CN104513257B - Substituted urea derivatives and application thereof in drugs - Google Patents

Substituted urea derivatives and application thereof in drugs Download PDF

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CN104513257B
CN104513257B CN201410498232.4A CN201410498232A CN104513257B CN 104513257 B CN104513257 B CN 104513257B CN 201410498232 A CN201410498232 A CN 201410498232A CN 104513257 B CN104513257 B CN 104513257B
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alkyl
base
alkoxyl
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CN104513257A (en
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郑常春
刘兵
章维红
张英俊
龙伯华
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings

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Abstract

The invention provides substituted urea derivatives represented by the formula (I) 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 its application in medicine
Invention field
The invention belongs to pharmaceutical field.The invention provides new substituted urea derivative of a class and combinations thereof and be used for controlling Treat the purposes of the disease that flt3 mediates or flt3-ITD causes.Such compound is a kind for the treatment of, alleviates or prevention and tyrosine The relevant disease of kinase activity or disease, or the new substituted carbamide compounds of the purposes of one or more symptom.
Background of invention
Protein kinase (PKs) is the oh group phosphoric acid in tyrosine, serine and the threonine residues of catalytic proteins The enzyme of change effect.Receptor protein tyrosine kinase (RTK) race of protein kinase, especially protein kinase, mainly as growth because Sub- receptor, plays an important role in the signal transduction pathway control aspect of many cell functions, such as cell cycle, cell life Length, cell differentiation and cell death.The imbalance of receptor protein tyrosine kinase (RPTK) activity or excessive, erratic activity are Through being observed under numerous disease situation, including optimum He pernicious Proliferative Disorders, inflammatory conditions, immune system disorder, It is caused by the unsuitable activation of immune system, can lead to such as autoimmune disease.
For the irregular activity of the receptor tyrosine kinase of PDGF receptor (PDGFR) race, as wherein One it has been found that it is relevant with various Proliferative Disorders.The gene amplification of PDGFR or rise are with glioma or meat Occur (referring to Kumabe etc., Oncogene, (1992) 7 in the patient of tumor:627-633；Ostman and Heldin Cancer Res.(2001)80:1-38).One member of PDGFR race, Flt3 (also referred to as Flk-2), in propagation and the change of hematopoietic stem cell Play an important role in different, the activated mutant of this receptor or overexpression are found (ginseng in AML (acute myelogenous cell leukemia) See Heinrich Mini-Reviews, pharmaceutical chemistry (2004) 4 (3):255-271；Kiyoi etc., lnt JHematol (2005) 82:85-92).Flt3 inhibitor known to many just conducts a research, some be expected to obtain anti-AML clinical effectiveness (referring to Levis etc., lnt J Hematol. (2005) 82:100-107).Flt3 receptor is also expressed in large quantities of dendritic cell precursors, And stimulate this receptor to lead to these precursors propagation and differentiation to become dendritic cell (DC).Because dendritic cell are T- cells The main initiators of the immunne response (including spontaneous immunne response) of mediation, Flt3 inhibitory action is to lower the inflammation of DC- mediation Disease and the mechanism of autoimmune response.Research display Flt3 inhibitor C EP-701 can be effectively reduced Autoimmune Encephalomyelitis (EAE) test, the myelin in multiple cerebral sclerosises mouse models loses (referring to Whartenby etc., PNAS (2005) 102: 16741-16746).Gao Shui is found in the patients serum with langerhans cell histiocytosises and systemic lupus erythematosus (sle) Flat Flt3 part, this implies further, and Flt3 is carried out in the dendritic cell precursor imbalance of those autoimmune diseases Signal transduction is (referring to Rolland etc., J Immunol. (2005) 174:3067-3071).
It is reported that, the small molecule of some suppression kinases FLT3 the cell of FLT3 kinase mutant can be withered effectively in inducible cell line Die, and the life cycle of the mice with medullary cell FLT3 mutation can be extended (referring to Levis etc., Blood (2002) 99:3885- 3891；Kelly etc., Cancer Cell1 (2002):421-432；Weisberg etc., Cancer Cell1 (2002) 433-443； Yee etc., Blood (2002) 100:2941-2949).
The ITD that FLT3 internal series-connection repeats is activated (flt3-ITD), in about 20% acute myeloid leukemia Find in people, and be associated with some poor prognosis.Substantial amounts of experimental data and clinical data, including early stage FLT3 inhibitor The shortage of clinical event it was demonstrated that making cancer occur when FLT3-ITD plays, when and make the angle of the body pathological changes that cancer maintains Color.It has been reported that, in some patients, especially there is the trend of recurrence after the treatment it may be possible to because flt3 kinase mutant is multiple Kinase inhibitor is (referring to Heidel, the .Blood such as F. (2006) 107:293–300.).There are some researches show, FLT3-ITD inhibitor Play a part hinder induction Incidence mechanism role and in patient AML effectively treatment target (referring to Catherine etc., Nature (2012) 485:260-263).
The mutation of Flt3 frequently occur in AML patient and the coding region of repetition (ITD) comprising the other internal series-connection of film or The tyrosine kinase domain (TKD) of the mutation of point.FLT3-ITD and FLT3-TKD is mutated dimerization and work due to flt3 receptor Property causes part independently to spread.The ratio of high variation wild-type allele of FLT3-ITD and the poor prognosis of adult and child Correlation is (referring to AS Moore etc., Leukemia (2012) 26:1462-1470).
The treatment that researchers are used for cancer for exploitation kinase inhibitor has sizable interest, has wherein had been reported that Urea derivative can alternatively property Flt3 inhibitor.
Abstract of invention
The invention provides for the substituted carbamide derivative of Drug therapy and its pharmaceutical composition and being used for adjusting Flt3 Kinase activity and for suppressing a series of substitute urea compounds of FLT3-ITD and being used for treat flt3 mediation or flt3-ITD The purposes of the disease causing.
On the one hand, a kind of substituted carbamide derivative that the present invention provides, it is the chemical combination with the structure as shown in formula (I) Thing, or the stereoisomer of the compound shown in formula (I), geometric isomer, tautomer, nitrogen oxides, hydrate, solvent Compound, metabolite, ester, pharmaceutically acceptable salt or its prodrug,
Wherein：
K ring is the heteroaryl groups of 5-6 unit；
Q and W is each independently CH or N；
Each L independently is amino, nitro, alkylthio group, alkyl, cycloalkyl, heterocyclic radical, haloalkyl, alkyl amino, hydroxyl Base, fluorine, chlorine, bromine, iodine, alkyl-C (=O)-NH-, alkoxyl, hydroxy alkyl or cyano group；
Each R1It independently is hydrogen, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-6Alkane Epoxide C1-6Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, C1-4Alkyl-C (=O)-NH-, C1-4Alkoxyl, hydroxyl C1-4Alkane Base or C1-4Alkylthio group；
E ring is bicyclic heteroaryl group or tricyclic heteroaryl group；In wherein said heteroaryl groups at least 2 miscellaneous Atom, each hetero atom independently is O, S, NR4Or N；
Each R4It independently is hydrogen, haloalkyl, alkyl-C (=O)-, alkoxyalkyl, hydroxy alkyl, benzyl, cycloalkyl, Heterocyclic radical or alkyl；
Each J independently is-G- (CH2)n-R；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R independently is hydrogen ,-NR3R2, alkoxyl, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, Cycloheteroalkylalkyl, heterocyclic radical, alkyl-S (=O)t-, alkoxyalkyl, hydroxy alkyl, hydroxy alkoxy base, aminoalkoxy, halogen For alkoxyl, alkylamino halogenated alkoxy, alkylaminoalkoxy, alkyloxy-alkoxy, alkoxy aryl, aryl alkane amino, miscellaneous Alkoxy aryl, heteroarylalkylamino, heterocyclic radical alkylamino, cycloalkyl oxy, cycloalkyl amino, heterocyclylalkoxy, carbocyclic ring Base alkoxyl, carbocylic radical alkylamino, aryloxy group alkyl epoxide, aryloxy group, heteroaryl epoxide, heteroaryl epoxide alkoxyl, heterocyclic radical Epoxide alkoxyl, carbocylic radical epoxide alkoxyl, heterocyclic radical epoxide, condensed-bicyclic base epoxide, condensed-bicyclic base alkyl, condense miscellaneous double Cyclylalkyl, condenses miscellaneous bicyclic group epoxide, condenses miscellaneous bicyclic group amino, condenses miscellaneous bicyclic group alkoxyl, condenses miscellaneous bicyclic group alkane Amino, condenses miscellaneous bicyclic group epoxide alkoxyl, condenses miscellaneous bicyclic group epoxide alkylamino, spiral shell miscellaneous bicyclic group alkyl, the miscellaneous bicyclic group of spiral shell Alkoxyl, bridge miscellaneous bicyclic group alkyl, bridge miscellaneous bicyclic group epoxide, bridge miscellaneous bicyclic group alkoxyl, bridge miscellaneous bicyclic group alkylamino, aryl, Aryl alkyl, heteroaryl alkyl, heteroaryl, the miscellaneous bicyclic group of bridge, the miscellaneous bicyclic group of spiral shell or condense miscellaneous bicyclic group；
Each R3And R2It independently is alkyl, haloalkyl, cycloalkyl, heterocyclic radical, alkoxyalkyl or hydroxy alkyl；
Each n independently is 1,2,3 or 4；
Each t independently is 0,1 or 2；
Each e independently is 0,1,2,3 or 4；
Each d independently is 1,2,3 or 4；
Each a independently is 0,1,2,3 or 4；
Each b independently is 2,3 or 4；
Wherein, described aryl, bicyclic heteroaryl group, tricyclic heteroaryl group, heteroaryl groups, alkoxyalkyl, Alkoxyl ,-G- (CH2)n- R ,-(O- (CH2)n)e- O- ,-(CH2)n- C (=O)-, alkyl-S (=O)t-, hydroxy alkyl, aryl alkane Base, heteroaryl alkyl, heteroaryl, heterocyclic radical, the miscellaneous bicyclic group of bridge, the miscellaneous bicyclic group of spiral shell, condense miscellaneous bicyclic group, alkyl, haloalkyl, Alkyl amino, hydroxy alkoxy base, aminoalkoxy, halogenated alkoxy, thiazolinyl, alkynyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, alkane Base-C (=O)-, benzyl, alkylamino halogenated alkoxy, alkylaminoalkoxy, alkyloxy-alkoxy, alkoxy aryl, aryl alkane Amino, heteroarylalkoxy, heteroarylalkylamino, heterocyclic radical alkylamino, cycloalkyl oxy, cycloalkyl amino, heterocyclylalkoxy Base, carbocyclylalkoxy, carbocylic radical alkylamino, aryloxy group alkyl epoxide, aryloxy group, heteroaryl epoxide, heteroaryl epoxide alkoxyl, Heterocyclic radical epoxide alkoxyl, carbocylic radical epoxide alkoxyl, heterocyclic radical epoxide, condensed-bicyclic base epoxide, condensed-bicyclic base alkyl is thick Close miscellaneous bicyclic group alkyl, condense miscellaneous bicyclic group epoxide, condense miscellaneous bicyclic group amino, condense miscellaneous bicyclic group alkoxyl, condense miscellaneous double Ring group alkylamino, condenses miscellaneous bicyclic group epoxide alkoxyl, condenses miscellaneous bicyclic group epoxide alkylamino, spiral shell miscellaneous bicyclic group alkyl, spiral shell is miscellaneous Bicyclic group alkoxyl, bridge miscellaneous bicyclic group alkyl, bridge miscellaneous bicyclic group epoxide, bridge miscellaneous bicyclic group alkoxyl, bridge miscellaneous bicyclic group alkylamino, Alkyl-C (=O)-NH-, alkylthio group, cycloalkyl and described B ring, can be independently by hydrogen, aminoalkyl, aminoacyl, fluorine, Chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)- NH-, oxo (=O), C1-4Alkyl-C (=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, wherein, described E ring is one of heteroaryl groups that following subformula is formed：
Wherein, X, Y, Z, Z1, Z2, Z3And Z4It is each independently N or CH；
T and T1It is each independently-O- ,-S- ,-NR4- or-CH2-；
Wherein, each R4It independently is H, C1-4Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or Hydroxyl C1-4Alkyl；
Each J independently is-G- (CH2)n-R；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R independently is hydrogen ,-NR3R2, C2-4Thiazolinyl, C2-4Alkynyl, C3-10Cycloalkyl, C3-10Cycloalkyl C1-4Alkyl, C2-10 Heterocyclic radical C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-6Alkoxy C1-6Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxyl, ammonia Base C1-4Alkoxyl, halo C1-4Alkoxyl, C1-4Alkylamino halo C1-4Alkoxyl, C1-4Alkylamino C1-4Alkoxyl, C1-4Alkoxyl C1-4Alkoxyl, C6-10Aryl C1-4Alkoxyl, C6-10Aryl C1-4Alkylamino, C1-9Heteroaryl C1-4Alkoxyl, C1-9Heteroaryl C1-4 Alkylamino, C2-10Heterocyclic radical C1-4Alkylamino, C3-10Cycloalkyl oxy, C3-10Cycloalkyl amino, C2-10Heterocyclic radical C1-4Alkoxyl, C3-10Carbocylic radical C1-4Alkoxyl, C3-10Carbocylic radical C1-4Alkylamino, C6-10Aryloxy group C1-4Alkoxyl, C6-10Aryloxy group, C1-9Heteroaryl Base epoxide, C1-9Heteroaryl epoxide C1-4Alkoxyl, C2-10Heterocyclic radical epoxide C1-4Alkoxyl, C3-10Carbocylic radical epoxide C1-4Alkoxyl, C2-10Heterocyclic radical epoxide, C1-4Alkoxyl, C1-4Alkyl, C1-4Haloalkyl, C6-10Aryl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl Base C1-6Alkyl, C1-9Heteroaryl,
Or each R independently is following subformula：
Wherein, each X8, X9And X10It independently is N or CH；
Each X1, X2, X3, X4, X5, X6And X7It independently is-CH2- ,-O- ,-NR4a- ,-S (=O)t- or-S-；
Each q, m, p, r and s independently are 0,1,2,3 or 4；
Each R3And R2It independently is C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Each R4aIt independently is H, C1-4Alkyl, C1-4Alkyl-C (=O)-, benzyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described B ring, E ring and each R, all can be independently by hydrogen, aminoalkyl, ammonia Base acyl group, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C1-4Alkyl-C (=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is many Replace.
In other embodiments, E ring of the present invention be the heteroaryl groups that formed of following subformula it One：
Each J independently is-G- (CH2)n-R；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R independently is hydrogen ,-NR3R2, C2-4Thiazolinyl, C2-4Alkynyl, C2-10Heterocyclic radical C1-4Alkyl, C1-6Alkyl-S (=O )t-, C1-4Alkoxy C1-4Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxyl, amino C1-4Alkoxyl, halo C1-4Alkoxyl, C1-4Alkylamino halo C1-4Alkoxyl, C1-4Alkylamino C1-4Alkoxyl, C1-4Alkoxy C1-4Alkoxyl, C1-4Alkoxyl, C1-4Alkane Base, C1-4Haloalkyl, C1-9Heteroaryl C1-6Alkyl,
Or each R independently is following subformula：
Each R3And R2It independently is methyl, ethyl, propyl group, isopropyl, the tert-butyl group, amyl group, isopentyl, cyclopropyl, ring penta Base, cyclohexyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described B ring, E ring and each R, all can be independently by hydrogen, aminoalkyl, ammonia Base acyl group, fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, propyl group, isopropyl, dimethylamino, Methylamino, diethylamino, ethylamino, hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-, ethyl group-C (=O)-, propyl-C (=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, the heteroaryl groups that the subformula that K ring of the present invention is as follows is formed One of：
Each L independently is the tert-butyl group.
In some embodiments, substituted carbamide derivative wherein of the present invention, has the change as shown in formula (II) Compound, or the stereoisomer of the compound as shown in formula (II), geometric isomer, tautomer, nitrogen oxides, hydration Thing, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug,
Or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolism is produced Thing, ester, pharmaceutically acceptable salt or its prodrug, wherein：
Q and W is each independently CH or N；
Each R1It independently is hydrogen, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-6Alkane Epoxide C1-6Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, C1-4Alkyl-C (=O)-NH-, C1-4Alkoxyl, hydroxyl C1-4Alkane Base or C1-4Alkylthio group；
E ring is one of heteroaryl groups that following subformula is formed：
Wherein, X, Y, Z, Z1, Z2, Z3And Z4It is each independently N or CH；
T and T1It is each independently-O- ,-S- ,-NR4- or-CH2-；
Wherein, the X on described E ring, Y, Z, T, T1, Z1, Z2, Z3And Z4Two are at least while had to be hetero atom；
Each R4It independently is H, C1-4Alkyl, C1-4Alkyl-C (=O)-, benzyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6 Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R independently is hydrogen ,-NR3R2, C2-4Thiazolinyl, C2-4Alkynyl, C3-10Cycloalkyl, C3-10Cycloalkyl C1-4Alkyl, C2-10 Heterocyclic radical C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-6Alkoxy C1-6Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxyl, ammonia Base C1-4Alkoxyl, halo C1-4Alkoxyl, C1-4Alkylamino halo C1-4Alkoxyl, C1-4Alkylamino C1-4Alkoxyl, C1-4Alkoxyl C1-4Alkoxyl, C3-10Cycloalkyl oxy, C6-10Aryl C1-4Alkoxyl, C6-10Aryl C1-4Alkylamino, C1-9Heteroaryl C1-4Alcoxyl Base, C1-9Heteroaryl C1-4Alkylamino, C2-10Heterocyclic radical C1-4Alkylamino, C3-10Cycloalkyl amino, C2-10Heterocyclic radical C1-4Alkoxyl, C3-10Carbocylic radical C1-4Alkoxyl, C3-10Carbocylic radical C1-4Alkylamino, C6-10Aryloxy group C1-4Alkoxyl, C6-10Aryloxy group, C1-9Heteroaryl Base epoxide, C1-9Heteroaryl epoxide C1-4Alkoxyl, C2-10Heterocyclic radical epoxide C1-4Alkoxyl, C3-10Carbocylic radical epoxide C1-4Alkoxyl, C2-10Heterocyclic radical epoxide, C1-4Alkoxyl, C1-4Alkyl, C1-4Haloalkyl, C6-10Aryl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl Base C1-6Alkyl, C1-9Heteroaryl or each R independently are following subformula：
Wherein, each X8, X9And X10It independently is N or CH；
Each X1, X2, X3, X4, X5, X6And X7It independently is-CH2- ,-O- ,-NR4a- ,-S (=O)t- or-S-；
Each q, m, p, r and s independently are 0,1,2,3 or 4；
D is 1；
Each n independently is 1,2,3 or 4；
Each R3And R2It independently is C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Each R4aIt independently is H, C1-4Alkyl, C1-4Alkyl-C (=O)-, benzyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described E ring and each R, all can be independently by hydrogen, aminoalkyl, aminoacyl Base, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C1-4Alkyl-C (=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is many Replace；
Each L independently is the tert-butyl group.
In other embodiments, E ring of the present invention be the heteroaryl groups that formed of following subformula it One：
Wherein, each subformula representated by described E ring all can be independently by hydrogen, aminoalkyl, aminoacyl, fluorine, Chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, propyl group, isopropyl, dimethylamino, methylamino, Diethylamino, ethylamino, hydroxyl, cyano group, nitro, methyl-C (=O)-, ethyl group-C (=O)-, propyl-C (= O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is polysubstituted.
