutical composition can be prepared by effective constituent and pharmaceutically acceptable carrier.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detailin J.Pharmaceutical Sciences, 66:1-19, described in 1977..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, 2 hydroxy propanoic acid salt, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate etc.The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-4alkyl) 4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.Amine salt, such as but not limited to N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkyl amine, quadrol, N-methyl glucamine, PROCAINE HCL, PHARMA GRADE, N-benzyl-1-phenylethylamine, the p-chlorobenzyl of 1--2-tetramethyleneimine-1 '-ylmethyl-benzoglyoxaline, diethylamine and other alkylamine, piperazine and three (methylol) aminomethane; Alkaline earth salt, such as but not limited to barium, calcium and magnesium; Transition metal salt, such as but not limited to zinc.
Time term " blocking group " or " Pg " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC), carbobenzoxy-(Cbz) (CBZ) and the sub-methoxycarbonyl (Fmoc) of 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH 2cH 2sO 2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl; 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl etc.Can reference for the general description of blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
In this manual, if there is any difference between chemical name and chemical structure, structure is dominant.
The abbreviation of any blocking group used in the present invention, amino acid and other compound; except as otherwise noted; abbreviation that is all normally used with them, that generally acknowledge is as the criterion; or with reference to IUPAC-IUBCommission on Biochemical Nomenclature (see Biochem.1972,11:942-944).
The description of the compounds of this invention
The invention provides for the substituted carbamide derivative of pharmacological agent and pharmaceutical composition thereof with for regulating Flt3 kinase activity and for suppressing a series of substitute urea compound of FLT3-ITD and being used for the treatment of the purposes of the disease that flt3 mediation or flt3-ITD cause.
On the one hand, the invention provides a kind of compound, it is the shown substitute urea compound of formula (I) or the steric isomer of the shown compound of formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
Q and W is CH or N independently of one another;
G is-O-,-S (=O) t-,-S-,-C (=O)-or five yuan of inferior heteroaryls;
R is-NR 3r 2, alkoxyl group, alkyl, thiazolinyl, alkynyl, haloalkyl, alkyl-S (=O) t-, alkoxyalkyl, hydroxyalkyl, hydroxy alkoxy base, aminoalkoxy, halogenated alkoxy, alkylamino halogenated alkoxy, alkylaminoalkoxy, alkyloxy-alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkyl oxy, cycloalkyl amino, heterocyclic radical, cycloheteroalkylalkyl, heterocyclic radical alkylamino, heterocyclylalkoxy, heterocyclyloxy base alkoxyl group, heterocyclyloxy base, carbocylic radical oxygen base alkoxyl group, carbocyclylalkoxy, carbocylic radical alkylamino, aryl, arylalkyl, aryloxy alkoxyl group, aryloxy, alkoxy aryl, aryl alkane amino, heteroarylalkyl, heteroaryl, heteroarylalkoxy, heteroarylalkylamino, heteroaryl oxygen base, heteroaryl oxygen base alkoxyl group, condensed-bicyclic base oxygen base, condensed-bicyclic base alkyl, condense assorted bicyclic group alkyl, condense assorted bicyclic group oxygen base, condense assorted bicyclic group amino, condense assorted bicyclic group alkoxyl group, condense assorted bicyclic group alkylamino, condense assorted bicyclic group oxygen base alkoxyl group, condense assorted bicyclic group oxygen base alkylamino, spiral shell is mixed bicyclic group alkyl, spiral shell is mixed bicyclic group alkoxyl group, bridge is mixed bicyclic group alkyl, bridge is mixed bicyclic group oxygen base, bridge is mixed bicyclic group alkoxyl group, bridge is mixed bicyclic group alkylamino, bridge is mixed bicyclic group, spiral shell is mixed bicyclic group or condense assorted bicyclic group,
K is the heteroaryl groups of 5-6 unit; Have 2 heteroatomss in wherein said heteroaryl groups at least, each heteroatoms is O, S, NR independently 4or N;
Each L is amino independently, nitro, C 1-4alkylthio, C 1-6alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 1-4haloalkyl, C 1-4alkylamino, hydroxyl, fluorine, chlorine, bromine, iodine, C 1-4alkyl-C (=O)-NH-, C 1-4alkoxyl group, hydroxyl C 1-4alkyl or cyano group;
E is bicyclic heteroaryl group;
Each R 1be hydrogen independently, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-6alkoxy C 1-6alkyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, C 1-4alkyl-C (=O)-NH-, C 1-4alkoxyl group, hydroxyl C 1-4alkyl or C 1-4alkylthio;
Each R 3and R 2be hydrogen independently, C 1-6alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Each R 4be H, C independently 1-4alkyl, C 3-10cycloalkyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Each d is 1,2,3 or 4 independently;
Each n is 1,2,3 or 4 independently;
Each t is 0,1 or 2 independently;
Each a is 0,1,2,3 or 4 independently;
Wherein, described aryl, bicyclic heteroaryl group, heteroaryl groups ,-(CH 2) n-C (=O)-, alkoxyl group, alkyl-S (=O) t-,-G-(CH 2) n-R, alkoxyalkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, heteroaryl, heterocyclic radical, bridge is mixed bicyclic group, spiral shell is mixed bicyclic group, condense assorted bicyclic group, alkyl, haloalkyl, alkylamino, hydroxy alkoxy base, aminoalkoxy, halogenated alkoxy, thiazolinyl, alkynyl, cycloalkylalkyl, cycloheteroalkylalkyl, alkoxyalkyl, hydroxyalkyl, alkylamino halogenated alkoxy, alkylaminoalkoxy, alkyloxy-alkoxy, cycloalkyl oxy, alkoxy aryl, aryl alkane amino, heteroarylalkoxy, heteroarylalkylamino, heterocyclic radical alkylamino, cycloalkyl oxy, cycloalkyl amino, heterocyclylalkoxy, carbocyclylalkoxy, carbocylic radical alkylamino, aryloxy alkoxyl group, aryloxy, heteroaryl oxygen base, heteroaryl oxygen base alkoxyl group, heterocyclyloxy base alkoxyl group, carbocylic radical oxygen base alkoxyl group, heterocyclyloxy base, condensed-bicyclic base oxygen base, condensed-bicyclic base alkyl, condense assorted bicyclic group alkyl, condense assorted bicyclic group oxygen base, condense assorted bicyclic group amino, condense assorted bicyclic group alkoxyl group, condense assorted bicyclic group alkylamino, condense assorted bicyclic group oxygen base alkoxyl group, condense assorted bicyclic group oxygen base alkylamino, spiral shell is mixed bicyclic group alkyl, spiral shell is mixed bicyclic group alkoxyl group, bridge is mixed bicyclic group alkyl, bridge is mixed bicyclic group oxygen base, bridge is mixed bicyclic group alkoxyl group, bridge is mixed bicyclic group alkylamino, alkyl-C (=O)-NH-, alkylthio, and cycloalkyl, can independently by hydrogen, aminoalkyl group, aminoacyl, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, C 1-4alkyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C 1-4alkyl-C (=O)-, C 2-10heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, wherein, described E is one of heteroaryl groups of following subformula formation:
Wherein, X, Y, Z, Z 1, Z 2, Z 3and Z 4be N or CH independently of one another;
T and T 1be-O-,-S-,-NR independently of one another 4-or-CH 2-;
Wherein, the X on described E ring, Y, Z, T, T 1, Z 1, Z 2, Z 3and Z 4there are two for heteroatoms at least simultaneously;
R is-NR 3r 2, C 2-4thiazolinyl, C 2-4alkynyl, C 3-10cycloalkyl, C 3-10cycloalkyl C 1-4alkyl, C 2-10heterocyclic radical C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-6alkoxy C 1-6alkyl, hydroxyl C 1-4alkyl, hydroxyl C 1-4alkoxyl group, amino C 1-4alkoxyl group, halo C 1-4alkoxyl group, C 1-4alkylamino halo C 1-4alkoxyl group, C 1-4alkylamino C 1-4alkoxyl group, C 1-4alkoxy C 1-4alkoxyl group, C 3-10cycloalkyl oxy, C 6-10aryl C 1-4alkoxyl group, C 6-10aryl C 1-4alkylamino, C 1-9heteroaryl C 1-4alkoxyl group, C 1-9heteroaryl C 1-4alkylamino, C 2-10heterocyclic radical C 1-4alkylamino, C 3-10cycloalkyl oxy, C 3-10cycloalkyl amino, C 2-10heterocyclic radical C 1-4alkoxyl group, C 3-10carbocylic radical C 1-4alkoxyl group, C 3-10carbocylic radical C 1-4alkylamino, C 6-10aryloxy C 1-4alkoxyl group, C 6-10aryloxy, C 1-9heteroaryl oxygen base, C 1-9heteroaryl oxygen base C 1-4alkoxyl group, C 2-10heterocyclyloxy base C 1-4alkoxyl group, C 3-10carbocylic radical oxygen base C 1-4alkoxyl group, C 2-10heterocyclyloxy base, C 1-4alkoxyl group, C 1-4alkyl, C 1-4haloalkyl, C 6-10aryl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 1-9heteroaryl, or R is following subformula:
Wherein, each X 8, X 9and X 10be N or CH independently;
Each X 1, X 2, X 3, X 4, X 5, X 6and X 7be-CH independently 2-,-O-,-NR 4a-,-S (=O) t-or-S-;
Each q, m, p, r and s are 0,1,2,3 or 4 independently;
Each R 3and R 2be C independently 1-6alkyl, C 3-10cycloalkyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Each R 4be H, C independently 1-4alkyl, C 3-10cycloalkyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Wherein, each subformula representated by described E and each R, all can independently by hydrogen, aminoalkyl group, aminoacyl, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, C 1-4alkyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C 1-4alkyl-C (=O)-, C 2-10heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
In other embodiments, wherein said E is one of heteroaryl groups of following subformula formation:
R is-NR 3r 2, C 2-4thiazolinyl, C 2-4alkynyl, C 2-10heterocyclic radical C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-4alkoxy C 1-4alkyl, hydroxyl C 1-4alkyl, hydroxyl C 1-4alkoxyl group, amino C 1-4alkoxyl group, halo C 1-4alkoxyl group, C 1-4alkylamino halo C 1-4alkoxyl group, C 1-4alkylamino C 1-4alkoxyl group, C 1-4alkoxy C 1-4alkoxyl group, C 1-4alkoxyl group, C 1-4alkyl, C 1-4haloalkyl, C 1-9heteroaryl C 1-6alkyl or R are following subformula:
Each R 3and R 2be methyl independently, ethyl, n-propyl, sec.-propyl, the tertiary butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Wherein, each subformula representated by described E and each R, all can independently by hydrogen, aminoalkyl group, aminoacyl; fluorine, chlorine, bromine, iodine, trifluoromethyl; chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl; sec.-propyl, dimethylamino, methylamino, diethylamino, ethylamino; hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-; ethyl-C (=O)-, n-propyl-C (=O)-, sec.-propyl-C (=O)-, C 2-10heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, wherein said G is-O-or furylidene.
In some embodiments, wherein said K is one of heteroaryl groups of subformula formation as follows:
Each L is cyclopropyl independently, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6heterocyclylalkyl, amino, cyano group, nitro, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, methyl, ethyl, butyl, n-propyl, sec.-propyl, the tertiary butyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, C 1-4alkyl-C (=O)-NH-, C 1-4alkoxyl group, hydroxyl C 1-4alkyl or C 1-4alkylthio.
