CN102086211B - Aromatic heterocyclic compounds serving as protein kinase inhibitor - Google Patents

Abstract

The present invention provides some aromatic heterocyclic compounds, salts and their pharmaceutically acceptable forms, which are used to regulate the activity of protein tyrosine kinase and the signal response between cells or inside cells. The invention also pertains to pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions to treat hyperproliferative disorders in mammals, especially in humans.

Description

Heteroaromatic compounds as protein kinase inhibitors

field of invention

The present invention belongs to the field of medicine and specifically relates to compounds, compositions, uses and methods thereof for treating cancer. In particular, the compounds described in the present invention are heteroaromatic compounds that can act as protein kinase inhibitors. the

Background of the invention

Protein kinases represent a large class of proteins that play an important role in maintaining control of cellular functions and in the regulation of various cellular pathologies. Protein tyrosine kinases can be classified as growth factor receptor (eg, VEGFR, EGFR, PDGFR, FGFR, and erbB2) or non-receptor (eg, c-src and bcr-abl) kinases. Receptor-type tyrosine kinases are further divided into 20 different subfamilies; non-receptor-type tyrosine kinases have many subfamilies. Receptor tyrosine kinases are a large class of enzymes that enable growth factors to cross the cell membrane and maintain the extracellular binding region. The transmembrane region and the intracellular part function as kinases, phosphorylation acts on a specific protein tyrosine residue, thereby affecting cell proliferation. Variant or inappropriate protein kinase activity can lead to exacerbation of the disease. the

The partial list of kinases includes abl, AATK, ALK, Akt, axl, bmx, bcr-abl, Blk, Brk, Btk, csk, c-kit, c-Met, c-src, c-fins, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, DDR1, DDR2, EPHA, EPHB, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FER, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, GSG2, GSK, Hck, ILK, INSRR, IRAK4, ITK, IGF-1R, INS-R, Jak, KSR1, KDR, LMTK2, LMTK3, LTK, Lck, Lyn, MATK, MERTK, MLTK, MST1R, MUSK,

NPR1, NTRK, MEK, PLK4, PTK, p38, PDGFR, PIK, PKC, PYK2, RET, ROR1, ROR2, RYK, ros, Ron, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, tie, tie2, TRK, Yes, and Zap70. Inhibition of these kinases has become an important therapeutic goal. Uncontrolled angiogenesis is known to be involved in certain diseases such as ocular neovascularization, retinopathy (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease , such as rheumatoid or rheumatoid inflammatory diseases, especially arthritis (rheumatoid arthritis), or other chronic inflammatory conditions, such as chronic asthma, arterial or post-transplant atherosclerosis, endometriosis and hyperplastic Diseases, such as so-called solid tumors and liquid tumors (such as leukemia). the

Angiogenesis is an essential component of general physiological processes such as embryo formation and wound healing, but variant angiogenesis can lead to pathological disturbances and even worse, tumor growth. VEGF-A (vascular endothelial growth factor A) is a key factor in promoting the formation of new blood vessels (angiogenesis) in tumors. VEGF induces endothelial cell proliferation and metastasis in response to signaling through two high-affinity receptors like the fms tyrosine kinase receptor, Flt-1, and a receptor containing a kinase insertion domain, KDR. These signaling responses are primarily dependent on receptor dimerization and activation of intrinsic receptor tyrosine kinases (RTKs). Bound VEGF acts as a dimeric disulfide to stimulate receptor dimerization and activation of RTK domains. Kinase activity autophosphorylates tyrosine residues on cytoplasmic receptors that serve as binding sites for molecular cascade signaling. the

Disruption of VEGF signaling is a very attractive target in the treatment of cancer because angiogenesis is essential for all solid tumor growth and mature endothelial tissue remains relatively quiescent. Many experimental approaches have been used to test inhibition of VEGF signaling, including the use of neutralizing antibody receptor antagonists, small molecule antagonists, antisense constructs, and dominant negative strategies ("Molecular basis for Sunitinib efficacy and future clinical development."Nature Review Drug Discovery , 2007, 6, 734; "Angiogenesis: organizing principle for drug discovery?" Nature Review Drug Discovery, 2007, 6, 273.). the

