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

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 derivatives and their application in medicine

field of invention

The invention belongs to the field of pharmacy. The present invention provides a new class of substituted urea derivatives and their compositions and uses for treating diseases mediated by flt3 or caused by flt3-ITD. Such compounds are novel substituted urea compounds for treating, relieving or preventing diseases or conditions related to tyrosine kinase activity, or one or more symptoms thereof.

Background of the invention

Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine and threonine residues of proteins. Protein kinases, especially the receptor protein tyrosine kinase (RTK) family of protein kinases, mainly serve as growth factor receptors and play an important role in the control of signal transduction pathways for many cellular functions, such as cell cycle, cell growth, Cell differentiation and cell death. Dysregulation or excessive, irregular activity of receptor protein tyrosine kinase (RPTK) activity has been observed in many disease conditions, including benign and malignant proliferative disorders, inflammatory disorders, immune system disorders, which are caused by immune Inappropriate activation of the system can lead to eg autoimmune diseases.

As one example, irregular activity of receptor tyrosine kinases of the platelet growth factor receptor (PDGFR) family has been found to be associated with various proliferation disorders. Gene amplification or upregulation of PDGFR occurs in patients with glioma or sarcoma (see Komabe et al., Oncogene, (1992) 7:627-633; Ostman and Heldin Cancer Res. (2001) 80:1-38) . A member of the PDGFR family, Flt3 (also known as Flk-2), plays an important role in the proliferation and variation of hematopoietic stem cells, and activating mutations or overexpression of this receptor have been found in AML (acute myeloid leukemia) (See Heinrich Mini-Reviews, Medicinal Chemistry (2004) 4(3):255-271; Kiyoi et al., lnt JHematol (2005) 82:85-92). Many known Flt3 inhibitors are under investigation and some are expected to have clinical effects against AML (see Levis et al., Int J Hematol. (2005) 82:100-107). The Flt3 receptor is also expressed on a large number of dendritic cell precursors, and stimulation of this receptor leads to the proliferation and differentiation of these precursors into dendritic cells (DC). Since dendritic cells are the major initiators of T-cell mediated immune responses, including autoimmune responses, Flt3 inhibition is a mechanism for the downregulation of DC-mediated inflammatory and autoimmune responses. Studies have shown that the Flt3 inhibitor CEP-701 can effectively reduce myelin loss in an experimental autoimmune encephalomyelitis (EAE), multiple sclerosis mouse model (see Whartenby et al., PNAS (2005) 102:16741-16746). High levels of Flt3 ligands were found in the sera of patients with Langerhans cell histiocytosis and systemic lupus erythematosus, further implicating Flt3 signaling in the dysregulation of dendritic cell precursors in those autoimmune diseases (See Rolland et al., J Immunol. (2005) 174:3067-3071).

It has been reported that some small molecules that inhibit the kinase FLT3 can effectively induce apoptosis in cell lines with FLT3 kinase mutations and prolong the survival of mice with FLT3 mutations in myeloid cells (see Levis et al., Blood (2002) 99: 3885-3891; Kelly et al., Cancer Cell 1 (2002):421-432; Weisberg et al., Cancer Cell 1 (2002) 433-443; Yee et al., Blood (2002) 100:2941-2949).

Activation of FLT3 internal tandem repeat ITD (flt3-ITD) is found in about 20% of acute myeloid leukemia patients and is associated with some poor prognosis. Extensive experimental and clinical data, including the lack of clinical activity of early FLT3 inhibitors, demonstrate that FLT3-ITD plays a role in the body pathology that sometimes enables and sometimes maintains cancer. A tendency to relapse has been reported in some patients, particularly after treatment, possibly due to flt3 kinase mutations with multiple kinase inhibitors (see Heidel, F. et al. Blood (2006) 107:293–300.). Studies have shown that FLT3-ITD inhibitors play a role in hindering the pathogenesis of inducing malignant tumors and serving as effective therapeutic targets in AML patients (see Catherine et al., Nature (2012) 485:260-263).

Mutations of Flt3 frequently occur in AML patients and include mutations in the coding region of paramembrane internal tandem duplications (ITD) or point mutations in the tyrosine kinase domain (TKD). FLT3-ITD and FLT3-TKD mutations cause ligand-independent diffusion due to dimerization and activity of the flt3 receptor. The proportion of highly variable wild-type alleles of FLT3-ITD is associated with poor prognosis in adults and children (see AS Moore et al., Leukemia (2012) 26:1462-1470).

There is considerable interest among researchers in developing kinase inhibitors for cancer treatment, among which urea derivatives have been reported as selective Flt3 inhibitors.

Summary of the invention

The present invention provides substituted urea derivatives and pharmaceutical compositions thereof for drug therapy, a series of substituted urea compounds for regulating Flt3 kinase activity and inhibiting FLT3-ITD and for treating flt3-mediated or flt3-ITD Uses for diseases caused by ITD.

In one aspect, the present invention provides a substituted urea derivative, which is a compound having the structure shown in formula (I), or a stereoisomer or geometric isomer of the compound shown in formula (I), Tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof,

in:

The K ring is a 5-6 membered heteroaryl group;

Q and W are each independently CH or N;

Each L is independently amino, nitro, alkylthio, alkyl, cycloalkyl, heterocyclyl, haloalkyl, alkylamino, hydroxy, fluorine, chlorine, bromine, iodine, alkyl-C(=O) -NH-, alkoxy, hydroxyalkyl or cyano;

Each R ¹ is independently hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 haloalkyl, C _1-4 alkyl, C _1-6 alkyl-S(=O) _t- , C _1-6 alkane Oxygen C _1-6 alkyl, C _1-4 alkylamino, hydroxyl, cyano, nitro, C _1-4 alkyl-C(=O)-NH-, C _1-4 alkoxy, hydroxyl C _1-4 alkyl or C _1-4 alkylthio;

Ring E is a bicyclic heteroaryl group or a tricyclic heteroaryl group; wherein the heteroaryl group has at least 2 heteroatoms, and each heteroatom is independently O, S, NR ⁴ or N;

each R is independently hydrogen, haloalkyl, alkyl ^- C(=O)-, alkoxyalkyl, hydroxyalkyl, benzyl, cycloalkyl, heterocyclyl or alkyl;

each J is independently -G-( _CH2 ) _n- R;

Each G is independently -O-, -S-, -S(=O) _t -, -C(=O)- or -(CH ₂ ) _n -C(=O)-;

Each R is independently hydrogen, -NR ³ R ² , alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, heterocyclyl, alkyl -S(=O) _t- , alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy Oxy, Arylalkoxy, Arylalkylamino, Heteroarylalkoxy, Heteroarylalkylamino, Heterocyclylalkylamino, Cycloalkyloxy, Cycloalkylamino, Heterocyclylalkoxy , carbocyclylalkoxy, carbocyclylalkylamino, aryloxyalkoxy, aryloxy, heteroaryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbon Cyclooxyalkoxy, heterocyclyloxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino , Fused Heterobicyclylalkoxy, Fused Heterobicyclylalkylamino, Fused Heterobicyclyloxyalkoxy, Fused Heterobicyclyloxyalkylamino, Spiroheterobicyclylalkyl, Spiroheterobicyclyl Alkoxy, Endobicyclylalkyl, Endoheterobicyclyloxy, Endoheterobicycloalkoxy, Endoheterobicycloalkylamino, Aryl, Arylalkyl, Heteroarylalkyl, Heteroaryl , bridged heterobicyclyl, spiro heterobicyclyl or fused heterobicyclyl;

each of ^R and R is independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxyalkyl or hydroxyalkyl ^;

each n is independently 1, 2, 3 or 4;

each t is independently 0, 1 or 2;

each e is independently 0, 1, 2, 3 or 4;

each d is independently 1, 2, 3 or 4;

each a is independently 0, 1, 2, 3 or 4;

each b is independently 2, 3 or 4;

Wherein, the aryl group, bicyclic heteroaryl group, tricyclic heteroaryl group, heteroaryl group, alkoxyalkyl group, alkoxyl group, -G-(CH ₂ ) _n -R, -(O-(CH ₂ ) _n ) _e -O-, -(CH ₂ ) _n -C(=O)-, alkyl-S(=O) _t -, hydroxyalkyl, arylalkyl, hetero Arylalkyl, Heteroaryl, Heterocyclyl, Bridged Heterobicyclyl, Spiroheterobicyclyl, Fused Heterobicyclyl, Alkyl, Haloalkyl, Alkylamino, Hydroxyalkoxy, Aminoalkoxy, Haloalkane Oxy, alkenyl, alkynyl, cycloalkylalkyl, heterocyclylalkyl, alkyl-C(=O)-, benzyl, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy Oxy, Arylalkoxy, Arylalkylamino, Heteroarylalkoxy, Heteroarylalkylamino, Heterocyclylalkylamino, Cycloalkyloxy, Cycloalkylamino, Heterocyclylalkoxy , carbocyclylalkoxy, carbocyclylalkylamino, aryloxyalkoxy, aryloxy, heteroaryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbon Cyclooxyalkoxy, heterocyclyloxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino , Fused Heterobicyclylalkoxy, Fused Heterobicyclylalkylamino, Fused Heterobicyclyloxyalkoxy, Fused Heterobicyclyloxyalkylamino, Spiroheterobicyclylalkyl, Spiroheterobicyclyl Alkoxy, bridged heterobicyclylalkyl, bridged heterobicyclyloxy, bridged heterobicyclylalkoxy, bridged heterobicyclylalkylamino, alkyl-C(=O)-NH-, alkylthio, ring The alkyl group and the B ring can be independently replaced by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, C _1-4 haloalkyl, C _1-4 alkyl, C _1-4 alkyl Amino, hydroxyl, cyano, nitro, amino, methyl-C(=O)-NH-, oxo(=O), C _1-4 alkyl-C(=O)-, benzyl, cyclopropyl base or phenyl, monosubstituted or identical or different multiple substitutions.

In some embodiments, wherein, the E ring is one of the heteroaryl groups formed by the following substructural formula:

Wherein, X, Y, Z, Z ¹ , Z ² , Z ³ and Z ⁴ are each independently N or CH;

T and T ¹ are each independently -O-, -S-, -NR ⁴ - or -CH ₂ -;

Wherein, each R ⁴ is independently H, C _1-4 alkyl, C _3-10 cycloalkyl, C _2-10 heterocycloalkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxyl C _1-4 alkyl;

each J is independently -G-( _CH2 ) _n- R;

Each G is independently -O-, -S-, -S(=O) _t -, -C(=O)- or -(CH ₂ ) _n -C(=O)-;

Each R is independently hydrogen, -NR ³ R ² , C _2-4 alkenyl, C _2-4 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl C _1-4 alkyl, C _2-10 heterocyclyl C _1-4 alkyl, C _1-6 alkyl-S(=O) _t -, C _1-6 alkoxy C _1-6 alkyl, hydroxy C _1-4 alkyl, Hydroxy C _1-4 alkoxy, Amino C _1-4 alkoxy, Halo C _1-4 alkoxy, C _1-4 alkylamino Halo C _1-4 alkoxy, C _1-4 alkylamino C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _6-10 aryl C _1-4 alkoxy, C _6-10 aryl C _1-4 alkylamino, C _1-9 Heteroaryl C _1-4 Alkoxy, C _1-9 Heteroaryl C _1-4 Alkylamino, C _2-10 Heterocyclyl C _1-4 Alkylamino, C _3-10 Cycloalkyl Oxygen, C _3-10 cycloalkylamino, C _2-10 heterocyclyl C _1-4 alkoxy, C _3-10 carbocyclyl C _1-4 alkoxy, C _3-10 carbocyclyl C _1-4 alkylamino, C _6-10 aryloxy C _1-4 alkoxy, C _6-10 aryloxy, C _1-9 heteroaryloxy, C _1-9 heteroaryloxy C _{1 -4} alkoxy, C _2-10 heterocyclyloxy C _1-4 alkoxy, C _3-10 carbocyclyloxy C _1-4 alkoxy, C _2-10 heterocyclyloxy, C _1-4 alkoxy, C _1-4 alkyl, C _1-4 haloalkyl, C _6-10 aryl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _1-9 heteroaryl,

Or each R is independently the following substructural formula:

Wherein, each X ⁸ , X ⁹ and X ¹⁰ are independently N or CH;

Each of X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ is independently -CH ₂ -, -O-, -NR ^4a -, -S(=O) _t - or -S- ;

each of q, m, p, r and s is independently 0, 1, 2, 3 or 4;

Each R ³ and R ² is independently C _1-6 alkyl, C _3-10 cycloalkyl, C _2-10 heterocycloalkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _{1 -4} alkyl;

Each R ^4a is independently H, C _1-4 alkyl, C _1-4 alkyl-C(=O)-, benzyl, C _3-10 cycloalkyl, C _2-10 heterocycloalkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _1-4 alkyl;

Wherein, said B ring, E ring and each substructural formula represented by each R can be independently replaced by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, C _1-4 haloalkyl, C _1-4 alkyl, C _1-4 alkylamino, hydroxyl, cyano, nitro, amino, methyl-C(=O)-NH-, oxo (=O), C _1-4 alkyl- C(=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different polysubstituted.

In some other embodiments, the E ring described in the present invention is one of the heteroaryl groups formed by the following substructural formula:

each J is independently -G-( _CH2 ) _n- R;

Each G is independently -O-, -S-, -S(=O) _t -, -C(=O)- or -(CH ₂ ) _n -C(=O)-;

Each R is independently hydrogen, -NR ³ R ² , C _2-4 alkenyl, C _2-4 alkynyl, C _2-10 heterocyclyl, C _1-4 alkyl, C _1-6 alkyl-S( =O) _t -, C _1-4 alkoxy C _1-4 alkyl, hydroxy C _1-4 alkyl, hydroxy C _1-4 alkoxy, amino C _1-4 alkoxy, halo C _{1 -4} alkoxy, C _1-4 alkylamino halo C _1-4 alkoxy, C _1-4 alkylamino C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy , C _1-4 alkoxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-9 heteroaryl C _1-6 alkyl,

Or each R is independently the following substructural formula:

Each of ^R3 and R2 is independently methyl, ethyl, ^propyl , isopropyl, tert-butyl, pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, _C2-10 heterocycle Alkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _1-4 alkyl;

Wherein, the substructural formulas represented by the B ring, the E ring and each R can be independently replaced by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl , trifluoroethyl, methyl, ethyl, propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxyl, cyano, nitro, oxo (=O ), methyl-C(=O)-, ethyl-C(=O)-, propanyl-C(=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different Multiple substitutions.

In some embodiments, the K ring described herein is one of the heteroaryl groups formed by the substructure shown below:

Each L is independently t-butyl.

In some embodiments, wherein the substituted urea derivatives described in the present invention have a compound represented by formula (II), or a stereoisomer or geometric isomer of a compound represented by formula (II), Tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof,

Or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug, wherein:

Q and W are each independently CH or N;

Each R ¹ is independently hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 haloalkyl, C _1-4 alkyl, C _1-6 alkyl-S(=O) _t- , C _1-6 alkane Oxygen C _1-6 alkyl, C _1-4 alkylamino, hydroxyl, cyano, nitro, C _1-4 alkyl-C(=O)-NH-, C _1-4 alkoxy, hydroxyl C _1-4 alkyl or C _1-4 alkylthio;

Ring E is one of the heteroaryl groups formed by the following substructure:

Wherein, X, Y, Z, Z ¹ , Z ² , Z ³ and Z ⁴ are each independently N or CH;

T and T ¹ are each independently -O-, -S-, -NR ⁴ - or -CH ₂ -;

Wherein, at least two of X, Y, Z, T, T ¹ , Z ¹ , Z ² , Z ³ and Z ⁴ on the E ring are heteroatoms;

Each R ⁴ is independently H, C _1-4 alkyl, C _1-4 alkyl-C(=O)-, benzyl, C _3-10 cycloalkyl, C _2-10 heterocycloalkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _1-4 alkyl;

Each G is independently -O-, -S-, -S(=O) _t -, -C(=O)- or -(CH ₂ ) _n -C(=O)-;

Each R is independently hydrogen, -NR ³ R ² , C _2-4 alkenyl, C _2-4 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl C _1-4 alkyl, C _2-10 heterocyclyl C _1-4 alkyl, C _1-6 alkyl-S(=O) _t -, C _1-6 alkoxy C _1-6 alkyl, hydroxy C _1-4 alkyl, Hydroxy C _1-4 alkoxy, Amino C _1-4 alkoxy, Halo C _1-4 alkoxy, C _1-4 alkylamino Halo C _1-4 alkoxy, C _1-4 alkylamino C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _3-10 cycloalkyloxy, C _6-10 aryl C _1-4 alkoxy, C _{6- 10} aryl C _1-4 alkylamino, C _1-9 heteroaryl C _1-4 alkoxy, C _1-9 heteroaryl C _1-4 alkylamino, C _2-10 heterocyclyl C _1-4 Alkylamino, C _3-10 cycloalkylamino, C _2-10 heterocyclyl C _1-4 alkoxy, C _3-10 carbocyclyl C _1-4 alkoxy, C _3-10 carbocyclyl C _1-4 alkylamino, C _6-10 aryloxy C _1-4 alkoxy, C _6-10 aryloxy, C _1-9 heteroaryloxy, C _1-9 heteroaryloxy C _{1 -4} alkoxy, C _2-10 heterocyclyloxy C _1-4 alkoxy, C _3-10 carbocyclyloxy C _1-4 alkoxy, C _2-10 heterocyclyloxy, C _1-4 alkoxy, C _1-4 alkyl, C _1-4 haloalkyl, C _6-10 aryl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _1-9 heteroaryl or each R is independently the following substructural formula:

Wherein, each X ⁸ , X ⁹ and X ¹⁰ are independently N or CH;

Each of X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ is independently -CH ₂ -, -O-, -NR ^4a -, -S(=O) _t - or -S- ;

each of q, m, p, r and s is independently 0, 1, 2, 3 or 4;

d is 1;

each n is independently 1, 2, 3 or 4;

Each R ³ and R ² is independently C _1-6 alkyl, C _3-10 cycloalkyl, C _2-10 heterocycloalkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _{1 -4} alkyl;

Each R ^4a is independently H, C _1-4 alkyl, C _1-4 alkyl-C(=O)-, benzyl, C _3-10 cycloalkyl, C _2-10 heterocycloalkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _1-4 alkyl;

Wherein, each substructural formula represented by the E ring and each R can be independently replaced by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, C _1-4 haloalkyl, C _1-4 Alkyl, C _1-4 alkylamino, hydroxyl, cyano, nitro, amino, methane-C(=O)-NH-, oxo (=O), C _1-4 alkyl-C(= O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different multiple substitutions;

Each L is independently t-butyl.