In some embodiments, the invention provides a kind of substituted carbamide derivative, it is the steric isomer of compound shown in the compound shown in formula (II) or formula (II), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
Q and W is CH or N independently of one another;
Each R 1be hydrogen independently, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-6alkoxy C 1-6alkyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, C 1-4alkyl-C (=O)-NH-, C 1-4alkoxyl group, hydroxyl C 1-4alkyl or C 1-4alkylthio;
Each L is the tertiary butyl independently;
D is 1;
Each n is 1,2,3 or 4 independently;
Each t is 0,1 or 2 independently;
Each a is 0,1,2,3 or 4 independently;
E is one of heteroaryl groups of following subformula formation:
R is-NR 3r 2, C 2-4thiazolinyl, C 2-4alkynyl, C 2-10heterocyclic radical C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-4alkoxy C 1-4alkyl, hydroxyl C 1-4alkyl, hydroxyl C 1-4alkoxyl group, amino C 1-4alkoxyl group, halo C 1-4alkoxyl group, C 1-4alkylamino halo C 1-4alkoxyl group, C 1-4alkylamino C 1-4alkoxyl group, C 1-4alkoxy C 1-4alkoxyl group, C 1-4alkoxyl group, C 1-4alkyl, C 1-4haloalkyl, C 1-9heteroaryl C 1-6alkyl, or R is following subformula:
Each R 3and R 2be methyl independently, ethyl, n-propyl, sec.-propyl, the tertiary butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Wherein, each subformula representated by described E and each R, all can independently by hydrogen, aminoalkyl group, aminoacyl; fluorine, chlorine, bromine, iodine, trifluoromethyl; chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl; sec.-propyl, dimethylamino, methylamino, diethylamino, ethylamino; hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-; ethyl-C (=O)-, n-propyl-C (=O)-, sec.-propyl-C (=O)-, C 2-10heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, the invention provides a kind of substituted carbamide derivative, it is for the compound shown in formula (III) is such as formula the steric isomer of compound (III) Suo Shi, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein, X, Y, Z, Z 1, Z 2, Z 3and Z 4be N or CH independently of one another;
Wherein, described X, Y, Z, Z 1, Z 2, Z 3and Z 4there are two for heteroatoms at least simultaneously.
In some embodiments, substituted carbamide derivative of the present invention, or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, have one of them structure following:
On the other hand, present invention also offers a kind of pharmaceutical composition, this pharmaceutical composition comprises compound of the present invention.
In some embodiments, pharmaceutical composition of the present invention, it further comprises pharmaceutically acceptable carrier, vehicle, thinner, at least one in assistant agent and vehicle.
In some embodiments, pharmaceutical composition of the present invention, it further comprises additional treatment agent, described additional treatment agent is chemotherapeutic agent, antiproliferative, anti-inflammatory reagent, immunosuppressor, immunostimulant, is used for the treatment of atherosclerotic medicine, is used for the treatment of medicine or their combination of pulmonary fibrosis.
In other embodiments, pharmaceutical composition of the present invention, wherein said additional treatment agent is Chlorambucil (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), Procarbazine (procarbazine), methotrexate (methotrexate), Fluracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), gengshengmeisu (dactinomycin), Dx (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogue (gonadorelin analogues), megestrol (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, A Pa is for Buddhist nun (apatinib), Axitinib (axitinib), Velcade (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), rhuMAb-VEGF (bevacizumab), brentuximab vedotin, block appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody (ofatumumab) difficult to understand, Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab) or their combination.
On the other hand, the present invention relates to described compound or pharmaceutical composition is preparing the purposes in medicine, wherein said medicine is used for preventing, process, alleviate or treat patient's proliferative disease, autoimmune disorders or inflammatory diseases.
In some embodiments, described proliferative disease is acute myeloid leukaemia, chronic myelogenous leukemia, gastrointestinal stromal tumors, acute myelocytic leukemia (AML), the chronic myelogenous leukemia (CML) of sudden change, acute lymphoblastic leukemia (ALL), colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, kidney, brain tumor, neck cancer, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukemia, lymphatic cancer, rheumatism, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinaemia, half molecular disease, monocytic leukemia, primary macroglobulinaemia purpura, Secondary cases benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, non-Hodgkin lymphoma, Sezary syndrome, infectious monocytosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colorectal carcinoma, the rectum cancer, polyposis intestinalis, small cell lung cancer, neuroblastoma, neuroendocrine cell tumour, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterus carcinoma, ovarian cancer, G. cephalantha, malignant tumor of digestive tract, nonsmall-cell lung cancer, cervical cancer, tumor of testis, bladder cancer or myelomatosis.
In some embodiments, described autoimmune disorders is rheumatic arthritis, lupus, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, inflammatory bowel, Crohn's disease or systemic lupus.
In some embodiments, described inflammatory diseases refers to diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, liver cirrhosis, cholecystitis, or chronic inflammatory diseases.
In some embodiments, described disease is the disease that FLT3 mediation or FLT3-ITD cause.
On the other hand, the present invention relates to described compound or pharmaceutical composition for preventing, processing, treat or alleviate patient's proliferative disease, the method of autoimmune disorders or inflammatory diseases, its method comprises effective therapeutic dose of patient's compound as described in the present invention or pharmaceutical composition of the present invention having this infection or suffer from disease.
In some embodiments, described disease is the disease that the kinase mediated or FLT3-ITD kinases of FLT3 causes.
On the other hand, the present invention relates to described compound or pharmaceutical composition for preventing, processing, treat or alleviate patient's proliferative disease, autoimmune disorders or inflammatory diseases.
The present invention relates to prevention on the other hand, processes, treats or alleviate patient's proliferative disease, the method for autoimmune disorders or inflammatory diseases, and described method comprises the pharmaceutically acceptable effective dose of use compound of the present invention and carries out administration to patient.
The present invention relates to prevention on the other hand, processes, treats or alleviate patient's proliferative disease, the method of autoimmune disorders or inflammatory diseases, the pharmaceutically acceptable effective dose that described method comprises the pharmaceutical composition of use containing compound of the present invention carries out administration to patient.
The present invention relates to a kind of compound of the present invention of use on the other hand and produces for prevention, process or treatment patient proliferative disease, autoimmune disorders or inflammatory diseases, and the purposes alleviating the medicine of its severity.
The object of another aspect of the present invention is to provide one to comprise described formula (I), formula (II) or formula (III) compound or the application of its pharmacy acceptable salt in the disease agent of preparation adjustment FLT3 mediation, particularly comprises described formula (I), formula (II) or formula (III) compound or its pharmacy acceptable salt, its isomer, solvate, hydrate or prodrug that give to treat significant quantity.
On the other hand, compound provided by the invention and composition effectively can regulate the activity of Ab1 protein-tyrosine family.
In some embodiments, compound provided by the invention and composition effectively can regulate the activity of class fms Tyrosylprotein kinase 3 receptor kinase (FLT-3 kinases).
In some embodiments, compound provided by the invention and composition effectively can suppress the activity of class fms Tyrosylprotein kinase 3 receptor kinase sudden change (FLT-3-ITD kinases).
In some embodiments, compound provided by the invention and composition effectively can regulate the activity of Src subfamily, and it comprises Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr and Yrk.
In some embodiments, compound provided by the invention and composition effectively can regulate one or more kinase whose activity, described kinases is selected from: sterile20, sterile11, sterile, camk subfamily (calmodulin regulates kinases and associated kinase), AGC subfamily (protein kinase A, protein kinase G and protein kinase C), CMGC subfamily (cdk, map kinases, glycogen synthase kinase and clk), sterile20 subfamily, Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak, Jak and Ack (and respective subfamily).
In other embodiments, the invention provides the compound disclosed in use and composition, or its pharmacy acceptable salt, solvate, hydrate or its prodrug are used for the method for the disease, illness and the discomfort that are regulated by kinase activity or otherwise affect of local or whole body therapeutic or prevention people and beast.
Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.Specifically, salt is pharmacy acceptable salt.It must be applicable to chemistry or toxicologically that term " pharmaceutically acceptable " comprises material or composition, relevant with other components of composition preparation and the Mammals that is used for the treatment of.The salt of compound of the present invention also comprise for the preparation of or the salt of the intermediate of purifying formula (I), formula (II) or formula (III) compound or the enantiomer of formula (I), formula (II) or formula (III) compound separation, but not necessarily pharmacy acceptable salt.
If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxysuccinic acid, Lactic acid Citric Acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, Phenylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid, trifluoromethanesulfonic acid etc. or their combination.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide, ammonium, N +(R 14) 4salt and alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, N +(R 14) 4salt, as R 14h, C 1-4alkyl, C 6-10aryl, C 6-10aryl C 1-4alkyl etc., and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.Also suitable, nontoxic ammonium is comprised, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
The composition of compound of the present invention
According to another aspect, the feature of pharmaceutical composition of the present invention comprises receptible salt or its prodrug in formula of the present invention (I), formula (II) or formula (III) compound, hydrate, solvate, isomer or physiology/pharmacy, compound listed by the present invention, or the compound of embodiment 1-34, with pharmaceutically acceptable carrier, assistant agent, or vehicle.Composition of the present invention can for the preparation of the application of medicine preventing, process, treat or alleviate protein kinase mediated disease.Pharmaceutical composition of the present invention is preparing the application in medicament as FLT3 kinases or FLT3-ITD kinase inhibitor.
Pharmaceutical composition of the present invention, its contained (I), formula (II) or formula (III) compound and pharmaceutically acceptable carrier thereof.Wherein, formula (I), formula (II) or formula (III) compound can also be combined into pharmacy composite with the compound of the second therapeutic activity.The pharmaceutical carrier used can be: solid, liquid or gas.The example of solid carrier comprises: lactose, terra alba, sucrose, talcum powder, gelatin, agar, pectin, gum arabic, Magnesium Stearate, stearic acid etc.The example of liquid vehicle comprises: syrup, peanut oil, sweet oil, water etc.The example of gaseous carrier comprises: carbonic acid gas and/or nitrogen.Equally, carrier or thinner can comprise time delay material disclosed in document, as glyceryl monostearate or glycerol stearate, separately or with wax with using.
On the other hand, the material that can be used as pharmaceutically acceptable carrier comprises, but is not limited to, ion-exchanger; Aluminium; Aluminum oxide; Aluminum stearate; Yelkin TTS; Serum protein is as human serum protein; Buffer substance is as phosphoric acid salt; Glycine; Sorbic Acid; Potassium sorbate; The partial glyceride mixtures of saturated vegetable fatty acid; Water; Ionogen as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate; Salt as sodium-chlor, zinc salt; Colloidal silicon; Magnesium Trisilicate; Polyvinylpyrrolidone; Polyacrylate; Wax; Polyethylene-polyoxypropylene-blocking-up polymer; Lanolin; Sugared as lactose, dextrose plus saccharose; Starch is as W-Gum and potato starch; Mierocrystalline cellulose and its derivative as Xylo-Mucine, ethyl cellulose and rhodia; Natural gum powder; Fructus Hordei Germinatus; Gelatin; Talcum powder; Auxiliary material is as cocoa butter and suppository wax; Oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil; Glycol compound, as propylene glycol and polyoxyethylene glycol; Ester class is as ethyl oleate and Ethyl Lauroyl acid esters; Agar; Buffer reagent is as magnesium hydroxide and aluminium hydroxide; Lalgine; Pyrogen-free water; Isotonic salt; Lin Ge (family name) solution; Ethanol; Phosphate buffer solution; With other nontoxic proper lubrication agent as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, coating agents, sweeting agent, seasonings and spices, sanitas and antioxidant.For simplicity, local anesthetic, sanitas, buffer reagent etc. can directly be dissolved in carrier.
The purposes of compound of the present invention and composition
Formula of the present invention (I), formula (II) or formula (III) compound or its pharmaceutical composition can be used for treating and have the active situation as Proliferative Disorders feature of unsuitable FLT3.FLT3 activity increases and includes but not limited to: in cell, FLT3 expresses increases or regenerate FLT3 expresses, the FLT3 that increases expresses or active and FLT3 the suddenlys change constitutive activation caused.Improper or abnormal FLT3 aglucon and FLT3 level or activity can use well-known method in document to determine.Such as, FLT3 horizontal abnormality is high, and commercially available ELISA kit can be used to determine.FLT3 level can use flow cytometric analysis, immunohistochemical analysis and hybridization in situ technique to determine.
A unsuitable FLT3 activates, can after FLT3 is attached to acceptor by one or more continue after the activity increase that occurs determine: the phosphorylation of (1) FLT3 or autophosphorylation; The phosphorylation of (2) FLT3 substrates, substrate is as Stat5, Ras; (3) related complex is as the activation of PI3K; (4) activation of acceptor molecule; (5) cell proliferation.These activities are easy to detect with well-known literature method.
Formula of the present invention (I), formula (II) or formula (III) compound or its pharmaceutical composition can also be used for the medicine as the following illness of preparation, described medicine comprises but is not limited thereto: by giving the formula (I) of patient's effective dose of the present invention, formula (II) or formula (III) compound or including the pharmaceutical composition of formula (I), formula (II) or formula (III) compound, preventing/treating patient proliferative disease, situation or disorder.Described illness comprises: cancer, especially hematopoietic system cancer, metastatic tumo(u)r, atheromatosis, pulmonary fibrosis disease.