In other embodiments, each G of the present invention independently is-O-；
Each R independently is hydrogen ,-NR3R2, C2-4Thiazolinyl, C2-4Alkynyl, C2-10Heterocyclic radical C1-4Alkyl, C1-6Alkyl-S (=O )t-, C1-4Alkoxy C1-4Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxyl, amino C1-4Alkoxyl, halo C1-4Alkoxyl, C1-4Alkylamino halo C1-4Alkoxyl, C1-4Alkylamino C1-4Alkoxyl, C1-4Alkoxy C1-4Alkoxyl, C1-4Alkoxyl, C1-4Alkane Base, C1-4Haloalkyl, C1-9Heteroaryl C1-6Alkyl,
Or each R independently is following subformula：
Each R3And R2It independently is methyl, ethyl, propyl group, isopropyl, the tert-butyl group, amyl group, isopentyl, cyclopropyl, ring penta Base, cyclohexyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described each R all can be independently by hydrogen, aminoalkyl, aminoacyl, fluorine, Chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, propyl group, isopropyl, dimethylamino, methylamino, Diethylamino, ethylamino, hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-, ethyl group-C (=O)-, third Alkyl-C (=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is polysubstituted.
On the other hand, present invention also offers a kind of pharmaceutical composition, this pharmaceutical composition comprises of the present inventionization Compound.
In some embodiments, pharmaceutical composition of the present invention, it further comprises pharmaceutically acceptable Carrier, excipient, diluent, at least one in adjuvant and vehicle.
In some embodiments, pharmaceutical composition of the present invention, it further comprises additional therapeutic agent, this A little additional therapeutic agents are chemotherapeutic agent, antiproliferative, anti-inflammatory reagent, immunosuppressant, and immunostimulant, for treating Atherosclerotic medicine, for treating medicine or the combinations thereof of pulmonary fibrosiss.
In other embodiments, pharmaceutical composition of the present invention, wherein said additional therapeutic agent is benzene Butanoic acid chlormethine (chlorambucil), melphalan (melphalan), cyclophosphamide (cyclophosphamide), different ring phosphinylidyne Amine (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), chain urea Assistant rhzomorph (streptozocin), cisplatin (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (methotrexate), fluorouracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinblastine (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), paclitaxel (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), etoposide (etoposide), ET-743 (trabectedin), dactinomycin (dactinomycin), doxorubicin (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analog (gonadorelin analogues), megestrol (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon-ALPHA (interferon alfa), calcium folinate (leucovorin), sirolimuss (sirolimus), temsirolimus (temsirolimus), everolimuses (everolimus), Afatinib (afatinib), alisertib, amuvatinib, A Pa replaces Buddhist nun (apatinib), Axitinib (axitinib), bortezomib (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, gram Zhuo replaces Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Erlotinib (erlotinib), foretinib, ganetespib, gefitinib (gefitinib), ibrutinib, angstrom gram replaces Buddhist nun (icotinib), imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib, Linifanib, linsitinib, Masitinib (masitinib), momelotinib, does not replace husky Buddhist nun (motesanib), comes that For Buddhist nun (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib), relaxes Buddhist nun replace Buddhist nun (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, Trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, Volasertib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), brentuximab vedotin, card Appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), difficult to understand (ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab), or combinations thereof.
On the other hand, the present invention relates to described compound or pharmaceutical composition be used for preventing, process, mitigating in preparation or Treatment patient's proliferative disease, the purposes in the medicine of autoimmune disease or inflammatory diseasess.
In some embodiments, purposes of the present invention, wherein said proliferative disease is acute myeloid leukaemia, slowly Property myelogenous leukemia, gastrointestinal stromal tumors, acute myeloid leukemia (AML), the chronic myelogenous leukemia (CML) of mutation, Acute lymphoblastic leukemia (ALL), colorectal cancer, gastric cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma, carcinoma of prostate, cancer of pancreas, thyroid Cancer, bladder cancer, renal carcinoma, cerebroma, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, Atherosclerosis Change, pulmonary fibrosiss, leukemia, lymphatic cancer, rheumatism, cryoglobulinemia, non-lymphoreticular system tumor, papular glutinous Proteinose, familial splenic anemia, multiple myeloma, amyloidosises, solitary plasmacytoma, heavy chain disease, light chain disease, Malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinaemia, half molecule disease, monocytic leukemia, primary Property macroglobulinemia purpura, Secondary cases benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, non-suddenly Very golden lymphoma, Sezary syndrome, infectious monocytosis, acute histocytic increase disease, Hodgkin lymphoma, Hairy cell leukemia, colon cancer, rectal cancer, polyposis intestinalises, small cell lung cancer, neuroblastoma, neuroendocrine cell swells Tumor, 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 myeloma.
In some embodiments, purposes of the present invention, wherein said autoimmune disease is rheumatic arthritis, wolf Skin ulcer, multiple sclerosiss, thyroiditiss, type i diabetes, sarcoidosises, inflammatory bowel, Crohn's disease or systemic lupus.
In some embodiments, purposes of the present invention, wherein said inflammatory diseasess refer to diverticulitiss, colitis, Pancreatitiss, hepatitis, chronic hepatitiss, liver cirrhosis, cholecystitis, or chronic inflammatory disease.
In some embodiments, purposes of the present invention, wherein said disease is FLT3 mediation or FLT3-ITD causes Disease.
On the other hand, the present invention relates to described compound or pharmaceutical composition preparing for preventing, process, treat or Mitigate patient's proliferative disease, the method for autoimmune disease or inflammatory diseasess, its method comprises to have given this infection or disease Patient's compound as described in the present invention or pharmaceutical composition of the present invention effectively treatment amount.
In some embodiments, method of the present invention, wherein said disease is that FLT3 is kinase mediated or FLT3-ITD The disease that kinases causes.
On the other hand, the present invention relates to described compound or pharmaceutical composition are used for preventing, process, treat or mitigate trouble Person's proliferative disease, autoimmune disease or inflammatory diseasess.
Another aspect of the present invention is related to prevention, processes, treats or mitigate patient's proliferative disease, autoimmune disease or inflammation The method of property disease, methods described comprise using the pharmaceutically acceptable effective dose of compound of the present invention, patient to be carried out to Medicine.
Another aspect of the present invention is related to prevention, processes, treats or mitigate patient's proliferative disease, autoimmune disease or inflammation Property disease method, the pharmaceutically acceptable of pharmaceutical composition that methods described comprises using the compound containing the present invention have Effect dosage is administered to patient.
Another aspect of the present invention is directed to use with a kind of compound of the present invention to produce for preventing, processing or treat patient Proliferative disease, autoimmune disease or inflammatory diseasess, and mitigate the purposes of the medicine of its order of severity.
The purpose of another aspect of the present invention is to provide one kind to comprise described formula (I) or formula (II) compound or its pharmacy Upper acceptable salt adjusts the application in the disease agent of FLT3 mediation in preparation, particularly comprises the institute giving therapeutically effective amount State formula (I) or formula (II) compound or its pharmaceutically acceptable salt, its isomer, solvate, hydrate, or precursor medicine Thing.
On the other hand, the compound that the present invention provides and compositionss can effectively adjust the work of Ab1 protein-tyrosine family Property.
In some embodiments, the compound that the present invention provides and compositionss can effectively adjust class fms tyrosine kinase 3 The activity of receptor kinase (FLT-3 kinases).
In some embodiments, the compound that the present invention provides and compositionss can effectively suppress class fms tyrosine kinase 3 The activity of receptor kinase mutation (FLT-3-ITD kinases).
In some embodiments, the compound that the present invention provides and compositionss can effectively adjust the activity of Src subfamily, It includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr and Yrk.
In some embodiments, the compound that the present invention provides and compositionss can effectively adjust one or more kinases Activity, described kinases is selected from：(calmodulin, CaM adjusts kinases and phase to sterile20, sterile11, sterile, camk subfamily Close kinases), 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 its respective subfamily).
In other embodiments, the invention provides using disclosed compound and compositionss, or it is pharmaceutically Acceptable salt, solvate, hydrate or its prodrug are used for locally or systemically treating or prevention people and the living by kinases of beast Property the method for disease, disease and discomfort that adjusts or otherwise affect.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects and other aspect Content is made more specific complete description below.
Detailed description of the invention book
Definition and general terms
The present invention will list the document corresponding to the content of the materialization determining in detail, and embodiment is all accompanied by structure Formula and the diagram of chemical formula.The present invention has and expectedly covers all of choice, variant and coordinate, and these may be as right It is included in existing invention field like that defined in requirement.Those skilled in the art will identify many similar or equivalent to This described method and material, these can apply in the practice of the present invention.The present invention is limited to absolutely not method and material Description.Have a lot of documents and similar material to distinguish with the present patent application or conflict, including but be not limited to term Definition, the usage of term, the technology of description, or the scope being controlled as the present patent application.
The present invention is by defined below for application unless other aspects show.According to the purpose of the present invention, chemical element is according to unit Plain periodic chart, CAS version and chemical drugss handbook, 75,thEd, 1994 defining.In addition, organic chemistry General Principle is shown in " Organic Chemistry,"Thomas Sorrell,University Science Books,Sausalito:1999, and"March′s Advanced Organic Chemistry,"by Michael B.Smith and Jerry March, John Wiley&Sons,New York:2007, therefore all of content has all merged list of references.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, such as General formula compound above, or as special example inside embodiment, subclass, and the class compound that the present invention is comprised. Should be appreciated that " optionally substituted " this term and " substituted or non-substituted " this term can exchange use.In general, art Before language " optionally " is whether located at term " substituted ", represent that one or more of given structure hydrogen atom can be by Concrete substituent group is replaced.Unless other aspects show, an optional substituted radical can have a substituent group in group Each commutable position is replaced.When in given structural formula, more than one position can be selected from one of concrete group Or multiple substituent group is replaced, then substituent group can replace in each position identical or differently.Wherein said substituent group Can be, but be not limited to：Hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, Alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkoxyl, alkylamino, alkylthio group, halogenated alkoxy, cyano group, virtue Base, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, ring third Base, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Terminology used in the present invention " alkyl " includes the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or side chain, wherein alkane Base can be replaced by one or more substituent groups described in the invention individually optionally.Some of them embodiment is, alkyl Group contains 1-10 carbon atom, and other embodiment is that alkyl group contains 1-8 carbon atom, other embodiment It is that alkyl group contains 1-6 carbon atom, other embodiment is that alkyl group contains 1-4 carbon atom, other Embodiment is that alkyl group contains 1-3 carbon atom.Alkyl group further example includes, but is not limited to, methyl, Ethyl, n-pro-pyl, isopropyl, normal-butyl, 2- methyl-propyl or isobutyl group, 1- methyl-propyl or sec-butyl, the tert-butyl group, positive penta Base, 2- amyl group, 3- amyl group, 2- methyl -2- butyl, 3- methyl -2- butyl, 3- methyl isophthalic acid-butyl, 2-methyl-1-butene base, just own Base, 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- first Base -3- amyl group, 2,3- dimethyl -2- butyl, 3,3- dimethyl -2- butyl, n-heptyl, n-octyl, etc..Term " alkyl " and Its prefix " alkane " is being used herein as, and all comprises 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, and wherein at least one position is insatiable hunger And state, that is, a C-C is sp tri- key, and wherein alkynyl group can be individually optionally by one or more described in the invention Substituent group is replaced, and specific example includes, but is not limited to, acetenylPropargylEtc..
Term " thiazolinyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, and wherein at least one position is insatiable hunger And state, that is, a C-C is sp2The group of double bond, wherein thiazolinyl can be retouched by one or more present invention individually optionally The substituent group stated is replaced, and has negation " just " or the positioning of " E " " Z " including group, and wherein specific example includes, but does not limit In vinyl (- CH=CH2), pi-allyl (- CH2CH=CH2), etc..
Term " alkylidene " and " alkylidene chain " refers to straight or branched, the divalent hydrocarbon that is only made up of carbon and hydrogen atom Chain, without unsaturated bond, has 1 to 8 carbon atoms, for example, methylene, ethylidene, propylidene, positive butylidene etc..Alkylidene Chain can be connected on the remainder of molecule by any two carbon atom in chain.
Term " alkenylene " or " alkenylene chain " refer to straight or branched, the unsaturation two that is only made up of carbon and hydrogen atom Valency group, has 1 to 8 carbon atoms, wherein unsaturated bond is only used as double bond presence, and double bond may reside in any two in chain Between individual carbon atom, for example, ethenylidene, propenylene, 2- butenylidene etc..Alkenylene chain can be by any in chain Two carbon atoms are connected on the remainder of molecule.
Term " alkynylene " or " sub- alkynes chain " refers to straight or branched, the unsaturated bivalence that is only made up of carbon and hydrogen atom Group, has 1 to 8 carbon atoms, and wherein unsaturated bond is only existed with three key-shaped formulas, and three keys may reside in any the two of carbochain Between individual carbon atom, for example, sub- acetylene, 1- Asia propine, 2- Aden alkynes, 1- Asia pentyne, 3- Asia pentyne etc..This sub- alkynes chain can lead to Cross any two carbon atom in chain to be connected on the remainder of molecule.
Terminology used in the present invention " halogen ", " halogen atom " or " halogen atom " includes fluorine, chlorine, bromine, iodine.
Term " amino " refers to-NH2.
Term " alkylamino " or " alkyl amino " inclusion " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino Group is separately replaced by one or two alkyl group, and wherein alkyl group has implication as described in the present invention. Some of them embodiment is that alkyl amino is one or two C1-6Alkyl is connected to the alkyl amino of the lower level on nitrogen-atoms Group.Other embodiment is that alkyl amino is C1-3Lower level alkylamino group.Suitable alkylamino group Can be alkyl monosubstituted amino or dialkyl amido, such example includes, but is not limited to, N- methylamino, N- ethylamino, N, N- Dimethylamino, N, N- lignocaine etc..
Term " alkoxyl " used in the present invention, is related to alkyl, as defined in the present invention, by oxygen atom even It is connected in main carbochain.Such embodiment includes, but is not limited to, methoxyl group, ethyoxyl, propoxyl group etc..
Term " alkoxyalkyl " or " alkyloxy-alkoxy ", represent that alkyl or alkoxyl can be by one or more identical Or the situation that different alkoxyl replaces, wherein alkyl and alkoxyl have implication as described in the present invention.Such embodiment Include, but is not limited to, methoxy methyl alkyl, (ethoxymethyl) alkyl, methoxy propoxy, methoxymethoxy etc..
Term " alkyl-S (=O)t- ", represent-S (=O)t- situation about 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 includes, but is not limited to, methyl-S (=O )2-, ethyl group-S (=O)2-, propyl-S (=O)2-, methyl-S (=O)-, ethyl group-S (=O)-, propyl-S (= O)-, methyl-S-, ethyl group-S-, propyl-S-, etc..
Term " alkyl-C (=O)-", represents the situation that acyl group (- C (=O) -) can be connected, wherein alkane with an alkyl Base has implication as described in the present invention.Such embodiment includes, but is not limited to, acetyl group (CH3- C (=O) -), propionyl Base (C2H5- C (=O) -) etc..
Term " haloalkyl " or " halogenated alkoxy " represent that alkyl or alkoxyl can be by one or more identical or not Situation about being replaced with halogen atom.Wherein alkyl and alkoxy base have implication as described in the present invention, such example Include, but is not limited to trifluoromethyl, trifluoromethoxy etc..
Term " alkylamino halogenated alkoxy " represents that halogenated alkoxy can be by one or more identical or different alkylaminos Situation about being replaced.Wherein alkylamino and halo alkoxy group have implication as described in the present invention, and such example includes, But it is not limited to methylamino difluoro-methoxy etc..
Term " hydroxy alkyl " or " hydroxy alkoxy base " represent that alkyl or alkoxyl can be taken by one or more hydroxyls The situation in generation.Wherein alkyl and alkoxy base have implication as described in the present invention, and such example includes, but is not limited to Methylol, 1- ethoxy, hydroxypropyl, 1,2- dihydroxypropyl, hydroxyl methoxyl group, 1- hydroxy ethoxy etc..
Term " aminoalkoxy " or " alkylaminoalkoxy " represent that alkoxyl can be by one or more amino or alkane ammonia The situation that base is replaced.Wherein alkylamino or alkoxy base have implication as described in the present invention, and such example includes, but It is not limited to aminomethoxy, 1- amino ethoxy, methylamino methoxyl group, ethylamino ethyoxyl etc..
Term " aryl " can be used alone or as " aralkyl ", a big portion of " aralkoxy " or " aryloxy alkyl " Point, can be monocyclic, bicyclic, and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, each of which Member ring systems comprise 3-7 atom.Term " aryl " can exchange with term " aromatic rings " and use, and such as aromatic rings can include benzene Base, naphthyl and anthracene.And described aryl can be substituted or non-substituted, and wherein substituent group can be, but is not limited to, hydrogen, Aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, halogen Substituted alkyl, hydroxy alkyl, alkoxyl, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, miscellaneous Ring group, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- Or alkoxyalkyl etc..Depending on structure, aryl can be monoradical or divalent group (that is, arlydene).
Term " heteroaryl ", " heteroaryl groups " are used interchangeably herein, can be used alone or as " heteroaryl alkane Base " or the part of " heteroarylalkoxy ", all referring to monocyclic, bicyclic, three rings or tetracyclic ring system, wherein, bicyclic heteroaryl Group, tricyclic heteroaryl group or four heteroaryl group system cyclization in the form of condensing.Wherein, heteroaryl groups system It is armaticity, on ring, one or more atoms are replaced that (hetero atom is selected from N, O, P, S, in this S by hetero atom individually optionally Or P is optionally replaced by one or more oxygen atoms and obtains as SO, SO2, PO, PO2Group).Heteroaryl system can be any It is connected on hetero atom or carbon atom in main structure thus forming stable compound.Heteroaryl system group can be 3-7 Former molecular monocyclic, or 7-10 is individual former molecular bicyclic, or 10-15 former molecular three rings.There is 7-10 atom Bicyclic can be bicyclo- [4,5], [5,5], [5,6] or [6,6] system, three rings with 10-15 atom can be three rings [5,5,6], [5,7,6] or [6,5,6] system.And described heteroaryl or heteroaryl groups can be substituted or non-substituted, Wherein substituent group can be, but is not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, Amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkoxyl, alkylamino, alkylthio group, haloalkoxy Base, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C= O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..Depending on structure, heteroaryl can be monovalent radical Group or divalent group (that is, inferior heteroaryl).