In some other embodiments, the E ring described in the present invention is one of the heteroaryl groups formed by the following substructural formula:

Wherein, each substructural formula represented by the E ring can be independently replaced by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl radical, ethyl, propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxyl, cyano, nitro, methane-C(=O)-, ethane -C(=O)-, propanyl-C(=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different polysubstituted.

In some other embodiments, each G described in the present invention is independently -O-;

Each R is independently hydrogen, -NR ³ R ² , C _2-4 alkenyl, C _2-4 alkynyl, C _2-10 heterocyclyl, C _1-4 alkyl, C _1-6 alkyl-S( =O) _t -, C _1-4 alkoxy C _1-4 alkyl, hydroxy C _1-4 alkyl, hydroxy C _1-4 alkoxy, amino C _1-4 alkoxy, halo C _{1 -4} alkoxy, C _1-4 alkylamino halo C _1-4 alkoxy, C _1-4 alkylamino C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy , C _1-4 alkoxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-9 heteroaryl C _1-6 alkyl,

Or each R is independently the following substructural formula:

Each of ^R3 and R2 is independently methyl, ethyl, ^propyl , isopropyl, tert-butyl, pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, _C2-10 heterocycle Alkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _1-4 alkyl;

Wherein, each substructural formula represented by each R can be independently replaced by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl Base, ethyl, propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxyl, cyano, nitro, oxo (=O), methyl-C ( =O)-, ethyl-C(=O)-, propanyl-C(=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different polysubstituted.

On the other hand, the present invention also provides a pharmaceutical composition comprising the compound described in the present invention.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.

In some embodiments, the pharmaceutical composition of the present invention further comprises additional therapeutic agents, these additional therapeutic agents are chemotherapeutic drugs, anti-proliferative agents, anti-inflammatory agents, immunosuppressants, immunostimulators, A drug for treating atherosclerosis, a drug for treating pulmonary fibrosis, or a combination thereof.

In some other embodiments, the pharmaceutical composition of the present invention, wherein the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosf Ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, Oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine ), mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan Topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, Daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, fluoride Flutamide, gonadorelin analogues, megestrol, prednidone, dexamethasone, methylprednisolone, thalidomide (thalidomide), interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib ( afatinib), alisertib, amuvatinib, apatinib, axitinib inib), bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib ( dasatinib), dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib ( lapatinib), lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, prazole Pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, card Catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab , ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, or combinations thereof.

In another aspect, the present invention relates to the use of said compound or pharmaceutical composition in the preparation of medicines for preventing, treating, alleviating or treating proliferative diseases, autoimmune diseases or inflammatory diseases in patients.

In some embodiments, the purposes of the present invention, wherein the proliferative disease is acute myelogenous leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumors, acute myelogenous leukemia (AML), mutant chronic myelogenous leukemia ( CML), Acute Lymphoblastic Leukemia (ALL), Colorectal Cancer, Stomach Cancer, Breast Cancer, Lung Cancer, Liver Cancer, Prostate Cancer, Pancreatic Cancer, Thyroid Cancer, Bladder Cancer, Kidney Cancer, Brain Tumor, CNS (Central Nervous System) Cancer , malignant glioma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic disease, cryoglobulinemia, nonlymphoreticular neoplasm, papular mucinosis, familial Splenemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinemia, hemimolecular disease, mononuclear Cellular leukemia, primary macroglobulinemia purpura, secondary benign monoclonal gammopathy, osteolytic lesions, lymphoblastoma, non-Hodgkin's lymphoma, Sezary syndrome, infectious mononucleosis Hypertrichosis, acute histiocytosis, Hodgkin's lymphoma, hairy cell leukemia, colon cancer, rectal cancer, intestinal polyps, small cell lung cancer, neuroblastoma, neuroendocrine cell tumors, islet cell tumors, medullary thyroid Carcinoma, melanoma, retinoblastoma, uterine cancer, ovarian cancer, head and neck squamous cell carcinoma, gastrointestinal malignancy, non-small cell lung cancer, cervical cancer, testicular tumor or myeloma.

In some embodiments, the use of the present invention, wherein the autoimmune disease is rheumatoid arthritis, lupus, multiple sclerosis, thyroiditis, type I diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or systemic lupus.

In some embodiments, in the use of the present invention, the inflammatory disease refers to diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, liver cirrhosis, cholecystitis, or chronic inflammation.

In some embodiments, the use according to the present invention, wherein the disease is a disease mediated by FLT3 or caused by FLT3-ITD.

In another aspect, the present invention relates to said compound or pharmaceutical composition for the preparation of a method for preventing, treating, treating or alleviating a proliferative disease, an autoimmune disease or an inflammatory disease in a patient, the method comprising administering An effective therapeutic amount of the compound of the present invention or the pharmaceutical composition of the present invention for patients.

In some embodiments, the method described herein, wherein the disease is a disease mediated by FLT3 kinase or caused by FLT3-ITD kinase.

In another aspect, the present invention relates to said compound or pharmaceutical composition for preventing, treating, treating or alleviating proliferative diseases, autoimmune diseases or inflammatory diseases in patients.

Another aspect of the present invention relates to a method for preventing, treating, treating or alleviating a proliferative disease, an autoimmune disease or an inflammatory disease in a patient, the method comprising administering to the patient a pharmaceutically effective dose of a compound of the present invention.

Another aspect of the present invention relates to a method for preventing, treating, treating or alleviating a proliferative disease, an autoimmune disease or an inflammatory disease in a patient, said method comprising using a pharmaceutically effective dose of a pharmaceutical composition containing a compound of the present invention Administer the drug to the patient.

Another aspect of the present invention relates to the use of a compound of the present invention for the manufacture of a medicament for preventing, treating or treating a proliferative, autoimmune or inflammatory disease in a patient, and reducing the severity thereof.

The purpose of another aspect of the present invention is to provide an application comprising the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for regulating FLT3-mediated diseases, especially comprising administering A therapeutically effective amount of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, isomer, solvate, hydrate, or prodrug thereof.

On the other hand, the compounds and compositions provided by the invention can effectively regulate the activity of Ab1 protein tyrosine family.

In some embodiments, the compounds and compositions provided herein can effectively modulate the activity of fms-like tyrosine kinase 3 receptor kinase (FLT-3 kinase).

In some embodiments, the compounds and compositions provided herein can effectively inhibit the activity of fms-like tyrosine kinase 3 receptor kinase mutation (FLT-3-ITD kinase).

In some embodiments, the compounds and compositions provided herein can effectively modulate the activity of the Src subfamily, which includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr and Yrk.

In some embodiments, the compounds and compositions provided herein are effective in modulating the activity of one or more kinases selected from the group consisting of: sterile20, sterile11, sterile, camk subfamily (calmodulin-regulated kinase and related kinases) ), AGC subfamily (protein kinase A, protein kinase G, and protein kinase C), CMGC subfamily (cdk, map kinase, glycogen synthase kinase, and clk), sterile20 subfamily, Frk, Btk, Csk, Abl, Zap70 , Fes, Fps, Fak, Jak, and Ack (and their respective subfamilies).

In other embodiments, the present invention provides the use of the disclosed compounds and compositions, or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof, for the local or systemic treatment or prevention of human and veterinary Methods of diseases, disorders and disorders modulated or otherwise affected by kinase activity.

The preceding description only outlines certain aspects of the invention, but is not limiting. These and other aspects will be described more specifically and fully below.

Detailed description of the invention

Definitions and General Terms

The present invention will list in detail the literature corresponding to the determined and embodied content, and the examples are all accompanied by illustrations of structural formulas and chemical formulas. The present invention is intended to cover all alternatives, modifications and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The invention is in no way limited to the description of the methods and materials. There are many documents and similar materials that differ from or contradict the present application, including but in no way limited to the definitions of terms, term usage, described techniques, or the scope of control like the present application.

The following definitions shall apply to the present invention unless otherwise indicated. For purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS Edition and Handbook of Chemicals, 75, ^th Ed, 1994. In addition, see "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, for general principles of organic chemistry. All content therefore incorporates references.

As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "optionally", whether or not preceded by the term "substituted", indicates that one or more hydrogen atoms in a given structure may be replaced by a particular substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently. The substituents mentioned therein can be, but are not limited to: hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl- S(=O) _t- , haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, Mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O)NH- or alkoxyalkyl Wait.

The term "alkyl" used in the present invention includes a saturated linear or branched monovalent hydrocarbon group of 1-20 carbon atoms, wherein the alkyl group can be independently and optionally substituted by one or more substituents described in the present invention. In some embodiments, the alkyl group contains 1-10 carbon atoms, in other embodiments, the alkyl group contains 1-8 carbon atoms, in other embodiments, the alkyl group contains 1-6 carbon atoms, in other embodiments, the alkyl group contains 1-4 carbon atoms, in other embodiments, the alkyl group contains 1-3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl or isobutyl, 1-methylpropyl Or sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1- Butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2 -pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, etc. The term "alkyl" and its prefix "alk" are used herein to include straight and branched saturated carbon chains.

The term "alkynyl" means a straight-chain or branched monovalent hydrocarbon group of 2-12 carbon atoms, wherein at least one position is unsaturated, that is, one CC is a sp triple bond, wherein the alkynyl group can be independently optionally replaced by One or more substituents described in the present invention are substituted, specific examples include, but are not limited to, ethynyl propargyl etc.

The term "alkenyl" means a straight-chain or branched monovalent hydrocarbon group of 2-12 carbon atoms, wherein at least one position is unsaturated, that is, one CC is a sp ² double bond, and the group of the alkenyl group can be independently selected substituted by one or more of the substituents described in the present invention, including groups with "reverse", "normal" or "E" and "Z" orientations, where specific examples include, but are not limited to, vinyl ( -CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), and the like.

The terms "alkylene" and "alkylene chain" refer to straight or branched divalent hydrocarbon chains consisting only of carbon and hydrogen atoms, free of unsaturated bonds, having from 1 to 8 carbon atoms, e.g. , methylene, ethylene, propylene, n-butylene, etc. The alkylene chain can be attached to the rest of the molecule through any two carbon atoms in the chain.

The term "alkenylene" or "alkenylene chain" refers to a straight or branched unsaturated divalent group consisting only of carbon and hydrogen atoms, having from 1 to 8 carbon atoms, in which the unsaturated bond is only It exists as a double bond, and a double bond may exist between any two carbon atoms in the chain, for example, ethenylene, 1,3-propenylene, 2-butenylene, and the like. The alkenylene chain can be attached to the remainder of the molecule through any two carbon atoms in the chain.

The term "alkynylene" or "alkynylene chain" refers to a straight or branched unsaturated divalent group consisting only of carbon and hydrogen atoms, having from 1 to 8 carbon atoms, in which the unsaturated bond consists only of Exist in the form of a triple bond, and the triple bond can exist between any two carbon atoms of the carbon chain, for example, acetylene, 1-propyne, 2-butyne, 1-pentyne, 3-pentyne, etc. The alkyne chain can be attached to the remainder of the molecule through any two carbon atoms in the chain.

The term "halogen", "halogen atom" or "halogen atom" as used in the present invention includes fluorine, chlorine, bromine, iodine.

The term "amino" refers to _-NH2 .

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are independently substituted by one or two alkyl groups, Wherein the alkyl group has the meaning as described in the present invention. In some embodiments, alkylamino is a lower alkylamino group with one or two C _1-6 alkyl groups attached to a nitrogen atom. In some other embodiments, the alkylamino is a C _1-3 lower alkylamino group. Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- -Diethylamino and the like.

The term "alkoxy" as used herein refers to an alkyl group, as defined herein, attached to the main carbon chain through an oxygen atom. Such examples include, but are not limited to, methoxy, ethoxy, propoxy, and the like.

The term "alkoxyalkyl" or "alkoxyalkoxy" means that an alkyl or alkoxy may be substituted by one or more of the same or different alkoxy, wherein the alkyl and alkoxy have Meaning as described in the present invention. Such examples include, but are not limited to, methoxymethane, ethoxymethane, methoxypropoxy, methoxymethoxy, and the like.

The term "alkyl-S(=O) _t -" means that -S(=O) _t - can be connected with an alkyl group, wherein the alkyl group has the meaning as described in the present invention. where t is 0, 1 or 2. Such examples include, but are not limited to, methyl-S(=O) ₂ -, ethyl-S(=O) _2- , propanyl-S(=O) _2- , methyl-S( =O)-, ethyl-S(=O)-, propanyl-S(=O)-, methyl-S-, ethyl-S-, propanyl-S-, and the like.

The term "alkyl-C(=O)-" means that an acyl group (-C(=O)-) can be connected with an alkyl group, wherein the alkyl group has the meaning as described in the present invention. Such examples include, but are not limited to, acetyl ( _CH3 -C(=O)-), propionyl ( _{C2H5 -} C(=O)-), and the like.

The term "haloalkyl" or "haloalkoxy" denotes an alkyl or alkoxy group which may be substituted by one or more of the same or different halogen atoms. Where alkyl and alkoxy groups have the meanings described herein, such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

The term "alkylaminohaloalkoxy" means that a haloalkoxy group may be substituted by one or more of the same or different alkylamino groups. Where alkylamino and haloalkoxy groups have the meanings described herein, such examples include, but are not limited to, methylaminodifluoromethoxy and the like.

The term "hydroxyalkyl" or "hydroxyalkoxy" denotes an alkyl or alkoxy group which may be substituted with one or more hydroxy groups. Where alkyl and alkoxy groups have meanings as described herein, examples of such include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, hydroxypropyl, 1,2-dihydroxypropyl, Hydroxymethoxy, 1-hydroxyethoxy, etc.

The term "aminoalkoxy" or "alkylaminoalkoxy" denotes an alkoxy group which may be substituted with one or more amino or alkylamino groups. Where an alkylamino or alkoxy group has a meaning as described herein, examples of such include, but are not limited to, aminomethoxy, 1-aminoethoxy, methylaminomethoxy, ethylaminoethoxy Wait.

The term "aryl" may be used alone or as part of "aralkyl", "aralkoxy" or "aryloxyalkyl", and may be monocyclic, bicyclic, and tricyclic carbocyclic ring systems, Wherein at least one ring system is aromatic, wherein each ring system contains 3-7 atoms. The term "aryl" may be used interchangeably with the term "aromatic ring", eg aromatic rings may include phenyl, naphthyl and anthracene. And the aryl group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, Amino, carboxyl, alkyl, alkyl-S(=O) _t- , haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, Alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C= O) NH- or alkoxyalkyl, etc. Depending on the structure, the aryl group can be a monovalent group or a divalent group (ie, an arylene group).