Compound of the present invention or its pharmaceutical composition also can be used for the medicine of the formation preparing treatment knurl, described knurl comprises cancer and metastatic cancer, includes but not limited to: bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer), esophagus cancer, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer, skin carcinoma (comprising squamous cell carcinoma); Lymphatic cells tumour (comprising leukemia, acute lymphoblastic leukemia, Acute Lymphoblastic Leukemia, B cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma and Burkett's lymphoma); Marrow sample hematopoietic system cancer (comprising acute and chronic granulocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia); The tumour (comprising fibrosarcoma and rhabdosarcoma and other sarcomas, as soft tissue and bone) of mesenchyme origin; Maincenter and peripheral nervous system neoplasms (comprising astrocytoma, neuroblastoma, neurospongioma and schwannoma) and other tumours (comprising melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma thyroid follcular carcinoma and Kaposi's sarcoma).
Compound of the present invention or its pharmaceutical composition also can be used for preparation or treatment FLT3 mediation, the disease medicament of FLT3-ITD mediation and/or CSF-1R mediation, this disease comprises: autoimmune disorder, kidney disease, tissue transplantation rejection, lupus erythematosus, multiple sclerosis, inflammatory bowel, rheumatoid arthritis, sacroiliitis, asthma etc.
Compound of the present invention or its pharmaceutical composition also can be used for preparation or treat diabetic situation as diabetic retinopathy and microangiopathy medicine, very useful.
Compound of the present invention or its pharmaceutical composition reduce also useful for volume of blood flow in tumour.
Compound of the present invention or its pharmaceutical composition also useful for the minimizing of metastases.
Compound of the present invention or its pharmaceutical composition useful except the treatment for the mankind, the treatment that also can be used for animal doctor, as pet, rare animal and farm-animals, comprises Mammals, rodent etc.Other say more specificly, and animal comprises horse, dog and cat.Formula of the present invention (I), formula (II) or formula (III) compound, comprise its pharmaceutically acceptable derivates in use.
Compound of the present invention or its pharmaceutical composition also can be used for preparing the medicine suppressing VEGF expression R or c-Met Growth of Cells, and this medicine comprises and connects cell and compound of the present invention or composition.Comprise about the repressed example of Growth of Cells: breast cancer cell, colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate cancer cell, lymphocytic cancer cell, colon cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cells, osteosarcoma cell, kidney cancer cell, liver cancer cell, transitional cell bladder carcinoma cell line, stomach cancer cell, G. cephalantha cell, melanoma cell or leukemia cell.
Compound of the present invention or its pharmaceutical composition also can be used for preparing the medicine suppressing VEGFR and/or c-Met kinase activity, and this medicine comprises and connects biological material and compound disclosed by the invention or composition.Term used herein " biological material ", refers to the organism sample of an outside work, includes but not limited to cell cultures or its extract; The biopsy material obtained from Mammals or its extract; Blood, saliva, urine, ight soil, seminal fluid, tears or other body fluid or its extract.The suppression of kinase activity, particularly VEGFR or c-Met kinase activity, be used for purposes disclosed in various kinds of document with biological material form.The example of this object includes but not limited to: blood transfusion, organ transplantation, biological specimen storage and biological assay.
The administration of the compounds of this invention and composition
Compound of the present invention, salt etc. or its pharmaceutical composition can simultaneously multiplely give, and also can give with single compound, salt etc.
Treatment of the present invention comprises: give study subject compound of the present invention or composition, comprise further: give study subject a kind of additional treatment agent (combination therapy), be selected from: chemotherapy or antiproliferative or a kind of anti-inflammatory agent, wherein, additional therapeutical agent is more applicable for the disease treatment for the treatment of, additional therapeutical agent gives together with compound disclosed by the invention or composition, can be used as single dosage form or separates the part as multiple doses form with compound and composition.Additives can give from compound disclosed by the invention simultaneously or asynchronously give.In the case of the latter, administration can be staggered, such as: 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
Typically treat the serum-concentration that significant quantity should produce the activeconstituents of about 0.1ng/ml to about 50-100 microgram/ml.Described pharmaceutical composition typically should provide from about 0.001mg to about 2000mg compound/every day/dosage of kg body weight.Pharmaceutical quantities unit form can be prepared and be about 1mg to about 1000mg to provide every dosage unit form, in certain embodiments, the required activeconstituents from about 10mg to about 500mg, from about 20mg to about 250mg or from about 25mg to about 100mg or the combination of neccessary composition.In certain embodiments, this pharmaceutical dosage unit forms can be prepared to provide the required activeconstituents of about 1mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg.In certain embodiments, this pharmaceutical dosage unit forms is prepared to provide the necessary activeconstituents of about 50mg.
In pharmaceutical composition, the activeconstituents of active compound can once daily, or is divided into some smaller doses and carrys out administration with certain hour interval.Should be appreciated that accurate dosage and treatment time length are the functions of the disease that will treat, it can adopt known experimental technique rule of thumb to determine, or by body or external experimental data to extrapolate acquisition.It should be noted that concentration and dose value also can change with the seriousness degree of the symptom that will alleviate.It is to be further understood that; for any concrete object; should according to individual demand and carry out administration or the administration of supervision group compound people professional judgement and adjust concrete dosage regimen in time; here the concentration range proposed has been only example effect, does not attempt the scope or the enforcement that limit claimed composition.
" significant quantity " of the present invention or " effective dose " refer to: effectively measure for treating or alleviating one or more aforesaid disorders.According to compound disclosed by the invention or composition, any effective quantity and any effective route of administration treatment can be used to treat or alleviate the seriousness of disorder or disease.Required exact amount by different according to different themes, according to species, age and the generalized case of theme, the severity, special preparation, administering mode etc. of infection.Compound or composition can also give together with one or more other drugs, as mentioned above.
Compound of the present invention or its pharmaceutical composition also can be used for wrapping up Implantable Medical Device, as artificial limb, artificial valve, artificial blood vessel, support and conduit.Intravascular stent overcomes restenosis (reducing again of vessel wall after injury) as being used to.But patient uses support or other implanted devices will emit the risk of blood clot formation or platelet activation.These detrimentally affects, can comprise its pharmaceutically acceptable composition of a kind of compound of the present invention, to stop or to alleviate by precoating on equipment.
When being used for the treatment of cancer patients, dosage can change according to cancer species, patient age, generalized case, the special compound given, toxicity existence or level, once bad kickback of using medicine and other factors.The representative example of a Suitable dosage ranges is from being low to moderate about 0.01mg/kg to as high as about 100mg/kg.But dosage is generally by doctors' free decision.
Methods for the treatment of gives formula of the present invention (I), formula (II) or formula (III) compound preferably by oral or parenteral.Term used herein " parenteral " comprising: intravenous injection, intramuscular injection or Intraperitoneal medication.The general preferred subcutaneous and intramuscular administration form of parenteral admin.The present invention can also by subcutaneous injection, collunarium, internal rectum, give formula of the present invention (I), formula (II) or formula (III) compound through skin or intravaginal.
Formula of the present invention (I), formula (II) or formula (III) compound or its pharmaceutical composition also can pass through " suction " administration." suction " refers to nasal cavity and oral inhalation administration.Dosage forms such as aerosol or the metered-dose inhaler of this administration obtain by general technology.
The preparation of the compounds of this invention and pharmaceutical composition and administration
Formula of the present invention (I), formula (II) or formula (III) compound or its pharmaceutical composition can make multi-medicament formulation.If use oral solid formulation, can be prepared into: the forms such as tablet, hard capsule, lozenge, lozenge, drops, lotion.The amount of solid carrier can be very different, but general from about 0.025mg to about 1g.If oral administration is liquid dosage form, typical preparation formulation is as syrup, emulsion, soft capsule, suspension or solution form.When using intravenous dosage forms, medicine can be solid or liquid form, and administration after can be made into direct administration or being applicable to restructuring.In Topical dosage forms is also included within, the example of Topical dosage forms is as solid, liquid and semisolid.Solid comprises except pulvis, application etc.Liquid comprises solution, suspension and emulsion.Semisolid comprises emulsifiable paste, ointment and gel etc.
The amount of formula of the present invention (I), formula (II) or formula (III) compound or its pharmaceutical composition local application changes according to the change of selected compounds, proterties and severity certainly, also can be different and different according to the tailoring power of doctor.Formula of the present invention (I), formula (II) or formula (III) compound local application amount are representational from the paramount about 2.0g of low about 0.01mg, administration one to four time in a day, preferably administration one to twice in a day.Activeconstituents for topical can comprise from about about 0.001% to about 10%W/W.
When for drops, aseptic or non-sterile water or oil solution or suspension can be comprised, by solubilize active ingredients is prepared in the suitable aqueous solution, optionally comprise the sanitas that sterilization and/or mycocide and/or any other are suitable, and tensio-active agent can be comprised selectively.Final solution makes it clarify by filtering, and transfers in suitable container, then seals, by autoclaving or maintain 98-100 degree Celsius of half hour sterilizing.In addition, this solution can filtration sterilization, and transfers to sterile chamber.The sterilization comprised in drops and mycocide example are: Phenylmercurinitrate or acetic acid (0.002%), benzalkonium chloride (0.01%) and chlorhexidine (0.01%).Suitable solvent for the preparation of oil solution comprises: glycerine, Diluted Alcohol and propylene glycol.
When for lotion, also comprise the lotion that those are applicable to being applied to skin or eyes.Eye lotions can comprise a kind of sterile aqueous solution, optionally containing sterilant, prepares by the similar approach preparing drops.Be applicable to lotion or the liniment of skin, also can comprise a kind of reagent, it can accelerate drying, and cooling skin is if alcohol or acetone and/or moistening agent are as glycerine or oil, and oil is as Viscotrol C or peanut oil.
The outer application semi-solid preparation of activeconstituents according to emulsifiable paste of the present invention, ointment or patch.They obtain by mixed active composition and grease sample or non-grease sample matrix, activeconstituents with divided mode or Micronised form, separately or in the solution or be suspended in water or on-aqueous liquid.Matrix can comprise hydrocarbon polymer, as: hard, soft or whiteruss, glycerine, beeswax; Metallic soap; A kind of cement; A kind of natural produce oil class as almond, coenzyme M, peanut, castor-oil plant or sweet oil; Wool fat or derivatives thereof, or lipid acid is if stearic acid or oleic acid are together with ethanol, and ethanol is as propylene glycol or tight gel.Preparation can mix any suitable tensio-active agent, as negatively charged ion, positively charged ion or nonionogenic tenside, as sorbitol ester or its polyoxyethylene deriv.Suspension agent, if natural gum, derivatived cellulose or inorganic materials are as silicate, also can comprise other compositions as lanolin.
Compound of the present invention or its pharmaceutical composition can also with the form administrations of coating, and suitable coating implanting device is known for those skilled in the art.Described coating is representative biocompatible polymeric material as aquogel polymer, poly-tetramethyldisiloxane, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), vinyl acetate between to for plastic and their mixture.Coating optionally further by a suitable plastic film covering, as: fluorosilicon oil, polysaccharidase, polyoxyethylene glycol, phosphatide or its mixture, make pharmaceutical composition have Co ntrolled release characteristic.Compound of the present invention also can be applied on Implantable Medical Device, jointly prepares as beads or with polymkeric substance or other molecule, provides a kind of " drug storage institute ", thus medicine is discharged in the long period, instead of with the form administration of pharmaceutical aqueous solution.
General synthetic method
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I), formula (II) or formula (III) compound.Reaction scheme below and embodiment are used for illustrating content of the present invention further.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except amendment that is described in the invention or that reaction conditions is made some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as AldrichChemical Company, Arco Chemical Company and Alfa Chemical Company, all not through being further purified, unless other aspects show during use.General reagent is from Xi Long chemical plant, Shantou, and Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited and Haiyang Chemical Plant, Qingdao buy and obtain.
Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 3, d 6-DMSO, CD 3oD or d 6-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplet).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS being equipped with G1312A binary pump and a G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the serial LC-MS of Agilent 6120 being equipped with G1311A quaternary pump and G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs are provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:
Table 1
Time (min) A(CH 3CN，0.1％HCOOH) B(H 2O，0.1％HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purifying is evaluated by Agilent 1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 DEG C.