Hepatocyte growth factor (HGF), or scatter factor, is a multifunctional growth factor that enhances transformation and tumor development through mitosis and cell motility. In order to produce cellular effects, HGF must bind to its receptor, c-Met, a receptor tyrosine kinase. c-Met is overexpressed in a significant percentage of different types of human tumors and also often amplifies the transition between primary tumors and metabolism. c-Met has also been implicated in atherosclerosis and pulmonary fibrosis ("Molecular cancer therapy: can our expectation be MET." Euro. J. Cancer, 2008, 44, 641-651). Invasive growth of cancer cells radically enhances tumor-stroma interactions, including the HGF/c-Met (HGF receptor) pathway. Binding of HGF to c-Met results in receptor phosphorylation and activation of the Ras/mitogen-activated protein kinase (MAPK) signaling response pathway, thereby reinforcing unfavorable cancer cell behavior. In addition, the stimulation of the HGF/c-Met pathway can lead to the induction of VEGF expression and can play a direct role in the activity of angiogenesis ("From Tpr-Met to Met, tumorigenesis and tubes."Oncogene.2007, 26, 1276; "Targeting the c-Met Signaling Pathway in Cancer. "Clin. Cancer Res. 2006, 12, 3657; "Drug development of MET inhibitors: targeting oncogene addiction and expedience. "Nature Review Drug Discovery, 2008, 7, 504.). the

Insulin-like growth factor 1 receptor (IGFR1R) is a whole membrane tyrosine kinase receptor that binds insulin-like growth factor (IGF) with high affinity. IGF1R plays a critical role in cell metastasis and human cancer. It is strongly overexpressed in most malignant tissues, and acts as an anti-apoptotic agent to improve cell survival through the PI3K and p53 pathways. IGF1R has been associated with a variety of disease states such as breast and ovarian cancer, metastatic pigmented melanoma, macular degeneration, intrauterine fetal growth retardation and postnatal growth retardation, among others ("IGF1R signaling and its inhibition. "Endocrine-Related Cancer. 2006, 13, S33-S43; "The new kid on the block (ade) of the IGF-1 receptor." Cancer Cell, 2004, 5, 201.). the

Targeting anti-tumor pathways in response to VEGF/VEGFR, HGF/c-Met and/or IGF/IGF1R signaling prevents the ability of tumor cells to overcome individual inhibition of VEGFR, HGFR or IGF1R and represents an improved approach to cancer therapy. The present invention describes small molecules that effectively inhibit the activity of protein tyrosine kinases such as the VEGF receptor KDR, the HGF receptor c-Met, or the IGF receptor IGF1R, among others. the

brief description of the invention

The present invention relates to novel aromatic heterocyclic compounds and methods for treating cell proliferation diseases. The compounds of the present invention have inhibitory effect on protein tyrosine kinase activity. It is more satisfactory that the compounds of the present invention have multiple inhibitory functions, which can inhibit the signal response of receptors like VEGF, HGF or IGF. Correspondingly, the present invention also provides a novel protein tyrosine kinase receptor signaling inhibitor, such as VEGF receptor signaling response, HGF receptor signaling response, or IGF receptor signaling response, including VEGF receptor KDR , HGF receptor c-Met, or insulin-like growth factor 1 (IGF1) receptor IGF1R. the

In particular, the compounds involved in the present invention, and pharmaceutically acceptable compositions thereof, can be effectively used as inhibitors of c-Met, KDR, or IGF1R. the

On the one hand, the present invention relates to a kind of compound as shown in formula (I):

Or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs; wherein R ³ , U ₁ , X ₁ , _Q1 and _Q2 are defined as follows.

On the other hand, the present invention relates to a kind of compound as shown in formula (IV):

or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs; wherein R ³ , U ₁ , V ₁ , V ₂ , V ₃ , V ₄ , X ₁ , X ₂ , Z and Q ₂ are defined as follows.

On the other hand, the present invention relates to a kind of compound as shown in formula (V):

or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs; wherein R ³ , U ₁ , V , X ₁ , X ₂ , X ₃ , Z ₁ , Z ₂ and Q ₂ are defined as follows.

Some of these embodiments are that _Q in formula (I) represents formula (IIa) or formula (IIb):

The definitions of V, V ₁ , V ₂ , V ₃ , V ₄ , X ₂ , X ₃ , Z, Z ₁ and Z ₂ are as follows.

Other embodiments are that formula (IIa) is selected from the following structural formulas:

Wherein R ^3a , R ⁵ , R ^5a and Z are defined as follows.

Other embodiments are that formula (IIb) is selected from the following structural formulas:

wherein Ar represents substituted or unsubstituted aryl or heteroaryl; and s is 0 or 1. the

Some of these embodiments are, formula (I), _Q in (IV) or (V) represents formula (III):

Where R ¹ , R ² , W ₁ , W ₂ , W ₃ , W ₄ and U ₂ are defined as follows.

Some of these embodiments are that _Q in formula (I), (IV) or (V) is selected from the following structural formulas:

The definitions of R ¹ , R ² and R ⁵ are as follows.