Other embodiment is that heteroaryl system (comprising heteroaryl, heteroaryl groups) includes example below, but does not limit In these examples：2- furyl, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, 4- methyl isoxazole -5- base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- base, pyridazine Base (as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (as 5- tetrazole radical), triazolyl is (as 2- triazole Base and 5- triazolyl), 2- thienyl, 3- thienyl, pyrazolyl (as 2- pyrazolyl), isothiazolyl, 1,2,3- di azoly, 1, 2,5- di azolies, 1,2,4- di azoly, 1,2,3-triazoles base, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1, 2,5- thio biphosphole bases, 1,3,4- thiadiazoles -2- base, pyrazinyl, pyrazine -2- base, 1,3,5-triazines base, benzo [d] thiazole -2- Base, imidazo [1,5-a] pyridine -6- base, benzimidazolyl, benzoxazolyl, 1,8- phthalazinyl, benzothienyl, Yin Diindyl base (as 2- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinoline), tetralyl, benzopyrazoles Base, acridinyl, benzimidazolyl, benzindole base, benzisoxa piperazine base, benzo [4,6] imidazo [1,2-a] pyridine radicals, benzene And [d] imidazoles [2,1-b] thiazolyl, benzofuranyl, naphtho-furan base, diazosulfide base, benzo thio-phenyl, benzo three Oxazolyl, benzo thiopyranyl, benzimidazole dihydrochloride base, benzoxazolyl group, benzothiazolyl, B-carboline base, carbazyl, adjacent diaza Naphthyl, dibenzofuran group, imidazopyridyl, Imidazothiazole base, indazolyl, indolizinyl, indyl, different benzo thianthrene Base, iso-dihydro-indole-group, isoquinolyl, isothiazole alkyl, isothiazolyl, naphthyridinyl, decahydro indyl, decahydro isoindolyl, Oxazolidinedione base, oxazolidinyl, azoles pyridine radicals, oxazolyl, Oxyranyle, embedding two pyridyls of tea, phenanthridinyl, luxuriant and rich with fragrance around Quinoline base, phenarsazine base, phenazinyl, phenothiazinyl, phenazinyl, phthalazinyl, pteridyl, pyridopyridine base, quinazolyl, quinoline Quinoline base, thio-phenyl, triazine radical, 2H- pyrrolo- [3,4-c] pyridine radicals, pyrazolo [2 ', 1 ':2,3] oxazole is simultaneously [4,5-c] Pyridine radicals, imidazo [2 ', 1 ':2,3] thiazole simultaneously [4,5-c] pyridine radicals, imidazo [2 ', 1 ':2,3] thiazole simultaneously [4,5-b] pyrrole Piperidinyl, imidazo [2 ', 1 ':2,3] thiazole simultaneously [5,4-b] pyridine radicals, pyrazolo [2 ', 1 ':2,3] thiazole simultaneously [4,5-b] pyrazine Base, 1H- benzo [4,5] thieno [2,3-d] imidazole radicals, 1- methyl isophthalic acid H- benzo [4,5] thieno [2,3-d] imidazole radicals, miaow Azoles simultaneously [2 ', 1 ':2,3] thiazole simultaneously [4,5-b] pyrazinyl, 1H- benzo [f] imidazo [4,5-b] [Isosorbide-5-Nitrae] sulfur azatropylidene base etc..
Term " heteroaryl ", " heteroaryl groups " are used interchangeably herein, can be used alone or as " heteroaryl alkane Base " or the part of " heteroarylalkoxy ", all referring to monocyclic, bicyclic, three rings or tetracyclic ring system, wherein, bicyclic heteroaryl Group, tricyclic heteroaryl group or four heteroaryl group system cyclization in the form of condensing.Wherein, heteroaryl groups system It is armaticity, on ring, one or more atoms are replaced that (hetero atom is selected from N, O, P, S, in this S by hetero atom individually optionally Or P is optionally replaced by one or more oxygen atoms and obtains as SO, SO2, PO, PO2Group).Heteroaryl system can be any It is connected on hetero atom or carbon atom in main structure thus forming stable compound.Heteroaryl system group can be 3-7 Former molecular monocyclic, or 7-10 is individual former molecular bicyclic, or 10-15 former molecular three rings.There is 7-10 atom Bicyclic can be bicyclo- [4,5], [5,5], [5,6] or [6,6] system, three rings with 10-15 atom can be three rings [5,5,6], [5,7,6] or [6,5,6] system.And described heteroaryl or heteroaryl groups can be substituted or non-substituted, Wherein substituent group can be, but is not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, Amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkoxyl, alkylamino, alkylthio group, haloalkoxy Base, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C= O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..Depending on structure, heteroaryl can be monovalent radical Group or divalent group (that is, inferior heteroaryl).
Other embodiment is that heteroaryl system (comprising heteroaryl, heteroaryl groups) includes example below, but does not limit In these examples：2- furyl, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, 4- methyl isoxazole -5- base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- base, pyridazine Base (as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (as 5- tetrazole radical), triazolyl is (as 2- triazole Base and 5- triazolyl), 2- thienyl, 3- thienyl, pyrazolyl (as 2- pyrazolyl), isothiazolyl, 1,2,3- di azoly, 1, 2,5- di azolies, 1,2,4- di azoly, 1,2,3-triazoles base, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1, 2,5- thio biphosphole bases, 1,3,4- thiadiazoles -2- base, pyrazinyl, pyrazine -2- base, 1,3,5-triazines base, benzo [d] thiazole -2- Base, imidazo [1,5-a] pyridine -6- base, benzimidazolyl, benzoxazolyl, 1,8- phthalazinyl, benzothienyl, Yin Diindyl base (as 2- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinoline), tetralyl, benzopyrazoles Base, acridinyl, benzimidazolyl, benzindole base, benzisoxa piperazine base, benzo [4,6] imidazo [1,2-a] pyridine radicals, benzene And [d] imidazoles [2,1-b] thiazolyl, benzofuranyl, naphtho-furan base, diazosulfide base, benzo thio-phenyl, benzo three Oxazolyl, benzo thiopyranyl, benzimidazole dihydrochloride base, benzoxazolyl group, benzothiazolyl, B-carboline base, carbazyl, adjacent diaza Naphthyl, dibenzofuran group, imidazopyridyl, Imidazothiazole base, indazolyl, indolizinyl, indyl, different benzo thianthrene Base, iso-dihydro-indole-group, isoquinolyl, isothiazole alkyl, isothiazolyl, naphthyridinyl, decahydro indyl, decahydro isoindolyl, Oxazolidinedione base, oxazolidinyl, azoles pyridine radicals, oxazolyl, Oxyranyle, embedding two pyridyls of tea, phenanthridinyl, luxuriant and rich with fragrance around Quinoline base, phenarsazine base, phenazinyl, phenothiazinyl, phenazinyl, phthalazinyl, pteridyl, pyridopyridine base, quinazolyl, quinoline Quinoline base, thio-phenyl, triazine radical, 2H- pyrrolo- [3,4-c] pyridine radicals, pyrazolo [2 ', 1 ':2,3] oxazole is simultaneously [4,5-c] Pyridine radicals, imidazo [2 ', 1 ':2,3] thiazole simultaneously [4,5-c] pyridine radicals, imidazo [2 ', 1 ':2,3] thiazole simultaneously [4,5-b] pyrrole Piperidinyl, imidazo [2 ', 1 ':2,3] thiazole simultaneously [5,4-b] pyridine radicals, pyrazolo [2 ', 1 ':2,3] thiazole simultaneously [4,5-b] pyrazine Base, 1H- benzo [4,5] thieno [2,3-d] imidazole radicals, 1- methyl isophthalic acid H- benzo [4,5] thieno [2,3-d] imidazole radicals, miaow Azoles simultaneously [2 ', 1 ':2,3] thiazole simultaneously [4,5-b] pyrazinyl, 1H- benzo [f] imidazo [4,5-b] [Isosorbide-5-Nitrae] sulfur azatropylidene base etc..
Term " bicyclic heteroaryl group ", " tricyclic heteroaryl group " system cyclization in the form of condensing.Wherein, heteroaryl Group system is armaticity, on ring one or more atoms replaced by hetero atom individually optionally (hetero atom is selected from N, O, P, S, are optionally replaced by one or more oxygen atoms in this S or P and obtain as SO, SO2, PO, PO2Group).Heteroaryl system Can be connected in main structure on any hetero atom or carbon atom thus forming stable compound.Heteroaryl system group can Being that 7-10 is former molecular bicyclic, or 10-15 former molecular three rings.Having the bicyclic of 7-10 atom can be two Ring [4,5], [5,5], [5,6] or [6,6] system, three rings with 10-15 atom can be three rings [5,5,6], [5,7,6] Or [6,5,6] system.Depending on structure, " bicyclic heteroaryl group ", " tricyclic heteroaryl group " system can for monoradical or Divalent group (that is, " sub- bicyclic heteroaryl ", " sub- tricyclic heteroaryl " system).
Other embodiment is that heteroaryl system includes example below, but is not limited to these examples：Benzo [d] thiazole- 2- base, imidazo [1,5-a] pyridine -6- base, benzimidazolyl, benzoxazolyl, 1,8- phthalazinyl, benzothienyl, Indyl (as 2- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinoline), tetralyl, benzo pyrrole Oxazolyl, acridinyl, benzimidazolyl, benzindole base, benzisoxa piperazine base, benzo [4,6] imidazo [1,2-a] pyridine radicals, Benzo [d] imidazoles [2,1-b] thiazolyl, benzofuranyl, naphtho-furan base, diazosulfide base, benzo thio-phenyl, benzo Triazolyl, benzo thiopyranyl, benzimidazole dihydrochloride base, benzoxazolyl group, benzothiazolyl, B-carboline base, carbazyl, adjacent phenodiazine Miscellaneous naphthyl, dibenzofuran group, imidazopyridyl, Imidazothiazole base, different benzo thienyl, iso-dihydro-indole-group, isoquinoline Quinoline base, naphthyridinyl, decahydro indyl, decahydro isoindolyl, azoles pyridine radicals, embedding two pyridyls of tea, phenanthridinyl, phenanthroline Base, phenarsazine base, pteridyl, pyridopyridine base, quinazolyl, quinolyl, 2H- pyrrolo- [3,4-c] pyridine radicals, pyrazoles And [2 ', 1 ':2,3] oxazole simultaneously [4,5-c] pyridine radicals, imidazo [2 ', 1 ':2,3] thiazole simultaneously [4,5-c] pyridine radicals, imidazo [2’,1’:2,3] thiazole simultaneously [4,5-b] pyridine radicals, imidazo [2 ', 1 ':2,3] thiazole simultaneously [5,4-b] pyridine radicals, pyrazolo [2’,1’:2,3] thiazole simultaneously [4,5-b] pyrazinyl, 1H- benzo [4,5] thieno [2,3-d] imidazole radicals, 1- methyl isophthalic acid H- benzo [4,5] thieno [2,3-d] imidazole radicals, imidazo [2 ', 1 ':2,3] thiazole simultaneously [4,5-b] pyrazinyl, 1H- benzo [f] imidazoles And [4,5-b] [1,4] sulfur azatropylidene base etc..
Term " carbocylic radical " or " annular aliphatic ", " carbocyclic ring ", " cycloalkyl " refers to monovalence or multivalence, non-aromatic, satisfies And/or part unsaturation ring, and do not comprise hetero atom, including the two of the monocyclic of 3-12 carbon atom or 7-12 carbon atom Ring or three rings.The bicyclic carbocyclic ring with 7-12 atom can be bicyclo- [4,5], [5,5], and [5,6] or [6,6] system has simultaneously The bicyclic carbocyclic ring having 9 or 10 atoms can be bicyclo- [5,6] or [6,6] system.Depending on structure, " carbocylic radical " or " ring-type fat Fat race ", " carbocyclic ring ", " cycloalkyl " can be monoradical or divalent group, that is, in certain embodiments of the present invention, can substitute Or as sub- carbocylic radical, cycloalkylidene uses.The example of cyclic aliphatic group further includes, but is not limited to, cyclopropyl, Cyclobutyl, cyclopenta, 1- cyclopenta -1- thiazolinyl, 1- cyclopenta -2- thiazolinyl, 1- cyclopenta -3- thiazolinyl, cyclohexyl, 1- hexamethylene Base -1- thiazolinyl, 1- cyclohexyl -2- thiazolinyl, 1- cyclohexyl -3- thiazolinyl, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, ring Decyl, ring undecyl, cyclo-dodecyl, adamantyl etc..And described " carbocylic radical " or " annular aliphatic ", " carbon Ring ", " cycloalkyl " can be substituted or non-substituted, and wherein substituent group can be, but is not limited to, hydrogen, aminoalkyl, amino Acyl group, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxyl alkane Base, alkoxyl, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitre Base, aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl Deng.
Term " heterocyclic radical ", " Heterocyclylalkyl ", " heterocycle ", " miscellaneous alicyclic " or " heterocycle " is used interchangeably herein, All referring to monocyclic, bicyclic, three rings or tetracyclic ring system, on its medium ring, one or more atoms are taken by hetero atom individually optionally In generation, ring can be fully saturated or comprise one or more degrees of unsaturation, but is definitely not the fragrant same clan.Depending on structure, " miscellaneous Ring group ", " Heterocyclylalkyl ", " heterocycle ", " miscellaneous alicyclic " can be monoradical or divalent group, that is, in some enforcements of the present invention In example, can substitute or use as sub- heterocyclic radical.Heterocyclic system can be connected to master on any hetero atom or carbon atom Thus forming stable compound in structure.One or more ring hydrogen atoms are individually optionally by one or more present invention Described substituent group is replaced.Some of them embodiment is, " heterocyclic radical ", " Heterocyclylalkyl ", " heterocycle ", " miscellaneous alicyclic " or " heterocycle " group be 3-7 yuan of rings monocyclic (1-6 carbon atom and be selected from N, the 1-3 hetero atom of O, P, S, appoint in this S or P Selection of land is replaced by one or more oxygen atoms and obtains as SO, SO2, PO, PO2Group；In addition, carbon atom can be by oxo, shape One-tenth-C=O-；When described ring is three-membered ring, only one of which hetero atom), or 7-10 former molecular bicyclic (4-9 Individual carbon atom and be selected from N, the 1-3 hetero atom of O, P, S, optionally replaced by one or more oxygen atoms in this S or P and obtain As SO, SO2, PO, PO2Group).
" heterocyclic radical " can be carbon-based or hetero atom base." heterocyclic radical " equally also includes heterocyclic group and saturation or part not Saturated rings or heterocycle simultaneously close formed group.The example of heterocycle includes, but is not limited to, 1,2,3,6- tetrahydro pyridyl, piperazine Piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, Tetrahydro thiapyran base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, glycidyl, azacycloheptyl, oxa- Suberyl, thia suberyl, N- morpholinyl, 2- morpholinyl, morpholinyl, thio-morpholinyl, homopiperazine base, 4- methoxyl group-piperazine Pyridine -1- base, oxygen azatropylidene base, diazepine base, sulfur azatropylidene base, pyrrolin -1- base, 2- pyrrolinyl, 3- pyrrolinyl, two Hydrogen indoles base, 2- indoline base, 2H- pyranose, 4H- pyranose, dioxacyclohexyl, 1,3- dioxy amyl group, dithiane base, two Thiophene cyclopentadienyl alkyl, dihydro-thiophene base, 1,2,3,4- tetrahydro isoquinolyl, 1,2,6- thiadiazine alkane 1,1- dioxy -2- base, hexahydro -2H- [1,4] dioxin [2,3-c] pyrrole radicals, 1,1- titanium dioxide thio-morpholinyl, 2,3,3a, 7a- tetrahydrochysene -1H- isoindolyl, different Yin Diindyl quinoline base, 1,2,3,4- tetrahydric quinoline group, N- pyridine radicals carbamide, dioxolanyl, dihydro pyrazine base, dihydropyridine base, dihydro Pyrazolyl, dihydro-pyrimidin base, pyrrolin base, 1,4- dithiane base, morpholinyl, decahydro indyl, decahydro isoindolyl, piperazine Base, piperidyl, pteridyl, purine radicals and pyrazinyl.And described heterocyclic radical can be substituted or non-substituted, wherein substituent group Can be, but be not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, Alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkoxyl, alkylamino, alkylthio group, halogenated alkoxy, cyano group, virtue Base, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, ring third Base, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..Such as 1- picoline -2 (1H) -one, hexamethylene -2,4- dienone Base, 2,6- dimethyl-purine base etc..
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " represents saturation or undersaturated condensed ring body System, is related to the bicyclic system of non-aromatic, at least one ring is nonaromatic.Depending on structure, " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " can be unit price or divalent group, that is, in certain embodiments of the present invention, permissible Substitute or use as sub- condensed-bicyclic base.Such system can comprise independent or conjugation undersaturated condition, but its core Core structure does not comprise aromatic rings or heteroaromatic (but aromatic series can be used as substituent group thereon).Each of condensed-bicyclic Or ring is carbocyclic ring is miscellaneous alicyclic, such example includes, but is not limited to, hexahydro-furan [3,2-b] furyl, 2,3,3a, 4,7,7a- hexahydro -1H- indenyls, 7- azabicyclo [2.2.1] heptane base, condensed-bicyclic [3.3.0] octyl, condense Bicyclic [3.1.0] hexyl, 1,2,3,4,4a, 5,8,8a- octahydro naphthyls, these are included within the system of condensed-bicyclic. And described condensed-bicyclic base can be substituted or non-substituted, and wherein substituent group can be, but is not limited to, hydrogen, amino alkane Base, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, Hydroxy alkyl, alkoxyl, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, mercapto Base, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alcoxyl Base alkyl etc..