The use of brief word below runs through the present invention:
BOC, Boc tert-butoxycarbonyl
CHCl 3chloroform
CDC1 3deuterochloroform
DMF DMF
DMAP DMAP
DMSO dimethyl sulfoxide (DMSO)
EDC, EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
EtOAc ethyl acetate
HCl hydrochloric acid
H 2hydrogen
H 2o 2hydrogen peroxide
Fe iron
MeOH, CH 3oH methyl alcohol
CH 2cl 2, DCM methylene dichloride
ML, ml milliliter
N 2nitrogen
Pd/C palladium/carbon
PE sherwood oil (60-90 DEG C)
RT rt room temperature
Rt retention time
MsCl methylsulfonyl chloride
NaHCO 3sodium bicarbonate
Na 2sO 4sodium sulfate
THF tetrahydrofuran (THF)
Et 3n, TEA triethylamine
TFA trifluoroacetic acid
NBS N-bromo-succinimide
H 2o water
The synthesis of intermediate
The synthesis of intermediate 2
Compound 2, can be prepared, wherein R, and n is had implication as described in the present invention by the method for following two kinds.Method one: compound 1A and compound 2A in the basic conditions, obtains compound 3A; Compound 3A chlorination generates compound 2.Method two: compound 1A and compound 4A in the basic conditions, generates compound 2.
The synthesis of intermediate 8A
Compound 8A, can prepare by the following method.Compound 5A and compound 6A in the basic conditions, obtains compound 7A; Compound 7A deprotection generates compound 8A.
The synthetic schemes of compound
Reaction scheme 1
Compound 6, can be prepared by the method for reaction scheme 1, wherein R 1, a, R, E, G and n have implication as described in the present invention.Compound 1 and compound 2 in the basic conditions, obtain compound 3.Compound 3 is carried out reduction reaction and obtains product 4, be obtained by reacting product 6 with compound 5 subsequently.
Reaction scheme 2
Compound 6, can be prepared by the method for reaction scheme 2, wherein R 1, a, R, E, G and n have implication as described in the present invention.Compound 4 and compound 7 are obtained by reacting product 6.
Reaction scheme 3
Compound 6, can be prepared by the method for reaction scheme 3, wherein R 1, a, R, E, G and n have implication as described in the present invention.Compound 1 and compound 2a in the basic conditions, obtain compound 3a.The hydroxyl of compound 3a is carried out protection and obtains compound 8, then carry out reduction reaction and obtain product 4, be obtained by reacting product 6 with compound 5 subsequently.
The following examples can the present invention will be further described, but these embodiments should as the restriction to scope of the present invention.
Embodiment
Embodiment 1
1-(5-(tertiary butyl) isoxzzole-3-base)-3-(4-(6-(3-morpholino propoxy-) imidazo [1,2-b] pyridazine-2-base) phenyl) urea
Step 1) 6-methoxyl group-2-(4-nitrophenyl) imidazo [1,2-b] pyridazine
3-amino-6-methoxyl group pyridazine (250mg, 2.0mmol) is dissolved in acetonitrile (50mL), then adds the bromo-4 '-nitro-acetophenone (970mg, 3.99mmol) of 2-.Vlil reaction 5h, after reaction terminates, direct suction filtration, after filter cake vacuum-drying, obtains product (408mg, 75.7%).
ESI-MS:(ESI,pos.ion)m/z：271.2[M+1] +.
Step 2) 2-(4-nitrophenyl) imidazo [1,2-b] pyridazine-6-alcohol
6-methoxyl group-2-(4-nitrophenyl) imidazo [1,2-b] pyridazine (540mg, 2.0mmol) and pyridine hydrochloride (1.15g, 10.0mmol) are mixed, is heated to 150 degrees Celsius of melting stirring reaction 5h.Residue is added water (100mL), extract with methylene dichloride (400mL), organic phase saturated sodium-chloride water solution (100mL) washs, anhydrous sodium sulfate drying, concentrating under reduced pressure, rapid column chromatography is separated (V (sherwood oil)/V (ethyl acetate)=5/1), obtains white solid (260mg, 50.7%).
ESI-MS:(ESI,pos.ion)m/z：257.1[M+1] +.
Step 3) 4-(3-((2-(4-nitrophenyl) imidazo [1,2-b] pyridazine-6-base) oxygen base) propyl group) morpholine
By 2-(4-nitrophenyl) imidazo [1,2-b] pyridazine-6-alcohol (256mg, 1.0mmol) be dissolved in acetonitrile (30mL), add 1-(3-chloropropyl)-morpholine (187mg successively, 1.14mmol) with salt of wormwood (430mg, 3.12mmol).Vlil reaction 10h, concentrating under reduced pressure, residue is added water (50mL), with methylene dichloride (300mL) extraction, organic phase saturated sodium-chloride water solution (50mL) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, rapid column chromatography is separated (V (DCM)/V (MeOH)=10/1), obtains white solid (276mg, 72%).
ESI-MS:(ESI,pos.ion)m/z：384.2[M+1] +.
Step 4) 4-(6-(3-morpholino propoxy-) imidazo [1,2-b] pyridazine-2-base) aniline
By 4-(3-((2-(4-nitrophenyl) imidazo [1,2-b] pyridazine-6-base) oxygen base) propyl group) morpholine (766mg, 2.0mmol) is dissolved in mixed solvent (V (MeOH)/V (H 2o)=3/1, 160mL), add ammonium chloride (830mg, 15.65mmol) with reduced iron powder (438mg, 7.83mmol), be warmed up to 80 degrees Celsius of stirring and refluxing reaction 3h, TLC monitoring reaction is complete, add saturated sodium bicarbonate solution (100mL) cancellation reaction, ethyl acetate (300mL) extracting and separating, organic phase washed with water (100mL) is washed, saturated nacl aqueous solution (50mL) is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography for separation (V (MeOH)/V (DCM)=1/10), obtain oily matter (550mg, 78.3%).
ESI-MS:(ESI,pos.ion)m/z：354.3[M+1] +.
Step 5) 1-(5-(tertiary butyl) isoxzzole-3-base)-3-(4-(6-(3-morpholino propoxy-) imidazo [1,2-b] pyridazine-2-base) phenyl) urea
By 4-(6-(3-morpholino propoxy-) imidazo [1,2-b] pyridazine-2-base) aniline (172mg, 0.5mmol) be dissolved in acetonitrile (30mL), add triethylamine (0.3mL successively, 2.2mmol) with phenyl N-(5-tertiary butyl isoxzzole-3-base) carbamate (0.29g, 1.1mmol), heated and stirred back flow reaction is spent the night, after reaction terminates, concentrating under reduced pressure, direct column chromatography for separation (V (MeOH)/V (DCM)=1/10), obtains white solid (50mg, 19.2%).
ESI-MS:(ESI,pos.ion)m/z：520.5[M+1] +.
1H NMR(400MHz,d 6-DMSO)δ9.89(s,2H),8.53(s,1H),7.98(d,J＝9.6Hz,1H),7.90(d,J＝8.4Hz,2H),7.53(d,J＝8.5Hz,2H),6.85(d,J＝9.6Hz,1H),6.54(s,1H),4.34(t,J＝6.5Hz,2H),3.58–3.56(m,4H),3.43(t,J＝6.3Hz,2H),2.48–2.39(m,4H),1.57(dd,J＝13.1,6.6Hz,2H),1.30(s,9H).
Embodiment 2
1-(5-(tertiary butyl) isoxzzole-3-base)-3-(4-(7-(3-morpholino propoxy-) imidazo [1,2-a] pyridine-2-base) phenyl) urea
Step 1) 7-methoxyl group-2-(4-nitrophenyl) imidazo [1,2-a] pyridine
2-amino-4-methoxyl pyridine (6.21g is added successively in reaction flask, 50.02mmol), the bromo-4'-nitro-acetophenone of 2-(6.3g, 75mmol), sodium bicarbonate (6.3g, 75mmol) and ethanol (125mL), reflux refluxes 1 hour.Mixed solution is cooled to 0 DEG C, then filters, and filter cake, with after a small amount of ethanol rinse, is crossed column purification (V (sherwood oil)/V (ethyl acetate)=3/2), obtained yellow solid (1.84g, 14%).
ESI-MS:(ESI,pos.ion)m/z：270.2[M+1] +。
Step 2) 2-(4-nitrophenyl) imidazo [1,2-a] pyridine-7-alcohol
7-methoxyl group-2-(4-nitrophenyl) imidazo [1 is added successively in reaction flask, 2-a] pyridine (1.84g, 6.83mmol) with DCM (300mL), under ice bath, drip boron tribromide (1.0mL) and stir at such a temperature after 0.5 hour, recovering stirred overnight at room temperature.By MS detect raw material reaction completely after, in reaction solution, add saturated sodium bicarbonate solution produce to without gas, continuation stirring is after 0.5 hour, solid collected by filtration drying under reduced pressure, obtains brown solid (1.48g, 85%).
ESI-MS:(ESI,pos.ion)m/z：256.0[M+1] +。
Step 3) 4-(3-((2-(4-nitrophenyl) imidazo [1,2-a] pyridin-7-yl) oxygen base) propyl group) morpholine
2-(4-nitrophenyl) imidazo [1 is added successively in reaction flask, 2-a] pyridine-7-alcohol (1.48g, 5.80mmol), salt of wormwood (2.4g, 17.39mmol), tetrabutyl iodate amine (0.43g, 1.16mmol), 4-(3-chloropropyl) morpholine (2.37g, 14.48mmol) with DMF (30mL), heating reflux reaction 6 hours.React complete, be chilled to room temperature, mixed solution is poured in water (200mL), and stirring at room temperature is after 1 hour, and filter, filter cake drying under reduced pressure, obtains brown solid (1.69g, 76%).
ESI-MS:(ESI,pos.ion)m/z：383.1[M+1] +。
Step 4) 4-(7-(3-morpholino propoxy-) imidazo [1,2-a] pyridine-2-base) aniline
4-(3-((2-(4-nitrophenyl) imidazo [1 is added successively in reaction flask, 2-a] pyridin-7-yl) oxygen base) propyl group) morpholine (1.69g, 4.42mmol), zinc powder (2.89g, 44.46mmol), ammonium chloride (0.95g, 17.68mmol) with ethanol/water (15/4,38mL), heating reflux reaction 4 hours.Solids removed by filtration, after filtrate decompression evaporate to dryness, adds methylene dichloride (100mL) and saturated sodium bicarbonate solution (100mL) in residue, extracting and separating, anhydrous sodium sulfate drying organic phase, obtains brown solid (1.48g, 95%) after concentrated.
ESI-MS:(ESI,pos.ion)m/z：353.1[M+1] +。
Step 5) 1-(5-(tertiary butyl) isoxzzole-3-base)-3-(4-(7-(3-morpholino propoxy-) imidazo [1,2-a] pyridine-2-base) phenyl) urea
4-(7-(3-morpholino propoxy-) imidazo [1 is added successively in reaction flask, 2-a] pyridine-2-base) aniline (0.6g, 1.70mmol) with dry methylene chloride (8mL), phenyl (5-(tertiary butyl) different azoles-3-base) carbamate (0.49g is added again successively under room temperature, 1.88mmol) with DMAP (12mg, 0.1mmol), methylene dichloride (0.1mL) solution of triethylamine (0.035mL) is dripped, heated overnight at reflux after stirring.Solid collected by filtration, with a small amount of methylene dichloride (10mL) drip washing, obtains white solid (208mg, 24%).
1H NMR(400MHz,d 6-DMSO):δ9.55(s,1H),8.90(s,1H),8.33(d,J＝7.2Hz,1H),8.10(s,1H),7.85(d,J＝8.8Hz,2H),7.52(d,J＝8.8Hz,2H),6.92(d,J＝2.0Hz,1H),6.56-6.58(dd,J＝2.4,7.2Hz,1H),6.53(s,1H),4.08-4.05(t,J＝6.0Hz,2H),3.58-3.56(t,J＝4.4Hz,4H),2.44-2.40(t,J＝6.8Hz,2H),2.36(s,4H),1.91-1.88(t,J＝6.8Hz,2H),1.30(s,9H).