The terms "heteroaryl", "heteroaryl group" are used interchangeably herein, either alone or as part of a "heteroarylalkyl" or "heteroarylalkoxy", all refer to a single ring , a bicyclic, tricyclic or tetracyclic ring system, wherein the bicyclic heteroaryl group, the tricyclic heteroaryl group or the tetracyclic heteroaryl group system forms a ring in a fused form. Wherein, the heteroaryl group system is aromatic, and one or more atoms on the ring are independently and optionally replaced by heteroatoms (heteroatoms are selected from N, O, P, S, where S or P is optionally Substitution by one or more oxygen atoms gives groups like SO, SO2, PO, _{PO2 )} . Heteroaryl systems can be attached to the main structure at any heteroatom or carbon atom to form stable compounds. The heteroaromatic group can be a monocyclic ring composed of 3-7 atoms, a bicyclic ring composed of 7-10 atoms, or a tricyclic ring composed of 10-15 atoms. Bicyclic rings with 7-10 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, tricyclic rings with 10-15 atoms can be tricyclic [5,5,6], [5,7,6] or [6,5,6] system. And the heteroaryl or heteroaryl groups may be substituted or unsubstituted, where the substituents may be, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluoro, chloro , bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S(=O) _t- , haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, Aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl , methyl-(C=O)NH- or alkoxyalkyl, etc. Depending on the structure, a heteroaryl group can be a monovalent group or a divalent group (ie, a heteroarylene).

Other examples are that heteroaryl systems (comprising heteroaryl, heteroaryl groups) include, but are not limited to, the following examples: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazole Base, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl , 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4- Pyrimidinyl, pyrimidin-5-yl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazole (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadi Azolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3 ,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3, 5-triazinyl, benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl, benzimidazolyl, benzoxazolyl, 1,8-diazepine Naphthyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), tetrahydronaphthyl , benzopyrazolyl, acridinyl, benzimidazolyl, benzindolyl, benzisoxazinyl, benzo[4,6]imidazo[1,2-a]pyridyl, benzo [d] Imidazo[2,1-b]thiazolyl, benzofuryl, naphthofuryl, benzothiadiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyran Base, benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carbolinyl, carbazolyl, phthalazinyl, dibenzofuranyl, imidazopyridyl, imidazothiazole yl, indazolyl, indolazinyl, indolyl, isobenzothianyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, naphthyridinyl, decahydroinyl Indolyl, decahydroisoindolyl, oxazolidinedione, oxazolidinyl, oxazolopyridyl, oxazolyl, oxirane, tea pyrene, phenanthridine, phenanthrene Arborinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyridopyridinyl, quinazolinyl, quinoxalinyl, thiophenyl , triazinyl, 2H-pyrrolo[3,4-c]pyridinyl, pyrazolo[2',1':2,3]oxazolo[4,5-c]pyridinyl, imidazo[2 ',1':2,3]thiazolo[4,5-c]pyridyl, imidazo[2',1':2,3]thiazolo[4,5-b]pyridyl, imidazo[2 ',1':2,3]thiazolo[5,4-b]pyridyl, pyrazolo[2',1':2,3]thiazolo[4,5-b]pyrazinyl, 1H- Benzo[4,5]thieno[2,3-d]imidazolyl, 1-methyl-1H- Benzo[4,5]thieno[2,3-d]imidazolyl, imidazo[2′,1′:2,3]thiazolo[4,5-b]pyrazinyl, 1H-benzo[ f] imidazo[4,5-b][1,4]thiazepine and so on.

The terms "heteroaryl", "heteroaryl group" are used interchangeably herein, either alone or as part of a "heteroarylalkyl" or "heteroarylalkoxy", all refer to a single ring , a bicyclic, tricyclic or tetracyclic ring system, wherein the bicyclic heteroaryl group, the tricyclic heteroaryl group or the tetracyclic heteroaryl group system forms a ring in a fused form. Wherein, the heteroaryl group system is aromatic, and one or more atoms on the ring are independently and optionally replaced by heteroatoms (heteroatoms are selected from N, O, P, S, where S or P is optionally Substitution by one or more oxygen atoms gives groups like SO, SO2, PO, _{PO2 )} . Heteroaryl systems can be attached to the main structure at any heteroatom or carbon atom to form stable compounds. The heteroaromatic group can be a monocyclic ring composed of 3-7 atoms, a bicyclic ring composed of 7-10 atoms, or a tricyclic ring composed of 10-15 atoms. Bicyclic rings with 7-10 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, tricyclic rings with 10-15 atoms can be tricyclic [5,5,6], [5,7,6] or [6,5,6] system. And the heteroaryl or heteroaryl groups may be substituted or unsubstituted, where the substituents may be, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluoro, chloro , bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S(=O) _t- , haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, Aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl , methyl-(C=O)NH- or alkoxyalkyl, etc. Depending on the structure, a heteroaryl group can be a monovalent group or a divalent group (ie, a heteroarylene).

Other examples are that heteroaryl systems (comprising heteroaryl, heteroaryl groups) include, but are not limited to, the following examples: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazole Base, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl , 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4- Pyrimidinyl, pyrimidin-5-yl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazole (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadi Azolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3 ,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3, 5-triazinyl, benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl, benzimidazolyl, benzoxazolyl, 1,8-diazepine Naphthyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), tetrahydronaphthyl , benzopyrazolyl, acridinyl, benzimidazolyl, benzindolyl, benzisoxazinyl, benzo[4,6]imidazo[1,2-a]pyridyl, benzo [d] Imidazo[2,1-b]thiazolyl, benzofuryl, naphthofuryl, benzothiadiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyran Base, benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carbolinyl, carbazolyl, phthalazinyl, dibenzofuranyl, imidazopyridyl, imidazothiazole yl, indazolyl, indolazinyl, indolyl, isobenzothianyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, naphthyridinyl, decahydroinyl Indolyl, decahydroisoindolyl, oxazolidinedione, oxazolidinyl, oxazolopyridyl, oxazolyl, oxirane, tea pyrene, phenanthridine, phenanthrene Arborinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyridopyridinyl, quinazolinyl, quinoxalinyl, thiophenyl , triazinyl, 2H-pyrrolo[3,4-c]pyridinyl, pyrazolo[2',1':2,3]oxazolo[4,5-c]pyridinyl, imidazo[2 ',1':2,3]thiazolo[4,5-c]pyridyl, imidazo[2',1':2,3]thiazolo[4,5-b]pyridyl, imidazo[2 ',1':2,3]thiazolo[5,4-b]pyridyl, pyrazolo[2',1':2,3]thiazolo[4,5-b]pyrazinyl, 1H- Benzo[4,5]thieno[2,3-d]imidazolyl, 1-methyl-1H- Benzo[4,5]thieno[2,3-d]imidazolyl, imidazo[2′,1′:2,3]thiazolo[4,5-b]pyrazinyl, 1H-benzo[ f] imidazo[4,5-b][1,4]thiazepine and so on.

The terms "bicyclic heteroaryl group", "tricyclic heteroaryl group" systems form rings in fused form. Wherein, the heteroaryl group system is aromatic, and one or more atoms on the ring are independently and optionally replaced by heteroatoms (heteroatoms are selected from N, O, P, S, where S or P is optionally Substitution by one or more oxygen atoms gives groups like SO, SO2, PO, _{PO2 )} . Heteroaryl systems can be attached to the main structure at any heteroatom or carbon atom to form stable compounds. The heteroaromatic group can be a bicyclic ring consisting of 7-10 atoms, or a tricyclic ring consisting of 10-15 atoms. Bicyclic rings with 7-10 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, tricyclic rings with 10-15 atoms can be tricyclic [5,5,6], [5,7,6] or [6,5,6] system. Depending on the structure, the "bicyclic heteroaryl group", "tricyclic heteroaryl group" systems may be monovalent or divalent (i.e., "bicyclic heteroaryl", "tricyclic heteroaryl aryl" system).

Some other examples are that heteroaryl systems include, but are not limited to, the following examples: benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl, benzimidazolyl , benzoxazolyl, 1,8-naphthyridine, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolyl, 3- quinolinyl, 4-quinoline), tetrahydronaphthyl, benzopyrazolyl, acridinyl, benzimidazolyl, benzindolyl, benzisoxazinyl, benzo[4,6] Imidazo[1,2-a]pyridyl, benzo[d]imidazo[2,1-b]thiazolyl, benzofuryl, naphthofuryl, benzothiadiazolyl, benzothiobenzene Base, benzotriazolyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carbolinyl, carbazolyl, o-naphthyridine, Dibenzofuryl, imidazopyridyl, imidazothiazolyl, isobenzothianyl, isoindolinyl, isoquinolyl, naphthyridinyl, decahydroindolyl, decahydroisoindole Base, oxazolopyridyl, tea pyridine, phenanthridinyl, phenanthrolinyl, phenpyrazinyl, pteridyl, pyridopyridyl, quinazolinyl, quinoxalinyl, 2H- Pyrrolo[3,4-c]pyridyl, pyrazolo[2',1':2,3]oxazolo[4,5-c]pyridyl, imidazo[2',1':2, 3]Thiazolo[4,5-c]pyridyl, imidazo[2',1':2,3]thiazolo[4,5-b]pyridyl, imidazo[2',1':2, 3]Thiazolo[5,4-b]pyridinyl, pyrazolo[2',1':2,3]thiazolo[4,5-b]pyrazinyl, 1H-benzo[4,5] Thieno[2,3-d]imidazolyl, 1-methyl-1H-benzo[4,5]thieno[2,3-d]imidazolyl, imidazo[2′,1′:2,3 ]thiazolo[4,5-b]pyrazinyl, 1H-benzo[f]imidazo[4,5-b][1,4]thiazepinyl, etc.

The terms "carbocyclyl" or "cycloaliphatic", "carbocycle", "cycloalkyl" refer to monovalent or polyvalent, non-aromatic, saturated or partially unsaturated rings, containing no heteroatoms, wherein A monocyclic ring comprising 3-12 carbon atoms or a bicyclic or tricyclic ring comprising 7-12 carbon atoms. Bicarbocycles with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, while bicarbocycles with 9 or 10 atoms It can be a bicyclic [5,6] or [6,6] system. Depending on the structure, "carbocyclyl" or "cycloaliphatic", "carbocycle", "cycloalkyl" can be a monovalent group or a divalent group, that is, in certain embodiments of the present invention, It can be used instead of or as a carbocyclylene or cycloalkylene. Examples of cycloaliphatic groups further include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, Cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, etc. And the "carbocyclyl" or "cycloaliphatic", "carbocycle", "cycloalkyl" can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydrogen, aminoalkyl , aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S(=O) _t- , haloalkyl, hydroxyalkyl, alkoxy, Alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C =O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O)NH- or alkoxyalkyl, etc.

The terms "heterocyclyl", "heterocycloalkyl", "heterocycle", "heteroalicyclic" or "heterocyclic" are used interchangeably herein to mean monocyclic, bicyclic, tricyclic or tetracyclic A ring system in which one or more atoms of the ring are independently optionally substituted with heteroatoms, the rings may be fully saturated or contain one or more degrees of unsaturation, but are never aromatic. Depending on the structure, "heterocyclyl", "heterocycloalkyl", "heterocycle", "heteroalicyclic" can be a monovalent group or a divalent group, that is, in some embodiments of the present invention , can be used instead of or as a heterocyclylene. The heterocyclic ring system can be attached to the main structure at any heteroatom or carbon atom to form a stable compound. One or more ring hydrogen atoms are independently optionally substituted with one or more substituents described herein. In some examples, a "heterocyclyl", "heterocycloalkyl", "heterocycle", "heteroalicyclic" or "heterocyclic" group is a monocyclic (1- 6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain like SO, SO ₂ , PO, PO ₂ In addition, the carbon atom can be oxo-substituted to form -C=O-; when the ring is a three-membered ring, there is only one heteroatom), or a bicyclic ring composed of 7-10 atoms (4- 9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain like SO, SO ₂ , PO, PO ₂ group).

"Heterocyclic group" may be carbon group or heteroatom group. "Heterocyclyl" also includes the combination of a heterocyclic group and a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrofuranyl, Hydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepanyl , oxepyl, thiepanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, homopiperazinyl, 4-methoxy-piperidine -1-yl, oxazepinyl, diazepinyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2- Indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl, dithianyl, dithianolyl, dihydrothienyl, 1, 2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinane 1,1-dioxo-2-yl, hexahydro-2H-[1,4]dioxin[2, 3-c]pyrrolyl, 1,1-dioxythiomorpholinyl, 2,3,3a,7a-tetrahydro-1H-isoindolyl, isoindolinyl, 1,2,3,4-tetra Hydroquinolyl, N-pyridylurea, dioxolanyl, dihydropyrazinyl, dihydropyridyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, 1,4-dithia Alkyl, morpholinyl, decahydroindolyl, decahydroisoindolyl, piperazinyl, piperidinyl, pteridinyl, purinyl and pyrazinyl. And the heterocyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl , amino, carboxyl, alkyl, alkyl-S(=O) _t- , haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl , alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C =O)NH- or alkoxyalkyl, etc. For example, 1-methylpyridin-2(1H)-one, cyclohexa-2,4-dienonyl, 2,6-dimethyl-morphinyl and the like.

The terms "fused bicyclic", "fused ring", "fused bicyclyl" or "fused cycloyl" denote saturated or unsaturated fused ring systems, referring to non-aromatic bicyclic ring systems, at least one ring of which is non-aromatic of. Depending on the structure, a "fused bicyclic", "fused ring", "fused bicyclyl" or "fused cycloyl" can be monovalent or divalent, i.e., in certain embodiments of the invention, can replace Or it can be used as a subfused bicyclic group. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic rings or aromatic heterocycles (although aromatics may serve as substituents thereon). Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic, examples of which include, but are not limited to, hexahydro-furo[3,2-b]furanyl, 2,3,3a,4 ,7,7a-hexahydro-1H-indenyl, 7-azabicyclo[2.2.1]heptanyl, fused bicyclo[3.3.0]octyl, fused bicyclo[3.1.0]hexyl , 1,2,3,4,4a,5,8,8a-octahydronaphthyl, which are included in the fused bicyclic system. And the fused bicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, Hydroxy, amino, carboxy, alkyl, alkyl-S(=O) _t- , haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl Base, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-( C=O)NH- or alkoxyalkyl, etc.

The term "fused heterobicyclyl" means a saturated or unsaturated condensed ring system, involving non-aromatic bicyclic ring systems, at least one ring is non-aromatic. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic rings or aromatic heterocycles (although aromatics may serve as substituents thereon). Depending on the structure, the "fused heterobicyclic group" can be a monovalent or divalent group, that is, in some embodiments of the present invention, it can replace or be used as a sub-fused heterobicyclic group. And at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 3-7 atoms, that is, contains 1-6 carbon atoms and 1-3 selected from N, O, P, S heteroatoms, where S or P is optionally substituted by one or more oxygen atoms to give groups like SO, SO ₂ , PO, PO ₂ , in addition, carbon atoms can also be substituted by oxo to form -C=O -; such examples include, but are not limited to, hexahydro-2H-[1,4]dioxin[2,3-c]pyrrolyl, 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]nonanyl 3-yl , 3-Azabicyclo[4.3.0]nonan-3-yl, 1,5-dioxo-8-azabicyclo[4.3.0]nonanyl, (1R,6S)-2,5-di Oxy-8-azabicyclo[4.3.0]nonyl, (1R,6R)-2,5-dioxo-8-azabicyclo[4.3.0]nonyl, isoindolinyl, 1 ,2,3,4-tetrahydroquinolinyl, (1S,5S)-1-hydroxyl-3-azabicyclo[3.1.0]hexyl, (1R,5S)-1-hydroxyl-3-nitrogen Heterobicyclo[3.1.0]hexyl, (1R,5S)-1-N,N-dimethylamino-3-azabicyclo[3.1.0]hexyl, (1S,5R,6R)- 1-methyl-6-ol-3-azabicyclo[3.2.0]heptyl, 3-aza-7-oxabicyclo[3.3.0]octyl, 3,7-diazabicyclo[ 3.3.0]octyl, 2,6-diazabicyclo[3.3.0]octyl, 3-ethyl-3,7-diazabicyclo[3.3.0]octyl, 2,7 -Diazabicyclo[3.3.0]octyl, 7-acetyl-2,7-diazabicyclo[3.3.0]octyl, 2,8-diazabicyclo[4.3.0]nonyl Alkyl, 2-methyl-2,8-diazabicyclo[4.3.0]nonyl, 3-oxo-8-azabicyclo[4.3.0]nonyl, 2-oxo-8-nitro Heterobicyclo[4.3.0]nonyl, 2,8-diaza-5-oxabicyclo[4.3.0]nonyl, (1S,6R)-2-methyl-2,8-diaza- 5-oxabicyclo[4.3.0]nonyl, 3-ethyl-3,9-diazabicyclo[4.3.0]nonyl, 4,9-diazabicyclo[4.3.0]nonyl Alkyl, 2,9-diazabicyclo[4.3.0]nonyl, 3-methyl-3,9-diazabicyclo[4.3.0]nonyl, 3-ethyl-3,7 -Diazabicyclo[4.3.0]nonyl, 3-methyl-3,7-diazabicyclo[4.3.0]nonyl, 2-ethyl-2,8-diazabicyclo[ 4.3.0] Nonyl, 3-oxo-2,4,8-triazabicyclo[4.3.0]nonyl, 3-oxo-4-oxo-2,8-diazabicyclo Cyclo[4.3.0]nonyl, 3-oxo-2,8-diazabicyclo[4.3.0]nonyl, 3,8-diazabicyclo[4.3.0]nonyl, 8 -Methyl-2,8-diazabicyclo[4.3.0]nonyl, 3,7-diazabicyclo[4.3.0]nonyl, 3,9-diazabicyclo[4.3.0 ]nonyl, 3-oxo-8-azabicyclo[4.3.0]nonyl, 3-thio-8-azabicyclo[4.3.0]nonyl, 9-methyl-3,9- Diazabicyclo[4.3.0]nonyl, 7-methyl-3,7-diazabicyclo[4.3.0]nonyl, 9-ethyl-3,9-diazabicyclo[4.3 .0]nonyl, 7-ethyl-3,7-diazabicyclo[4.3.0]nonyl, 8-ethyl-2,8-diazabicyclo[4.3.0]nonyl , 5,6-dihydro-4H-pyrrolo[3,4-c]isoxazolyl, 3-ethyl-[1,2,4]triazol[4,3-a]piperidinyl , [1,2,4]triazolo[4,3-a]piperidinyl, 3-methyl-isoxazolo[4,3-c]piperidinyl, 3-methyl-5, 6-dihydro-4H-pyrrolo[3,4-c]isoxazolyl, 2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridyl , 2-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridyl, 2-methyl-4,5,6,7-tetrahydro-1H-thiazolo[ 4,5-c]pyridyl, isoxazolo[4,3-c]piperidinyl, 4,5,6,7-tetrahydroisoxazolo[3,4-c]pyridyl, [1 ,2,4]triazolo[4,3-a]piperazinyl, 3-trifluoromethyl-[1,2,4]triazolo[4,3-a]piperazinyl, 3 -Methyl-[1,2,4]triazolo[4,3-a]piperazinyl, 2-oxo-3-oxo-8-azabicyclo[4.3.0]nonyl, 1 ,3-Dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinyl, 2-oxo-7-azabicyclo[4.4.0]decane Base, 1,5-dioxo-9-azabicyclo[4.4.0]decyl, 2,3-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4, 3-c]pyridinyl, 3-azabicyclo[4.4.0]decyl, 5-benzyl-2-oxo-5,8-diazabicyclo[4.3.0]nonyl, 2, 7-diazadecalinyl or 2-oxo-8-azabicyclo[4.4.0]decyl, etc. And the fused heterobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine , hydroxy, amino, carboxyl, alkyl, alkyl-S(=O) _t- , haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, hetero Aryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl- (C=O)NH- or alkoxyalkyl, etc.