Term " condensing miscellaneous bicyclic group " represents saturation or undersaturated fused ring system, is related to the bicyclic body of non-aromatic System, at least one ring is nonaromatic.Such system can comprise independent or conjugation undersaturated condition, but its core Core structure does not comprise aromatic rings or heteroaromatic (but aromatic series can be used as substituent group thereon).Depending on structure, " condense miscellaneous Bicyclic group " can be unit price or divalent group, that is, in certain embodiments of the present invention, can substitute or condense as Asia miscellaneous bicyclic Base uses.And at least one member ring systems comprises one or more hetero atoms, each of which member ring systems comprise 3-7 atom composition Ring, that is, comprise 1-6 carbon atom and be selected from N, the 1-3 hetero atom of O, P, S, in this S or P optionally by one or more oxygen Atom is replaced to be obtained as SO, SO2, PO, PO2Group, in addition, carbon atom can also be by oxo formation-C=O-；Such reality Example includes, but is not limited to, hexahydro -2H- [Isosorbide-5-Nitrae] dioxin [2,3-c] pyrrole radicals, 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] nonyl Alkane 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, different Yin Diindyl quinoline base, 1,2,3,4- tetrahydric quinoline group, (1S, 5S) -1- hydroxyl -3- azabicyclo [3.1.0] hexyl, (1R, 5S) -1- hydroxyl Base -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- diazabicyclos [3.3.0] octyl, 2,6- diazabicyclos [3.3.0] octyl, 3- ethyl -3,7- diazabicyclo [3.3.0] octyl, 2,7- diazabicyclos [3.3.0] octyl, 7- acetyl group -2,7- diazabicyclo [3.3.0] octane Base, 2,8- diazabicyclos [4.3.0] nonyl, 2- methyl -2,8- diazabicyclo [4.3.0] nonyl, 3- oxygen -8- azepine Bicyclic [4.3.0] nonyl, 2- oxygen -8- azabicyclo [4.3.0] nonyl, 2,8- phenodiazine -5- oxabicyclo [4.3.0] nonanes Base, (1S, 6R) -2- methyl -2,8- phenodiazine -5- oxabicyclo [4.3.0] nonyl, 3- ethyl -3,9- diazabicyclo [4.3.0] nonyl, 4,9- diazabicyclos [4.3.0] nonyl, 2,9- diazabicyclos [4.3.0] nonyl, 3- methyl- 3,9- diazabicyclos [4.3.0] nonyl, 3- ethyl -3,7- diazabicyclo [4.3.0] nonyl, 3- methyl -3,7- bis- Azabicyclo [4.3.0] nonyl, 2- ethyl -2,8- diazabicyclo [4.3.0] nonyl, 3- oxo -2,4,8- tri- azepines Bicyclic [4.3.0] nonyl, 3- oxo -4- oxygen -2,8- diazabicyclo [4.3.0] nonyl, 3- oxo -2,8- diaza is double Ring [4.3.0] nonyl, 3,8- diazabicyclos [4.3.0] nonyl, 8- methyl -2,8- diazabicyclo [4.3.0] nonane Base, 3,7- diazabicyclos [4.3.0] nonyl, 3,9- diazabicyclos [4.3.0] nonyl, 3- oxygen -8- azabicyclo [4.3.0] nonyl, 3- sulfur -8- azabicyclo [4.3.0] nonyl, 9- methyl -3,9- diazabicyclo [4.3.0] nonane Base, 7- methyl -3,7- diazabicyclo [4.3.0] nonyl, 9- ethyl -3,9- diazabicyclo [4.3.0] nonyl, 7- second Base -3,7- diazabicyclo [4.3.0] nonyl, 8- ethyl -2,8- diazabicyclo [4.3.0] nonyl, 5,6- dihydros - 4H- pyrrolo- [3,4-c] isoxazolyl, 3- ethyl-[1,2,4] triazole [4,3-a] piperidyl, [1,2,4] triazole [4, 3-a] and piperidyl, 3- methyl-isoxazole simultaneously [4,3-c] piperidyl, 3- methyl -5,6- dihydro -4H- pyrrolo- [3,4-c] is different Oxazolyl, 2- methyl -4,5,6,7- tetrahydrochysene -1H- imidazo [4,5-c] pyridine radicals, 2- methyl -4,5,6,7- tetrahydrochysene oxazoles are simultaneously [4,5-c] pyridine radicals, 2- methyl -4,5,6,7- tetrahydrochysene -1H- thiazole simultaneously [4,5-c] pyridine radicals, isoxazole simultaneously [4,3-c] piperidines Base, 4,5,6,7- tetrahydrochysene isoxazoles simultaneously [3,4-c] pyridine radicals, [1,2,4] triazole simultaneously [4,3-a] piperazinyl, 3- trifluoromethyl- [1,2,4] triazole simultaneously [4,3-a] piperazinyl, 3- methyl-[1,2,4] triazole simultaneously [4,3-a] piperazinyl, 2- oxo -3- oxygen - 8- azabicyclo [4.3.0] nonyl, 1,3- dimethyl -4,5,6,7- tetrahydrochysene -1H- pyrazolo [4,3-c] pyridin-2-yls, 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- diaza is double Ring [4.3.0] nonyl, 2,7- diaza decahydro naphthyls or 2- oxygen -8- azabicyclo [4.4.0] decyl etc..And it is described thick It can be substituted or non-substituted for closing miscellaneous bicyclic group, and wherein substituent group can be, but is not limited to, hydrogen, aminoalkyl, aminoacyl Base, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, Alkoxyl, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, Aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Term " bridge bicyclic group " represents saturation or undersaturated bridged-ring system, is related to the bicyclic system of non-aromatic.This The system of sample can comprise independent or conjugation undersaturated condition, but its core texture does not comprise aromatic rings or heteroaryl groups (but aromatic series can be used as substituent group thereon).Each of which member ring systems comprise 3-7 atom, such example bag Include, but be not limited to, bicyclic [2.2.1] heptane base, 2- methyl-miscellaneous bicyclo- [2.2.1] heptane base, etc..And described bridge is bicyclic Base can be substituted or non-substituted, and wherein substituent group can be, but is not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkoxyl, Alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, Hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Term " the miscellaneous bicyclic group of bridge " represents saturation or undersaturated bridged-ring system, is related to the bicyclic system of non-aromatic. Depending on structure, " the miscellaneous bicyclic group of bridge " can be monoradical or divalent group, that is, in certain embodiments of the present invention, can replace Generation or use as the miscellaneous bicyclic group of sub- bridge.Such system can comprise independent or conjugation undersaturated condition, but its core Structure does not comprise aromatic rings or heteroaromatic (but aromatic series can be used as substituent group thereon).And at least one member ring systems comprises One or more hetero atoms, each of which member ring systems comprise 3-7 atom, that is, comprise 1-6 carbon atom and be selected from N, O, P, S 1-3 hetero atom, optionally replaced by one or more oxygen atoms in this S or P and obtain as SO, SO2, PO, PO2Group, In addition, carbon atom can also be by oxo formation-C=O-；Such example includes, but is not limited to 2- oxygen -5- azabicyclo [2.2.1] heptane base, 2- thio -5- azabicyclo [2.2.1] heptane base, 2- oxo -5- azabicyclo [2.2.1] heptane base, 2,5- diazabicylos [2.2.1] heptane base, 2- methyl -2,5- diazabicylo [2.2.1] heptane base etc..And described bridge is miscellaneous Bicyclic group can be substituted or non-substituted, and wherein substituent group can be, but is not limited to, hydrogen, aminoalkyl, aminoacyl, Oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkane Epoxide, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, virtue Epoxide, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Term " cycloalkyl-alkyl " refers to alkyl by one or more cycloalkyl substituted, wherein, alkyl and group of naphthene base There is implication as described in the present invention, wherein embodiment may be, but not limited to, Cvclopropvlmethvl, cyclohexyl methyl, cyclohexyl Ethyl etc..
Term " cycloheteroalkylalkyl " refers to that alkyl is replaced by one or more heterocyclic radicals, wherein, alkyl and heterocyclyl groups There is implication as described in the present invention, wherein embodiment may be, but not limited to, ring propoxy methyl, morpholinyl methyl, piperidines Base ethyl etc..
Term " cycloalkyl oxy " or " carbocylic radical epoxide " include optionally substituted cycloalkyl or carbocylic radical, as institute of the present invention Definition, it is connected on oxygen atom, and is connected with remaining molecule by oxygen atom, such example includes, but is not limited to ring Propyl group epoxide, cyclopentyloxy, cyclohexyl epoxide, cyclopropyl epoxide that hydroxyl replaces etc..
Term " cycloalkyl amino " represents that amino group is replaced by one or two group of naphthene base, wherein cycloalkyl tool There is implication as described in the present invention, such example includes, but is not limited to cyclopropylamino, clopentylamino, cyclohexyl ammonia Base, the cyclopropylamino that hydroxyl replaces, dicyclohexyl amino, Bicyclopropyl amino etc..
Term " alkoxy aryl " represents that alkoxy base is replaced by one or more aryl, wherein aryl and alkoxyl There is implication of the present invention, such example includes, but is not limited to, Phenylmethoxy, phenyl ethoxy, p-methylphenyl Methoxyl group, phenyl-propoxy etc..
Term " aryl alkane amino " represents that alkylamino radicals are replaced by one or more aromatic yl groups, wherein aryl and alkane Amino has implication of the present invention, and such example includes, but is not limited to, phenyl methylamino, phenylethylamino, phenyl Third amino, p-methylphenyl methylamino etc..
Term " heteroarylalkoxy " represent alkoxy base replaced by one or more heteroaryls, wherein heteroaryl and Alkoxyl has implication of the present invention, and such example includes, but is not limited to, pyridine -2- ylmethoxy, thiazole -2- Base oxethyl, imidazoles -2- base oxethyl, pyrimidine -2-base propoxyl group, pyrimidine -2-base methoxyl group etc.
Term " heteroarylalkylamino " is included heteroarylalkyl group and is connected in other groups by nitrogen-atoms, wherein miscellaneous Aryl alkyl has implication as described in the present invention, and such example includes, but is not limited to, pyridine -2- base methylamino, thiophene Azoles -2- base ethylamino, imidazoles -2- base ethylamino, pyrimidine -2-base third amino, pyrimidine -2-base methylamino etc..
Term " heterocyclylalkoxy " includes the alkoxyl that heterocyclic radical replaces, wherein the remainder phase of oxygen atom and molecule Even；Term " heterocyclic radical alkylamino " includes the alkylamino that heterocyclic radical replaces, and wherein nitrogen-atoms are connected with the remainder of molecule.Its Middle heterocyclic radical, alkoxyl and alkylamino have implication as described in the present invention, and such example includes, but is not limited to, and morpholine- 4- base oxethyl, piperazine -4- base oxethyl, piperidin-4-yl ethylamino etc..
Term " cycloalkyl alkoxy ", or " carbocyclylalkoxy " expression alkoxy base is by one or more cycloalkyl bases Group or carbocylic radical group are replaced, and wherein group of naphthene base or carbocylic radical group and alkoxy base have as described in the present invention Implication, such example includes, but is not limited to, cyclo propyl methoxy, cyclopropylethoxy, cyclopenta ethyoxyl, cyclohexyl Ethyoxyl, cyclohexyl methoxy, cyclopropyl propoxyl group etc..
Term " amino-n-cycloalkyl " or " carbocylic radical alkylamino " represent alkylamino radicals by one or more cycloalkyl bases Group or carbocylic radical group are replaced, and wherein group of naphthene base or carbocylic radical group and alkylamino radicals have as described in the present invention Implication, such example includes, but is not limited to, cyclopropyl methylamino, cyclopropyl ethylamino, cyclopenta ethylamino, cyclohexyl Ethylamino, cyclohexyl-methyl-amino, cyclopropyl propylamino etc..
Term " aryloxy group alkyl epoxide " represent alkoxyl replaced by one or more aryloxy group, wherein alkoxyl and Aryloxy group has implication as described in the present invention, and such example includes, but is not limited to, phenoxy group methoxyl group, benzene oxygen Base oxethyl, Phenoxypropoxy etc..
Term " heteroaryl epoxide alkoxyl " represents that alkoxyl is replaced by one or more heteroaryl epoxide groups, wherein Alkoxyl and heteroaryl epoxide group have implication as described in the present invention, and such example includes, but is not limited to, pyridine radicals Oxymethoxy, pyrimidine radicals epoxide ethyoxyl, thiazolyl epoxide propoxyl group etc..
Term " aryloxy group " or " aryloxy " include optionally substituted aryl, as defined herein, are connected to oxygen On atom, and it is connected with molecule remainder by oxygen atom, wherein aromatic yl group has implication as described in the present invention, so Example include, but is not limited to, phenoxy group, toloxyl, ethylbenzene epoxide etc..
Term " heteroaryl epoxide " includes optionally substituted heteroaryl, as defined herein, is connected on oxygen atom, And it is connected with molecule remainder by oxygen atom, wherein heteroaryl groups have implication as described in the present invention, such reality Example includes, but is not limited to, pyridine -2- epoxide, thiazole -2- epoxide, imidazoles -2- epoxide, pyrimidine -2- epoxide etc..
Term " heterocyclic radical epoxide alkoxyl " represents that alkoxyl is replaced by one or more heterocyclic radical epoxide groups, wherein Alkoxyl and heterocyclic radical epoxide group have implication as described in the present invention, and such example includes, but is not limited to, and pyrroles- 2- Oxymethoxy, pyrroles's -3- epoxide ethyoxyl, piperidines -2- epoxide ethyoxyl, piperidines -3- epoxide ethyoxyl, piperazine -2- oxygen Ylmethoxy, piperidines -4- epoxide ethyoxyl etc..
Term " carbocylic radical epoxide alkoxyl " represents that alkoxyl is replaced by one or more carbocylic radical epoxide groups, wherein Alkoxyl and carbocylic radical epoxide group have implication as described in the present invention, and such example includes, but is not limited to, cyclopropyl Oxymethoxy, cyclopropyl epoxide ethyoxyl, cyclopentyloxy ethyoxyl, cyclohexyl epoxide ethyoxyl, cyclohexenyl group -3- epoxide Ethyoxyl etc..
Term " heterocyclic radical epoxide " includes optionally substituted heterocyclic radical, as defined herein, is connected on oxygen atom, Wherein oxygen atom is connected with the remainder of molecule, and such example includes, but is not limited to, pyrroles's -2- epoxide, pyrroles -3- Epoxide, piperidines -2- epoxide, piperidines -3- epoxide, piperazine -2- epoxide, piperidines -4- epoxide etc..
Term " condensed-bicyclic base epoxide " includes optionally substituted condensed-bicyclic base, as defined in the present invention, is connected to On oxygen atom, and it is connected with molecule remainder by oxygen atom, such example includes, but is not limited to, 1,2,3,4,4a, 5,8,8a- octahydro naphthyl epoxides, condensed-bicyclic [3.3.0] octane -2- epoxide, condensed-bicyclic [3.1.0] hexane -2- epoxide etc..
Term " condensing miscellaneous bicyclic group epoxide " includes optionally substituted condensing miscellaneous bicyclic group, as defined in the present invention, even It is connected on oxygen atom, and is connected with molecule remainder by oxygen atom, such example includes, but is not limited to, hexahydro- Furo [3,2-b] furan -2- base epoxide, 7- azabicyclo [2.3.0] heptane -2- base epoxide, 7- azabicyclo [2.3.0] heptan Alkane -4- base epoxide etc..
Term " condensed-bicyclic base amino " represents that amino group is replaced by one or two condensed-bicyclic base, wherein condenses Bicyclic group has implication as described in the present invention, and such example includes, but is not limited to, 1,2,3,4,4a, 5,8,8a- octahydros Naphthyl-amino, two (1,2,3,4,4a, 5,8,8a- octahydro naphthyl) amino, condensed-bicyclic [3.3.0] octyl amino, condense double Ring [3.1.0] hexyl amino etc..
Term " condensing miscellaneous bicyclic group amino " represents that amino group is condensed miscellaneous bicyclic group by one or two and replaces, wherein Condense miscellaneous bicyclic group and there is implication as described in the present invention, such example includes, but is not limited to, hexahydro-furo [3,2-b] Furan -2- base amino, 7- azabicyclo [2.3.0] heptane -2- base amino, 7- azabicyclo [2.3.0] heptane -4- base amino Deng.
Term " condensed-bicyclic base alkylamino " represents that alkylamino radicals are replaced by one or two condensed-bicyclic base, wherein Condensed-bicyclic base has implication as described in the present invention, and such example includes, but is not limited to, and 1,2,3,4,4a, 5,8,8a- Octahydro napthylmethylamino, two (1,2,3,4,4a, 5,8,8a- octahydro naphthyl) methylamino, condensed-bicyclic [3.3.0] octyl first ammonia Base, condensed-bicyclic [3.1.0] hexyl methylamino etc..
Term " condensing miscellaneous bicyclic group alkylamino " represents that alkylamino radicals are condensed miscellaneous bicyclic group by one or two and replace, Wherein condense miscellaneous bicyclic group and there is implication as described in the present invention, such example includes, but is not limited to, hexahydro-furo [3, 2-b] furan -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 " represents that alkoxyl is replaced by one or more condensed-bicyclic base groups, wherein Alkoxyl and condensed-bicyclic base have implication as described in the present invention, and such example includes, but is not limited to, and 1,2,3,4, 4a, 5,8,8a- octahydro naphthylmethoxy, 1,2,3,4,4a, 5,8,8a- octahydro naphthyl ethyoxyls, condensed-bicyclic [3.3.0] is pungent Alkane-ethyoxyl, condensed-bicyclic [3.1.0] hexane-propoxyl group etc..
Term " condensing miscellaneous bicyclic group alkoxyl " represents that alkoxyl is condensed miscellaneous bicyclic group group and replaces by one or more, Wherein alkoxyl and condense miscellaneous bicyclic group there is implication as described in the present invention, such example includes, but is not limited to, and six Hydrogen-furo [3,2-b] furan -2- base propoxyl group, 7- azabicyclo [2.2.1] heptane -2- base oxethyl, 7- azabicyclo [2.3.0] heptane -4- base propoxyl group, hexahydro-furo [3,2-b] furan -2- base oxethyl, 7- azabicyclo [2.3.0] heptane - 2- base propoxyl group, 7- azabicyclo [2.3.0] heptane -4- base oxethyl etc..
Term " condensed-bicyclic base alkyl " represents that alkyl is replaced by one or more condensed-bicyclic base groups, wherein alkyl With condensed-bicyclic base, there is implication as described in the present invention, such example includes, 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, condense Bicyclic [3.1.0] hexane-propyl group etc..
Term " condensing miscellaneous bicyclic group alkyl " represents that alkyl is condensed miscellaneous bicyclic group group and replaces by one or more, wherein Alkyl and condense miscellaneous bicyclic group and have implication as described in the present invention, such example includes, but is not limited to, hexahydro-furo [3,2-b] furan -2- base propyl group, 7- azabicyclo [2.2.1] heptane -2- base ethyl, 7- azabicyclo [2.3.0] heptane -4- Base propyl group, hexahydro-furo [3,2-b] furan -2- base ethyl, 7- azabicyclo [2.3.0] heptane -2- base propyl group, 7- azepine is double Ring [2.3.0] heptane -4- base ethyl etc..
Term " condensing miscellaneous bicyclic group epoxide alkoxyl " represents that alkoxyl is condensed miscellaneous bicyclic group epoxide base by one or more Group is replaced, wherein alkoxyl with condense miscellaneous bicyclic group epoxide there is implication as described in the present invention, such example includes, but It is not limited to, hexahydro-furo [3,2-b] furan -2- base epoxide propoxyl group, 7- azabicyclo [2.2.1] heptane -2- base epoxide second Epoxide, 7- azabicyclo [2.3.0] heptane -4- base epoxide propoxyl group, hexahydro-furo [3,2-b] furan -2- base epoxide ethoxy Base, 7- azabicyclo [2.3.0] heptane -2- base epoxide propoxyl group, 7- azabicyclo [2.3.0] heptane -4- base epoxide ethyoxyl Deng.
Term " condensing miscellaneous bicyclic group epoxide alkylamino " represents that alkylamino is condensed miscellaneous bicyclic group epoxide base by one or more Group is replaced, wherein alkylamino with condense miscellaneous bicyclic group epoxide there is implication as described in the present invention, such example includes, but It is not limited to, hexahydro-furo [3,2-b] furan -2- base epoxide the third amino, 7- azabicyclo [2.2.1] heptane -2- base epoxide second Amino, 7- azabicyclo [2.3.0] heptane -4- base epoxide the third amino, hexahydro-furo [3,2-b] furan -2- base epoxide second ammonia Base, 7- azabicyclo [2.3.0] heptane -2- base epoxide the third amino, 7- azabicyclo [2.3.0] heptane -4- base epoxide ethylamino Deng.
Term " bridge miscellaneous bicyclic group alkoxyl " represents that alkoxy base is replaced by the miscellaneous bicyclic group of one or more bridges, wherein The miscellaneous bicyclic group of bridge and alkoxy base have implication as described in the present invention, and such example includes, but is not limited to, and 2- oxygen- 5- azabicyclo [2.2.1] heptane ylmethoxy, 2,5- diazabicylos [2.2.1] heptane base oxethyl, 2- methyl -2,5- bis- Azabicyclic [2.2.1] heptane base propoxyl group etc..
Term " bridge miscellaneous bicyclic group alkyl " represents that alkyl group is replaced by the miscellaneous bicyclic group of one or more bridges, and its jackshaft is miscellaneous Bicyclic group and alkyl group have implication as described in the present invention, and such example includes, but is not limited to, 2- oxygen -5- azepine Bicyclic [2.2.1] heptane ylmethyl, 2,5- diazabicylos [2.2.1] heptane base ethyl, 2- methyl -2,5- diazabicylo [2.2.1] heptane base propyl group etc..
Term " bridge miscellaneous bicyclic group alkylamino " represents that alkylamino radicals are replaced by the miscellaneous bicyclic group of one or more bridges, wherein The miscellaneous bicyclic group of bridge and alkylamino radicals have implication as described in the present invention, and such example includes, but is not limited to, and 2- oxygen- 5- azabicyclo [2.2.1] heptane base methylamino, 2,5- diazabicylos [2.2.1] heptane base ethylamino, 2- methyl -2,5- bis- Azabicyclic [2.2.1] heptane base third amino etc..