ESI-MS:(ESI,pos.ion)m/z：519.4[M+1] +。
Embodiment 3
1-(5-(tertiary butyl) isoxzzole-3-base)-3-(4-(6-(3-morpholino propoxy-) imidazo [1,2-a] pyridine-2-base) phenyl) urea
Step 1) 6-methoxyl group-2-(4-nitrophenyl) imidazo [1,2-a] pyridine
2-amino-5-methoxypyridine (6.21g is added successively in reaction flask, 50.02mmol), the bromo-4'-nitro-acetophenone of 2-(6.3g, 75mmol), sodium bicarbonate (6.3g, 75mmol) and ethanol (125mL), reflux refluxes 1 hour.Mixed solution is cooled to 0 degree Celsius, then filters, and filter cake is with after a small amount of ethanol rinse, and column chromatography for separation (V (sherwood oil)/V (ethyl acetate)=3/2), obtains yellow solid (1.84g, 14%).
ESI-MS:(ESI,pos.ion)m/z：270.2[M+1] +。
Step 2) 2-(4-nitrophenyl) imidazo [1,2-a] pyridine-6-alcohol
6-methoxyl group-2-(4-nitrophenyl) imidazo [1 is added successively in reaction flask, 2-a] pyridine (1.84g, 6.83mmol) with methylene dichloride (300mL), under ice bath, drip boron tribromide (1.0mL) and stir at such a temperature after 0.5 hour, recovering stirred overnight at room temperature.By LC-MS detect raw material reaction completely after, in reaction solution, add saturated sodium bicarbonate solution produce to without gas, continuation stirring is after 0.5 hour, solid collected by filtration drying under reduced pressure, obtains brown solid (1.48g, 85%).
ESI-MS:(ESI,pos.ion)m/z：256.0[M+1] +。
Step 3) 4-(3-((2-(4-nitrophenyl) imidazo [1,2-a] pyridine-6-base) oxygen base) propyl group) morpholine
2-(4-nitrophenyl) imidazo [1 is added successively in reaction flask, 2-a] pyridine-6-alcohol (0.51g, 1.99mmol), salt of wormwood (0.83g, 6.01mmol), tetrabutylammonium iodide (0.15g, 0.41mmol), 4-(3-chloropropyl) morpholine hydrochloride (0.8g, 4mmol) with DMF (20mL), heating reflux reaction 6 hours.React complete, be chilled to room temperature, mixed solution is poured in water (200mL), and stirring at room temperature is after 1 hour, and filter, filter cake drying under reduced pressure, obtains brown solid (0.61g, 80%).
ESI-MS:(ESI,pos.ion)m/z：383.2[M+1] +
Step 4) 4-(6-(3-morpholino propoxy-) imidazo [1,2-a] pyridine-2-base) aniline
4-(3-((2-(4-nitrophenyl) imidazo [1 is added successively in reaction flask, 2-a] pyridine-6-base) oxygen base) propyl group) morpholine (0.61g, 1.60mmol), zinc powder (1.31g, 20mmol), ammonium chloride (0.5g) and ethanol/water (15/4,40mL), heating reflux reaction 4 hours.Solids removed by filtration, after filtrate decompression evaporate to dryness, adds methylene dichloride (300mL) and saturated sodium bicarbonate solution (100mL) in residue, extracting and separating, anhydrous sodium sulfate drying organic phase, obtains brown solid (0.4g, 70%) after concentrating under reduced pressure.
ESI-MS:(ESI,pos.ion)m/z：353.2[M+1]+。
Step 5) 1-(5-(tertiary butyl) isoxzzole-3-base)-3-(4-(6-(3-morpholino) imidazo [1,2-a] pyridine-2-base) phenyl) urea
4-(6-(3-morpholino propoxy-) imidazo [1 is added successively in reaction flask, 2-a] pyridine-2-base) aniline (0.4g, 1.13mmol) with dry methylene chloride (20mL), phenyl (5-(tertiary butyl) different azoles-3-base) carbamate (1.04g is added again successively under room temperature, 4.0mmol) with DMAP (20mg), drip triethylamine (0.3mL) after stirring, heating reflux reaction spends the night.Solid collected by filtration, with a small amount of methylene dichloride (10mL) drip washing, obtains white solid (176mg, 30%).
ESI-MS:(ESI,pos.ion)m/z：519.3[M+1] +。
1H NMR(400MHz,d 6-DMSO)δ9.57(s,1H),8.93(s,1H),8.21–8.04(m,2H),7.88(d,J＝8.6Hz,2H),7.55(d,J＝8.7Hz,2H),7.45(d,J＝9.7Hz,1H),6.98(dd,J＝9.7,2.2Hz,1H),6.55(s,1H),3.91(t,J＝6.2Hz,2H),3.54(m,8H),2.36(m,6H),1.94–1.70(m,2H),1.28(s,9H).
Embodiment 4
1-(5-(tertiary butyl) isoxzzole-3-base)-3-(4-(6-(3-((4aR, 7aS)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) propoxy-) imidazo [1,2-a] pyridine-2-base) phenyl) urea
Step 1) 6-methoxyl group-2-(4-nitrophenyl) imidazo [1,2-a] pyridine
2-amino-5-methoxypyridine (6.21g, 50.02mmol), the bromo-4'-nitro-acetophenone of 2-(6.3g, 75mmol) with sodium bicarbonate (6.3g, 75mmol) prepare yellow solid (1.84g, 14%) according to the synthetic method of embodiment 2 step 1.
ESI-MS:(ESI,pos.ion)m/z：270.2[M+1] +。
Step 2) 2-(4-nitrophenyl) imidazo [1,2-a] pyridine-6-alcohol
6-methoxyl group-2-(4-nitrophenyl) imidazo [1,2-a] pyridine (1.84g, 6.83mmol) with boron tribromide (1.0mL) according to embodiment 2 step 2-in-1 become method prepare brown solid (1.48g, 85%).
ESI-MS:(ESI,pos.ion)m/z：256.0[M+1] +。
Step 3) (4aR, 7aS)-6-(3-((2-(4-nitrophenyl) imidazo [1,2-a] pyridine-6-base) oxygen base) propyl group) six hydrogen-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles
2-(4-nitrophenyl) imidazo [1,2-a] pyridine-6-alcohol (0.51g, 1.99mmol), salt of wormwood (0.83g, 6.01mmol), tetrabutylammonium iodide (0.15g, 0.41mmol), (4aR, 7aS)-6-(3-chloropropyl) six hydrogen-2H-[1,4] dioxin [2,3-c] pyrroles (0.82g, 3.99mmol) obtain brown solid (0.7g, 83%) with DMF (10mL) according to embodiment 2 step 3 synthetic method.
ESI-MS:(ESI,pos.ion)m/z：425.1[M+1] +。
Step 4) 4-(6-(3-((4aR, 7aS)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) propoxy-) imidazo [1,2-a] pyridine-2-base) aniline
(4aR, 7aS)-6-(3-((2-(4-nitrophenyl) imidazo [1,2-a] pyridine-6-base) oxygen base) propyl group) six hydrogen-2H-[1,4] dioxin [2,3-c] pyrroles (0.7g, 1.65mmol), zinc powder (1.31g, 20.15mmol) and ammonium chloride (0.43g, 8.04mmol) obtain brown solid (0.32g, 41%) according to embodiment 2 step 4 synthetic method.
ESI-MS:(ESI,pos.ion)m/z：395.2[M+1] +。
Step 5) 1-(5-(tertiary butyl) isoxzzole-3-base)-3-(4-(6-(3-((4aR, 7aS)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) propoxy-) imidazo [1,2-a] pyridine-2-base) phenyl) urea
4-(6-(3-((4aR, 7aS)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) propoxy-) imidazo [1,2-a] pyridine-2-base) aniline (0.32g, 0.81mmol), phenyl (5-(tertiary butyl) different azoles-3-base) carbamate (0.23g, 0.88mmol), DMAP (6mg, 0.05mmol) obtain white solid (52mg, 11%) with triethylamine (0.1mL) according to embodiment 2 step 5 synthetic method.
1H NMR(400MHz,d 6-DMSO):δ9.53(s,1H),8.90(s,1H),8.21-8.22(d,J＝2.0Hz,1H),8.19(s,1H),7.85(d,J＝8.4Hz,2H),7.52(d,J＝8.8Hz,2H),7.46(d,J＝9.6Hz,1H),7.01(dd,J＝2.4,10.0Hz,1H),6.52(s,1H),4.02-3.99(t,J＝6.4Hz,4H),3.72-3.68(m,2H),3.47-3.44(m,2H),2.87-2.83(m,2H)2.70-2.67(m,2H),2.65-2.61(t,J＝7.2Hz,2H),1.90-1.85(m,2H),1.31(s,9H).
ESI-MS:(ESI,pos.ion)m/z：561.3[M+1] +。
Embodiment 5
1-(5-tertiary butyl isoxzzole-3-base)-3-{4-[6-(2-morpholine oxyethyl group) imidazo [1,2-b] pyridazine-3-base] phenyl } urea
Step 1) the bromo-6-of 3-[2-(morpholine-4-base) oxyethyl group]-imidazo [1,2-b] pyridazine
By N-hydroxyethyl morpholine (1.15g, 8.4mmol) be dissolved in 50mL THF, be cooled to-10 degrees Celsius, add t-BuOK (1.45g, 12.6mmol), then be warming up to stirring at room temperature 30min, then be cooled to-10 degrees Celsius, drip 3-bromo-6-chlorine imidazoles [1,2-b] pyridazine (1.5g, THF (30mL) solution 6.5mmol), finishes, and stirred at ambient temperature reaction is spent the night.Add a small amount of water (10mL) cancellation reaction, concentrating under reduced pressure, resistates is dissolved in 200mL methylene dichloride, organic layer saturated sodium-chloride water solution (50mL) is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=15/1), obtain yellow solid (1.86g, 88%).
ESI-MS:(ESI,pos.ion)m/z：327.1[M+1] +。
Step 2) 4-[6-(2-morpholine oxyethyl group) imidazo [1,2-b] pyridazine-3-base] the Phenyl-carbamic acid tert-butyl ester
The bromo-6-of 3-[2-(morpholine-4-base) oxyethyl group]-imidazo [1 is added in 250ml single port bottle, 2-b] pyridazine (700mg, 2.14mmol) with potassium acetate (460mg, 4.64mmol), then add 100mL DMF and 25mL water, under then stirring, add PdCl successively 2(dppf) (180mg; 0.24mmol) with [4-(4; 4,5,5-tetramethyl--1; 3; 2-dioxy boron pentane-2-base) phenyl] t-butyl carbamate (770mg, 2.41mmol), finish; to bleed ventilation three times, be warming up to 80 degrees Celsius of stirring reactions under nitrogen protection and spend the night.Be cooled to room temperature, reaction solution is concentrated, resistates is dissolved in 300mL methylene dichloride, wash once with saturated sodium-chloride water solution (50mL), anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=15/1), obtain yellow oil (350mg, 37.22%).
ESI-MS:(ESI,pos.ion)m/z：440.3[M+1] +。
Step 3) 4-[6-(2-morpholine oxyethyl group) imidazo [1,2-b] pyridazine-3-base] aniline
By 4-[6-(2-morpholine oxyethyl group) imidazo [1,2-b] pyridazine-3-base] the Phenyl-carbamic acid tert-butyl ester (350mg, 0.796mmol) is dissolved in 20mL methylene dichloride, is cooled to 0 degree Celsius, drip 5mL trifluoroacetic acid, slowly return to stirring at room temperature reaction 3h.Concentrating under reduced pressure, resistates adds saturated sodium bicarbonate aqueous solution (50mL) cancellation, ethyl acetate (400mL) extracts, separate organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtain yellow oil (232mg, 85.5%).
ESI-MS:(ESI,pos.ion)m/z：340.2[M+1] +。
Step 4) 1-(5-tertiary butyl isoxzzole-3-base)-3-{4-[6-(2-morpholine oxyethyl group) imidazo [1,2-b] pyridazine-3-base] phenyl } urea
By 4-[6-(2-morpholine oxyethyl group) imidazo [1,2-b] pyridazine-3-base] aniline (232mg, 0.684mmol) be dissolved in 30mL methylene dichloride, 5-(tertiary butyl) isoxzzole-3-base is added successively under stirring) phenyl carbamate (0.78g, 3.0mmol) with DMAP (45mg, 0.37mmol), then drip triethylamine (0.3mL), finish, temperature rising reflux reaction is spent the night.TLC monitoring reaction is complete, be cooled to room temperature, organic phase washed with water (10mL) and saturated sodium-chloride water solution (10mL) are washed, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtains faint yellow solid (180mg, 54%).