The term "bridged bicyclyl" denotes a saturated or unsaturated bridged ring system, referring to non-aromatic bicyclic ring systems. Such systems may contain isolated or conjugated unsaturations, but their core structure does not contain aromatic rings or heteroaryl groups (although aromatics may serve as substituents thereon). wherein each ring system contains 3-7 atoms, examples of such include, but are not limited to, bicyclo[2.2.1]heptanyl, 2-methyl-heterobicyclo[2.2.1]heptanyl, etc. . And the bridged bicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl , amino, carboxyl, alkyl, alkyl-S(=O) _t- , haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl , alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C =O)NH- or alkoxyalkyl, etc.

The term "bridged heterobicyclyl" denotes a saturated or unsaturated bridged ring system, involving non-aromatic bicyclic ring systems. Depending on the structure, the "bridged heterobicyclic group" can be a monovalent group or a divalent group, that is, in some embodiments of the present invention, it can replace or be used as a bridged heterobicyclic group. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic rings or aromatic heterocycles (although aromatics may serve as substituents thereon). And at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 atoms, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , where S or P is optionally substituted by one or more oxygen atoms to obtain groups like SO, SO ₂ , PO, PO ₂ , in addition, carbon atoms can also be oxo-formed -C=O-; Examples include, but are not limited to, 2-oxo-5-azabicyclo[2.2.1]heptanyl, 2-thio-5-azabicyclo[2.2.1]heptanyl, 2-oxo- 5-Azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-methyl-2,5-diazabicyclo[2.2.1 ] Heptyl etc. And the bridged heterobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, Hydroxy, amino, carboxy, alkyl, alkyl-S(=O) _t- , haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl Base, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-( C=O)NH- or alkoxyalkyl, etc.

The term "cycloalkylalkyl" means that an alkyl group is substituted by one or more cycloalkyl groups, wherein the alkyl and cycloalkyl groups have the meanings described in the present invention, where examples may be, but not limited to , cyclopropylmethyl, cyclohexylmethyl, cyclohexylethyl, etc.

The term "heterocyclylalkyl" refers to an alkyl group substituted by one or more heterocyclyl groups, wherein the alkyl and heterocyclyl groups have the meanings described in the present invention, where examples may be, but not limited to , cyclopropoxymethyl, morpholinomethyl, piperidinylethyl, etc.

The term "cycloalkyloxy" or "carbocyclyloxy" includes an optionally substituted cycloalkyl or carbocyclyl, as defined herein, attached to an oxygen atom and connected by the oxygen atom to the rest of the molecule , such examples include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy, and the like.

The term "cycloalkylamino" means that an amino group is substituted by one or two cycloalkyl groups, wherein cycloalkyl has the meaning described in the present invention, such examples include, but are not limited to, cyclopropylamino , cyclopentylamino, cyclohexylamino, hydroxy-substituted cyclopropylamino, dicyclohexylamino, dicyclopropylamino, etc.

The term "arylalkoxy" means that an alkoxy group is substituted by one or more aryl groups, wherein aryl and alkoxy have the meanings described herein, examples of which include, but are not limited to, benzene Phenylmethoxy, phenylethoxy, p-tolylmethoxy, phenylpropoxy, etc.

The term "arylalkylamino" means that an alkylamino group is substituted by one or more aryl groups, wherein aryl and alkylamino have the meanings described herein, examples of which include, but are not limited to, phenyl Methylamino, phenylethylamino, phenylpropylamino, p-tolylmethylamino, etc.

The term "heteroarylalkoxy" means that an alkoxy group is substituted by one or more heteroaryl groups, wherein heteroaryl and alkoxy have the meanings described herein, examples of which include, but are not Limited to, pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, etc.

The term "heteroarylalkylamino" includes heteroarylalkyl groups attached to other groups through a nitrogen atom, wherein heteroarylalkyl has the meaning described herein, examples of which include, but are not limited to , pyridin-2-ylmethylamino, thiazol-2-ylethylamino, imidazol-2-ylethylamino, pyrimidin-2-ylpropylamino, pyrimidin-2-ylmethylamino, etc.

The term "heterocyclylalkoxy" includes heterocyclyl-substituted alkoxy groups wherein the oxygen atom is attached to the remainder of the molecule; the term "heterocyclylalkylamino" includes heterocyclyl-substituted alkylamino groups wherein the nitrogen atom is bonded to the rest of the molecule; The rest of the molecule is connected. Where heterocyclyl, alkoxy and alkylamino have the meanings described herein, such examples include, but are not limited to, morpholin-4-ylethoxy, piperazin-4-ylethoxy, Piperidin-4-ylethylamino, etc.

The term "cycloalkylalkoxy", or "carbocyclylalkoxy" means that an alkoxy group is substituted with one or more cycloalkyl or carbocyclyl groups, wherein the cycloalkyl group Or carbocyclyl groups and alkoxy groups have meanings as described in the present invention, such examples include, but are not limited to, cyclopropylmethoxy, cyclopropylethoxy, cyclopentylethoxy base, cyclohexylethoxy, cyclohexylmethoxy, cyclopropylpropoxy, etc.

The term "cycloalkylalkylamino" or "carbocyclylalkylamino" means that an alkylamino group is substituted by one or more cycloalkyl or carbocyclyl groups, wherein the cycloalkyl or carbocyclyl and alkylamino groups have the meanings described herein, examples of which include, but are not limited to, cyclopropylmethylamino, cyclopropylethylamino, cyclopentylethylamino, cyclohexylethylamino, cyclo Hexylmethylamino, cyclopropylpropylamino, etc.

The term "aryloxyalkoxy" means that an alkoxy group is substituted by one or more aryloxy groups, wherein the alkoxy and aryloxy groups have the meanings described herein, examples of which include, But not limited to, phenoxymethoxy, phenoxyethoxy, phenoxypropoxy and the like.

The term "heteroaryloxyalkoxy" means an alkoxy group substituted by one or more heteroaryloxy groups, wherein the alkoxy and heteroaryloxy groups have the meanings described herein , such examples include, but are not limited to, pyridyloxymethoxy, pyrimidinyloxyethoxy, thiazolyloxypropoxy, and the like.

The terms "aryloxy" or "aryloxy" include optionally substituted aryl groups, as defined herein, attached to and through the oxygen atom to the remainder of the molecule, wherein the aryl group has Examples of such, within the meaning of the present invention, include, but are not limited to, phenoxy, tolyloxy, ethylphenoxy, and the like.

The term "heteroaryloxy" includes optionally substituted heteroaryl groups, as defined herein, attached to and through the oxygen atom to the remainder of the molecule, wherein the heteroaryl group has Examples of such meanings include, but are not limited to, pyridin-2-oxyl, thiazole-2-oxyl, imidazol-2-oxyl, pyrimidin-2-oxyl, and the like.

The term "heterocyclyloxyalkoxy" means that an alkoxy group is substituted by one or more heterocyclyloxy groups, wherein the alkoxy and heterocyclyloxy groups have the meanings described herein , such examples include, but are not limited to, pyrrole-2-oxymethoxy, pyrrole-3-oxyethoxy, piperidine-2-oxyethoxy, piperidine-3-oxyethoxy Oxy, piperazine-2-oxymethoxy, piperidine-4-oxyethoxy, etc.

The term "carbocyclyloxyalkoxy" means that an alkoxy group is substituted by one or more carbocyclyloxy groups, wherein the alkoxy and carbocyclyloxy groups have the meanings described herein , such examples include, but are not limited to, cyclopropyloxymethoxy, cyclopropyloxyethoxy, cyclopentyloxyethoxy, cyclohexyloxyethoxy, cyclohexenyl -3-oxyethoxy and the like.

The term "heterocyclyloxy" includes optionally substituted heterocyclyl groups, as defined herein, attached to an oxygen atom where the oxygen atom is attached to the rest of the molecule, examples of which include, but are not limited to, Pyrrole-2-oxyl, pyrrole-3-oxyl, piperidine-2-oxyl, piperidine-3-oxyl, piperazine-2-oxyl, piperidine-4-oxyl and the like.

The term "fused bicyclyloxy" includes optionally substituted fused bicyclyl groups, as defined herein, attached to an oxygen atom and connected by the oxygen atom to the rest of the molecule, examples of which include, but do not limited to, 1,2,3,4,4a,5,8,8a-octahydronaphthyloxy, fused bicyclo[3.3.0]octane-2-oxyl, fused bicyclo[3.1.0]hexyl Alk-2-oxyl, etc.

The term "fused heterobicyclyloxy" includes optionally substituted fused heterobicyclyl groups, as defined herein, attached to an oxygen atom and connected by the oxygen atom to the rest of the molecule, examples of which include, but Not limited to, hexahydro-furo[3,2-b]furan-2-yloxy, 7-azabicyclo[2.3.0]heptane-2-yloxy, 7-azabicyclo[2.3. 0] Heptan-4-yloxy and the like.

The term "fused bicyclylamino" means that the amino group is substituted by one or two fused bicyclic groups, wherein the fused bicyclic group has the meaning as described in the present invention, such examples include, but are not limited to, 1, 2,3,4,4a,5,8,8a-octahydronaphthylamino, di(1,2,3,4,4a,5,8,8a-octahydronaphthyl)amino, fused bicyclic [3.3 .0]octylamino, fused bicyclo[3.1.0]hexylamino, etc.

The term "fused heterobicyclylamino" means that the amino group is substituted by one or two fused heterobicyclyl groups, wherein the fused heterobicyclyl has the meaning as described in the present invention, such examples include, but are not limited to , Hexahydro-furo[3,2-b]furan-2-ylamino, 7-azabicyclo[2.3.0]heptane-2-ylamino, 7-azabicyclo[2.3.0]heptane- 4-ylamino, etc.

The term "fused bicyclylalkylamino" means that an alkylamino group is substituted by one or two fused bicyclic groups, wherein the fused bicyclic groups have the meanings described in the present invention, examples of which include, but are not limited to, 1,2,3,4,4a,5,8,8a-octahydronaphthylmethylamino, di(1,2,3,4,4a,5,8,8a-octahydronaphthyl)methylamino, condensed Fused bicyclo[3.3.0]octylmethylamino, fused bicyclo[3.1.0]hexylmethylamino, etc.

The term "fused heterobicyclylalkylamino" means that an alkylamino group is substituted by one or two fused heterobicyclyl groups, wherein fused heterobicyclyl groups have the meanings described herein, such examples include, but do not Not limited to, hexahydro-furo[3,2-b]furan-2-ylmethylamino, 7-azabicyclo[2.3.0]heptan-2-ylmethylamino, 7-azabicyclo[2.3.0 ] heptane-4-ylmethylamino and the like.

The term "fused bicyclylalkoxy" means that an alkoxy group is substituted by one or more fused bicyclyl groups, wherein alkoxy and fused bicyclyl have the meanings described herein, examples of which include , but not limited to, 1,2,3,4,4a,5,8,8a-octahydronaphthylmethoxy, 1,2,3,4,4a,5,8,8a-octahydronaphthyl Ethoxy, fused bicyclo[3.3.0]octane-ethoxy, fused bicyclo[3.1.0]hexane-propoxy, etc.

The term "fused heterobicyclylalkoxy" means that an alkoxy group is substituted by one or more fused heterobicyclyl groups, wherein alkoxy and fused heterobicyclyl have the meanings described herein, such that Examples include, but are not limited to, hexahydro-furo[3,2-b]furan-2-ylpropoxy, 7-azabicyclo[2.2.1]heptan-2-ylethoxy, 7 -Azabicyclo[2.3.0]heptan-4-ylpropoxy, hexahydro-furo[3,2-b]furan-2-ylethoxy, 7-azabicyclo[2.3.0]heptan Alk-2-ylpropoxy, 7-azabicyclo[2.3.0]heptan-4-ylethoxy and the like.

The term "fused bicyclylalkyl" means that an alkyl group is substituted by one or more fused bicyclyl groups, wherein alkyl and fused bicyclyl have the meanings described herein, examples of which include, but do not Not limited to, 1,2,3,4,4a,5,8,8a-octahydronaphthylmethyl, 1,2,3,4,4a,5,8,8a-octahydronaphthylethyl, condensed Fused bicyclo[3.3.0]octane-ethyl, fused bicyclo[3.1.0]hexane-propyl, etc.

The term "fused heterobicyclylalkyl" means that an alkyl group is substituted by one or more fused heterobicyclyl groups, wherein alkyl and fused heterobicyclyl have the meanings described herein, examples of which include , but not limited to, hexahydro-furo[3,2-b]furan-2-ylpropyl, 7-azabicyclo[2.2.1]heptan-2-ylethyl, 7-azabicyclo[ 2.3.0]heptan-4-ylpropyl, hexahydro-furo[3,2-b]furan-2-ylethyl, 7-azabicyclo[2.3.0]heptan-2-ylpropyl , 7-azabicyclo[2.3.0]heptan-4-ylethyl, etc.

The term "fused heterobicyclyloxyalkoxy" means that an alkoxy group is substituted by one or more fused heterobicyclyloxy groups, wherein the alkoxy and fused heterobicyclyloxy groups have Examples of such meanings include, but are not limited to, hexahydro-furo[3,2-b]furan-2-yloxypropoxy, 7-azabicyclo[2.2.1]heptane- 2-yloxyethoxy, 7-azabicyclo[2.3.0]heptan-4-yloxypropoxy, hexahydro-furo[3,2-b]furan-2-yloxyethoxy Oxy, 7-azabicyclo[2.3.0]heptan-2-yloxypropoxy, 7-azabicyclo[2.3.0]heptan-4-yloxyethoxy, etc.

The term "fused heterobicyclyloxyalkylamino" means that an alkylamino group is substituted by one or more fused heterobicyclyloxy groups, wherein the alkylamino and fused heterobicyclyloxy groups have meaning, such examples include, but are not limited to, hexahydro-furo[3,2-b]furan-2-yloxypropylamino, 7-azabicyclo[2.2.1]heptan-2-yloxy ylethylamino, 7-azabicyclo[2.3.0]heptan-4-yloxypropylamino, hexahydro-furo[3,2-b]furan-2-yloxyethylamino, 7-aza Bicyclo[2.3.0]heptan-2-yloxypropylamino, 7-azabicyclo[2.3.0]heptan-4-yloxyethylamino, etc.

The term "bridged heterobicyclylalkoxy" means that an alkoxy group is substituted by one or more bridged heterobicyclyl groups, wherein the bridged heterobicyclyl and alkoxy groups have the meanings described in the present invention, such Examples include, but are not limited to, 2-oxo-5-azabicyclo[2.2.1]heptylmethoxy, 2,5-diazabicyclo[2.2.1]heptylethoxy, 2-Methyl-2,5-diazabicyclo[2.2.1]heptylpropoxy, etc.