Term " bridge miscellaneous bicyclic group epoxide " includes the miscellaneous bicyclic group of optionally substituted bridge, as defined in the present invention, is connected to On oxygen atom, and it is connected with molecule remainder by oxygen atom, such example includes, but is not limited to, 2- methyl -2,5- Diazabicylo [2.2.1] alkyl oxy in heptan, 2,5- diazabicylos [2.2.1] alkyl oxy in heptan etc..
Term " aryl alkyl " represents that alkyl group is replaced by one or more aromatic yl groups, wherein alkyl group and virtue Base group has implication as described in the present invention, and such example includes, but is not limited to phenethyl, and benzyl, to toluene second Base, etc..
Term " heteroaryl alkyl " represents that alkyl group is replaced by one or more heteroaryl groups, wherein alkyl group With heteroaryl groups, there is implication as described in the present invention, such example includes, but is not limited to, pyridine -2- ethyl, thiophene Azoles -2- methyl, imidazoles -2- ethyl, pyrimidine -2- propyl group etc..
Term " alkylthio group " includes C1-10The alkyl of straight or branched is connected on the sulphur atom of bivalence, wherein alkyl group There is implication as described in the present invention.Some of them embodiment is that alkylthio group is the C of lower level1-3Alkylthio group, such example Include, but is not limited to, methyl mercapto (CH3S-), ethylmercapto group etc..
Term " aminoacyl " refers to-C (=O) NH2.
Term " alkyl-C (=O) NH- " includes C1-10The alkyl of straight or branched is connected on-C (=O) NH-, wherein alkane Base group has implication as described in the present invention.Such example includes, but is not limited to, acetamido (CH3C (=O) NH-), propionamido- (C2H5C (=O) NH-) etc..
Term " volution base ", " volution ", " spiral shell bicyclic group ", it is special on another ring that " spiral shell is bicyclic " represents that a ring originates from Ring-type carbon.For example, as disclosed below, the bridged-ring system (ring B and B ') of a saturation is referred to as " condensed-bicyclic ", otherwise Ring A and ring B shares a carbon atom in the member ring systems of two saturations, then be referred to as " volution ".Each ring inside volution Or be carbocyclic ring be miscellaneous alicyclic.Such example includes, but is 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 Base -5- azaspiro [2.4] heptane -5- base etc..And described spiral shell bicyclic group can be substituted or non-substituted, and wherein substituent group can To be, but it is not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkane Base, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkoxyl, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, Heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, Phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Term " the miscellaneous bicyclic group of spiral shell " represents that a ring originates from particularly ring-shaped carbon on another ring.For example, as institute above Description, the bridged-ring system (ring B and B ') of a saturation is referred to as " condensed-bicyclic ", otherwise ring A and ring B is in the ring of two saturations Share a carbon atom in system, be then referred to as " volution ".And at least one member ring systems comprises one or more hetero atoms, wherein Each member ring systems comprises 3-7 atom, that is, comprise 1-6 carbon atom and be selected from N, the 1-3 hetero atom of O, P, S, in this S or P is optionally replaced by one or more oxygen atoms and obtains as SO, SO2, PO, PO2Group, such example includes, but not It is limited to 4- azaspiro [2.4] heptane base, 4- oxaspiro [2.4] heptane base, 5- azaspiro [2.4] heptane base, 7- hydroxyl -5- azepine Spiral shell [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 bases, 2- sulfur -6- azepine spiroheptane base 2- mono- Oxide, 2- sulfur -6- azepine spiroheptane base 2,2- dioxide etc..And the miscellaneous bicyclic group of described spiral shell can be replace or Non-substituted, wherein substituent group can be, but is not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, Iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkoxyl, alkylamino, alkylthio group, Halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkane Base-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Term " spiral shell miscellaneous bicyclic group alkoxyl " represents that alkoxy base is replaced by the miscellaneous bicyclic group of one or more spiral shells, wherein The miscellaneous bicyclic group of spiral shell and alkoxy base have implication as described in the present invention, and such example includes, but is not limited to, 4- azepine Spiral shell [2.4] heptane -5- ylmethoxy, 4- azaspiro [2.4] heptane -2- base oxethyl, 4- oxaspiro [2.4] heptane -5- base second Epoxide, 5- azaspiro [2.4] heptane -5- base propoxyl group etc..
Term " spiral shell miscellaneous bicyclic group alkyl " represents that alkyl group is replaced by the miscellaneous bicyclic group of one or more spiral shells, and wherein spiral shell is miscellaneous Bicyclic group and alkyl group have implication as described in the present invention, and such example includes, but is not limited to, 4- azaspiro [2.4] heptane -5- ylmethyl, 4- azaspiro [2.4] heptane -2- base ethyl, 4- oxaspiro [2.4] heptane -5- base ethyl, 5- nitrogen Miscellaneous spiral shell [2.4] heptane -5- base propyl group etc..
" antiproliferative " refers to antimetabolite (for example, 5- fluoro-uracil, methotrexate, fludarabine), anti-micro- Pipe agent (for example, Vinca alkaloids such as vincristine, vincaleucoblastine, taxane such as paclitaxel, polyenoid taxol), alkylation examination Agent (such as cyclophosphamide, melphalan, carmustine, nitroso ureas such as double chlorethylnitrosoureas and hydroxyurea), platinum reagent are (for example Cisplatin, NSC-241240, Oxalipratin, JM-216, Cl-973), anthracyclines (such as doxrubicin, rubidomycin), Antitumor antibiotics (such as mitomycin, jaundice element, amycin, rubidomycin), topoisomerase inhibitors (for example sufficient leaf second Glycoside, camptothecine), anti-angiogenic agent (such as and Bevacizumab) or any cytotoxic agent (estramustine phosphate, sprinkle Buddhist nun Chlormethine), hormone or hormone agonist, antagonist, partial agonist agent or topical antagonist, kinase inhibitor and radiation control Treat.
As described in the present invention, substituent R is bonded, by one, the member ring systems formed on the ring at the center of being connected to and represents substituent R Can any on ring may replace or any rational position is replaced.For example, formula a represents any possible quilt on A ring or B ring The position replacing all can be replaced by R, such as formula b, formula c, formula d, formula e, formula f, formula g, and shown in formula h.
As described in the present invention, substituent group (R)nBy one, the member ring systems formed are bonded on the ring at the center of being connected to and represent n Substituent R can be replaced any commutable position on ring.For example, formula i represents and any on A ring or B ring may be taken The position in generation all can be replaced by n R.
As described in the invention, ring C there are two junction points can be connected with molecule remainder, for example, as formula j institute Show, expression both can be E end can also be that E ' end is connected with the remainder of molecule, and that is, the connected mode at two ends can be exchanged.
As described in the present invention, attachment point can be connected with molecule remainder any attachable position on ring.Example As formula k represents any position that may be connected on A ring or B ring all can be used as the point connecting.
As described in the present invention, attachment point can be connected with molecule remainder any attachable position on ring, with When the two ends that connect can exchange.For example, formula y represent any position that may be connected on ring all can as the point connecting, with When junction point two ends can exchange.
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode that herein adopts in the whole text " each ... and ... independently be ", " ... and ... be each independently " and " ... with ... separately for " can be exchanged, and should do Broadly understood, it both may refer in different groups, does not affect mutually between same-sign between expressed concrete option, Can also represent in identical group, not affect mutually between expressed concrete option between same-sign.For example, structure The concrete option of formula l and structural formula m each G between the two is unaffected from each other, meanwhile, in same structure formula, such as formula 1 is many The concrete option of individual G is unaffected each other；The concrete option of multiple n is unaffected each other；Or as formula m, multiple G's Concrete option is unaffected from each other；The concrete option of multiple n is unaffected from each other.
The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to documents below：S.P.Parker,Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley＆Sons, Inc., New York, the compound of 1994. present invention can comprise asymmetric center or chiral centre, therefore There are different stereoisomers.The all of stereoisomeric forms in any ratio of compound of the present invention, including but not limited to, diastereomeric Body, enantiomer, atropisomer, and their mixture, such as racemic mixture, constitute the part of the present invention. A lot of organic compound are all existed with optical active forms, i.e. the plane of their capable Plane of rotation polarized light.In description light When learning reactive compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use Come to name compound linearly polarized light rotation symbol, (-) or l refer to that compound is left-handed, prefix (+) or d refer to chemical combination Thing is dextrorotation.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.Specifically stand Body isomer can be enantiomer, and the mixture of isomer is commonly referred to enantiomeric mixture.50:50 enantiomer mixing Thing is referred to as racemic mixture or racemic modification, and this may lead to do not have stereo selectivity or three-dimensional fixed in chemical reaction process Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack light Learn activity.
The isomerss of term " tautomer " or " tautomeric form " expression different-energy can pass through relatively low The mutual inversion of phases of energy barrier.Such example includes, but is not limited to, and proton tautomer (i.e. prototropic change isomer) includes The isomerization of the change being migrated by proton, such as keto-enol and imine-enamine.Atomicity tautomer bag Include 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 includes chemical quantity or non-chemically The water that equivalent is combined by non-covalent intermolecular forces, also can say it is the associated complex that solvent molecule is water is formed.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention is formed Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.
" ester " of the present invention refers to that the formula containing hydroxyl (I) or formula (II) compound can form hydrolyzable ester in vivo.This The ester of sample is the pharmaceutically acceptable ester that hydrolysis produces parent alcohol for example in human or animal's body.Formula containing hydroxyl (I) or In formula (II) compound body, the group of hydrolyzable ester includes, but not limited to phosphate, acetoxymethoxy, 2,2- diformazans Base propionyloxy methoxyl group, alkanoyl, benzoyl, benzene first and second acyl group, alkoxy carbonyl, dialkyl carbamoyl and N- (di-alkyaminoethyl group)-N- alkyl-carbamoyl etc..
" nitrogen oxides " of the present invention refer to when compound contains several amine functional group, can 1 or former more than the nitrogen of 1 Son oxidation forms N- oxide.The particular example of N- oxide is the N- oxide of tertiary amine or the N- oxidation of nitrogen heterocyclic ring nitrogen-atoms Thing.Available oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) process corresponding amine formed N- oxide (referring to Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages).Especially It is that N- oxide can be prepared (Syn.Comm.1977,7,509-514) with the method for L.W.Deady, wherein for example molten in inertia In agent such as dichloromethane, amines are made to react with m- chloroperoxybenzoic acid (MCPBA).
Compound there may be multiple difference geometric isomers and tautomer, described formula (I) or formula (II) compound bag Include all such forms.For avoid feel uncertain, when compound with one of several geometric isomers or tautomer exist and only It is clear that all other form is included in formula (I) or formula (II) when specifically describing or showing a kind of.
Term " prodrug " used in the present invention, represents a compound and is converted in vivo shown in formula (I) or formula (II) Compound.Such conversion is hydrolyzed in blood by prodrug or is precursor structure through enzymatic conversion in blood or tissue Impact.Pro-drug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester as prodrug Class, aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamatess and amino acid esters.The such as present invention In a compound comprise hydroxyl, you can be acylated the compound obtaining prodrug form.Other prodrug Form includes phosphate ester, and such as these phosphate compounds are to obtain through the di on parent.With regard to prodrug Complete discussion may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.
Unless other aspects show, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless other aspects show, the structural formula of compound described in the invention includes one or more different former The enriched isotope of son.
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention Adopt as stating and experimentally characterized.Such product can be by being administered compound through peroxidating, reducing, water Solution, amidated, desamido- acts on, esterification, degreasing, and enzymatic lysises etc. method obtains.Correspondingly, the present invention includes compound Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.
The various pharmaceutically acceptable salt forms of the compounds of this invention are all useful.Term is " pharmaceutically acceptable Salt " refers to that those salt forms are it will be apparent that being that they are substantially nontoxic and be provided that required for pharmaceutical chemistry man Pharmacokinetic property, palatability, absorption, distribution, metabolism or excretion.Other factors, more practical in nature, for choosing Select also critically important, these are：The stream of the cost of raw material, easy, yield, stability, the hygroscopicity of crystallization and result crude drug Dynamic property.Simply, pharmaceutical composition can be prepared with pharmaceutically acceptable carrier by effective ingredient.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt of compound and the inorganic salt of the present invention.Medicine On, acceptable salt is known to us in art, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66: 1-19,1977. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion exchange is obtaining these salt.Other pharmaceutically acceptable salts include adipate, 2 hydroxy propanoic acid Salt, alginate, Ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora Hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, anti-fourth Enedioic acid salt, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- Hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, first sulphur Hydrochlorate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenyl Propionate, picrate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valeric acid Salt, etc..Alkali metal, alkaline-earth metal, ammonium and N are included by the salt that suitable alkali obtains+(C1-4Alkyl)4Salt.The present invention The quaternary ammonium salt that the compound of the group that plan contemplates any comprised N is formed.Water solublity or oil-soluble or dispersion product are permissible Obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt Further include the amine cation that suitable, nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, Carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.Amine salt, such as but not limited to N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkyl amine, ethylenediamine, N- methyl reduces Glycosamine, procaine, N- benzyl-1-phenylethylamine, 1- p- chlorobenzyl -2- pyrrolidine -1 '-ylmethyl-benzimidazole, diethylamine and Other alkylamines, piperazine and three (methylol) aminomethane；Alkali salt, such as but not limited to barium, calcium and magnesium；Transition metal Salt, such as but not limited to zinc.
When term " blocking group " or " Pg " refer to a substituent group and other reacted with functional groups, it is commonly used to hinder Feature disconnected or that protection is special.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or in protection compound amino feature, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to the replacement of hydroxyl Base is used for blocking or protect the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl-protecting group Group " refers to the substituent group of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group refers to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
In this manual, if there is any difference between chemical name and chemical constitution, structure is dominant.
The abbreviation of any blocking group used in the present invention, aminoacid and other compound, unless otherwise stated, all with Abbreviation that they are usually used, generally acknowledging is defined, or with reference to IUPAC-IUBCommission on Biochemical Nomenclature (referring to Biochem.1972,11：942-944).
The description of the compounds of this invention
On the one hand, a kind of substituted carbamide derivative that the present invention provides, it is the chemical combination with the structure as shown in formula (I) Thing, or the stereoisomer of the compound shown in formula (I), geometric isomer, tautomer, nitrogen oxides, hydrate, solvent Compound, metabolite, ester, pharmaceutically acceptable salt or its prodrug,
Wherein：
K ring is the heteroaryl groups of 5-6 unit；
Q and W is each independently CH or N；
Each L independently is amino, nitro, alkylthio group, alkyl, cycloalkyl, heterocyclic radical, haloalkyl, alkyl amino, hydroxyl Base, fluorine, chlorine, bromine, iodine, alkyl-C (=O)-NH-, alkoxyl, hydroxy alkyl or cyano group；
Each R1It independently is hydrogen, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-6Alkane Epoxide C1-6Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, C1-4Alkyl-C (=O)-NH-, C1-4Alkoxyl, hydroxyl C1-4Alkane Base or C1-4Alkylthio group；
E ring is bicyclic heteroaryl group or tricyclic heteroaryl group；In wherein said heteroaryl groups at least 2 miscellaneous Atom, each hetero atom independently is O, S, NR4Or N；
Each R4It independently is hydrogen, haloalkyl, alkyl-C (=O)-, alkoxyalkyl, hydroxy alkyl, benzyl, cycloalkyl, Heterocyclic radical or alkyl；
Each J independently is-G- (CH2)n-R；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R independently is hydrogen ,-NR3R2, alkoxyl, alkyl, thiazolinyl, alkynyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, Cycloheteroalkylalkyl, heterocyclic radical, alkyl-S (=O)t-, alkoxyalkyl, hydroxy alkyl, hydroxy alkoxy base, aminoalkoxy, halogen For alkoxyl, alkylamino halogenated alkoxy, alkylaminoalkoxy, alkyloxy-alkoxy, alkoxy aryl, aryl alkane amino, miscellaneous Alkoxy aryl, heteroarylalkylamino, heterocyclic radical alkylamino, cycloalkyl oxy, cycloalkyl amino, heterocyclylalkoxy, carbocyclic ring Base alkoxyl, carbocylic radical alkylamino, aryloxy group alkyl epoxide, aryloxy group, heteroaryl epoxide, heteroaryl epoxide alkoxyl, heterocyclic radical Epoxide alkoxyl, carbocylic radical epoxide alkoxyl, heterocyclic radical epoxide, condensed-bicyclic base epoxide, condensed-bicyclic base alkyl, condense miscellaneous double Cyclylalkyl, condenses miscellaneous bicyclic group epoxide, condenses miscellaneous bicyclic group amino, condenses miscellaneous bicyclic group alkoxyl, condenses miscellaneous bicyclic group alkane Amino, condenses miscellaneous bicyclic group epoxide alkoxyl, condenses miscellaneous bicyclic group epoxide alkylamino, spiral shell miscellaneous bicyclic group alkyl, the miscellaneous bicyclic group of spiral shell Alkoxyl, bridge miscellaneous bicyclic group alkyl, bridge miscellaneous bicyclic group epoxide, bridge miscellaneous bicyclic group alkoxyl, bridge miscellaneous bicyclic group alkylamino, aryl, Aryl alkyl, heteroaryl alkyl, heteroaryl, the miscellaneous bicyclic group of bridge, the miscellaneous bicyclic group of spiral shell or condense miscellaneous bicyclic group；
Each R3And R2It independently is alkyl, haloalkyl, cycloalkyl, heterocyclic radical, alkoxyalkyl or hydroxy alkyl；
Each n independently is 1,2,3 or 4；
Each t independently is 0,1 or 2；
Each e independently is 0,1,2,3 or 4；
Each d independently is 1,2,3 or 4；
Each a independently is 0,1,2,3 or 4；
Each b independently is 2,3 or 4；
Wherein, described aryl, bicyclic heteroaryl group, tricyclic heteroaryl group, heteroaryl groups, alkoxyalkyl, Alkoxyl ,-G- (CH2)n- R ,-(O- (CH2)n)e- O- ,-(CH2)n- C (=O)-, alkyl-S (=O)t-, hydroxy alkyl, aryl alkane Base, heteroaryl alkyl, heteroaryl, heterocyclic radical, the miscellaneous bicyclic group of bridge, the miscellaneous bicyclic group of spiral shell, condense miscellaneous bicyclic group, alkyl, haloalkyl, Alkyl amino, hydroxy alkoxy base, aminoalkoxy, halogenated alkoxy, thiazolinyl, alkynyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, alkane Base-C (=O)-, benzyl, alkylamino halogenated alkoxy, alkylaminoalkoxy, alkyloxy-alkoxy, alkoxy aryl, aryl alkane Amino, heteroarylalkoxy, heteroarylalkylamino, heterocyclic radical alkylamino, cycloalkyl oxy, cycloalkyl amino, heterocyclylalkoxy Base, carbocyclylalkoxy, carbocylic radical alkylamino, aryloxy group alkyl epoxide, aryloxy group, heteroaryl epoxide, heteroaryl epoxide alkoxyl, Heterocyclic radical epoxide alkoxyl, carbocylic radical epoxide alkoxyl, heterocyclic radical epoxide, condensed-bicyclic base epoxide, condensed-bicyclic base alkyl is thick Close miscellaneous bicyclic group alkyl, condense miscellaneous bicyclic group epoxide, condense miscellaneous bicyclic group amino, condense miscellaneous bicyclic group alkoxyl, condense miscellaneous double Ring group alkylamino, condenses miscellaneous bicyclic group epoxide alkoxyl, condenses miscellaneous bicyclic group epoxide alkylamino, spiral shell miscellaneous bicyclic group alkyl, spiral shell is miscellaneous Bicyclic group alkoxyl, bridge miscellaneous bicyclic group alkyl, bridge miscellaneous bicyclic group epoxide, bridge miscellaneous bicyclic group alkoxyl, bridge miscellaneous bicyclic group alkylamino, Alkyl-C (=O)-NH-, alkylthio group, cycloalkyl and described B ring, can be independently by hydrogen, aminoalkyl, aminoacyl, fluorine, Chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)- NH-, oxo (=O), C1-4Alkyl-C (=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, wherein, described E ring is one of heteroaryl groups that following subformula is formed：
Wherein, X, Y, Z, Z1, Z2, Z3And Z4It is each independently N or CH；
T and T1It is each independently-O- ,-S- ,-NR4- or-CH2-；
Wherein, each R4It independently is H, C1-4Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or Hydroxyl C1-4Alkyl；
Each J independently is-G- (CH2)n-R；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R independently is hydrogen ,-NR3R2, C2-4Thiazolinyl, C2-4Alkynyl, C3-10Cycloalkyl, C3-10Cycloalkyl C1-4Alkyl, C2-10 Heterocyclic radical C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-6Alkoxy C1-6Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxyl, ammonia Base C1-4Alkoxyl, halo C1-4Alkoxyl, C1-4Alkylamino halo C1-4Alkoxyl, C1-4Alkylamino C1-4Alkoxyl, C1-4Alkoxyl C1-4Alkoxyl, C6-10Aryl C1-4Alkoxyl, C6-10Aryl C1-4Alkylamino, C1-9Heteroaryl C1-4Alkoxyl, C1-9Heteroaryl C1-4 Alkylamino, C2-10Heterocyclic radical C1-4Alkylamino, C3-10Cycloalkyl oxy, C3-10Cycloalkyl amino, C2-10Heterocyclic radical C1-4Alkoxyl, C3-10Carbocylic radical C1-4Alkoxyl, C3-10Carbocylic radical C1-4Alkylamino, C6-10Aryloxy group C1-4Alkoxyl, C6-10Aryloxy group, C1-9Heteroaryl Base epoxide, C1-9Heteroaryl epoxide C1-4Alkoxyl, C2-10Heterocyclic radical epoxide C1-4Alkoxyl, C3-10Carbocylic radical epoxide C1-4Alkoxyl, C2-10Heterocyclic radical epoxide, C1-4Alkoxyl, C1-4Alkyl, C1-4Haloalkyl, C6-10Aryl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl Base C1-6Alkyl, C1-9Heteroaryl,
Or each R independently is following subformula：
Wherein, each X8, X9And X10It independently is N or CH；
Each X1, X2, X3, X4, X5, X6And X7It independently is-CH2- ,-O- ,-NR4a- ,-S (=O)t- or-S-；
Each q, m, p, r and s independently are 0,1,2,3 or 4；
Each R3And R2It independently is C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Each R4aIt independently is H, C1-4Alkyl, C1-4Alkyl-C (=O)-, benzyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described B ring, E ring and each R, all can be independently by hydrogen, aminoalkyl, ammonia Base acyl group, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C1-4Alkyl-C (=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is many Replace.