ESI-MS:(ESI,pos.ion)m/z：506.3[M+1] +。
1H-NMR(400MHz,CDCl 3)δ:8.04(d,J＝8.7Hz,2H),7.90(s,1H),7.87(d,J＝9.6Hz,1H),7.68(d,J＝8.7Hz,2H),6.76(d,J＝9.6Hz,1H),5.95(s,1H),4.52(t,J＝5.5Hz,2H),3.77(m,4H),2.88(t,J＝5.5Hz,2H),2.61(s,4H),1.38(s,9H).
Embodiment 6
1-(5-tertiary butyl isoxzzole-3-base)-3-{4-[6-(3-morpholine propoxy-) imidazo [1,2-b] pyridazine-3-base] phenyl } urea
Step 1) the bromo-6-of 3-[3-(morpholine-4-base) propoxy-]-imidazo [1,2-b] pyridazine
By N-hydroxypropyl morpholine (1.39g, 9.50mmol) be dissolved in 35mL THF, be cooled to 0 degree Celsius, add t-BuOK (1.65g, 14.4mmol), then be warming up to stirring at room temperature 30min, then be cooled to 0 degree Celsius, under stirring, add 3-bromo-6-chlorine imidazoles [1,2-b] pyridazine (1.5g, THF (25mL) solution 6.5mmol), finishes, and stirred at ambient temperature reaction is spent the night.Add a small amount of water (10mL) cancellation reaction, concentrating under reduced pressure, resistates is dissolved in 200mL methylene dichloride, organic phase saturated sodium-chloride water solution (50mL) is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=20/1), obtain yellow solid (1.65g, 75%).
ESI-MS:(ESI,pos.ion)m/z：341.1[M+1] +
Step 2) 4-[6-(3-morpholine propoxy-) imidazo [1,2-b] pyridazine-3-base] the Phenyl-carbamic acid tert-butyl ester
The bromo-6-of 3-[3-(morpholine-4-base) propoxy-]-imidazo [1 is added in 250ml single port bottle, 2-b] pyridazine (900mg, 2.64mmol) with potassium acetate (520mg, 5.31mmol), then add 80mL DMF and 20mL water, under then stirring, add PdCl successively 2(dppf) (200mg; 0.27mmol) with [4-(4; 4,5,5-tetramethyl--1; 3; 2-dioxy boron pentane-2-base) phenyl] t-butyl carbamate (960mg, 3.00mmol), finish; to bleed ventilation three times, be warming up to 80 degrees Celsius of stirring reactions under nitrogen protection and spend the night.TLC monitoring reaction is complete, be cooled to room temperature, reaction solution is concentrated, resistates is dissolved in 300mL methylene dichloride, then uses saturated sodium-chloride water solution (50mL) to wash once, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtains yellow oil (357mg, 29.8%).
ESI-MS:(ESI,pos.ion)m/z：454.3[M+1] +
Step 3) 4-[6-(3-morpholine propoxy-) imidazo [1,2-b] pyridazine-3-base] aniline
By 4-[6-(3-morpholine propoxy-) imidazo [1,2-b] pyridazine-3-base] the Phenyl-carbamic acid tert-butyl ester (320mg, 0.70mmol) is dissolved in 20mL methylene dichloride, is cooled to 0 degree Celsius, drip 5mL trifluoroacetic acid, slowly return to stirring at room temperature reaction 4h.Concentrating under reduced pressure, resistates adds saturated sodium bicarbonate aqueous solution (50mL) cancellation, ethyl acetate (400mL) extracts, separate organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtain yellow oil (205mg, 82.2%).
ESI-MS:(ESI,pos.ion)m/z：354.2[M+1] +
Step 4) 1-(5-tertiary butyl isoxzzole-3-base)-3-{4-[6-(3-morpholine propoxy-) imidazo [1,2-b] pyridazine-3-base] phenyl } urea
By 4-[6-(3-morpholine propoxy-) imidazo [1,2-b] pyridazine-3-base] aniline (205mg, 0.58mmol) be dissolved in 30mL methylene dichloride, 5-(tertiary butyl) isoxzzole-3-base is added successively under stirring) phenyl carbamate (0.34g, 1.16mmol) with DMAP (40mg, 0.33mmol), then drip triethylamine (0.3mL), finish, temperature rising reflux reaction is spent the night.TLC monitoring reaction is complete, be cooled to room temperature, organic phase washed with water (10mL) and saturated sodium-chloride water solution (10mL) are washed, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtains faint yellow solid (120mg, 39.8%).
ESI-MS:(ESI,pos.ion)m/z：520.4[M+1] +
1H NMR(600MHz,CDCl 3)δ8.06(d,J＝8.7Hz,2H),7.89(dd,J＝36.9,19.9Hz,2H),7.68(d,J＝8.7Hz,2H),6.72(d,J＝9.6Hz,1H),5.93(s,1H),4.43(t,J＝6.2Hz,2H),3.75(t,J＝4.5Hz,4H),2.58-2.51(m,6H),2.18–1.90(m,2H),1.39(s,9H).
Embodiment 7
1-[5-(tertiary butyl) isoxzzole-3-base]-3-{4-[7-(2-morpholino oxyethyl group) pyrazolo [1,5-a] pyrimidin-3-yl] phenyl } urea
Step 1) the iodo-pyrazolo of the chloro-3-of 7-[1,5-a] pyrimidine
7-chlorine pyrazolo [1,5-a] pyrimidine (3.0g, 19.5mmol) is dissolved in 30mL DMF, adds NIS (5.3g, 23mmol), stirring at room temperature reaction 12h.In system, add 25mL water, have a large amount of solid to separate out, continue to stir 15min, suction filtration, by filter cake vacuum-drying, obtains off-white color solid (4.8g, 88%).
ESI-MS:(ESI,pos.ion)m/z：280.0[M+1] +
Step 2) 4-{2-[(3-iodine pyrazolo (1,5-a) pyrimidin-7-yl) oxygen base] ethyl } morpholine
Potassium tert.-butoxide (0.60g, 5.0mmol) is dissolved in THF (50mL), is cooled to 0 degree Celsius, more slowly drip N-hydroxyethyl morpholine (0.71g, 5.4mmol), stirring reaction 30min under zero degrees celsius.Slowly add the chloro-5-of 7-iodo-pyrazolo [1,5-a] pyrimidine (1.0g, 3.6mmol) again, keep temperature to be no more than 10 degrees Celsius, finish, keep 0 degree Celsius to react 2h.(30mL) cancellation that adds water is reacted, concentrating under reduced pressure, residue from dichloromethane (300mL) is extracted, organic phases washed with water (50mL), saturated common salt washing (50mL), anhydrous sodium sulfate drying, concentrating under reduced pressure obtains faint yellow solid (0.98g, 73%).Do not need to be further purified, directly cast single step reaction.
ESI-MS:(ESI,pos.ion)m/z：375.1[M+1] +
Step 3) { 4-[7-(2-morpholino oxyethyl group) pyrazoles [1,5-a] pyrimidin-3-yl] phenyl } t-butyl carbamate
4-{2-[(3-iodine pyrazolo (1 is added in 250ml single port bottle, 5-a) pyrimidin-7-yl) oxygen base] ethyl } morpholine (800mg, 2.14mmol) with potassium acetate (460mg, 4.64mmol), then add 100mL DMF and 25mL water, add PdCl successively 2(dppf) (180mg; 0.24mmol) with [4-(4; 4,5,5-tetramethyl--1; 3; 2-dioxy boron pentane-2-base) phenyl] t-butyl carbamate (770mg, 2.41mmol), finish; solution is bled ventilation three times, is warming up to 80 degrees Celsius of stirring reactions under nitrogen protection and spends the night.TLC monitoring reaction is complete, be cooled to room temperature, concentrated by reaction solution, resistates is dissolved in 200mL methylene dichloride, uses water (50mL) and saturated sodium-chloride water solution (50mL) respectively to wash once successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, column chromatography for separation (V (MeOH)/V (DCM)=1/15), obtain yellow oil (250mg, 27.12%).
ESI-MS:(ESI,pos.ion)m/z 440.3[M+1] +
Step 4) 4-[7-(2-morpholino oxyethyl group) pyrazoles [1,5-a] pyrimidin-3-yl] aniline
By { 4-[7-(2-morpholino oxyethyl group) pyrazoles [1,5-a] pyrimidin-3-yl] phenyl } t-butyl carbamate (250mg, 0.57mmol) is dissolved in 20mL methylene dichloride, is cooled to 0 degree Celsius, drip 5mL trifluoroacetic acid, slowly return to stirring at room temperature reaction 4h.Concentrating under reduced pressure, resistates adds saturated sodium bicarbonate aqueous solution (50mL) cancellation, ethyl acetate (400mL) extracts, separate organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtain yellow oil (150mg, 78.1%).
ESI-MS:(ESI,pos.ion)m/z：340.2[M+1] +
Step 5) 1-[5-(tertiary butyl) isoxzzole-3-base]-3-{4-[7-(2-morpholino oxyethyl group) pyrazolo [1,5-a] pyrimidin-3-yl] phenyl } urea
By 4-[7-(2-morpholino oxyethyl group) pyrazoles [1,5-a] pyrimidin-3-yl] aniline (75mg, 0.23mmol) be dissolved in 40mL methylene dichloride, add 5-(tertiary butyl) isoxzzole-3-base successively) phenyl carbamate (117mg, 0.45mmol) with DMAP (45mg, 0.37mmol), then drip triethylamine (0.3mL), finish, solution warms back flow reaction is spent the night.TLC monitoring reaction is complete, solution is cooled to room temperature, organic phase washed with water (10mL) and saturated nacl aqueous solution are washed (10mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtain faint yellow solid (18mg, 16%).
ESI-MS:(ESI,pos.ion)m/z 506.2[M+1] +
1H NMR(400MHz,CDCl 3)δ9.25(s,1H),8.44(d,J＝12.0Hz,1H),8.29(s,1H),7.97(d,J＝8.5Hz,2H),7.59(d,J＝8.5Hz,2H),6.40(d,J＝7.5Hz,1H),5.95(s,1H),5.37(s,1H),4.63(t,J＝5.7Hz,2H),3.79–3.72(m,4H),2.88(t,J＝5.7Hz,2H),2.65–2.57(m,4H),1.38(s,9H).
Embodiment 81-(4-(6-(2-(2-oxa--6-azepine spiroheptane-6-base) oxyethyl group) imidazo [1,2-a] pyridine-2-base) phenyl)-3-(5 (tertiary butyl) isoxzzole-3-base) urea
Step 1) 2 – ((2-(4-nitrophenyl) imidazo [1,2-a] pyridine-6-base) oxygen base) ethanol
By 2-(4-nitrophenyl) imidazo [1, 2-a] pyridine-6-alcohol (2.0g, 7.84mmol) be dissolved in DMF (30mL), add salt of wormwood (14g successively, 101.30mmol) with ethylene bromohyrin (3.0mL, 42.33mmol), solution is heated to 80 degree of stirring reaction 6h, concentrating under reduced pressure, ethyl acetate (3X100mL) extracts, organic phase washed with water (100mL) is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure, rapid column chromatography is separated, column chromatography for separation (V (MeOH)/V (DCM)=1/10), obtain brown solid (1.5g, 64%).
MS-ESI:(ESI,pos.ion)m/z：300.1[M+1] +
Step 2) 2-((2-(4-nitrophenyl) imidazo [1,2-a] pyridine-6-base) oxygen base) ethyl methane sulfonate ester
By 2-((2-(4-nitrophenyl) imidazo [1,2-a] pyridine-6-base) oxygen base) ethanol (1.0g, 3.34mmol) be dissolved in THF (50mL), be cooled to 0 degree, drip triethylamine (2.5mL successively, 18mmol) with MsCl (0.52mL, 6.7mmol), slowly return to stirring at room temperature reaction 2h, add saturated sodium bicarbonate aqueous solution (50mL) cancellation reaction, ethyl acetate (300mL) extracts, anhydrous sodium sulfate drying, concentrating under reduced pressure and be fully directly used in next step reaction after drying.