The term "bridged heterobicyclylalkyl" means that an alkyl group is substituted by one or more bridged heterobicyclyl groups, wherein the bridged heterobicyclyl and alkyl groups have the meanings described herein, examples of which include, But not limited to, 2-oxo-5-azabicyclo[2.2.1]heptylmethyl, 2,5-diazabicyclo[2.2.1]heptylethyl, 2-methyl- 2,5-diazabicyclo[2.2.1]heptylpropyl, etc.

The term "bridged heterobicyclylalkylamino" means that an alkylamino group is substituted by one or more bridged heterobicyclyl groups, wherein the bridged heterobicyclyl and alkylamino groups have the meanings described in the present invention, such examples include, But not limited to, 2-oxo-5-azabicyclo[2.2.1]heptylmethylamino, 2,5-diazabicyclo[2.2.1]heptylethylamino, 2-methyl- 2,5-diazabicyclo[2.2.1]heptylpropylamino, etc.

The term "bridged heterobicyclyloxy" includes optionally substituted bridged heterobicyclyl groups, as defined herein, attached to an oxygen atom and connected by the oxygen atom to the rest of the molecule, examples of which include, but do not Limited to, 2-methyl-2,5-diazabicyclo[2.2.1]heptanyloxy, 2,5-diazabicyclo[2.2.1]heptanyloxy, etc.

The term "arylalkyl" means that an alkyl group is substituted by one or more aryl groups, wherein the alkyl group and aryl group have the meanings described herein, examples of which include, but do not Not limited to phenethyl, benzyl, p-tolylethyl, etc.

The term "heteroarylalkyl" means that an alkyl group is substituted by one or more heteroaryl groups, wherein the alkyl group and the heteroaryl group have the meanings described herein, examples of which include , but not limited to, pyridine-2-ethyl, thiazol-2-methyl, imidazol-2-ethyl, pyrimidine-2-propyl, etc.

The term "alkylthio" includes a C _1-10 linear or branched alkyl group connected to a divalent sulfur atom, wherein the alkyl group has the meaning as described in the present invention. In some embodiments, the alkylthio group is a lower C _1-3 alkylthio group, such examples include, but are not limited to, methylthio (CH ₃ S-), ethylthio and the like.

The term "aminoacyl" refers to -C(=O) _NH2 .

The term "alkyl-C(=O)NH-" includes C _1-10 linear or branched alkyl attached to -C(=O)NH-, wherein the alkyl group has meaning. Such examples include, but are not limited to, acetamido ( _CH3C (=O)NH-), propionamido _{( C2H5C} (=O)NH-), and the like.

The terms "spirocyclyl", "spirocycle", "spirobicyclyl", "spirobicyclyl" indicate that one ring is derived from a specific cyclic carbon on another ring. For example, as described below, a saturated bridged ring system (rings B and B') is called a "fused bicyclic ring", whereas rings A and B share a carbon atom in two saturated ring systems, then Known as a "spiral". Each ring within a spirocycle is either carbocyclic or heteroalicyclic. Examples of such include, but are not limited to, 4-azaspiro[2.4]heptan-5-yl, 4-oxaspiro[2.4]heptan-5-yl, 5-azaspiro[2.4]heptane -5-yl, spiro[2.4]heptanyl, spiro[4.4]nonyl, 7-hydroxy-5-azaspiro[2.4]heptan-5-yl, etc. And the spirobicyclyl can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl , amino, carboxyl, alkyl, alkyl-S(=O) _t- , haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl , alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C =O)NH- or alkoxyalkyl, etc.

The term "spiroheterobicyclyl" means that one ring is derived from a specific cyclic carbon on another ring. For example, as described above, a saturated bridged ring system (rings B and B') is called a "fused bicyclic ring", whereas rings A and B share a carbon atom in two saturated ring systems, then Known as a "spiral". And at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 atoms, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , where S or P is optionally substituted with one or more oxygen atoms to obtain groups like SO, SO ₂ , PO, PO ₂ , examples of which include, but are not limited to, 4-azaspiro[2.4] Heptyl, 4-oxaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, 7-hydroxy-5-azaspiro[2.4]heptyl, 2-azaspiro[ 4.5]decyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[4.4]nonyl, 2-methyl-2,6-diazaspiro[4.5]decyl, 3-Azaspiro[5.4]decyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-oxo-6-azaspiro[3.3]heptanyl, 2,6-di Azaspiro[3.3]heptyl, 2-thio-6-azaspiro[3.3]heptyl 2-monoxide, 2-thio-6-azaspiro[3.3]heptanyl 2,2- Dioxide etc. And the spiroheterobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, Hydroxy, amino, carboxy, alkyl, alkyl-S(=O) _t- , haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl Base, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-( C=O)NH- or alkoxyalkyl, etc.

The term "spiroheterobicyclylalkoxy" means that an alkoxy group is substituted by one or more spiroheterobicyclyl groups, wherein the spiroheterobicyclyl and alkoxy groups have the meanings as described in the present invention, such Examples include, but are not limited to, 4-azaspiro[2.4]heptan-5-ylmethoxy, 4-azaspiro[2.4]heptan-2-ylethoxy, 4-oxaspiro[ 2.4] Heptan-5-ylethoxy, 5-azaspiro[2.4]heptan-5-ylpropoxy, etc.

The term "spiroheterobicyclylalkyl" means that an alkyl group is substituted by one or more spiroheterobicyclyl groups, wherein spiroheterobicyclyl and alkyl groups have the meanings described herein, examples of which include, But not limited to, 4-azaspiro[2.4]heptane-5-ylmethyl, 4-azaspiro[2.4]heptane-2-ylethyl, 4-oxaspiro[2.4]heptane- 5-ylethyl, 5-azaspiro[2.4]heptan-5-ylpropyl, etc.

"Antiproliferative agent" refers to antimetabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine, taxanes such as paclitaxel , polyene taxol), alkylating agents (e.g. cyclophosphamide, melphalan, carmustine, nitrosoureas such as dichloroethylnitrosourea and hydroxyurea), platinum agents (e.g. cisplatin , Carboplatin, Oxyplatin, JM-216, Cl-973), anthracyclines (such as doxrubicin, daunomycin), antineoplastic antibiotics (such as mitomycin, flavin, doxorubicin, daunomycin ), topoisomerase inhibitors (eg, etoposide, camptothecin), antiangiogenic agents (eg, and Bevacizumab), or any cytotoxic agent (estramustine phosphate, prednimustine), hormones, or Agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors and radiation therapy.

As described in the present invention, the ring system formed by the substituent R connected to the central ring by a bond means that the substituent R can be substituted at any substitutable or any reasonable position on the ring. For example, formula a represents that any possible substituted position on ring A or ring B can be substituted by R, as shown in formula b, formula c, formula d, formula e, formula f, formula g, and formula h.

As described in the present invention, the substituent (R) _n is connected to the central ring by a bond to form a ring system representing that n substituents R can be substituted at any substitutable position on the ring. For example, formula i represents that any possible substituted position on ring A or ring B can be substituted by n Rs.

As described in the present invention, there are two connection points on ring C that can be connected to the rest of the molecule, for example, as shown in formula j, which means that either the E end or the E' end can be connected to the rest of the molecule, namely The connections at both ends are interchangeable.

As described herein, the point of attachment can be attached to the rest of the molecule at any attachable position on the loop. For example, formula k represents that any possible linking position on ring A or ring B can be used as a linking point.

As described herein, the point of attachment can be attached to the rest of the molecule at any attachable position on the loop, and the two ends of the attachment can be interchanged. For example, the formula y represents that any position on the ring that may be connected can be used as a connection point, and at the same time, the two ends of the connection point can be interchanged.

In addition, it should be noted that, unless otherwise clearly stated, the descriptions used throughout this article are "each...and...independently", "...and...are independently" and "...and ...are independently "" and can be interchanged, which should be understood in a broad sense. It can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or they can be expressed in the same group , the specific options expressed by the same symbol do not affect each other. For example, the specific options of each G between the structural formula 1 and the structural formula m are not affected by each other, and at the same time, in the same structural formula, such as formula 1, the specific options of multiple Gs are not affected by each other; The specific options are not affected by each other; or as in formula m, the specific options of multiple G are not affected by each other; the specific options of multiple n are not affected by each other.

Definitions of stereochemistry and usage of conventions in the present invention are generally referred to in the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. , "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and thus exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center. The prefixes d, l or (+), (-) are used to name the symbol of the plane polarized light rotation of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are the same, but their three-dimensional structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is known as a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during a chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

The term "tautomer" or "tautomeric form" means that isomers of different energies can be interconverted via a lower energy barrier. Examples of this include, but are not limited to, proton tautomers (i.e., prototropic isomers) including interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations effect. Valence tautomers include recombination interconversions of some of the bonding electrons.

The "hydrate" of the present invention refers to the compound provided by the present invention or its salt, which also includes water combined by non-covalent intermolecular forces in chemical or non-stoichiometric amounts, and it can also be said that the solvent molecules are formed by water. association.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol.

"Ester" in the present invention means that a compound of formula (I) or formula (II) containing a hydroxyl group can form an ester which is hydrolyzable in vivo. Such esters are, for example, pharmaceutically acceptable esters which hydrolyze in the human or animal body to yield the parent alcohol. In vivo hydrolyzable ester groups of compounds of formula (I) or formula (II) containing hydroxyl include, but are not limited to, phosphate, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy group, alkanoyl group, benzoyl group, benzoacetyl group, alkoxycarbonyl group, dialkylcarbamoyl group and N-(dialkylaminoethyl)-N-alkylcarbamoyl group, etc.

The "nitrogen oxide" in the present invention means that when the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids such as peroxycarboxylic acids to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), wherein an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as dichloromethane reaction.

Compounds may exist in a variety of different geometric isomers and tautomers, and said compounds of formula (I) or formula (II) include all such forms. For the avoidance of doubt, when a compound exists as one of several geometric isomers or tautomers and only one is specifically described or shown, it is evident that all other forms are included in formula (I) or formula (II).

The term "prodrug" used in the present invention means that a compound is transformed into a compound represented by formula (I) or formula (II) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug with phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters. For example, a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium 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 SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2528-23 .

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

"Metabolite" refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.

Various pharmaceutically acceptable salt forms of the compounds of the invention are useful. The term "pharmaceutically acceptable salts" refers to those salt forms which are obvious to a pharmaceutical chemist, i.e., which are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism, or excretion. Other factors, which are more practical in nature, are also important for selection, these are: cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting drug substance. Briefly, the pharmaceutical composition can be prepared from active ingredients and pharmaceutically acceptable carriers.

The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, 2-hydroxypropionate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate , Butyrate, Camphorate, Camphorsulfonate, Cyclopentylpropionate, Digluconate, Lauryl Sulfate, Ethylate, Formate, Fumarate, Glucose Heptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, lauric acid Salt, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate Salt, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valeric acid salt, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _{1 -8} sulfonates and aromatic sulfonates. Amine salts such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucose Amines, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkaline earth metal salts such as but not limited to barium, calcium and magnesium; transition metal salts such as but not limited to zinc.

The term "protecting group" or "Pg" refers to a substituent that reacts with another functional group, usually to block or protect specific functionality. For example, "amino-protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of carboxyl to block or protect the functionality of carboxyl. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane base) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl phosphino)ethyl, nitroethyl, etc. For a general description of protecting groups, refer to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

In this specification, if there is any discrepancy between a chemical name and a chemical structure, the structure shall prevail.

The abbreviations of any protecting groups, amino acids and other compounds used in the present invention, unless otherwise specified, are based on their commonly used and recognized abbreviations, or refer to IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem.1972, 11: 942-944).

DESCRIPTION OF THE COMPOUNDS OF THE INVENTION

In one aspect, the present invention provides a substituted urea derivative, which is a compound having the structure shown in formula (I), or a stereoisomer or geometric isomer of the compound shown in formula (I), Tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof,

in:

The K ring is a 5-6 membered heteroaryl group;

Q and W are each independently CH or N;

Each L is independently amino, nitro, alkylthio, alkyl, cycloalkyl, heterocyclyl, haloalkyl, alkylamino, hydroxy, fluorine, chlorine, bromine, iodine, alkyl-C(=O) -NH-, alkoxy, hydroxyalkyl or cyano;

Each R ¹ is independently hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 haloalkyl, C _1-4 alkyl, C _1-6 alkyl-S(=O) _t- , C _1-6 alkane Oxygen C _1-6 alkyl, C _1-4 alkylamino, hydroxyl, cyano, nitro, C _1-4 alkyl-C(=O)-NH-, C _1-4 alkoxy, hydroxyl C _1-4 alkyl or C _1-4 alkylthio;

Ring E is a bicyclic heteroaryl group or a tricyclic heteroaryl group; wherein the heteroaryl group has at least 2 heteroatoms, and each heteroatom is independently O, S, NR ⁴ or N;

each R is independently hydrogen, haloalkyl, alkyl ^- C(=O)-, alkoxyalkyl, hydroxyalkyl, benzyl, cycloalkyl, heterocyclyl or alkyl;

each J is independently -G-( _CH2 ) _n- R;

Each G is independently -O-, -S-, -S(=O) _t -, -C(=O)- or -(CH ₂ ) _n -C(=O)-;

Each R is independently hydrogen, -NR ³ R ² , alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, heterocyclyl, alkyl -S(=O) _t- , alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy Oxy, Arylalkoxy, Arylalkylamino, Heteroarylalkoxy, Heteroarylalkylamino, Heterocyclylalkylamino, Cycloalkyloxy, Cycloalkylamino, Heterocyclylalkoxy , carbocyclylalkoxy, carbocyclylalkylamino, aryloxyalkoxy, aryloxy, heteroaryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbon Cyclooxyalkoxy, heterocyclyloxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino , Fused Heterobicyclylalkoxy, Fused Heterobicyclylalkylamino, Fused Heterobicyclyloxyalkoxy, Fused Heterobicyclyloxyalkylamino, Spiroheterobicyclylalkyl, Spiroheterobicyclyl Alkoxy, Endobicyclylalkyl, Endoheterobicyclyloxy, Endoheterobicycloalkoxy, Endoheterobicycloalkylamino, Aryl, Arylalkyl, Heteroarylalkyl, Heteroaryl , bridged heterobicyclyl, spiro heterobicyclyl or fused heterobicyclyl;

each of ^R and R is independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxyalkyl or hydroxyalkyl ^;

each n is independently 1, 2, 3 or 4;

each t is independently 0, 1 or 2;

each e is independently 0, 1, 2, 3 or 4;

each d is independently 1, 2, 3 or 4;

each a is independently 0, 1, 2, 3 or 4;

each b is independently 2, 3 or 4;

Wherein, the aryl group, bicyclic heteroaryl group, tricyclic heteroaryl group, heteroaryl group, alkoxyalkyl group, alkoxyl group, -G-(CH ₂ ) _n -R, -(O-(CH ₂ ) _n ) _e -O-, -(CH ₂ ) _n -C(=O)-, alkyl-S(=O) _t -, hydroxyalkyl, arylalkyl, hetero Arylalkyl, Heteroaryl, Heterocyclyl, Bridged Heterobicyclyl, Spiroheterobicyclyl, Fused Heterobicyclyl, Alkyl, Haloalkyl, Alkylamino, Hydroxyalkoxy, Aminoalkoxy, Haloalkane Oxy, alkenyl, alkynyl, cycloalkylalkyl, heterocyclylalkyl, alkyl-C(=O)-, benzyl, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy Oxy, Arylalkoxy, Arylalkylamino, Heteroarylalkoxy, Heteroarylalkylamino, Heterocyclylalkylamino, Cycloalkyloxy, Cycloalkylamino, Heterocyclylalkoxy , carbocyclylalkoxy, carbocyclylalkylamino, aryloxyalkoxy, aryloxy, heteroaryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbon Cyclooxyalkoxy, heterocyclyloxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino , Fused Heterobicyclylalkoxy, Fused Heterobicyclylalkylamino, Fused Heterobicyclyloxyalkoxy, Fused Heterobicyclyloxyalkylamino, Spiroheterobicyclylalkyl, Spiroheterobicyclyl Alkoxy, bridged heterobicyclylalkyl, bridged heterobicyclyloxy, bridged heterobicyclylalkoxy, bridged heterobicyclylalkylamino, alkyl-C(=O)-NH-, alkylthio, ring The alkyl group and the B ring can be independently replaced by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, C _1-4 haloalkyl, C _1-4 alkyl, C _1-4 alkyl Amino, hydroxyl, cyano, nitro, amino, methyl-C(=O)-NH-, oxo(=O), C _1-4 alkyl-C(=O)-, benzyl, cyclopropyl base or phenyl, monosubstituted or identical or different multiple substitutions.