In other embodiments, E ring of the present invention be the heteroaryl groups that formed of following subformula it One：
Each J independently is-G- (CH2)n-R；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R independently is hydrogen ,-NR3R2, C2-4Thiazolinyl, C2-4Alkynyl, C2-10Heterocyclic radical C1-4Alkyl, C1-6Alkyl-S (=O )t-, C1-4Alkoxy C1-4Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxyl, amino C1-4Alkoxyl, halo C1-4Alkoxyl, C1-4Alkylamino halo C1-4Alkoxyl, C1-4Alkylamino C1-4Alkoxyl, C1-4Alkoxy C1-4Alkoxyl, C1-4Alkoxyl, C1-4Alkane Base, C1-4Haloalkyl, C1-9Heteroaryl C1-6Alkyl,
Or each R independently is following subformula：
Each R3And R2It independently is methyl, ethyl, propyl group, isopropyl, the tert-butyl group, amyl group, isopentyl, cyclopropyl, ring penta Base, cyclohexyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described B ring, E ring and each R, all can be independently by hydrogen, aminoalkyl, ammonia Base acyl group, fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, propyl group, isopropyl, dimethylamino, Methylamino, diethylamino, ethylamino, hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-, ethyl group-C (=O)-, propyl-C (=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, the heteroaryl groups that the subformula that K ring of the present invention is as follows is formed One of：
Each L independently is the tert-butyl group.
In some embodiments, substituted carbamide derivative wherein of the present invention, has the change as shown in formula (II) Compound, or the stereoisomer of the compound as shown in formula (II), geometric isomer, tautomer, nitrogen oxides, hydration Thing, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug,
Or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolism is produced Thing, ester, pharmaceutically acceptable salt or its prodrug, wherein：
Q and W is each independently CH or N；
Each R1It independently is hydrogen, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-6Alkane Epoxide C1-6Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, C1-4Alkyl-C (=O)-NH-, C1-4Alkoxyl, hydroxyl C1-4Alkane Base or C1-4Alkylthio group；
E ring is one of heteroaryl groups that following subformula is formed：
Wherein, X, Y, Z, Z1, Z2, Z3And Z4It is each independently N or CH；
T and T1It is each independently-O- ,-S- ,-NR4- or-CH2-；
Wherein, the X on described E ring, Y, Z, T, T1, Z1, Z2, Z3And Z4Two are at least while had to be hetero atom；
Each R4It independently is H, C1-4Alkyl, C1-4Alkyl-C (=O)-, benzyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6 Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R independently is hydrogen ,-NR3R2, C2-4Thiazolinyl, C2-4Alkynyl, C3-10Cycloalkyl, C3-10Cycloalkyl C1-4Alkyl, C2-10 Heterocyclic radical C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-6Alkoxy C1-6Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxyl, ammonia Base C1-4Alkoxyl, halo C1-4Alkoxyl, C1-4Alkylamino halo C1-4Alkoxyl, C1-4Alkylamino C1-4Alkoxyl, C1-4Alkoxyl C1-4Alkoxyl, C3-10Cycloalkyl oxy, C6-10Aryl C1-4Alkoxyl, C6-10Aryl C1-4Alkylamino, C1-9Heteroaryl C1-4Alcoxyl Base, C1-9Heteroaryl C1-4Alkylamino, C2-10Heterocyclic radical C1-4Alkylamino, C3-10Cycloalkyl amino, C2-10Heterocyclic radical C1-4Alkoxyl, C3-10Carbocylic radical C1-4Alkoxyl, C3-10Carbocylic radical C1-4Alkylamino, C6-10Aryloxy group C1-4Alkoxyl, C6-10Aryloxy group, C1-9Heteroaryl Base epoxide, C1-9Heteroaryl epoxide C1-4Alkoxyl, C2-10Heterocyclic radical epoxide C1-4Alkoxyl, C3-10Carbocylic radical epoxide C1-4Alkoxyl, C2-10Heterocyclic radical epoxide, C1-4Alkoxyl, C1-4Alkyl, C1-4Haloalkyl, C6-10Aryl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl Base C1-6Alkyl, C1-9Heteroaryl or each R independently are following subformula：
Wherein, each X8, X9And X10It independently is N or CH；
Each X1, X2, X3, X4, X5, X6And X7It independently is-CH2- ,-O- ,-NR4a- ,-S (=O)t- or-S-；
Each q, m, p, r and s independently are 0,1,2,3 or 4；
D is 1；
Each n independently is 1,2,3 or 4；
Each R3And R2It independently is C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Each R4aIt independently is H, C1-4Alkyl, C1-4Alkyl-C (=O)-, benzyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described E ring and each R, all can be independently by hydrogen, aminoalkyl, aminoacyl Base, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C1-4Alkyl-C (=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is many Replace；
Each L independently is the tert-butyl group.
In other embodiments, E ring of the present invention be the heteroaryl groups that formed of following subformula it One：
Wherein, each subformula representated by described E ring all can be independently by hydrogen, aminoalkyl, aminoacyl, fluorine, Chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, propyl group, isopropyl, dimethylamino, methylamino, Diethylamino, ethylamino, hydroxyl, cyano group, nitro, methyl-C (=O)-, ethyl group-C (=O)-, propyl-C (= O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is polysubstituted.
In other embodiments, each G of the present invention independently is-O-；
Each R independently is hydrogen ,-NR3R2, C2-4Thiazolinyl, C2-4Alkynyl, C2-10Heterocyclic radical C1-4Alkyl, C1-6Alkyl-S (=O )t-, C1-4Alkoxy C1-4Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxyl, amino C1-4Alkoxyl, halo C1-4Alkoxyl, C1-4Alkylamino halo C1-4Alkoxyl, C1-4Alkylamino C1-4Alkoxyl, C1-4Alkoxy C1-4Alkoxyl, C1-4Alkoxyl, C1-4Alkane Base, C1-4Haloalkyl, C1-9Heteroaryl C1-6Alkyl,
Or each R independently is following subformula：
Each R3And R2It independently is methyl, ethyl, propyl group, isopropyl, the tert-butyl group, amyl group, isopentyl, cyclopropyl, ring penta Base, cyclohexyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described each R all can be independently by hydrogen, aminoalkyl, aminoacyl, fluorine, Chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, propyl group, isopropyl, dimethylamino, methylamino, Diethylamino, ethylamino, hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-, ethyl group-C (=O)-, third Alkyl-C (=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, substituted carbamide derivative of the present invention, or its stereoisomer, geometrical isomerism Body, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or it before Medicine, has the structure of one of：
On the other hand, present invention also offers a kind of pharmaceutical composition, this pharmaceutical composition comprises of the present inventionization Compound.
In some embodiments, pharmaceutical composition of the present invention, it further comprises pharmaceutically acceptable Carrier, excipient, diluent, at least one in adjuvant and vehicle.
In some embodiments, pharmaceutical composition of the present invention, it further comprises additional therapeutic agent, this A little additional therapeutic agents are chemotherapeutic agent, antiproliferative, anti-inflammatory reagent, immunosuppressant, and immunostimulant, for treating Atherosclerotic medicine, for treating medicine or the combinations thereof of pulmonary fibrosiss.
In other embodiments, pharmaceutical composition of the present invention, wherein said additional therapeutic agent is benzene Butanoic acid chlormethine (chlorambucil), melphalan (melphalan), cyclophosphamide (cyclophosphamide), different ring phosphinylidyne Amine (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), chain urea Assistant rhzomorph (streptozocin), cisplatin (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (methotrexate), fluorouracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinblastine (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), paclitaxel (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), etoposide (etoposide), ET-743 (trabectedin), dactinomycin (dactinomycin), doxorubicin (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analog (gonadorelin analogues), megestrol (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon-ALPHA (interferon alfa), calcium folinate (leucovorin), sirolimuss (sirolimus), temsirolimus (temsirolimus), everolimuses (everolimus), Afatinib (afatinib), alisertib, amuvatinib, A Pa replaces Buddhist nun (apatinib), Axitinib (axitinib), bortezomib (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, gram Zhuo replaces Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Erlotinib (erlotinib), foretinib, ganetespib, gefitinib (gefitinib), ibrutinib, angstrom gram replaces Buddhist nun (icotinib), imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib, Linifanib, linsitinib, Masitinib (masitinib), momelotinib, does not replace husky Buddhist nun (motesanib), comes that For Buddhist nun (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib), relaxes Buddhist nun replace Buddhist nun (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, Trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, Volasertib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), brentuximab vedotin, card Appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), difficult to understand (ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab), or combinations thereof.
On the other hand, the present invention relates to described compound or pharmaceutical composition be used for preventing, process, mitigating in preparation or Treatment patient's proliferative disease, the purposes in the medicine of autoimmune disease or inflammatory diseasess.
In some embodiments, purposes of the present invention, wherein said proliferative disease is acute myeloid leukaemia, slowly Property myelogenous leukemia, gastrointestinal stromal tumors, acute myeloid leukemia (AML), the chronic myelogenous leukemia (CML) of mutation, Acute lymphoblastic leukemia (ALL), colorectal cancer, gastric cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma, carcinoma of prostate, cancer of pancreas, thyroid Cancer, bladder cancer, renal carcinoma, cerebroma, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, Atherosclerosis Change, pulmonary fibrosiss, leukemia, lymphatic cancer, rheumatism, cryoglobulinemia, non-lymphoreticular system tumor, papular glutinous Proteinose, familial splenic anemia, multiple myeloma, amyloidosises, solitary plasmacytoma, heavy chain disease, light chain disease, Malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinaemia, half molecule disease, monocytic leukemia, primary Property macroglobulinemia purpura, Secondary cases benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, non-suddenly Very golden lymphoma, Sezary syndrome, infectious monocytosis, acute histocytic increase disease, Hodgkin lymphoma, Hairy cell leukemia, colon cancer, rectal cancer, polyposis intestinalises, small cell lung cancer, neuroblastoma, neuroendocrine cell swells Tumor, 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 myeloma.
In some embodiments, purposes of the present invention, wherein said autoimmune disease is rheumatic arthritis, wolf Skin ulcer, multiple sclerosiss, thyroiditiss, type i diabetes, sarcoidosises, inflammatory bowel, Crohn's disease or systemic lupus.
In some embodiments, purposes of the present invention, wherein said inflammatory diseasess refer to diverticulitiss, colitis, Pancreatitiss, hepatitis, chronic hepatitiss, liver cirrhosis, cholecystitis, or chronic inflammatory disease.
In some embodiments, purposes of the present invention, wherein said disease is FLT3 mediation or FLT3-ITD causes Disease.
On the other hand, the present invention relates to described compound or pharmaceutical composition preparing for preventing, process, treat or Mitigate patient's proliferative disease, the method for autoimmune disease or inflammatory diseasess, its method comprises to have given this infection or disease Patient's compound as described in the present invention or pharmaceutical composition of the present invention effectively treatment amount.
In some embodiments, method of the present invention, wherein said disease is that FLT3 is kinase mediated or FLT3-ITD The disease that kinases causes.
Unless other aspects show, all of stereoisomer of compound of the present invention, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug broadly fall into the model of the present invention Enclose.Specifically, salt is pharmaceutically acceptable salt." pharmaceutically acceptable " material or compositionss of including of term must be suitable Combination or toxicologically, with other components of composition preparation and relevant for the mammal for the treatment of.The compound of the present invention Salt also include separating for preparation or the intermediate of purification formula (I) or formula (II) compound or formula (I) or formula (II) compound Enantiomer salt, but be not necessarily pharmaceutically acceptable salt.
If the compound of the present invention is alkaline, conceivable salt can be any suitable by provide on document Method prepares, for example, using mineral acid, example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid etc..Or using organic Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, acetone acid, malic acid, Lactic acid citric acid, Oxalic acid, glycolic and salicylic acid；Pyrans saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and winestone Acid；Aminoacid, such as aspartic acid and glutamic acid；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, benzene Sulfonic acid, methanesulfonic acid, ethyl sulfonic acid, trifluoromethanesulfonic acid etc. or combinations thereof.
If the compound of the present invention is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide, ammonium, N+(R14)4Salt and alkaline earth gold Belong to hydroxide, etc..Suitable salt includes, but is not limited to, the organic salt obtaining from aminoacid, such as glycine and smart ammonia Acid, ammonia, such as primaquine, parahelium and tertiary ammonia, N+(R14)4Salt, such as R14It is H, C1-4Alkyl, C6-10Aryl, C6-10Aryl C1-4Alkyl Deng, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, ferrum, copper, zinc, aluminum and lithium obtain inorganic salt. Also suitable, nontoxic ammonium, the amine cation of quaternary ammonium salt and gegenions formation, such as halogenide, hydroxide, carboxylation are included Thing, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
The compositionss of the compound of the present invention
According on the other hand, the feature of the pharmaceutical composition of the present invention includes formula of the present invention (I) or formula (II) is changed Receptible salt or its prodrug in compound, hydrate, solvate, isomer or physiology/pharmacy, listed by the present invention Compound, or the compound of embodiment 1-5, and pharmaceutically acceptable carrier, adjuvant, or excipient.The combination of the present invention Thing can be used for the application prepared prevention, process, treat or alleviate the protein kinase mediated medicine of disease.The medicine group of the present invention Compound is preparing the application in medicament as FLT3 kinases or FLT3-ITD kinase inhibitor.
The pharmaceutical composition of the present invention, it comprises formula (I) or formula (II) compound and its pharmaceutically acceptable carrier.Its In, formula (I) or formula (II) compound can also be combined into pharmacy composite with the compound of second therapeutic activity.The system using Drug carrier can be：Solid, liquid or gas.The example of solid carrier includes：Lactose, Gypsum Fibrosum powder, sucrose, Pulvis Talci, gelatin, Agar, pectin, arabic gum, magnesium stearate, stearic acid etc..The example of liquid-carrier includes：Syrup, Oleum Arachidis hypogaeae semen, olive oil, water Deng.The example of gaseous carrier includes：Carbon dioxide and/or nitrogen.Equally, carrier or diluent can be included disclosed in document Time delay material, such as glyceryl monostearate or distearin, individually or with wax with use.
On the other hand, can include, but is not limited to as the material of pharmaceutically acceptable carrier, ion-exchanger；Aluminum；Oxygen Change aluminum；Aluminium stearate；Lecithin；Serum albumin such as human albumin；Buffer substance such as phosphate；Glycine；Sorbic acid；Pyrusussuriensiss Sour potassium；The partial glyceride mixtures of saturated vegetable fatty acid；Water；Electrolyte such as protamine sulfate, disodium hydrogen phosphate, phosphoric acid Hydrogen potassium；Salt such as sodium chloride, zinc salt；Colloidal silicon；Magnesium trisilicate；Polyvinylpyrrolidone；Polyacrylate；Wax；Polyethylene-polyoxy Propylene-blocking-up polymer；Lanoline；Sugar such as Lactose, dextrose and saccharose；Starch such as corn starch and potato starch；Cellulose With its derivant such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate；Gum powder；Fructus Hordei Germinatus；Gelatin；Pulvis Talci； Adjuvant such as cocoa butter and suppository wax；Oil such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum Sesami, olive oil, Semen Maydis oil and Oleum Glycines； Glycol compound, such as propylene glycol and Polyethylene Glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer agent is such as Magnesium hydroxide and aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethanol；Phosphate buffer solution；With Other nontoxic suitable lubricant such as sodium laurylsulfate and magnesium stearate, coloring agent, releasing agent, coating agents, sweeting agent, adjust Taste agent and spice, preservative and antioxidant.For convenience, local anesthetic, preservative, buffer agent etc. can be directly dissolved in load In body.
The compound of the present invention and the purposes of compositionss
The formula (I) of the present invention or formula (II) compound or its pharmaceutical composition can be used for treatment and have unsuitable FLT3 work The situation of property such as Proliferative Disorders feature.Improperly FLT3 activity increases and includes but is not limited to：In cell, FLT3 expression increases or weight New generation FLT3 expression, increased FLT3 expression or activity and FLT3 are mutated the constitutive activation leading to.Improper or abnormal FLT3 aglucon and FLT3 levels or activity can be determined using method well-known in document.For example, FLT3 horizontal abnormality is high, Can be determined using commercially available ELISA kit.FLT3 level can use flow cytometric analysis, immunohistochemical analysis Determine with hybridization in situ technique.