MS-ESI:(ESI,pos.ion)m/z：378.1[M+1] +。
Step 3) 6-(2-((2-(4-nitrophenyl) imidazo [1,2-a] pyridine-6-base) oxygen base) ethyl)-2-oxa--6-azepine spiroheptane
By 2-((2-(4-nitrophenyl) imidazo [1,2-a] pyridine-6-base) oxygen base) ethyl methane sulfonate ester (100mg, 0.265mmol) be dissolved in acetonitrile (20mL), add 2-oxa--6-azepine spiroheptane (80mg successively, 0.4233mmol), salt of wormwood (0.21g, 1.5mmol) with potassiumiodide (25mg, 0.15mmol), vlil reaction 7h, filter, filtrate reduced in volume, direct column chromatography for separation (V (MeOH)/V (DCM)=1/10), obtain brown solid (70mg, 70%).
MS-ESI:(ESI,pos.ion)m/z：381.2[M+1] +
Step 4) 4-(6-(2-(2-oxa--6-azepine spiroheptane-6-base) oxyethyl group)-imidazo [1,2-a] pyridine-2-base) aniline
6-(2-((2-(4-nitrophenyl) imidazo [1 is added in 100mL single port bottle, 2-a] pyridine-6-base) oxygen base) ethyl)-2-oxa--6-azepine spiroheptane (80mg, 0.21mmol) be dissolved in methanol/water solution (V/V, 3/1, 40mL), add ammonium chloride (170mg successively, 3.21mmol) with reduced iron powder (100mg, 1.79mmol), vlil reaction 4h, concentrating under reduced pressure, ethyl acetate (200mL) extracts, anhydrous sodium sulfate drying, concentrating under reduced pressure, direct column chromatography for separation (V (MeOH)/V (DCM)=1/10), obtain brown solid (40mg, 55%).
MS-ESI:(ESI,pos.ion)m/z：351.2[M+1] +
Step 5) 1-(4-(6-(2-(2-oxa--6-azepine spiroheptane-6-base) oxyethyl group) imidazo [1,2-a] pyridine-2-base) phenyl)-3-(5 (tertiary butyl) isoxzzole-3-base) urea
By 4-(6-(2-(2-oxa--6-azepine spiroheptane-6-base) oxyethyl group)-imidazo [1,2-a] pyridine-2-base) aniline (140mg, 0.40mmol) be dissolved in DCM (20mL), add triethylamine (0.6mL successively, 4mmol) with phenyl (5-(tertiary butyl) different azoles-3-base) carbamate (0.21g, 0.81mmol), vlil reaction 4h, concentrating under reduced pressure, direct column chromatography for separation (V (MeOH)/V (DCM)=1/10), obtain brown solid (80mg, 39%).
MS-ESI:(ESI,pos.ion)m/z：517.3[M+1] +
1H NMR(600MHz,CD 3OD)δ8.12(d,J＝2.0Hz,1H),8.09(s,1H),7.90-7.83(m,2H),7.57(d,J＝8.7Hz,2H),7.47(d,J＝9.7Hz,2H),7.38(t,J＝8.4Hz,1H),7.14(dd,J＝9.7,2.3Hz,1H),6.43(s,1H),4.57(s,4H),4.06(t,J＝5.1Hz,2H),3.69(s,4H),3.00(dd,J＝11.0,6.0Hz,2H),1.38(s,9H).
Embodiment 9-23
Adopt suitable starting raw material, embodiment 9-23 obtains according to the synthetic method of embodiment 1-7:
Embodiment 24-34
Adopt suitable starting raw material, embodiment 24-34 obtains according to the synthetic method of embodiment 8:
Embodiment 35FLT3 kinase inhibition assay
Experimental technique:
Representative implication of abridging in following experiment is as follows:
HEPES: hydroxyethyl piperazine second thiosulfonic acid; Brij-35: Brij-35; DTT: dithiothreitol (DTT); EDTA: ethylenediamine tetraacetic acid (EDTA); EGFR: Human epidermal growth factor receptor; HER2: human epidermal growth factor receptor 2; EGFR T790M: Human epidermal growth factor receptor 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 agent
1.1 × kinase buffer liquid and the preparation of termination test buffer:
(1) 1 × not containing MnCl 2kinase buffer liquid (50mM HEPES, pH 7.5,0.0015%Brij-35,10mM MgCl 2, 2mM DTT);
(2) test buffer (100mM HEPES, pH 7.5,0.015%Brij-35,0.2%Coating Reagent#3,50mM EDTA) is stopped.
2. the compound of test kinase prepares: compound serial dilution
(1) adopt 100%DMSO by the highest final concentration 50 times of diluted chemical compound.The compound solution of 100 these concentration of μ L is transferred to a hole of 96 orifice plates.
(2) in ratio diluted compounds 10 concentration successively that 20 μ L original solutions dilute with 60 μ L DMSO.
(3) 100 μ L 100%DMSO solution are joined in two emptying apertures, contrast as without compound control with without enzyme.
(4) prepare an intermediate plate, respectively each concentration compound of 10 μ L is transferred to intermediate plate from raw sheet, and add 90 μ L 1 × kinase buffer liquid, vibration mixing 10 minutes.
(5) preparing experiment plate: corresponding aperture transferase 45 μ L compound solution is in 384 orifice plates of correspondence from the intermediate plate of 96 orifice plates.
3. kinase reaction
(1) 2.5 × enzyme solution is prepared: added by enzyme in 1 × kinase buffer liquid.
(2) 2.5 × peptide solution is prepared: FAM-labeled peptide and ATP are added in 1 × kinase buffer liquid.
(3) being joined by 10 μ L 2.5 × enzyme solution containing 5 μ L DMSO content is in 384 hole brassboards of the compound solution of 10%, incubated at room 10 minutes.
(4) 10 μ L 2.5 × peptide solutions are added in 384 hole brassboards.
(5) kinase reaction and termination: hatch the corresponding time for 28 degrees Celsius, adds 25 μ L stop buffer termination reactions.
4. DATA REASONING
Reading of data is also collected.
5. fitting of a curve
(1) data of also converted measurement are copied
(2) inhibiting rate is converted to
Inhibiting rate=(maximum value-sample value)/(maximum value-minimum value) × 100;
" maximum value " is DMSO control value; " minimum value " is without kinase control hole count value.
(3) data are inputted corresponding analysis software Xlfit and draw IC 50value.
Experimental result is as follows:
Table 2 the compounds of this invention is to the IC50 value of flt3 kinase inhibitory activity
Embodiment is numbered FLT3(IC 50,nM)
2 107
3 50
4 <3
Experiment conclusion:
Result shows, and majority of compounds of the present invention has good external zymetology inhibit activities, has good restraining effect to flt3 kinases.
Experimental example 36MV4-11 cell inhibitory effect is tested
Experimental technique:
Cell experiment condition:
1) plating cells:
Cell counting is carried out with Vi-Cell XR cell counter.With corresponding substratum adjustment cell density to 1.5 × 10 5individual/milliliter, every hole kind enters 100 μ L cell suspension 96 orifice plates that saturating wall is white the end of to, and the ultimate density of cell is 15000/100 μ L/ holes.At 37 DEG C, 5%CO 2spend the night with culturing cell in the cell culture incubator of 95% humidity.
2) preparation of compound and interpolation:
I) preparation (being diluted to 10 concentration in DMSO) of compound plate:
With DMSO, compound is mixed with the storage liquid of 10mM, the used time is diluted to 4mM, then is diluted to 0.4mM with DMSO, take 0.4mM as maximum concentration, with DMSO progressively 3 times of dilutions, obtains the compound of 10 concentration gradients.Staurosporine is as positive control drug.
Ii) interpolation of compound:
A. from corresponding compound plate, pipette 0.5 μ L add in the Tissue Culture Plate of incubated overnight.
B. at 37 degrees Celsius.72 hours are hatched in incubator.
2) detect and analyze
A. compound treatment is after 72 hours, observation of cell form under inverted microscope, and the cell growth state in DMSO control wells is normal, there are no contamination phenomenon.
B. Tissue Culture Plate is placed in room temperature and balance 30 minutes.
C. CellTiter-Glo detection method is adopted to measure compound to the proliferation inhibition activity of MV-4-11 cell.
D. the experimental result of record analysis gained.
Table 3 representation compound of the present invention is to the inhibit activities of MV4-11 cell proliferation
Experiment conclusion
Table 3 result shows, and compound of the present invention all has good inhibit activities to MV4-11 cell proliferation.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.

Claims (17)

1. a compound, it is the steric isomer of compound shown in the compound shown in formula (I) or formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
Q and W is CH or N independently of one another;
G is-O-,-S (=O) t-,-S-,-C (=O)-or five yuan of inferior heteroaryls;
R is-NR 3r 2, alkoxyl group, alkyl, thiazolinyl, alkynyl, haloalkyl, alkyl-S (=O) t-, alkoxyalkyl, hydroxyalkyl, hydroxy alkoxy base, aminoalkoxy, halogenated alkoxy, alkylamino halogenated alkoxy, alkylaminoalkoxy, alkyloxy-alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkyl oxy, cycloalkyl amino, heterocyclic radical, cycloheteroalkylalkyl, heterocyclic radical alkylamino, heterocyclylalkoxy, heterocyclyloxy base alkoxyl group, heterocyclyloxy base, carbocylic radical oxygen base alkoxyl group, carbocyclylalkoxy, carbocylic radical alkylamino, aryl, arylalkyl, aryloxy alkoxyl group, aryloxy, alkoxy aryl, aryl alkane amino, heteroarylalkyl, heteroaryl, heteroarylalkoxy, heteroarylalkylamino, heteroaryl oxygen base, heteroaryl oxygen base alkoxyl group, condensed-bicyclic base oxygen base, condensed-bicyclic base alkyl, condense assorted bicyclic group alkyl, condense assorted bicyclic group oxygen base, condense assorted bicyclic group amino, condense assorted bicyclic group alkoxyl group, condense assorted bicyclic group alkylamino, condense assorted bicyclic group oxygen base alkoxyl group, condense assorted bicyclic group oxygen base alkylamino, spiral shell is mixed bicyclic group alkyl, spiral shell is mixed bicyclic group alkoxyl group, bridge is mixed bicyclic group alkyl, bridge is mixed bicyclic group oxygen base, bridge is mixed bicyclic group alkoxyl group, bridge is mixed bicyclic group alkylamino, bridge is mixed bicyclic group, spiral shell is mixed bicyclic group or condense assorted bicyclic group,
K is the heteroaryl groups of 5-6 unit; Have 2 heteroatomss in wherein said heteroaryl groups at least, each heteroatoms is O, S, NR independently 4or N;
Each L is amino independently, nitro, C 1-4alkylthio, C 1-6alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 1-4haloalkyl, C 1-4alkylamino, hydroxyl, fluorine, chlorine, bromine, iodine, C 1-4alkyl-C (=O)-NH-, C 1-4alkoxyl group, hydroxyl C 1-4alkyl or cyano group;
E is bicyclic heteroaryl group;
Each R 1be hydrogen independently, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-6alkoxy C 1-6alkyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, C 1-4alkyl-C (=O)-NH-, C 1-4alkoxyl group, hydroxyl C 1-4alkyl or C 1-4alkylthio;
Each R 3and R 2be hydrogen independently, C 1-6alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Each R 4be H, C independently 1-4alkyl, C 3-10cycloalkyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Each d is 1,2,3 or 4 independently;
Each n is 1,2,3 or 4 independently;
Each t is 0,1 or 2 independently;
Each a is 0,1,2,3 or 4 independently;
Wherein, described aryl, bicyclic heteroaryl group, heteroaryl groups, alkoxyl group, alkyl-S (=O) t-,-G-(CH 2) n-R, arylalkyl, heteroarylalkyl, heteroaryl, heterocyclic radical, bridge is mixed bicyclic group, spiral shell is mixed bicyclic group, condense assorted bicyclic group, alkyl, haloalkyl, alkylamino, hydroxy alkoxy base, aminoalkoxy, halogenated alkoxy, thiazolinyl, alkynyl, cycloalkylalkyl, cycloheteroalkylalkyl, alkoxyalkyl, hydroxyalkyl, alkylamino halogenated alkoxy, alkylaminoalkoxy, alkyloxy-alkoxy, alkoxy aryl, aryl alkane amino, heteroarylalkoxy, heteroarylalkylamino, heterocyclic radical alkylamino, cycloalkyl oxy, cycloalkyl amino, heterocyclylalkoxy, carbocyclylalkoxy, carbocylic radical alkylamino, aryloxy alkoxyl group, aryloxy, heteroaryl oxygen base, heteroaryl oxygen base alkoxyl group, heterocyclyloxy base alkoxyl group, carbocylic radical oxygen base alkoxyl group, heterocyclyloxy base, condensed-bicyclic base oxygen base, condensed-bicyclic base alkyl, condense assorted bicyclic group alkyl, condense assorted bicyclic group oxygen base, condense assorted bicyclic group amino, condense assorted bicyclic group alkoxyl group, condense assorted bicyclic group alkylamino, condense assorted bicyclic group oxygen base alkoxyl group, condense assorted bicyclic group oxygen base alkylamino, spiral shell is mixed bicyclic group alkyl, spiral shell is mixed bicyclic group alkoxyl group, bridge is mixed bicyclic group alkyl, bridge is mixed bicyclic group oxygen base, bridge is mixed bicyclic group alkoxyl group, bridge is mixed bicyclic group alkylamino, alkyl-C (=O)-NH-, alkylthio and cycloalkyl, can independently by hydrogen, aminoalkyl group, aminoacyl, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, C 1-4alkyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C 1-4alkyl-C (=O)-, C 2-10heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