In some embodiments, wherein, the E ring is one of the heteroaryl groups formed by the following substructural formula:

Wherein, X, Y, Z, Z ¹ , Z ² , Z ³ and Z ⁴ are each independently N or CH;

T and T ¹ are each independently -O-, -S-, -NR ⁴ - or -CH ₂ -;

Wherein, each R ⁴ is independently H, C _1-4 alkyl, C _3-10 cycloalkyl, C _2-10 heterocycloalkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxyl C _1-4 alkyl;

each J is independently -G-( _CH2 ) _n- R;

Each G is independently -O-, -S-, -S(=O) _t -, -C(=O)- or -(CH ₂ ) _n -C(=O)-;

Each R is independently hydrogen, -NR ³ R ² , C _2-4 alkenyl, C _2-4 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl C _1-4 alkyl, C _2-10 heterocyclyl C _1-4 alkyl, C _1-6 alkyl-S(=O) _t -, C _1-6 alkoxy C _1-6 alkyl, hydroxy C _1-4 alkyl, Hydroxy C _1-4 alkoxy, Amino C _1-4 alkoxy, Halo C _1-4 alkoxy, C _1-4 alkylamino Halo C _1-4 alkoxy, C _1-4 alkylamino C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _6-10 aryl C _1-4 alkoxy, C _6-10 aryl C _1-4 alkylamino, C _1-9 Heteroaryl C _1-4 Alkoxy, C _1-9 Heteroaryl C _1-4 Alkylamino, C _2-10 Heterocyclyl C _1-4 Alkylamino, C _3-10 Cycloalkyl Oxygen, C _3-10 cycloalkylamino, C _2-10 heterocyclyl C _1-4 alkoxy, C _3-10 carbocyclyl C _1-4 alkoxy, C _3-10 carbocyclyl C _1-4 alkylamino, C _6-10 aryloxy C _1-4 alkoxy, C _6-10 aryloxy, C _1-9 heteroaryloxy, C _1-9 heteroaryloxy C _{1 -4} alkoxy, C _2-10 heterocyclyloxy C _1-4 alkoxy, C _3-10 carbocyclyloxy C _1-4 alkoxy, C _2-10 heterocyclyloxy, C _1-4 alkoxy, C _1-4 alkyl, C _1-4 haloalkyl, C _6-10 aryl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _1-9 heteroaryl,

Or each R is independently the following substructural formula:

Wherein, each X ⁸ , X ⁹ and X ¹⁰ are independently N or CH;

Each of X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ is independently -CH ₂ -, -O-, -NR ^4a -, -S(=O) _t - or -S- ;

each of q, m, p, r and s is independently 0, 1, 2, 3 or 4;

Each R ³ and R ² is independently C _1-6 alkyl, C _3-10 cycloalkyl, C _2-10 heterocycloalkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _{1 -4} alkyl;

Each R ^4a is independently H, C _1-4 alkyl, C _1-4 alkyl-C(=O)-, benzyl, C _3-10 cycloalkyl, C _2-10 heterocycloalkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _1-4 alkyl;

Wherein, said B ring, E ring and each substructural formula represented by each R can be independently replaced by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, C _1-4 haloalkyl, C _1-4 alkyl, C _1-4 alkylamino, hydroxyl, cyano, nitro, amino, methyl-C(=O)-NH-, oxo (=O), C _1-4 alkyl- C(=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different polysubstituted.

In some other embodiments, the E ring described in the present invention is one of the heteroaryl groups formed by the following substructural formula:

each J is independently -G-( _CH2 ) _n- R;

Each G is independently -O-, -S-, -S(=O) _t -, -C(=O)- or -(CH ₂ ) _n -C(=O)-;

Each R is independently hydrogen, -NR ³ R ² , C _2-4 alkenyl, C _2-4 alkynyl, C _2-10 heterocyclyl, C _1-4 alkyl, C _1-6 alkyl-S( =O) _t -, C _1-4 alkoxy C _1-4 alkyl, hydroxy C _1-4 alkyl, hydroxy C _1-4 alkoxy, amino C _1-4 alkoxy, halo C _{1 -4} alkoxy, C _1-4 alkylamino halo C _1-4 alkoxy, C _1-4 alkylamino C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy , C _1-4 alkoxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-9 heteroaryl C _1-6 alkyl,

Or each R is independently the following substructural formula:

Each of ^R3 and R2 is independently methyl, ethyl, ^propyl , isopropyl, tert-butyl, pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, _C2-10 heterocycle Alkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _1-4 alkyl;

Wherein, the substructural formulas represented by the B ring, the E ring and each R can be independently replaced by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl , trifluoroethyl, methyl, ethyl, propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxyl, cyano, nitro, oxo (=O ), methyl-C(=O)-, ethyl-C(=O)-, propanyl-C(=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different Multiple substitutions.

In some embodiments, the K ring described herein is one of the heteroaryl groups formed by the substructure shown below:

Each L is independently t-butyl.

In some embodiments, wherein the substituted urea derivatives described in the present invention have a compound represented by formula (II), or a stereoisomer or geometric isomer of a compound represented by formula (II), Tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof,

Or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug, wherein:

Q and W are each independently CH or N;

Each R ¹ is independently hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 haloalkyl, C _1-4 alkyl, C _1-6 alkyl-S(=O) _t- , C _1-6 alkane Oxygen C _1-6 alkyl, C _1-4 alkylamino, hydroxyl, cyano, nitro, C _1-4 alkyl-C(=O)-NH-, C _1-4 alkoxy, hydroxyl C _1-4 alkyl or C _1-4 alkylthio;

Ring E is one of the heteroaryl groups formed by the following substructure:

Wherein, X, Y, Z, Z ¹ , Z ² , Z ³ and Z ⁴ are each independently N or CH;

T and T ¹ are each independently -O-, -S-, -NR ⁴ - or -CH ₂ -;

Wherein, at least two of X, Y, Z, T, T ¹ , Z ¹ , Z ² , Z ³ and Z ⁴ on the E ring are heteroatoms;

Each R ⁴ is independently H, C _1-4 alkyl, C _1-4 alkyl-C(=O)-, benzyl, C _3-10 cycloalkyl, C _2-10 heterocycloalkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _1-4 alkyl;

Each G is independently -O-, -S-, -S(=O) _t -, -C(=O)- or -(CH ₂ ) _n -C(=O)-;

Each R is independently hydrogen, -NR ³ R ² , C _2-4 alkenyl, C _2-4 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl C _1-4 alkyl, C _2-10 heterocyclyl C _1-4 alkyl, C _1-6 alkyl-S(=O) _t -, C _1-6 alkoxy C _1-6 alkyl, hydroxy C _1-4 alkyl, Hydroxy C _1-4 alkoxy, Amino C _1-4 alkoxy, Halo C _1-4 alkoxy, C _1-4 alkylamino Halo C _1-4 alkoxy, C _1-4 alkylamino C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _3-10 cycloalkyloxy, C _6-10 aryl C _1-4 alkoxy, C _{6- 10} aryl C _1-4 alkylamino, C _1-9 heteroaryl C _1-4 alkoxy, C _1-9 heteroaryl C _1-4 alkylamino, C _2-10 heterocyclyl C _1-4 Alkylamino, C _3-10 cycloalkylamino, C _2-10 heterocyclyl C _1-4 alkoxy, C _3-10 carbocyclyl C _1-4 alkoxy, C _3-10 carbocyclyl C _1-4 alkylamino, C _6-10 aryloxy C _1-4 alkoxy, C _6-10 aryloxy, C _1-9 heteroaryloxy, C _1-9 heteroaryloxy C _{1 -4} alkoxy, C _2-10 heterocyclyloxy C _1-4 alkoxy, C _3-10 carbocyclyloxy C _1-4 alkoxy, C _2-10 heterocyclyloxy, C _1-4 alkoxy, C _1-4 alkyl, C _1-4 haloalkyl, C _6-10 aryl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _1-9 heteroaryl or each R is independently the following substructural formula:

Wherein, each X ⁸ , X ⁹ and X ¹⁰ are independently N or CH;

Each of X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ is independently -CH ₂ -, -O-, -NR ^4a -, -S(=O) _t - or -S- ;

each of q, m, p, r and s is independently 0, 1, 2, 3 or 4;

d is 1;

each n is independently 1, 2, 3 or 4;

Each R ³ and R ² is independently C _1-6 alkyl, C _3-10 cycloalkyl, C _2-10 heterocycloalkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _{1 -4} alkyl;

Each R ^4a is independently H, C _1-4 alkyl, C _1-4 alkyl-C(=O)-, benzyl, C _3-10 cycloalkyl, C _2-10 heterocycloalkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _1-4 alkyl;

Wherein, each substructural formula represented by the E ring and each R can be independently replaced by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, C _1-4 haloalkyl, C _1-4 Alkyl, C _1-4 alkylamino, hydroxyl, cyano, nitro, amino, methane-C(=O)-NH-, oxo (=O), C _1-4 alkyl-C(= O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different multiple substitutions;

Each L is independently t-butyl.

In some other embodiments, the E ring described in the present invention is one of the heteroaryl groups formed by the following substructural formula:

Wherein, each substructural formula represented by the E ring can be independently replaced by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl radical, ethyl, propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxyl, cyano, nitro, methane-C(=O)-, ethane -C(=O)-, propanyl-C(=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different polysubstituted.

In some other embodiments, each G described in the present invention is independently -O-;

Each R is independently hydrogen, -NR ³ R ² , C _2-4 alkenyl, C _2-4 alkynyl, C _2-10 heterocyclyl, C _1-4 alkyl, C _1-6 alkyl-S( =O) _t -, C _1-4 alkoxy C _1-4 alkyl, hydroxy C _1-4 alkyl, hydroxy C _1-4 alkoxy, amino C _1-4 alkoxy, halo C _{1 -4} alkoxy, C _1-4 alkylamino halo C _1-4 alkoxy, C _1-4 alkylamino C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy , C _1-4 alkoxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-9 heteroaryl C _1-6 alkyl,

Or each R is independently the following substructural formula:

Each of ^R3 and R2 is independently methyl, ethyl, ^propyl , isopropyl, tert-butyl, pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, _C2-10 heterocycle Alkyl, C _1-6 alkoxy C _1-6 alkyl or hydroxy C _1-4 alkyl;

Wherein, each substructural formula represented by each R can be independently replaced by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl Base, ethyl, propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxyl, cyano, nitro, oxo (=O), methyl-C ( =O)-, ethyl-C(=O)-, propanyl-C(=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different polysubstituted.

In some embodiments, the substituted urea derivatives of the present invention, or their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, A pharmaceutically acceptable salt or its prodrug has one of the following structures:

On the other hand, the present invention also provides a pharmaceutical composition comprising the compound described in the present invention.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.

In some embodiments, the pharmaceutical composition of the present invention further comprises additional therapeutic agents, these additional therapeutic agents are chemotherapeutic drugs, anti-proliferative agents, anti-inflammatory agents, immunosuppressants, immunostimulators, A drug for treating atherosclerosis, a drug for treating pulmonary fibrosis, or a combination thereof.

In some other embodiments, the pharmaceutical composition of the present invention, wherein the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosf Ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, Oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine ), mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan Topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, Daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, fluoride Flutamide, gonadorelin analogues, megestrol, prednidone, dexamethasone, methylprednisolone, thalidomide (thalidomide), interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib ( afatinib), alisertib, amuvatinib, apatinib, axitinib inib), bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib ( dasatinib), dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib ( lapatinib), lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, prazole Pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, card Catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab , ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, or combinations thereof.

In another aspect, the present invention relates to the use of said compound or pharmaceutical composition in the preparation of medicines for preventing, treating, alleviating or treating proliferative diseases, autoimmune diseases or inflammatory diseases in patients.

In some embodiments, the purposes of the present invention, wherein the proliferative disease is acute myelogenous leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumors, acute myelogenous leukemia (AML), mutant chronic myelogenous leukemia ( CML), Acute Lymphoblastic Leukemia (ALL), Colorectal Cancer, Stomach Cancer, Breast Cancer, Lung Cancer, Liver Cancer, Prostate Cancer, Pancreatic Cancer, Thyroid Cancer, Bladder Cancer, Kidney Cancer, Brain Tumor, CNS (Central Nervous System) Cancer , malignant glioma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic disease, cryoglobulinemia, nonlymphoreticular neoplasm, papular mucinosis, familial Splenemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinemia, hemimolecular disease, mononuclear Cellular leukemia, primary macroglobulinemia purpura, secondary benign monoclonal gammopathy, osteolytic lesions, lymphoblastoma, non-Hodgkin's lymphoma, Sezary syndrome, infectious mononucleosis Hypertrichosis, acute histiocytosis, Hodgkin's lymphoma, hairy cell leukemia, colon cancer, rectal cancer, intestinal polyps, small cell lung cancer, neuroblastoma, neuroendocrine cell tumors, islet cell tumors, medullary thyroid Carcinoma, melanoma, retinoblastoma, uterine cancer, ovarian cancer, head and neck squamous cell carcinoma, gastrointestinal malignancy, non-small cell lung cancer, cervical cancer, testicular tumor or myeloma.

In some embodiments, the use of the present invention, wherein the autoimmune disease is rheumatoid arthritis, lupus, multiple sclerosis, thyroiditis, type I diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or systemic lupus.

In some embodiments, in the use of the present invention, the inflammatory disease refers to diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, liver cirrhosis, cholecystitis, or chronic inflammation.

In some embodiments, the use according to the present invention, wherein the disease is a disease mediated by FLT3 or caused by FLT3-ITD.

In another aspect, the present invention relates to said compound or pharmaceutical composition for the preparation of a method for preventing, treating, treating or alleviating a proliferative disease, an autoimmune disease or an inflammatory disease in a patient, the method comprising administering An effective therapeutic amount of the compound of the present invention or the pharmaceutical composition of the present invention for patients.

In some embodiments, the method described herein, wherein the disease is a disease mediated by FLT3 kinase or caused by FLT3-ITD kinase.

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are Belong to the scope of the present invention. In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically appropriate in relation to the other ingredients making up the formulation and the mammal being used for treatment. Salts of the compounds of the present invention also include salts of intermediates of compounds of formula (I) or (II) or isolated enantiomers of compounds of formula (I) or (II), but not necessarily It is a pharmaceutically acceptable salt.

If the compound of the present invention is basic, the desired salt may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Or use organic acids such as acetic, maleic, succinic, mandelic, fumaric, malonic, pyruvic, malic, 2-hydroxypropionic, citric, oxalic, glycolic, and salicylic ; pyranonic acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids, such as citric acid and tartaric acid; amino acids, such as aspartic acid and glutamic acid; aromatic acids, such as benzoic acid and cinnamic acid; Sulfonic acids, such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, etc. or combinations thereof.

If the compound of the invention is acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium , N ⁺ (R ¹⁴ ) ₄ salts and alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, salts of N ⁺ (R ¹⁴ ) ₄ such as R ¹⁴ is H, C _1-4 alkyl, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, etc., and cyclic ammonia, such as piperidine, morpholine and piperazine, etc., and from sodium, Calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium give inorganic salts. Also included are suitable, nontoxic ammonium, quaternary ammonium salts and amine cations formed by counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 sulfonates and Aromatic sulfonates.

Compositions of compounds of the invention

According to another aspect, the characteristics of the pharmaceutical composition of the present invention include the compound of formula (I) or formula (II), hydrate, solvate, isomer or physiologically/pharmaceutically acceptable salt of the present invention, or Its prodrugs, the compounds listed in the present invention, or the compounds of Examples 1-5, and pharmaceutically acceptable carriers, adjuvants, or excipients. The composition of the present invention can be used in the preparation of medicines for preventing, treating, treating or alleviating diseases mediated by protein kinases. The pharmaceutical composition of the present invention is used as an inhibitor of FLT3 kinase or FLT3-ITD kinase in the preparation of medicaments.

The pharmaceutical composition of the present invention comprises a compound of formula (I) or formula (II) and a pharmaceutically acceptable carrier thereof. Wherein, the compound of formula (I) or formula (II) can also be combined with a second therapeutically active compound to form a pharmaceutical composition. The pharmaceutical carrier used can be: solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Examples of liquid carriers include: syrup, peanut oil, olive oil, water, and the like. Examples of gaseous carriers include: carbon dioxide and/or nitrogen. Likewise, the carrier or diluent may include time delay materials disclosed in the literature, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

In another aspect, substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum oxide; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphate; Glycine; Sorbic acid; Potassium sorbate; Partial glyceride mixture of saturated vegetable fatty acids; Water; Electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate; Salts such as sodium chloride, zinc salts; Colloidal silicon; Trisilicon magnesium oxide; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives substances such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered gums; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower Oils, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and hydrogen Aluminum oxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solution; and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants , release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants. For convenience, local anesthetics, preservatives, buffers, etc. can be directly dissolved in the vehicle.