One unsuitable FLT3 activation, can pass through after FLT3 is attached to receptor one or more continue after generation work Property increase is determining：(1) phosphorylation of FLT3 or autophosphorylation；The phosphorylation of (2) FLT3 substrates, substrate such as Stat5, Ras；(3) activation of related complex such as PI3K；(4) activation of acceptor molecule；(5) cell proliferation.These activities are easy to use Well-known literature method detection.
The formula (I) of the present invention or formula (II) compound or its pharmaceutical composition can be also used for as preparing following disease Medicine, described medicine includes but not limited to this：By give the formula (I) of patient's effective dose of the present invention or formula (II) compound or Person includes formula (I) or the pharmaceutical composition of formula (II) compound, preventing/treating patient's proliferative disease, situation or disorder.Institute State disease to include：Cancer, especially hematopoietic system cancer, metastatic tumo(u)r, atheromatosiss, pulmonary fibrosis disease.
The compound of the present invention or its pharmaceutical composition can be additionally used in preparing the medicine of the formation for the treatment of tumor, and described tumor includes Cancer and metastatic cancer, including but not limited to：Bladder cancer, breast carcinoma, colon cancer, renal carcinoma, hepatocarcinoma, pulmonary carcinoma (include minicell Pulmonary carcinoma), esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, cancer of pancreas, gastric cancer, cervical cancer, thyroid carcinoma, carcinoma of prostate, skin carcinoma (include Squamous cell carcinoma)；Lymphatic cells tumor (includes leukemia, acute lymphoblastic leukemia, the white blood of acute lymphoblast Disease, B cell lymphoma, T- cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma and Bai Kete Lymphoma)；Marrow sample hematopoietic system cancer (includes acute and chronic myelocytic leukemia, myelodysplastic syndrome and front Myelocytic leukemia)；The tumor of mesenchyme origin (includes fibrosarcoma and rhabdomyosarcoma and other sarcomas, such as soft tissue And bone)；Maincenter and peripheral nervous system neoplasms (include astrocytoma, neuroblastoma, glioma and nerve sheath Tumor) and other tumors (include melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, Keratoctanthoma thyroid follcular carcinoma and Kaposi's sarcoma).
The compound of the present invention or its pharmaceutical composition can also be used for preparing or treat FLT3 mediation, and FLT3-ITD mediates And/or the disease medicament of CSF-1R mediation, this disease includes：Autoimmune disease, kidney disease, tissue transplantation rejection, red Yabbi skin ulcer, multiple sclerosis, inflammatory bowel, rheumatoid arthritis, arthritis, asthma etc..
The compound of the present invention or its pharmaceutical composition can be additionally used in preparing or treat diabetic situation such as diabetic Retinopathy and microangiopathy medicine, highly useful.
The compound of the present invention or its pharmaceutical composition are also useful for blood flow minimizing in tumor.
The compound of the present invention or its pharmaceutical composition are also useful for the minimizing of neoplasm metastasis.
The compound of the present invention or its pharmaceutical composition except for the mankind treat beneficial it can also be used to the treatment of veterinary As house pet, rare animal and farm-animals, including mammal, rodent etc..Other say more specificly, and animal includes Horse, Canis familiaris L. and cat.The formula (I) of the present invention or formula (II) compound, include its pharmaceutically acceptable derivates when using.
The compound of the present invention or its pharmaceutical composition can be additionally used in preparation suppression VEGF expression R or c-Met cell growth Medicine, this medicine includes compound or the compositionss connecting cell and the present invention.With regard to cell growth repressed example bag Include：Breast cancer cell, colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate gland cancer cell, lymphocytic cancer cell, knot Colon-cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system's cancerous cell, osteosarcoma cell, renal carcinoma Cell, hepatoma carcinoma cell, transitional cell bladder carcinoma cell line, stomach cancer cell, G. cephalantha cell, melanoma cell, or leukaemia.
The compound of the present invention or its pharmaceutical composition can be additionally used in preparing suppression VEGFR and/or c-Met kinase activity Medicine, this medicine includes connecting Biosample and compound disclosed by the invention or compositionss.Term " biological examination used herein Sample ", refers to the organism sample of the work of an outside, including but not limited to cell culture or its extract；Take from mammal The biopsy material obtaining or its extract；Blood, saliva, urine, feces, seminal fluid, tear or other body fluid or its extract.Kinases The suppression of activity, particularly VEGFR or c-Met kinase activity, the use disclosed in various kinds of document is used for Biosample form On the way.The example of this purpose includes but is not limited to：Blood transfusion, organ transplantation, biological specimen storage and bioassay.
The compounds of this invention and the administration of compositionss
The compound of the present invention, salt etc. or its pharmaceutical composition can simultaneously multiple give it is also possible to single chemical combination Thing, salt etc. give.
Treatment of the present invention includes：Give compound or the compositionss of the study subject present invention, further include： Give a kind of additional therapeutic agent of study subject (therapeutic alliance), be selected from：Chemotherapy or antiproliferative or a kind of antiinflammatory, wherein, attached Plus therapeutic agent more suitable for the disease treatment treated, additional therapeutic agent and compound disclosed by the invention or Compositionss give together, can separate as multiple dose form as single dosage form or with compound and compositionss Point.Additives give simultaneously or asynchronously can be given from compound disclosed by the invention.In the case of the latter, administration can To stagger, for example：6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
Typically therapeutically effective amount should produce the active component of about 0.1ng/ml to about 50-100 microgram/ml serum dense Degree.Described pharmaceutical composition typically should be provided from about 0.001mg to the compound of about 2000mg/daily/kg body weight Dosage.Pharmaceutical quantities unit form can be prepared to provide every dosage unit form about 1mg to about 1000mg, in some embodiments In, from about 10mg to about 500mg, the required active component from about 20mg to about 250mg or from about 25mg to about 100mg or must Want the combination of composition.In certain embodiments, can prepare this pharmaceutical dosage unit forms with provide about 1mg, 20mg, The required active component of 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg.In certain embodiments, make This pharmaceutical dosage unit forms standby are to provide the necessary active component of about 50mg.
In pharmaceutical composition, the active component of reactive compound with once daily, or can be divided into some smaller doses with one Fix time interval being administered.It should be appreciated that accurate dosage and treatment persistent period are the functions of disease to be treated, it can Rule of thumb to be determined using known experimental technique, or acquisition of being extrapolated by inner or in vitro experimental data.Should note Meaning concentration and dose value also can change with the seriousness degree of symptom to be alleviated.It is to be further understood that for appoint What concrete object it should according to individual demand and the professional judgement of people that is administered or supervises compositionss administration and adjust in time Whole specific dosage regimen, the concentration range proposing here has been only example effect, is not intended to limit claimed compositionss Scope or enforcement.
" effective dose " of the present invention or " effective dose " refer to：For treatment or mitigate one or more aforesaid Disorderly effectively amount.According to compound disclosed by the invention or compositionss, it is possible to use any effective quantity and any have The route of administration treatment treatment of effect or the seriousness mitigating disorder or disease.Required exact amount is by according to different themes And it is different, according to the ordinary circumstance of species, age and theme, the order of severity of infection, special preparation, administering mode etc..Chemical combination Thing or compositionss can also be given, as mentioned above together with one or more other drugs.
The compound of the present invention or its pharmaceutical composition can also be used for wrapping up Implantable Medical Device, such as artificial limb, artificial lobe Film, artificial blood vessel, support and conduit.Intravascular stent such as has been used for overcoming restenosiss (reducing again of vessel wall after injury).So And, patient will risk blood clot formation or the risk of platelet activation using support or other implanting device.These harmful effects, can So that a kind of its pharmaceutically acceptable compositions of compound of the present invention are comprised by pre-coating on equipment, to stop or to subtract Gently.
When for treating cancer patient, dosage can according to cancer species, patient age, ordinary circumstance, give Special compound, toxicity exist or level, once bad kickback of using medicine and other factors are changed.One Suitable dosage ranges Representative example is from as little as about 0.01mg/kg up to about 100mg/kg.However, dosage is typically freely cut out by doctor Amount.
Therapeutic Method preferably gives formula (I) or formula (II) compound of the present invention by oral or parenteral.Here make Term " parenteral " includes：Intravenous injection, intramuscular injection or Intraperitoneal medication.Parenteral is generally preferably subcutaneous and flesh Inner injecting and administering form.The present invention can also give the present invention's by subcutaneous injection, collunarium, internal rectum, percutaneous or intravaginal Formula (I) or formula (II) compound.
The formula (I) of the present invention or formula (II) compound or its pharmaceutical composition can also be administered by " suction "." suction " Refer to nasal cavity and oral inhalation administration.The dosage forms of this administration such as aerosol or metered-dose inhaler can pass through general technology system ?.
The preparation of the compounds of this invention and pharmaceutical composition and administration
The formula (I) of the present invention or formula (II) compound or its pharmaceutical composition can make multi-medicament dosage form.If made With oral solid formulation, can be prepared into：The forms such as tablet, hard capsule, buccal tablet, lozenge, drop, lotion.The amount of solid carrier can Be very different, but general from 0.025mg about to about 1g.If oral administration is liquid dosage form, typically prepare dosage form As：Syrup, Emulsion, soft capsule, suspension or solution form.When using intravenous dosage forms, medicine can be solid or liquid shape Formula, and can be made into direct administration or be administered after being suitable for restructuring.In Topical dosage forms are also included within, the example of Topical dosage forms As：Solid, liquid and semisolid.Solid includes gumming agent, application etc..Liquid includes solution, suspension and emulsion.Semi-solid bag Include emulsifiable paste, ointment and gel etc..
The amount of the formula (I) of the present invention or formula (II) compound or its pharmaceutical composition local application is certainly according to selected chemical combination Thing, character and the change of the order of severity and change it is also possible to the tailoring power according to doctor is different and different.The formula (I) of the present invention Or formula (II) compound local application amount is representational is administered one to four time within one day from the paramount about 2.0g of low about 0.01mg, excellent Select administration one in a day to twice.Active component for local administration can be included from about 0.001% about to about 10%W/W.
When for drop, it may include aseptic or non-sterile water or oil solution or suspension, can be by active component be dissolved Suitable aqueous solution prepares, is optionally included with sterilization and/or antifungal and/or any other is suitably anti- Rotten agent, and can selectively include surfactant.Final solution can make it clarify by filtration, transfers to suitable container In, then seal, by autoclaving or maintain the sterilizing of 98-100 DEG C of half an hour.In addition, this solution may filter that sterilizing, And transfer to sterile chamber.The sterilization comprising in drop and antifungal example are：Phenylmercuric nitrate or acetic acid (0.002%), benzene Prick oronain (0.01%) and chlorhexidine (0.01%).Suitable solvent for preparing oil solution includes：Glycerol, Diluted Alcohol and the third two Alcohol.
When for lotion, also include the lotion that those are suitably applied skin or eyes.Eye lotions may include a kind of nothing Bacterium aqueous solution, optionally contains antibacterial, can be prepared by preparing the similar approach of drop.It is applied to skin Lotion or liniment, may also include a kind of reagent, and it can accelerate drying, and cooling skin such as ethanol or acetone and/or humidizer are such as Glycerol or oil, oil such as Oleum Ricini or Oleum Arachidis hypogaeae semen.
It is the outer application semi-solid preparation of active component according to emulsifiable paste of the present invention, ointment or patch.They can pass through Mixed active composition and oils and fatss sample or non-grease sample substrate obtain, active component with divided mode or Micronised form, individually Or in the solution or be suspended in water or on-aqueous liquid.Substrate may include Hydrocarbon, such as：Firmly, soft or liquid paraffin, sweet Oil, Cera Flava；Metallic soap；A kind of cement；A kind of natural oil-producing class such as Semen Armeniacae Amarum, coenzyme M, Semen arachidis hypogaeae, Semen Ricini or olive oil；Pilus Caprae seu Oviss fat Or derivatives thereof, or fatty acid such as stearic acid or Oleic acid be together with ethanol, ethanol such as propylene glycol or macrogel.Preparation can mix Any suitable surfactant, such as anion, cation or nonionic surfactant, such as sorbitol ester or its polyoxyethylene Derivant.Suspending agent such as natural gum, cellulose derivative or inorganic material such as silicate, may also include other compositions such as Pilus Caprae seu Oviss Fat.
The compound of the present invention or its pharmaceutical composition can also be administered in the form of coating, and suitable coating implants equipment Know for those skilled in the art.Described coating be representative biocompatible polymeric material such as：Aquogel polymer, Poly- tetramethyldisiloxane, polycaprolactone, Polyethylene Glycol, polylactic acid, vinyl acetate and their mixture.Coating is alternative Ground is covered by a suitable thin film, such as further：Fluorosilicon oil, polyase, Polyethylene Glycol, phospholipid or its mixture, make medicine Compositionss have control release characteristic.The compound of the present invention also can be applied on Implantable Medical Device, such as beads or with poly- Compound or other molecule are prepared jointly, provide a kind of " drug storage institute ", so that medicine discharged in the long period, rather than It is administered in the form of pharmaceutical aqueous solution.
General synthetic method
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I) or formula (II).Following reaction scheme and embodiment are used for lifting further Example explanation present disclosure.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds of many present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, according to the present invention, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art Completed by method of modifying, such as suitable protection disturbs group, by using reagent known to other except described in the invention , or modification reaction condition being made some routines.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, not through being further purified, unless other aspects show during use.General reagent is from western Gansu Province, Shantou chemical industry Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, dragon chemistry examination is risen in Qingdao Agent company limited, and Haiyang Chemical Plant, Qingdao is commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide and N, N- Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually to cover a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb all suitable rubber closures beyond the Great Wall, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum with CDC13,d6-DMSO,CD3OD or d6- acetone is solvent (report is in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When multiplet occurs, by using following abbreviation：S (singlet, unimodal), d (doublet, double Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant, is represented with hertz (Hz).
By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) Agilent6320 series LC-MS spectrogrph measuring, G1329A automatic sampler and G1315B DAD detector It is applied to analyze, ESI source is applied to LC-MS spectrogrph.
Algorithm (MS) data is by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) Agilent6120 series LC-MS spectrogrph measuring, G1329A automatic sampler and the application of G1315D DAD detector In analysis, ESI source is applied to LC-MS spectrogrph.
Both the above spectrogrph is provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Note It is to be determined by sample concentration that beam amasss；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength is recording reading.Mobile phase be 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1：
Table 1
Time (min) A(CH3CN, B(H2O,
0.1%HCOOH) 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 purification to be evaluated by Agilent1100 series of high efficiency liquid chromatograph (HPLC), and wherein UV detects At 210nm and 254nm, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, and flow velocity is 0.6mL/min, (0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.
The use of brief word runs through the present invention below：
CHCl3Chloroform
CDC13Deuterochloroform
DEAD diethyl azodiformate
DMF N,N-dimethylformamide
DMAP DMAP
DMSO dimethyl sulfoxide
d6- DMSO deuterated dimethyl sulfoxide
CH2Cl2, DCM dichloromethane
ML, ml milliliter
N2Nitrogen
RT rt room temperature
Rt retention time
H2O water
Reaction scheme 1
Compound 9, can be prepared by the method for reaction scheme 1, wherein R, E, R1, a, G and n have as the present invention Described implication.In the basic conditions, reaction obtains compound 3 for compound 1 and compound 2.Compound 3 is carried out reduction reaction Obtain product 4, subsequent compound 4 and rhodanate cyclization, obtain compound 5, after compound 5 is reacted with compound 6, through also Former reaction, obtains compound 7, further obtains product 9 with compound 8 reaction.
Reaction scheme 2
Compound 15, can be prepared by the method for reaction scheme 2, wherein R, R1, a, G and n have as the present invention Described implication.Compound 10 obtains compound 11 by bromo-reaction, and bromo- 4 '-nitro-acetophenone reacts compound 11 with 2- Obtain compound 12, compound 12 and glycol monoethyl ether reaction obtain compound 13, and compound 13, through reduction reaction, obtains Compound 14, further obtains product 15 with compound 8 reaction.
The following examples can the present invention will be further described, however, these embodiments should not be used as to this The restriction of bright scope.
Embodiment
Embodiment 1
1- (4- (double (2- methoxy ethoxy) benzo [d] imidazo [2,1-b] thiazol-2-yl of 6,7-) phenyl) -3- (5- (tert-butyl group) isoxazole -3- base) urea
Step 1) double (2- the methoxy ethoxy) -4- Nitrobenzol of 1,2-
Sequentially add in reaction bulb 4- Nitrocatechol (3.1g, 19.99mmol), 2- bromo-ethyl-methyl ether (6.12g, 44.03mmol), potassium carbonate (8.29g, 59.98mmol) and DMF (10mL), is heated to 100 DEG C of backflows overnight.After cooling, will mix Close liquid to pour in the separatory funnel filling hydrochloric acid (1mol/L, 200mL), add ethyl acetate (200mL) extraction, organic layer is anhydrous Sodium sulfate be dried after, concentrating under reduced pressure, directly carry out next step, obtain brown liquid (5.4g,>100%).
LC-MS：272.2[M+1]+.
Step 2) double (2- methoxy ethoxy) aniline of 3,4-
1,2- double (2- methoxy ethoxy) -4- Nitrobenzol (5.4g, 19.91mmol), second is sequentially added in reaction bulb Alcohol (80mL) and palladium/carbon (0.5g, 10%), are stirred at room temperature reaction under hydrogen shield, after detecting that raw material reaction is complete by MS, After solids removed by filtration, concentrating under reduced pressure filtrate, directly carry out next step, obtain brown liquid (5.0g,>100%).
LC-MS：242.2[M+1]+.
Step 3) double (2- methoxy ethoxy) benzo [d] thiazole -2- amine of 5,6-
Under room temperature, sequentially add ammonium thiocyanate (2.73g, 35.86mmol) and glacial acetic acid (100mL) in reaction bulb, stir Mix lower Deca bromine (3.82g, 23.90mmol), after then proceeding to stir 30 minutes, solids removed by filtration.Filtrate added drop-wise is arrived In the acetum (100mL) of 3,4- double (2- methoxy ethoxy) aniline (4.8g, 19.89mmol), charging mixes after finishing Liquid continues to react at room temperature overnight.Acetic acid is removed under reduced pressure, adds saturated sodium bicarbonate solution in debris to no gas puerperal Afterwards, add ethyl acetate (200mL x 3) extraction, after organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure, cross column purification (V (two Chloromethanes)/V (methanol)=25/1), obtain brown solid (3.13g, 53%).
LC-MS：299.2[M+1]+.
Step 4) double (2- methoxy ethoxy) -2- (4- nitrobenzophenone) benzo [d] imidazo [2,1-b] thiazole of 6,7-
Sequentially add in reaction bulb double (2- methoxy ethoxy) benzo [d] thiazole -2- amine of 5,6- (3.13g, 10.49mmol), the bromo- 4 '-nitro-acetophenone of 2- (2.56g, 10.49mmol) and ethanol (60mL), are heated to reflux 6 hours.Mixing Liquid is cooled to 0 DEG C, then filters, a small amount of ethanol rinse of filter cake, drying under reduced pressure, obtains yellow solid (2.06g, 44%).
LC-MS：444.2[M+1]+.