2. compound according to claim 1, wherein,
E is one of heteroaryl groups of following subformula formation:
Wherein, X, Y, Z, Z 1, Z 2, Z 3and Z 4be N or CH independently of one another;
T and T 1be-O-,-S-,-NR independently of one another 4-or-CH 2-;
Wherein, the X on described E ring, Y, Z, T, T 1, Z 1, Z 2, Z 3and Z 4there are two for heteroatoms at least simultaneously;
R is-NR 3r 2, C 2-4thiazolinyl, C 2-4alkynyl, C 3-10cycloalkyl, C 3-10cycloalkyl C 1-4alkyl, C 2-10heterocyclic radical C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-6alkoxy C 1-6alkyl, hydroxyl C 1-4alkyl, hydroxyl C 1-4alkoxyl group, amino C 1-4alkoxyl group, halo C 1-4alkoxyl group, C 1-4alkylamino halo C 1-4alkoxyl group, C 1-4alkylamino C 1-4alkoxyl group, C 1-4alkoxy C 1-4alkoxyl group, C 3-10cycloalkyl oxy, C 6-10aryl C 1-4alkoxyl group, C 6-10aryl C 1-4alkylamino, C 1-9heteroaryl C 1-4alkoxyl group, C 1-9heteroaryl C 1-4alkylamino, C 2-10heterocyclic radical C 1-4alkylamino, C 3-10cycloalkyl oxy, C 3-10cycloalkyl amino, C 2-10heterocyclic radical C 1-4alkoxyl group, C 3-10carbocylic radical C 1-4alkoxyl group, C 3-10carbocylic radical C 1-4alkylamino, C 6-10aryloxy C 1-4alkoxyl group, C 6-10aryloxy, C 1-9heteroaryl oxygen base, C 1-9heteroaryl oxygen base C 1-4alkoxyl group, C 2-10heterocyclyloxy base C 1-4alkoxyl group, C 3-10carbocylic radical oxygen base C 1-4alkoxyl group, C 2-10heterocyclyloxy base, C 1-4alkoxyl group, C 1-4alkyl, C 1-4haloalkyl, C 6-10aryl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 1-9heteroaryl,
Or R is following subformula:
Wherein, each X 8, X 9and X 10be N or CH independently;
Each X 1, X 2, X 3, X 4, X 5, X 6and X 7be-CH independently 2-,-O-,-NR 4a-,-S (=O) t-or-S-;
Each q, m, p, r and s are 0,1,2,3 or 4 independently;
Each R 3and R 2be C independently 1-6alkyl, C 3-10cycloalkyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Each R 4aand R 4be H, C independently 1-4alkyl, C 3-10cycloalkyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Wherein, each subformula representated by described E and each R, all can independently by hydrogen, aminoalkyl group, aminoacyl, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, C 1-4alkyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C 1-4alkyl-C (=O)-, C 2-10heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
3. compound according to claim 2, wherein,
E is one of heteroaryl groups of following subformula formation:
R is-NR 3r 2, C 2-4thiazolinyl, C 2-4alkynyl, C 2-10heterocyclic radical C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-4alkoxy C 1-4alkyl, hydroxyl C 1-4alkyl, hydroxyl C 1-4alkoxyl group, amino C 1-4alkoxyl group, halo C 1-4alkoxyl group, C 1-4alkylamino halo C 1-4alkoxyl group, C 1-4alkylamino C 1-4alkoxyl group, C 1-4alkoxy C 1-4alkoxyl group, C 1-4alkoxyl group, C 1-4alkyl, C 1-4haloalkyl, C 1-9heteroaryl C 1-6alkyl or R are following subformula:
Each R 3and R 2be methyl independently, ethyl, propyl group, sec.-propyl, the tertiary butyl, amyl group, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Wherein, each subformula representated by described E and each R, all can independently by hydrogen, aminoalkyl group, aminoacyl; fluorine, chlorine, bromine, iodine, trifluoromethyl; chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl; sec.-propyl, dimethylamino, methylamino, diethylamino, ethylamino; hydroxyl, cyano group, nitro, oxo (=O); methyl-C (=O)-, ethyl-C (=O)-, n-propyl-C (=O)-, C 2-10heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
4. compound according to claim 1, wherein,
G is-O-or furylidene.
5. compound according to claim 1, wherein, K is one of heteroaryl groups of subformula formation as follows:
Each L is cyclopropyl independently, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6heterocyclylalkyl, amino, cyano group, nitro, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, methyl, ethyl, butyl, n-propyl, sec.-propyl, the tertiary butyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, C 1-4alkyl-C (=O)-NH-, C 1-4alkoxyl group, hydroxyl C 1-4alkyl or C 1-4alkylthio.
6. compound according to claim 1, it is wherein the steric isomer of compound shown in the compound shown in formula (II) or formula (II), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
Q and W is CH or N independently of one another;
Each R 1be hydrogen independently, fluorine, chlorine, bromine, iodine, C 1-4haloalkyl, C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-6alkoxy C 1-6alkyl, C 1-4alkylamino, hydroxyl, cyano group, nitro, C 1-4alkyl-C (=O)-NH-, C 1-4alkoxyl group, hydroxyl C 1-4alkyl or C 1-4alkylthio;
Each L is the tertiary butyl independently;
D is 1;
Each n is 1,2,3 or 4 independently;
Each t is 0,1 or 2 independently;
Each a is 0,1,2,3 or 4 independently;
E is one of heteroaryl groups of following subformula formation:
R is-NR 3r 2, C 2-4thiazolinyl, C 2-4alkynyl, C 2-10heterocyclic radical C 1-4alkyl, C 1-6alkyl-S (=O) t-, C 1-4alkoxy C 1-4alkyl, hydroxyl C 1-4alkyl, hydroxyl C 1-4alkoxyl group, amino C 1-4alkoxyl group, halo C 1-4alkoxyl group, C 1-4alkylamino halo C 1-4alkoxyl group, C 1-4alkylamino C 1-4alkoxyl group, C 1-4alkoxy C 1-4alkoxyl group, C 1-4alkoxyl group, C 1-4alkyl, C 1-4haloalkyl, C 1-9heteroaryl C 1-6alkyl or R are following subformula:
Each R 3and R 2be methyl independently, ethyl, propyl group, sec.-propyl, the tertiary butyl, amyl group, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C 2-10heterocyclylalkyl, C 1-6alkoxy C 1-6alkyl or hydroxyl C 1-4alkyl;
Wherein, each subformula representated by described E and each R, all can independently by hydrogen, aminoalkyl group, aminoacyl; fluorine, chlorine, bromine, iodine, trifluoromethyl; chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl; sec.-propyl, dimethylamino, methylamino, diethylamino, ethylamino; hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-; ethyl-C (=O)-, n-propyl-C (=O)-, sec.-propyl-C (=O)-, C 2-10heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
7. compound according to claim 1, it is the steric isomer of compound shown in the compound shown in formula (III) or formula (III), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein, X, Y, Z, Z 1, Z 2, Z 3and Z 4be N or CH independently of one another;
Wherein, described X, Y, Z, Z 1, Z 2, Z 3and Z 4there are two for heteroatoms at least simultaneously.
8. compound according to claim 1, has one of them structure following:
Or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug.
9. a pharmaceutical composition, it comprises the compound as described in any one of claim 1-8.
10. pharmaceutical composition according to claim 9, comprises pharmaceutically acceptable carrier, vehicle, thinner further, at least one in assistant agent and vehicle.
11. pharmaceutical compositions according to claim 9, wherein further comprise additional treatment agent, described additional treatment agent is chemotherapeutic agent, antiproliferative, anti-inflammatory reagent, immunosuppressor, immunostimulant, be used for the treatment of atherosclerotic medicine, be used for the treatment of medicine or their combination of pulmonary fibrosis.
12. pharmaceutical compositions according to claim 11, wherein said additional treatment agent is Chlorambucil, melphalan, endoxan, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cis-platinum, carboplatin, oxaliplatin, Dacarbazine Temozolomide, Procarbazine, methotrexate, Fluracil, cytosine arabinoside, gemcitabine, purinethol, fludarabine, vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol, Docetaxel, topotecan, irinotecan, Etoposide, ET-743, gengshengmeisu, Dx, epirubicin, daunomycin, mitoxantrone, bleomycin, ametycin, ipsapirone, tamoxifen, flutamide, gonadorelin analogue, megestrol, prednisone, dexamethasone, methylprednisolone, Thalidomide, interferon alpha, Calciumlevofolinate, sirolimus, temsirolimus, everolimus, Ah method is for Buddhist nun, alisertib, amuvatinib, A Pa is for Buddhist nun, Axitinib, Velcade, SKI-606, brivanib, cabozantinib, AZD2171, crenolanib, Ke Zhuo is for Buddhist nun, dabrafenib, dacomitinib, danusertib, Dasatinib, dovitinib, Tarceva, foretinib, ganetespib, Gefitinib, ibrutinib, Conmana, imatinib, iniparib, lapatinibditosylate, 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, Xarelto, Sutent, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474, veliparib, Wei Luofeini, vismodegib, volasertib, alemtuzumab, rhuMAb-VEGF, brentuximab vedotin, block appropriate rope monoclonal antibody, Cetuximab, ground promise monoclonal antibody, lucky trastuzumab, her monoclonal antibody, Buddhist nun's trastuzumab, method wood monoclonal antibody difficult to understand, Victibix, Rituximab, tositumomab, Herceptin or their combination.
Compound described in 13. any one of claim 1-8 or the pharmaceutical composition described in any one of claim 9-12 are preparing the purposes in medicine, and described medicine is used for preventing, process, alleviate or treat proliferative disease, autoimmune disorders or inflammatory diseases.
14. purposes according to claim 13, wherein said proliferative disease is acute myeloid leukaemia, chronic myelogenous leukemia, gastrointestinal stromal tumors, acute myelocytic leukemia (AML), the chronic myelogenous leukemia (CML) of sudden change, acute lymphoblastic leukemia (ALL), colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, bladder cancer, kidney, brain tumor, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukemia, lymphatic cancer, rheumatism, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinaemia, half molecular disease, monocytic leukemia, primary macroglobulinaemia purpura, Secondary cases benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, non-Hodgkin lymphoma, Sezary syndrome, infectious monocytosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colorectal carcinoma, the rectum cancer, polyposis intestinalis, small cell lung cancer, neuroblastoma, neuroendocrine cell tumour, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterus carcinoma, ovarian cancer, G. cephalantha, malignant tumor of digestive tract, nonsmall-cell lung cancer, cervical cancer, tumor of testis or myelomatosis.
15. purposes according to claim 13, wherein said autoimmune disorders is rheumatic arthritis, lupus, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, inflammatory bowel, Crohn's disease or systemic lupus.
16. purposes according to claim 13, wherein said inflammatory diseases refers to diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, liver cirrhosis, cholecystitis or chronic inflammatory diseases.
17. purposes according to any one of claim 13-16, wherein said disease is the disease that FLT3 mediation or FLT3-ITD cause.
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