Uses of the compounds and compositions of the present invention

Compounds of formula (I) or formula (II) of the present invention, or pharmaceutical compositions thereof, are useful in the treatment of conditions characterized by inappropriate FLT3 activity such as proliferative disorders. Inappropriate increases in FLT3 activity include, but are not limited to: increased or de novo FLT3 expression in cells, increased FLT3 expression or activity, and constitutive activation by FLT3 mutations. Inappropriate or abnormal FLT3 ligands and FLT3 levels or activity can be determined using methods well known in the literature. For example, abnormally high levels of FLT3 can be determined using commercially available ELISA kits. FLT3 levels can be determined using flow cytometric analysis, immunohistochemical analysis, and in situ hybridization techniques.

An inappropriate activation of FLT3 is identified by one or more subsequent increases in activity following FLT3 binding to the receptor: (1) phosphorylation or autophosphorylation of FLT3; (2) activation of a FLT3 substrate Phosphorylation, substrates such as Stat5, Ras; (3) activation of related complexes such as PI3K; (4) activation of receptor molecules; (5) cell proliferation. These activities are easily detected with well-known literature methods.

The compound of formula (I) or formula (II) or its pharmaceutical composition of the present invention can also be used as the medicine for preparing the following diseases, and said medicine includes but not limited thereto: by giving the formula (I) of the present invention effective dose or a compound of formula (II) or a pharmaceutical composition comprising a compound of formula (I) or formula (II), for preventing/treating a proliferative disease, condition or disorder in a patient. Such conditions include: cancers, especially hematopoietic cancers, metastatic tumors, atherosclerotic diseases, pulmonary fibrotic diseases.

The compound of the present invention or its pharmaceutical composition can also be used for the preparation of the medicament for the formation of tumor, and said tumor includes cancer and metastatic cancer, including but not limited to: bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including small cell lung cancer), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer (including squamous cell carcinoma); lymphoid hematopoietic tumors (including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pilocytic lymphoma, and Burkett's lymphoma); myeloid hematopoietic system Neoplasms (including acute and chronic myelogenous leukemias, myelodysplastic syndromes, and promyelocytic leukemias); neoplasms of mesenchymal origin (including fibrosarcomas and rhabdomyosarcomas and other sarcomas, such as soft tissue and bone); central and peripheral Nervous system tumors (including astrocytoma, neuroblastoma, glioma, and schwannoma) and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma carcinoma and Kaposi's sarcoma).

The compounds of the present invention or their pharmaceutical compositions can also be used for the preparation or treatment of FLT3-mediated, FLT3-ITD-mediated and/or CSF-1R-mediated disease drugs, which include: autoimmune diseases, kidney diseases, tissue transplantation Rejection, lupus erythematosus, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, arthritis, asthma, etc.

The compound of the present invention or its pharmaceutical composition can also be used in the preparation or treatment of diabetic conditions such as diabetic retinopathy and microvascular disease drugs, which is very useful.

The compounds of the present invention or pharmaceutical compositions thereof are also useful for reducing blood flow in tumors.

The compounds of the present invention or pharmaceutical compositions thereof are also useful for the reduction of tumor metastasis.

In addition to being beneficial to the treatment of human beings, the compound of the present invention or its pharmaceutical composition can also be used for the treatment of veterinary medicine such as pets, rare animals and farm animals, including mammals, rodents and the like. Other, more specifically, animals include horses, dogs, and cats. The compounds of formula (I) or formula (II) of the present invention include their pharmaceutically acceptable derivatives when used.

The compound of the present invention or its pharmaceutical composition can also be used to prepare a medicament for inhibiting the growth of cells expressing VEGFR or c-Met, and the medicament includes linking cells with the compound or composition of the present invention. Examples of inhibited cell growth include: breast cancer cells, colorectal cancer cells, lung cancer cells, papillary cancer cells, prostate cancer cells, lymphoma cells, colon cancer cells, pancreatic cancer cells, ovarian cancer cells, cervical cancer cells, Central nervous system cancer cells, osteosarcoma cells, kidney cancer cells, liver cancer cells, bladder cancer cells, gastric cancer cells, head and neck squamous cell carcinoma cells, melanoma cells, or leukemia cells.

The compound of the present invention or its pharmaceutical composition can also be used to prepare a drug for inhibiting the activity of VEGFR and/or c-Met kinase, and the drug includes linking a biological sample with the compound or composition disclosed in the present invention. The term "biological sample" as used herein refers to an external sample of a living organism including, but not limited to, cell cultures or extracts thereof; biopsy material or extracts thereof obtained from mammals; blood, saliva, urine, Feces, semen, tears or other bodily fluids or extracts thereof. Inhibition of kinase activity, in particular VEGFR or c-Met kinase activity, in the form of biological samples for various uses disclosed in the literature. Examples of such purposes include, but are not limited to: blood transfusions, organ transplants, biospecimen storage, and bioassays.

Administration of Compounds and Compositions of the Invention

Multiple compounds, salts, etc. of the present invention or pharmaceutical compositions thereof may be administered simultaneously, or may be administered as a single compound, salt, or the like.

The treatment of the present invention includes: administering the compound or composition of the present invention to the subject, further comprising: administering to the subject an additional therapeutic agent (combination therapy), selected from: chemotherapy or anti-proliferative agents or an anti-inflammatory wherein the additional therapeutic agent is appropriate for the treatment of the disease being treated, the additional therapeutic agent is administered together with the compound or composition disclosed herein, either as a single dosage form or separately from the compound and composition as multiple dosage forms part. Adjuncts may be administered at the same time or at different times as the compounds disclosed herein. In the latter case, the administration may be staggered, for example: 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.

Typically a therapeutically effective amount should result in a serum concentration of active ingredient of from about 0.1 ng/ml to about 50-100 micrograms/ml. The pharmaceutical composition will typically provide a dosage of from about 0.001 mg to about 2000 mg of compound per day per kilogram of body weight. Pharmaceutical dosage unit forms can be prepared to provide from about 1 mg to about 1000 mg, in certain embodiments, from about 10 mg to about 500 mg, from about 20 mg to about 250 mg, or from about 25 mg to about 100 mg, of the requisite active ingredient per dosage unit form or a combination of the necessary ingredients. In certain embodiments, the pharmaceutical dosage unit forms can be prepared to provide about 1 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the necessary active ingredient. In certain embodiments, the pharmaceutical dosage unit forms are prepared to provide about 50 mg of the requisite active ingredient.

The active ingredient of the active compound in the pharmaceutical composition can be administered at one time, or divided into several smaller doses and administered at regular time intervals. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and can be determined empirically using known experimental procedures or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the symptoms to be alleviated. It is further to be understood that, for any particular subject, the specific dosing regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges set forth here are illustrative only. , is not intended to limit the scope or practice of the claimed compositions.

The "effective amount" or "effective dose" in the present invention refers to the amount effective for treating or alleviating one or more of the aforementioned disorders. A compound or composition disclosed herein may be used in any effective amount and by any effective route of administration to treat or lessen the severity of a disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, severity of infection, particular formulation, mode of administration, etc. A compound or composition can also be administered with one or more other drugs, as described above.

The compounds of the present invention or their pharmaceutical compositions can also be used to wrap implantable medical devices, such as artificial limbs, artificial valves, artificial blood vessels, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implanted devices run the risk of clot formation or platelet activation. These adverse effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a compound of the invention.

When used to treat cancer patients, the dosage administered may vary depending on the type of cancer, age of the patient, general condition, the particular compound administered, the presence or level of toxicity, adverse reactions from previous medications, and other factors. A representative example of a suitable dosage range is from as low as about 0.01 mg/kg to as high as about 100 mg/kg. However, the dosage administered will generally be at the discretion of the physician.

The method of treatment is preferably by oral or parenteral administration of the compound of formula (I) or formula (II) of the present invention. The term "parenteral" as used herein includes intravenous, intramuscular or intraperitoneal administration. Parenteral administration is generally preferred in the form of subcutaneous and intramuscular injections. The present invention can also administer the compound of formula (I) or formula (II) of the present invention by subcutaneous injection, nasal drop, rectal, transdermal or intravaginal administration.

The compound of formula (I) or formula (II) of the present invention or the pharmaceutical composition thereof can also be administered by "inhalation". "Inhalation" refers to nasal and oral inhalation administration. Suitable dosage forms for such administration, such as aerosols or metered dose inhalers, are available by conventional techniques.

Preparation and Administration of Compounds of the Present Invention and Pharmaceutical Compositions

The compound of formula (I) or formula (II) of the present invention or its pharmaceutical composition can be made into various pharmaceutical dosage forms. If the oral solid preparation is used, it can be prepared into: tablets, hard capsules, buccal tablets, lozenges, drops, lotions and other forms. The amount of solid carrier can vary widely but will generally be from about 0.025 mg to about 1 g. If the oral administration is a liquid dosage form, typical preparation dosage forms are in the form of syrup, emulsion, soft capsule, suspension or solution. When intravenous dosage forms are used, the drug may be in solid or liquid form and may be formulated for immediate administration or suitable for reconstitution. Topical dosage forms are also included, examples of which are solid, liquid and semi-solid. Solids include powders, dressings, and the like. Liquids include solutions, suspensions and emulsions. Semisolids include creams, ointments, gels, and the like.

The amount of the compound of formula (I) or formula (II) of the present invention or the pharmaceutical composition thereof for topical application will of course vary according to the selected compound, the character and the severity, and may also vary according to the doctor's discretion. The topical dosage of the compound of formula (I) or formula (II) of the present invention is typically from a low of about 0.01 mg to a high of about 2.0 g, one to four times a day, preferably one to two times a day. Active ingredients for topical administration may comprise from about 0.001% or so to about 10% w/w.

When in the form of drops, they may include sterile or non-sterile aqueous or oily solutions or suspensions prepared by dissolving the active ingredient in a suitable aqueous solution, optionally containing bactericidal and/or fungicidal agents and and/or any other suitable preservative, and may optionally include a surfactant. The final solution may be clarified by filtration, transferred to a suitable container, which is then sealed, and sterilized by autoclaving or maintaining at 98-100°C for half an hour. Alternatively, the solution can be filter sterilized and transferred to sterile containers. Examples of bactericidal and fungicidal agents contained in the drops are: phenylmercuric nitrate or acetic acid (0.002%), benzalkonium chloride (0.01%) and chlorhexidine (0.01%). Suitable solvents for preparing oil solutions include: glycerol, dilute ethanol and propylene glycol.

When lotions are included, those suitable for application to the skin or eyes are also included. Eye lotions may comprise a sterile aqueous solution, optionally containing an antiseptic, prepared by a method similar to that used for the preparation of drops. Lotions or liniments for application to the skin may also include an agent that hastens drying and cools the skin such as alcohol or acetone and/or a moisturizer such as glycerin or an oil such as castor oil or peanut oil.

The cream, ointment or patch according to the present invention is a semi-solid preparation for external application of active ingredients. They can be obtained by mixing the active ingredient with a greasy or non-greasy base, the active ingredient in separate or micronized form, alone or in solution, or suspended in an aqueous or non-aqueous liquid. The base may include hydrocarbons such as: hard, soft, or liquid paraffin, glycerin, beeswax; metallic soaps; a sticky substance; a naturally occurring oil such as almond, coenzyme M, peanut, castor, or olive oil; lanolin or derivatives thereof, or fatty acids such as stearic acid or oleic acid together with ethanol, ethanol such as propylene glycol or macrogel. The formulations may incorporate any suitable surfactant, such as anionic, cationic or nonionic surfactants, such as sorbitol esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicates, may also contain other ingredients such as lanolin.

The compounds of the present invention or pharmaceutical compositions thereof may also be administered in the form of coatings, and suitable coated implant devices are well known to those skilled in the art. The coating is representative of biocompatible polymeric materials such as: hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, vinyl acetate and their mixture. The coating can optionally be further covered with a suitable film, such as: fluorosilicone oil, polysaccharase, polyethylene glycol, phospholipids or mixtures thereof, to give the pharmaceutical composition controlled release properties. The compounds of the present invention can also be coated on implantable medical devices such as beads or co-prepared with polymers or other molecules to provide a "drug depot" so that the drug is released over a longer period of time rather than in an aqueous solution of the drug form of administration.

General Synthesis Method

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, and unless otherwise specified, the definitions of the substituents are as shown in formula (I) or formula (II). The following reaction schemes and examples serve to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or by incorporating Reaction conditions with some routine modifications. In addition, reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of this invention.

In the examples described below, unless indicated otherwise, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Factory.

Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by reflux drying over sodium metal. Anhydrous dichloromethane and chloroform were obtained by refluxing and drying over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

The following reactions were generally carried out under a positive pressure of nitrogen or argon or over anhydrous solvents with a dry tube (unless otherwise indicated), the reaction vials were fitted with suitable rubber stoppers, and the substrate was introduced by syringe. Glassware is dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. NMR spectra were performed using CDC1 ₃ , d ⁶ -DMSO, CD ₃ OD or d ⁶ -acetone as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broadened peak), dd (doublet of doublets, quartet), dt (doublet of triplets, double triplet). Coupling constants are expressed in Hertz (Hz).

Low-resolution mass spectrometry (MS) data was determined by an Agilent6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C), and a G1329A autosampler and G1315B DAD detector were used for analysis , the ESI source was applied to the LC-MS spectrometer.

Low-resolution mass spectrometry (MS) data is measured by the spectrometer of Agilent6120 series LC-MS equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 ° C), G1329A automatic sampler and G1315D DAD detector are used for analysis, ESI sources are applied to LC-MS spectrometers.

The above two spectrometers are equipped with Agilent Zorbax SB-C18 column, the specification is 2.1×30mm, 5μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL/min; HPLC peaks were recorded and read by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in Table 1:

Table 1

time (min) A( _CH3CN , B(H ₂ O,

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 is evaluated by Agilent1100 series high performance liquid chromatography (HPLC), wherein UV detection is at 210nm and 254nm, Zorbax SB-C18 column, specification is 2.1 * 30mm, 4 μ m, 10 minutes, flow rate is 0.6mL/min, 5-95% (0.1% formic acid acetonitrile solution) of (0.1% formic acid aqueous solution), the column temperature is kept at 40°C.

The following abbreviations are used throughout this disclosure:

CHCl ₃ Chloroform

CDC1 ₃ deuterated chloroform

DEAD diethyl azodicarboxylate

DMF N,N-Dimethylformamide

DMAP 4-Dimethylaminopyridine

DMSO dimethyl sulfoxide

d ₆ -DMSO deuterated dimethyl sulfoxide

CH ₂ Cl ₂ , DCM dichloromethane

mL,ml milliliter

N ₂ Nitrogen

RT rt room temperature

Rt retention time

_H2O water

Reaction scheme 1

Compound 9 can be prepared by the method of Reaction Scheme 1, wherein R, E, R ¹ , a, G and n have the meanings as described in the present invention. Compound 1 and compound 2 were reacted under basic conditions to obtain compound 3. Compound 3 is subjected to a reduction reaction to obtain product 4, and then compound 4 is cyclized with thiocyanate to obtain compound 5. After compound 5 is reacted with compound 6, compound 7 is obtained through reduction reaction, and then further reacted with compound 8 to obtain product 9 .

Reaction scheme 2

Compound 15 can be prepared by the method of Reaction Scheme 2, wherein R, R ¹ , a, G and n have the meanings as described in the present invention. Compound 10 is subjected to a bromination reaction to obtain compound 11, compound 11 is reacted with 2-bromo-4'-nitroacetophenone to obtain compound 12, compound 12 is reacted with ethylene glycol monomethyl ether to obtain compound 13, and compound 13 is subjected to a reduction reaction, Compound 14 was obtained, which was further reacted with compound 8 to obtain product 15.

The following examples can further describe the present invention, however, these examples should not be construed as limiting the scope of the present invention.

Example

Example 1

1-(4-(6,7-bis(2-methoxyethoxy)benzo[d]imidazo[2,1-b]thiazol-2-yl)phenyl)-3-(5- (tert-butyl)isoxazol-3-yl)urea

Step 1) 1,2-bis(2-methoxyethoxy)-4-nitrobenzene

Add 4-nitrocatechol (3.1g, 19.99mmol), 2-bromoethyl methyl ether (6.12g, 44.03mmol), potassium carbonate (8.29g, 59.98mmol) and DMF (10mL ), heated to 100°C and refluxed overnight. After cooling, pour the mixture into a separatory funnel filled with hydrochloric acid (1mol/L, 200mL), add ethyl acetate (200mL) for extraction, dry the organic layer over anhydrous sodium sulfate, concentrate under reduced pressure, and proceed directly to the next step , a brown liquid (5.4 g, >100%) was obtained.

LC-MS: 272.2 [M+1] ⁺ .

Step 2) 3,4-bis(2-methoxyethoxy)aniline

Add 1,2-bis(2-methoxyethoxy)-4-nitrobenzene (5.4g, 19.91mmol), ethanol (80mL) and palladium/carbon (0.5g, 10%) to the reaction flask in sequence , Stir the reaction at room temperature under the protection of hydrogen. After the complete reaction of the raw materials is detected by MS, after the solid is removed by filtration, the filtrate is concentrated under reduced pressure, and the next step is directly carried out to obtain a brown liquid (5.0g, >100%).