Step 5) 4- (double (2- methoxy ethoxy) benzo [d] imidazo [2,1-b] thiazol-2-yl of 6,7-) aniline
Double (2- methoxy ethoxy) -2- (4- nitrobenzophenone) benzo [d] imidazo of 6,7- is sequentially added in reaction bulb [2,1-b] thiazole (2.06g, 46.45mmol), zinc powder (3.04g, 46.76mmol), ammonium chloride (0.99g, 18.58mmol) and Ethanol/water (4/1,50mL), heating reflux reaction 3 hours.Solids removed by filtration, after filtrate decompression is evaporated, adds in residue Enter dichloromethane (300mL) and saturated sodium bicarbonate solution (100mL), extract and separate, anhydrous sodium sulfate drying organic faciess, concentrate After obtain brown solid (1.48g, 77%).
LC-MS：414.2[M+1]+.
Step 6) 1- (4- (double (2- methoxy ethoxy) benzo [d] imidazo [2,1-b] thiazol-2-yl of 6,7-) benzene Base) -3- (5- (tert-butyl group) isoxazole -3- base) urea
Sequentially add in reaction bulb 4- (double (2- methoxy ethoxy) benzo [d] imidazo [2,1-b] thiazole of 6,7-- 2- yl) aniline (0.6g, 1.45mmol) and dry methylene chloride (8mL), (5- (tert-butyl group) is different to sequentially add phenyl under room temperature Azoles -3- base) carbamate (0.42g, 15.96mmol) and DMAP (11mg), the two of Deca triethylamine (0.03mL) after stirring Chloromethanes (0.1mL) solution, heated overnight at reflux.Solid is collected by filtration, with a small amount of dichloromethane (10mL) drip washing, obtains white Solid (278mg, 33%).
1H NMR(400MHz,d6-DMSO):δ9.57(s,1H),8.90(s,1H),8.58(s,1H),7.77-7.75(t,J =4.4Hz, 3H), 7.67 (s, 1H), 7.53-7.51 (d, J=8.8Hz, 2H), 6.53 (s, 1H), 4.24-4.22 (t, J= 6.0Hz, 2H), 4.17-4.15 (t, J=4.4Hz, 2H), 3.76-3.74 (t, J=4.8Hz, 2H), 3.71-3.69 (t, J= 4.4Hz,2H),3.35(overlapping,3H),3.34(s,3H),1.30(s,9H).
LC-MS：580.3[M+1]+.
Embodiment 2
1- (5- (tert-butyl group) isoxazole -3- base) -3- 4- [7- methoxyl group -6- (2- methoxy ethoxy) imidazo [1, 2-a] pyridine -2- base] phenyl } urea
Step 1) 2- amino-4-methoxyl -5- bromopyridine
2- amino-4-methoxyl pyridine (1.24g, 10mmol) is dissolved in 100mL acetic acid, after being cooled to 0 degree, Deca bromine Acetic acid (30mL) solution of plain (1.92g, 12mmol).Completion of dropping, solution reacts in 30 degree.4h, TLC monitoring raw material is anti- The sodium sulfite aqueous solution of 40mL saturation, 25 degree of stirring reactions 0.5h, concentrating under reduced pressure, remnants completely, should be added in reactant liquor Thing is extracted with ethyl acetate (150mL × 3), anhydrous sodium sulfate drying, filters, filtrate reduced in volume, column chromatography for separation (V (dichloro Methane)/V (methanol)=20/1), obtain faint yellow solid (1.45g, 73%).
MS-ESI:(ESI,pos.ion)m/z：202.9[M+1]+
Step 2) 6- bromo- 7- methoxyl group -2- (4- nitrobenzophenone) imidazo [1,2-a] pyridine
By 2- amino-4-methoxyl -5- bromopyridine (500mg, 2.5mmol) and the bromo- 4 '-nitro-acetophenone of 2- (1.21g, 5.0mmol) it is dissolved in acetonitrile (40mL), solution, in 85 degree of stirring reactions 5h, after being cooled to room temperature, has a large amount of yellow solid analysis Go out, filter, filter cake is pulled an oar with methanol (10mL), filters again, filter cake is vacuum dried, and obtains yellow solid (360mg, 42%).
MS-ESI:(ESI,pos.ion)m/z：347.8[M+1]+
1H NMR(600MHz,d6- DMSO) δ 9.22 (s, 1H), 8.64 (s, 1H), 8.41 (d, J=8.8Hz, 2H), 8.18 (d, J=8.8Hz, 2H), 7.25 (s, 1H), 4.09 (s, 3H).
Step 3) 7- methoxyl group -6- (2- methoxy ethoxy) -2- (4- nitrobenzophenone) imidazo [1,2-a] pyridine
Glycol monoethyl ether (395mg, 7.20mmol) is dissolved in 40mL dry DMF, -10 degree add hydrogen sodium (249.6mg, 10.4mmol), finishes, and keeps this temperature stirring 0.5h, adds 6- bromo- 7- methoxyl group -2- (4- nitrobenzophenone) Dry DMF (20mL) solution of imidazo [1,2-a] pyridine (360mg, 1.04mmol), completion of dropping, 50 degree of reaction 10h, plus 50mL water quenching is gone out reaction, concentrating under reduced pressure, residue with ethyl acetate (400mL) is extracted, anhydrous sodium sulfate drying, filters, filter Liquid concentrating under reduced pressure, column chromatography for separation (V (petroleum ether)/V (ethyl acetate)=1/10), obtain faint yellow solid (126mg, 39%).
MS-ESI:(ESI,pos.ion)m/z：344.20[M+1]+
1H NMR(400MHz,CDCl3) δ 8.32 (s, 2H), 8.08 (d, J=6.3Hz, 2H), 7.83 (s, 1H), 7.54 (s, 2H), 7.00 (d, J=11.6Hz, 2H), 5.37 (d, J=8.8Hz, 3H), 4.00 (s, 3H).
Step 4) 4- [7- methoxyl group -6- (2- methoxy ethoxy) imidazo [1,2-a] pyridine -2- base] aniline
By 7- methoxyl group -6- (2- methoxy ethoxy) -2- (4- nitrobenzophenone) imidazo [1,2-a] pyridine (126mg, 0.37mmol), reduced iron powder (103.6mg, 1.85mmol) and ammonium chloride (199.8mg, 3.70mmol) are placed in 100mL single port bottle In, add 10mL water and 30mL ethanol, solution is in 85 degree of lower stirring reactions 4h.Filter, filtrate reduced in volume, then use acetic acid second Ester (200mL) extracts, anhydrous sodium sulfate drying, filters, filtrate reduced in volume, column chromatography for separation (V (methanol)/V (dichloromethane) =1/50), obtain yellow solid (76mg, 66%).
MS-ESI:(ESI,pos.ion)m/z：314.20[M+1]+
Step 5) 1- (5- (tert-butyl group) isoxazole -3- base) -3- { 4- [7- methoxyl group -6- (2- methoxy ethoxy) imidazoles And [1,2-a] pyridine -2- base] phenyl urea
By 4- [7- methoxyl group -6- (2- methoxy ethoxy) imidazo [1,2-a] pyridine -2- base] aniline (76mg, 0.25mmol), phenyl (5- (tert-butyl group) isoxazole -3- base) t-butyl carbamate (130mg, 0.50mmol) is dissolved in 10mL second Nitrile, Deca triethylamine (0.3mL), solution heating reflux reaction overnight, has pale solid to separate out, filters, filter cake methanol (5mL) pull an oar, filter again, obtain pale solid (23mg, 20%).
MS-ESI:(ESI,pos.ion)m/z：480.35[M+1]+
1H NMR(400MHz,d6- DMSO) δ 9.56 (s, 1H), 8.99 (s, 1H), 7.93 (d, J=4.5Hz, 2H), 7.90 (s, 1H), 7.50 (d, J=8.6Hz, 2H), 6.64 (d, J=1.4Hz, 1H), 6.53 (s, 1H), 6.11 (d, J=1.8Hz, 1H),4.47–4.42(m,2H),3.84(s,3H),3.83–3.77(m,2H),3.38(s,3H),1.31(s,9H).
Embodiment 3-5
By from suitable initiation material, the synthetic method that embodiment 3-5 is referred to embodiment 1 or 2 prepares.
Embodiment 6 flt3 kinase inhibiting activity
Experimental technique：
Representative implication of abridging in following experiments is as follows：
HEPES：Hydroxyethyl piperazine second sulfacid；Brij-35：Brij-35；DTT：Dithiothreitol, DTT； EDTA：Ethylenediaminetetraacetic acid；EGFR：Human epidermal growth factor acceptor；HER2：Human epidermal growth factor receptor 2；EGFR T790M：Human epidermal growth factor acceptor T790M mutant；Peptide FAM-P22：FAM-labeled peptide 22；ATP：Triphosphoric acid Adenosine monophosphate；DMSO：Dimethyl sulfoxide；Staurosporine：Staurosporine；Coating Reagent#3：#3 fruit glaze agent
1. 1 × kinase buffer liquid and termination test buffer are prepared：
(1) 1x does not contain MnCl2Kinase buffer liquid (50mM HEPES, Ph7.5,0.0015%Brij-35,10mM MgCl2, 2mM DTT)；
(2) test buffer (100mM HEPES, Ph7.5,0.015%Brij-35,0.2%Coating are terminated Reagent#3,50mM EDTA).
2. the compound of test kinase prepares：Compound serial dilution
(1) adopt 100%DMSO by 50 times of diluted chemical compound to highest final concentration.Compound by this concentration of 100mL Solution is transferred to a hole of 96 orifice plates.
(2) ratio 10 concentration of diluted compounds successively being diluted with 60mL DMSO in 20mL original solution.
(3) 100mL100%DMSO solution is added in two emptying apertures, as no compound control and no enzyme comparison.
(4) prepare an intermediate plate, respectively each for 10mL concentration compound is transferred to intermediate plate from raw sheet, and add 90mL 1x kinase buffer liquid,
Vibration mixes 10 minutes.
(5) preparing experiment plate：From the intermediate plate of 96 orifice plates, corresponding aperture transferase 45 mL compound solution is to corresponding 384 holes In plate.
3. kinase reaction
(1) prepare 2.5x enzymatic solution：Enzyme is added in 1x kinase buffer liquid.
(2) prepare 2.5x peptide solution：FAM-labeled peptide and ATP are added in 1x kinase buffer liquid.
(3) 10mL2.5x enzymatic solution is added to 384 holes realities of the compound solution being 10% containing 5mL DMSO content Test in plate, incubated at room 10 minutes.
(4) 10mL2.5x peptide solution is added in 384 hole brassboards.
(5) kinase reaction and termination：28 DEG C of incubation corresponding times, add 25mL stop buffer terminating reaction.
4. DATA REASONING
Read data and collect.
5. curve matching
(1) data of copy converted measurement
(2) be converted to suppression ratio
Suppression ratio=(maximum-sample value)/(maximum-minima) * 100；
" maximum " is DMSO control value；" minima " is no kinase control hole count value.
(3) enter data into corresponding analysis software Xlfit and draw IC50Value.
Experimental result is as follows：
The flt3 kinase inhibiting activity of table 2 the compounds of this invention
Embodiment is numbered FLT3(IC50,nm)
1 6.9
Experiment conclusion：
Result shows, the compounds of this invention has preferably external zymetology inhibitory activity.
The proliferation inhibition activity of experimental example 7 MV-4-11 cell
Experimental technique：
Cytoactive detection
Cell experiment condition：
Plating cells：
Carry out cell counting with Vi-Cell XR cell counter.With corresponding culture medium adjustment cell density to 1.5 × 105Individual/milliliter, every hole kind enters 100 μ l cell suspension to 96 white orifice plates of bottom transmural, and the ultimate density of cell is 15000/ 100 μ l/ holes.At 37 DEG C, 5%CO2With cultured cells in the cell culture incubator of 95% humidity overnight.
The preparation of compound and interpolation:
The preparation (being diluted to 10 concentration in DMSO) of compound plate：
With DMSO, compound is configured to the storing liquid of 10mM, the used time is diluted to 4mM, then is diluted to 0.4mM with DMSO, with 0.4mM is maximum concentration, with DMSO progressively 3 times of dilutions, obtains the compound of 10 Concentraton gradient.Staurosporine conduct Positive control drug.
The interpolation of compound:
A. pipette from corresponding compound plate in the Tissue Culture Plate that 0.5 μ l adds incubated overnight.
B. it is incubated 72 hours in 37 DEG C of incubators.
Detection and analysis
A. compound treatment is after 72 hours, observation of cell form under inverted microscope, the cell life in DMSO control wells Long status are normal, there are no contamination phenomenon.
B. Tissue Culture Plate holding chamber warming middle-JIAO is balanced 30 minutes.
C. CellTiter-Glo detection method is adopted to measure the proliferation inhibition activity to MV-4-11 cell for the compound.
D. the experimental result of record analyses gained.
Embodiment is numbered MV4-11(IC50,Nm)
1 0.3
Experiment conclusion
Result shows, the compound of the present invention has preferable inhibitory activity to MV4-11 cell proliferation.
Although, above used general explanation, specific embodiment and test, the present invention made retouch in detail State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art 's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed Scope.

Claims (17)

1. a kind of compound, it is the compound having as shown in formula (II), or the compound as shown in formula (II) is pharmaceutically Acceptable salt,
Wherein：
Q and W is each independently CH；
Each R1It independently is hydrogen；
A is 0,1,2,3 or 4；
E ring is one of heteroaryl groups of following subformula composition：
Wherein, X, Y, Z, Z1, Z2And Z3It is each independently N or CH；
T is-O- ,-S- ,-NR4- or-CH2-；
Wherein, X, Y, Z, T, Z on described E ring1、Z2And Z3Two are at least while had to be hetero atom；
Each R4It independently is H or C1-4Alkyl；
Each G independently is-O-；
Each R independently is hydroxyl C1-4Alkoxyl, amino C1-4Alkoxyl, halo C1-4Alkoxyl or C1-4Alkoxyl；
D is 1；
Each n independently is 1,2,3 or 4；
Each L independently is the tert-butyl group.
2. compound according to claim 1, wherein：
E ring is one of heteroaryl groups of following subformula composition：
3. compound according to claim 1, wherein, each G independently is-O-；
Each R independently is methoxyl group, ethyoxyl or propoxyl group.
4. compound according to claim 1, has the structure of one of：
Or its medicine Acceptable salt on.
5. a kind of pharmaceutical composition, it comprises described compound as arbitrary in claim 1-4.
6. pharmaceutical composition according to claim 5, comprises pharmaceutically acceptable carrier, excipient, dilution further At least one in agent, adjuvant and vehicle.
7. pharmaceutical composition according to claim 5, wherein further comprises additional therapeutic agent, these additional treatment Agent is chemotherapeutic agent, antiproliferative, anti-inflammatory preparation, immunosuppressant, immunostimulant, is used for treating Atherosclerosis The medicine of change, medicine or combinations thereof for treating pulmonary fibrosiss.
8. pharmaceutical composition according to claim 7, wherein said additional therapeutic agent be chlorambucil, melphalan, Cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, reach Carbazine temozolomide, procarbazine, methotrexate, fluorouracil, cytosine arabinoside, gemcitabine, purinethol, fluorine reach and draw Shore, vinblastine, vincristine, vinorelbine, paclitaxel, Docetaxel, topotecan, irinotecan, etoposide, bent shellfish For fixed, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, ametycin, Yi Sha Grand, tamoxifen, flutamide, gonadorelin, megestrol, prednisone, dexamethasone, methylprednisolone, Thalidomide, interferon α, calcium folinate, sirolimuss, sirolimuss, everolimuses, Afatinib, alisertib, amuvatinib, Ah handkerchief replace Buddhist nun, Axitinib, bortezomib, SKI-606, brivanib, cabozantinib, AZD2171, crenolanib, a gram Zhuo replace Buddhist nun, dabrafenib, dacomitinib, danusertib, Dasatinib, dovitinib, Erlotinib, foretinib, Ganetespib, gefitinib, ibrutinib, Conmana, imatinib, iniparib, Lapatinib, lenvatinib, Linifanib, linsitinib, Masitinib, momelotinib, do not replace husky Buddhist nun, HKI-272, nilotinib, Niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, Regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, Sorafenib, Shu Ni For Buddhist nun, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, Fan Deta Buddhist nun, veliparib, Wei Luofeini, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab Vedotin, catumaxomab, Cetuximab, promise monoclonal antibody, lucky trastuzumab, her monoclonal antibody, Buddhist nun's trastuzumab, method wood difficult to understand Monoclonal antibody, Victibix, Rituximab, tositumomab, Herceptin or combinations thereof.
9. the compound described in claim 1 or the pharmaceutical composition described in claim 5 be used for preventing, process in preparation, Purposes in the medicine for the treatment of or mitigation autologous patient immunological diseases, inflammatory diseasess or proliferative disease.
10. purposes according to claim 9, wherein said proliferative disease is gastrointestinal stromal tumors, colorectal cancer, stomach Cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma, carcinoma of prostate, cancer of pancreas, thyroid carcinoma, bladder cancer, renal carcinoma, cerebroma, central nervous system's Cancer, glioblastoma, myeloproliferative disease, atherosclerosiss, pulmonary fibrosiss, leukemia, lymphatic cancer, rheumatism, non- Lymphoreticular system tumor, papular mucinosis, familial splenic anemia, amyloidosises, solitary plasmacytoma, weight Chain disease, light chain disease, malignant lymphoma, half molecule disease, Secondary cases benign monoclonal gammopathy, osteolytic lesion, Sezary syndrome, infectious monocytosis, acute histocytic increase disease, colon cancer, rectal cancer, polyposis intestinalises, Neuroblastoma, neuroendocrine cell tumor, islet cell tumor, melanoma, retinoblastoma, uterus carcinoma, ovum Nest cancer, G. cephalantha, malignant tumor of digestive tract, cervical cancer or tumor of testis.
11. purposes according to claim 10, wherein said leukemia is acute myeloid leukaemia, the white blood of chronic Myelogenous Disease, acute lymphoblastic leukemia, cryoglobulinemia, chronic lymphocytic leukemia, primary macroglobulinaemia, monokaryon Chronic myeloid leukemia, or hairy cell leukemia；
Described pulmonary carcinoma is small cell lung cancer or nonsmall-cell lung cancer；
Described thyroid carcinoma is medullary thyroid carcinoma；
Described myeloproliferative disease is myeloma；
Described lymphatic cancer is lymphoblastoma, non-Hodgkin lymphoma or Hodgkin lymphoma.
12. purposes according to claim 11, wherein said acute myeloid leukaemia is acute myeloid leukemia；
Described chronic myelogenous leukemia is the chronic myelogenous leukemia of mutation；
Described primary macroglobulinaemia is primary macroglobulinaemia purpura；
Described myeloma is multiple myeloma.
13. purposes according to claim 9, wherein said autoimmune disease be rheumatic arthritis, multiple sclerosiss, Thyroiditiss, type i diabetes, sarcoidosises, inflammatory bowel, Crohn's disease or lupus.
14. purposes according to claim 13, wherein said lupus is systemic lupus.
15. purposes according to claim 9, wherein said inflammatory diseasess refer to diverticulitiss, colitis, pancreatitiss, liver Inflammation, liver cirrhosis, cholecystitis or chronic inflammatory disease.
16. purposes according to claim 15, described chronic inflammatory disease is chronic hepatitiss.
17. purposes according to claim 9, wherein said disease is that FLT3 is kinase mediated or FLT3-ITD kinases causes Disease.
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