LC-MS: 242.2 [M+1] ⁺ .

Step 3) 5,6-bis(2-methoxyethoxy)benzo[d]thiazol-2-amine

At room temperature, ammonium thiocyanate (2.73g, 35.86mmol) and glacial acetic acid (100mL) were successively added to the reaction flask, and bromine (3.82g, 23.90mmol) was added dropwise under stirring, and then continued to stir for 30 minutes before being removed by filtration. solid. The filtrate was added dropwise to 3,4-bis(2-methoxyethoxy)aniline (4.8 g, 19.89 mmol) in acetic acid solution (100 mL), and the mixture was left to react overnight at room temperature after the addition was complete. Acetic acid was removed under reduced pressure, saturated sodium bicarbonate solution was added to the residual liquid until there was no gas, and ethyl acetate (200mL x 3) was added for extraction. After the organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure and purified by column (V( (dichloromethane)/V(methanol)=25/1) to obtain a brown solid (3.13 g, 53%).

LC-MS: 299.2 [M+1] ⁺ .

Step 4) 6,7-bis(2-methoxyethoxy)-2-(4-nitrophenyl)benzo[d]imidazo[2,1-b]thiazole

Add 5,6-bis(2-methoxyethoxy)benzo[d]thiazol-2-amine (3.13g, 10.49mmol), 2-bromo-4'-nitrophenylethyl Ketone (2.56g, 10.49mmol) and ethanol (60mL), heated to reflux for 6 hours. The mixture was cooled to 0°C, then filtered, the filter cake was rinsed with a small amount of ethanol, and dried under reduced pressure to obtain a yellow solid (2.06 g, 44%).

LC-MS: 444.2 [M+1] ⁺ .

Step 5) 4-(6,7-bis(2-methoxyethoxy)benzo[d]imidazo[2,1-b]thiazol-2-yl)aniline

Add 6,7-bis(2-methoxyethoxy)-2-(4-nitrophenyl)benzo[d]imidazo[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), heated to reflux for 3 hours. The solid was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure. Dichloromethane (300 mL) and saturated sodium bicarbonate solution (100 mL) were added to the residue for extraction and separation. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a brown solid (1.48 g, 77%).

LC-MS: 414.2 [M+1] ⁺ .

Step 6) 1-(4-(6,7-bis(2-methoxyethoxy)benzo[d]imidazo[2,1-b]thiazol-2-yl)phenyl)-3- (5-(tert-butyl)isoxazol-3-yl)urea

Add 4-(6,7-bis(2-methoxyethoxy)benzo[d]imidazo[2,1-b]thiazol-2-yl)aniline (0.6g, 1.45 mmol) and dry dichloromethane (8mL), then added phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate (0.42g, 15.96mmol) and DMAP (11mg) successively at room temperature, After stirring, a solution of triethylamine (0.03 mL) in dichloromethane (0.1 mL) was added dropwise, and heated to reflux overnight. The solid was collected by filtration and rinsed with a small amount of dichloromethane (10 mL) to give a white solid (278 mg, 33%).

¹ H NMR (400MHz,d ₆ -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=4.4 Hz, 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] ⁺ .

Example 2

1-(5-(tert-butyl)isoxazol-3-yl)-3-{4-[7-methoxy-6-(2-methoxyethoxy)imidazo[1,2- a]pyridin-2-yl]phenyl}urea

Step 1) 2-amino-4-methoxy-5-bromopyridine

2-Amino-4-methoxypyridine (1.24g, 10mmol) was dissolved in 100mL of acetic acid, and after cooling to 0°C, a solution of bromine (1.92g, 12mmol) in acetic acid (30mL) was added dropwise. After the dropwise addition, the solution reacted at 30°C. 4h, TLC monitors that the raw materials have reacted completely, add 40mL saturated aqueous sodium sulfite solution to the reaction solution, stir at 25°C for 0.5h, concentrate under reduced pressure, extract the residue with ethyl acetate (150mL×3), dry over anhydrous sodium sulfate, After filtration, the filtrate was concentrated under reduced pressure and separated by column chromatography (V (dichloromethane)/V (methanol) = 20/1) to obtain a light yellow solid (1.45 g, 73%).

MS-ESI: (ESI, pos.ion) m/z: 202.9[M+1] ⁺

Step 2) 6-Bromo-7-methoxy-2-(4-nitrophenyl)imidazo[1,2-a]pyridine

2-Amino-4-methoxy-5-bromopyridine (500mg, 2.5mmol) and 2-bromo-4'-nitroacetophenone (1.21g, 5.0mmol) were dissolved in acetonitrile (40mL), and the solution The reaction was stirred at 85°C for 5 h. After cooling to room temperature, a large amount of yellow solid precipitated out. After filtration, the filter cake was slurried with methanol (10 mL), filtered again, and the filter cake was vacuum-dried to obtain a yellow solid (360 mg, 42%).

MS-ESI: (ESI, pos.ion) m/z: 347.8[M+1] ⁺

¹ H NMR (600MHz,d ₆ -DMSO)δ9.22(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-methoxy-6-(2-methoxyethoxy)-2-(4-nitrophenyl)imidazo[1,2-a]pyridine

Dissolve ethylene glycol monomethyl ether (395mg, 7.20mmol) in 40mL of anhydrous DMF, add sodium hydrogen (249.6mg, 10.4mmol) at -10°C, after the addition is complete, keep stirring at this temperature for 0.5h, then add 6-bromo -7-Methoxy-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (360mg, 1.04mmol) in anhydrous DMF (20mL) solution, dropwise, react at 50°C for 10h , add 50mL water to quench the reaction, concentrate under reduced pressure, the residue is extracted with ethyl acetate (400mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, column chromatography separation (V (petroleum ether) / V ( ethyl acetate) = 1/10) to obtain a pale yellow solid (126 mg, 39%).

MS-ESI: (ESI, pos.ion) m/z: 344.20[M+1] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ8.32(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-methoxy-6-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-yl]aniline

7-methoxy-6-(2-methoxyethoxy)-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (126mg, 0.37mmol), reduced iron powder (103.6mg, 1.85mmol) and ammonium chloride (199.8mg, 3.70mmol) were placed in a 100mL single-necked bottle, 10mL of water and 30mL of ethanol were added, and the solution was stirred at 85°C for 4h. Filtration, the filtrate was concentrated under reduced pressure, then extracted with ethyl acetate (200mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, separated by column chromatography (V (methanol)/V (dichloromethane) = 1/50 ) to give a yellow solid (76 mg, 66%).

MS-ESI: (ESI, pos.ion) m/z: 314.20[M+1] ⁺

Step 5) 1-(5-(tert-butyl)isoxazol-3-yl)-3-{4-[7-methoxy-6-(2-methoxyethoxy)imidazo[1 ,2-a]pyridin-2-yl]phenyl}urea

4-[7-methoxy-6-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-yl]aniline (76mg, 0.25mmol), phenyl(5- (tert-butyl)isoxazol-3-yl)tert-butyl carbamate (130mg, 0.50mmol) was dissolved in 10mL of acetonitrile, triethylamine (0.3mL) was added dropwise, and the solution was heated under reflux to react overnight, and an off-white solid precipitated out. After filtration, the filter cake was slurried with methanol (5 mL), and filtered again to obtain an off-white solid (23 mg, 20%).

MS-ESI: (ESI, pos.ion) m/z: 480.35[M+1] ⁺

¹ H NMR (400MHz,d ₆ -DMSO)δ9.56(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).

Example 3-5

By selecting appropriate starting materials, Examples 3-5 can be prepared by referring to the synthesis method of Example 1 or 2.

Example 6 flt3 kinase inhibitory activity

experimental method:

The meanings represented by the abbreviations in the following experiments are as follows:

HEPES: hydroxyethylpiperazine ethanesulfonic acid; Brij-35: lauryl polyethylene glycol ether; DTT: dithiothreitol; EDTA: ethylenediaminetetraacetic acid; EGFR: human epidermal growth factor receptor; HER2: human epidermal growth factor receptor 2; EGFRT790M: human epidermal growth factor receptor T790M mutant; Peptide FAM-P22: fluorescein-labeled peptide 22; ATP: adenosine triphosphate; DMSO: dimethylsulfoxide; Staurosporine : Staurosporine; Coating Reagent#3: #3 coating agent

1. Preparation of 1× kinase buffer and stop assay buffer:

(1) 1x Kinase buffer without MnCl ₂ (50mM HEPES, Ph7.5, 0.0015% Brij-35, 10mM MgCl ₂ , 2mM DTT);

(2) Stop experiment buffer (100 mM HEPES, Ph7.5, 0.015% Brij-35, 0.2% Coating Reagent#3, 50 mM EDTA).

2. Compound Preparation for Testing Kinases: Serial Dilution of Compounds

(1) The compound was diluted to 50 times of the highest final concentration with 100% DMSO. 100 mL of the compound solution at this concentration was transferred to one well of a 96-well plate.

(2) According to the ratio of diluting 20 mL of the original solution with 60 mL of DMSO, 10 concentrations of the compound were sequentially diluted.

(3) 100 mL of 100% DMSO solution was added to two empty wells as no compound control and no enzyme control.

(4) Prepare an intermediate plate, transfer 10mL of each concentration compound from the original plate to the intermediate plate, and add 90mL 1x kinase buffer,

Vortex to mix for 10 minutes.

(5) Prepare the experimental plate: transfer 5 mL of the compound solution from the corresponding well in the middle plate of the 96-well plate to the corresponding 384-well plate.

3. Kinase Reaction

(1) Prepare 2.5x enzyme solution: Add enzyme to 1x kinase buffer.

(2) Prepare 2.5x peptide solution: add fluorescein-labeled peptide and ATP to 1x kinase buffer.

(3) Add 10 mL of 2.5x enzyme solution to a 384-well assay plate containing 5 mL of compound solution with 10% DMSO content, and incubate at room temperature for 10 minutes.

(4) Add 10 mL of 2.5x peptide solution into a 384-well assay plate.

(5) Kinase reaction and termination: Incubate at 28°C for a corresponding time, then add 25 mL of termination buffer to terminate the reaction.

4. Data measurement

Read data and collect.

5. Curve Fitting

(1) Copy and convert the measured data

(2) Converted to inhibition rate

Inhibition rate = (maximum value - sample value) / (maximum value - minimum value) * 100;

"Maximum value" is the value of DMSO control; "Minimum value" is the value of no kinase control well.

(3) Input the data into the corresponding analysis software Xlfit to obtain the IC ₅₀ value.

The experimental results are as follows:

Table 2 flt3 kinase inhibitory activity of compounds of the present invention

Example number FLT3 (IC ₅₀ ,nm) 1 6.9

Experimental results:

The results show that the compound of the present invention has better in vitro enzyme inhibitory activity.

Experimental Example 7 Proliferation inhibitory activity of MV-4-11 cells

experimental method:

Cell Viability Assay

Cell experiment conditions:

Cell Plating:

Cell counts were performed with a Vi-Cell XR cell counter. Use the corresponding medium to adjust the cell density to 1.5×10 ⁵ cells/ml, plant 100 μl of cell suspension into each well of a 96-well plate with a transmural white bottom, and the final concentration of cells is 15,000 cells/100 μl/well. Incubate cells overnight in a cell incubator at 37 °C, 5% _CO2 , and 95% humidity.

Compound preparation and addition:

Preparation of compound plates (diluted to 10 concentrations in DMSO):

The compound was prepared into a 10 mM stock solution with DMSO, diluted to 4 mM when used, and then diluted to 0.4 mM with DMSO, with 0.4 mM as the highest concentration, and gradually diluted 3 times with DMSO to obtain 10 compounds with concentration gradients. Staurosporine was used as a positive control drug.

Addition of compounds:

a. Pipette 0.5 μl from the corresponding compound plate and add to the cell culture plate for overnight culture.

b. Incubate in a 37°C incubator for 72 hours.

Detection and Analysis

a. After the compound was treated for 72 hours, the cell morphology was observed under an inverted microscope. The cell growth status in the DMSO control well was normal, and no pollution was found.

b. Place the cell culture plate at room temperature for 30 minutes to equilibrate.

c. CellTiter-Glo detection method was used to determine the proliferation inhibitory activity of the compound on MV-4-11 cells.

d. Record and analyze the experimental results obtained.

Example number MV4-11 (IC ₅₀ ,Nm) 1 0.3

Experimental results

The results show that the compound of the present invention has better inhibitory activity on MV4-11 cell proliferation.

Although, the present invention has been described in detail with general description, specific implementation and test above, but on the basis of the present invention, some modifications or improvements can be made to it, which will be obvious to those skilled in the art . Therefore, the modifications or improvements made on the basis of not departing from the spirit of the present invention all belong to the protection scope of the present invention.

Claims (17)

1. A compound, which is a compound as shown in formula (II), or a pharmaceutically acceptable salt of a compound as shown in formula (II), in: Q and W are each independently CH; each R is independently hydrogen ^; a is 0, 1, 2, 3 or 4; Ring E is one of the heteroaryl groups consisting of the following substructural formulas: Wherein, X, Y, Z, Z ¹ , Z ² and Z ³ are each independently N or CH; T is -O-, -S-, -NR ⁴ - or -CH ₂ -; Wherein, at least two of X, Y, Z, T, Z ¹ , Z ² and Z ³ on the E ring are heteroatoms at the same time; each R ⁴ is independently H or C _1-4 alkyl; each G is independently -O-; Each R is independently hydroxy C _1-4 alkoxy, amino C _1-4 alkoxy, halogenated C _1-4 alkoxy or C _1-4 alkoxy; d is 1; each n is independently 1, 2, 3 or 4; Each L is independently t-butyl. 2. The compound according to claim 1, wherein: Ring E is one of the heteroaryl groups consisting of the following substructural formulas: 3. The compound according to claim 1, wherein each G is independently -O-; Each R is independently methoxy, ethoxy or propoxy. 4. The compound according to claim 1, having the structure of one of the following: or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition comprising a compound according to any one of claims 1-4. 6. The pharmaceutical composition according to claim 5, further comprising at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle. 7. The pharmaceutical composition according to claim 5, wherein further comprising additional therapeutic agents, these additional therapeutic agents are chemotherapeutic drugs, antiproliferative agents, anti-inflammatory agents, immunosuppressants, immunostimulators, for A drug to treat atherosclerosis, a drug to treat pulmonary fibrosis, or a combination thereof. 8. The pharmaceutical composition according to claim 7, wherein said additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, loxamethylene Mustin, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludala Bin, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, Daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin, megestrol, prednisone, Semethasone, methylprednisolone, thalidomide, interferon α, leucovorin, sirolimus, sirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, a Sitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, Gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib , niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib , tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, Gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, or a combination thereof. 9. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 5 in the preparation of medicines for preventing, treating, treating or alleviating autoimmune diseases, inflammatory diseases or proliferative diseases in patients. 10. The use according to claim 9, wherein the proliferative disease is gastrointestinal stromal tumor, colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer , brain tumors, cancers of the central nervous system, malignant gliomas, myeloproliferative disorders, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic diseases, nonlymphoreticular neoplasms, papular mucinosis , familial splenemia, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, hemimolecular disease, secondary benign monoclonal gammopathy, osteolytic lesions, Sezary syndrome Infectious mononucleosis, acute histiocytosis, colon cancer, rectal cancer, intestinal polyps, neuroblastoma, neuroendocrine cell tumors, islet cell tumors, melanoma, retinoblastoma, uterine cancer , ovarian cancer, squamous cell carcinoma of the head and neck, malignant tumors of the digestive tract, cervical cancer or testicular tumors. 11. The use according to claim 10, wherein said leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, cryoglobulinemia, chronic lymphocytic leukemia, primary macroglobulinemia , monocytic leukemia, or hairy cell leukemia; The lung cancer is small cell lung cancer or non-small cell lung cancer; The thyroid cancer is medullary thyroid carcinoma; The myeloproliferative disorder is myeloma; The lymphoma is lymphoblastoma, non-Hodgkin's lymphoma or Hodgkin's lymphoma. 12. The use according to claim 11, wherein the acute myeloid leukemia is acute myeloid leukemia; The chronic myelogenous leukemia is mutated chronic myelogenous leukemia; The primary macroglobulinemia is primary macroglobulinemia purpura; The myeloma is multiple myeloma. 13. The use according to claim 9, wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or lupus . 14. The use according to claim 13, wherein said lupus is systemic lupus. 15. The use according to claim 9, wherein said inflammatory disease refers to diverticulitis, colitis, pancreatitis, hepatitis, liver cirrhosis, cholecystitis or chronic inflammation. 16. The use according to claim 15, said chronic inflammation is chronic hepatitis. 17. The use according to claim 9, wherein the disease is a disease mediated by FLT3 kinase or caused by FLT3-ITD kinase.