In some embodiments, R ¹ is independently selected from R ^5a R ⁵ N-, -OC(=O)NR ⁵ R ^5a , -OC(=O)OR ⁵ , -NR ⁵ C(=O)NR ⁵ R ^5a , -NR ⁵ C(=O)-R ^5a , R ⁵ R ^5a NO ₂ S-, R ⁵ O ₂ S-, R ⁵ O ₂ SR ^5a N-, R ⁵ (S=O)-alkyl, R ⁵ R ^5a NC(=O)-alkyl, R ⁵ S(=O)-alkoxy, R ⁵ R ^5a NC(=O)-alkoxy, hydroxy-substituted aminoalkoxy, amino-substituted Haloalkoxy, hydroxy-substituted haloalkoxy, hydroxy-substituted cyclopropylalkoxy, R ⁵ S(=O) ₂ O-substituted cyclopropylalkoxy, heterocyclyl(aminoalkoxy), Heteroaryl (hydroxyalkoxy), fused bicyclyl, fused heterobicyclyl, fused bicyclylaliphatic, fused heterobicyclylaliphatic, fused bicyclyloxy, fused heterobicyclyloxy , Fused Bicyclylamino, Fused Heterobicyclylamino, Fused Bicyclyloxyalkoxy, Fused Heterobicyclyloxyalkoxy, Fused Bicyclylaminoalkoxy, Fused Heterobicyclylamino Alkoxy, fused bicyclyl-C(=O)-, fused bicyclyl-C(=O)O-, fused heterobicyclyl-C(=O)-, fused heterobicyclyl-C( =O)O-, fused bicyclylamino-C(=O)-, fused heterobicyclylamino-C(=O)-, fused bicyclyl-C(=O)NR ⁵ -, fused hetero Bicyclyl-C(=O)NR ⁵ -, spirobicyclyl, spiroheterobicyclyl, spirobicyclylaliphatic, spiroheterobicyclylaliphatic, spirobicyclyloxy, spiroheterobicyclyloxy, spirobicyclyl Amino, spiroheterobicyclylamino, spirobicyclyloxyalkoxy, spiroheterobicyclyloxyalkoxy, spirobicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spirobicyclyl-C( =O)-, spirobicyclyl-C(=O)O-, spiroheterobicyclyl-C(=O)-, spiroheterobicyclyl-C(=O)O-, spirobicyclylamino-C(= O)-, spiroheterobicyclylamino-C(=O)-, spirobicyclyl-C(=O)NR ⁵ - or spiroheterobicyclyl-C(=O)NR ⁵ -.

In other embodiments, R ¹ is independently selected from R ^5a R ⁵ N-, -OC(=O)NR ⁵ R ^5a , -OC(=O)OR ⁵ , -NR ⁵ C(=O)NR ⁵ R ^5a , -NR ⁵ C(=O)-R ^5a , R ⁵ R ^5a NO ₂ S-, R ⁵ O ₂ S-, R ⁵ O ₂ SR ^5a N-, R ⁵ (S=O)-alkyl, R ⁵ R ^5a N-(C=O)-C _1-6 alkyl, R ⁵ (S=O)-alkoxy, R ⁵ R ^5a N-(C=O)-alkoxy, hydroxyl substituted C _1-6 aminoalkoxy, amino substituted C _1-6 haloalkoxy, hydroxy substituted C _1-6 haloalkoxy, C _4-10 heterocyclyl (amino C _1-6 alkoxy), C _1-10 heteroaryl (hydroxyalkoxy), hydroxyl substituted cyclopropyl C _1-6 alkoxy, R ⁵ S(=O) ₂ O-substituted cyclopropyl C _1-6 alkoxy, C _5-12 fused bicyclyl, C _5-12 fused heterobicyclyl, C _5-12 fused bicyclyl C _1-6 aliphatic, C _5-12 fused heterobicyclyl C _1-6 aliphatic, C _5-12 fused bicyclyloxy, C _5-12 fused heterobicyclyloxy, C _5-12 fused bicyclylamino, C _5-12 fused heterobicyclylamino, C _5-12 fused Bicyclyloxy C _1-6 alkoxy, C _5-12 fused heterobicyclyloxy C _1-6 alkoxy, C _5-12 fused bicyclyl-C(=O)-, C _{5- 12} Fused bicyclyl-C(=O)O-, C _5-12 Fused heterobicyclyl-C(=O)-, C _5-12 Fused heterobicyclyl-C(=O)O-, C _5-12 fused bicyclylamino-C(=O)-, C _5-12 fused heterobicyclylamino-C(=O)-, C _5-12 fused bicyclyl-C(=O)NR ⁵ -, C _5-12 fused heterobicyclyl-C(=O)NR ⁵ -, C _5-12 spirobicyclyl, C _5-12 spiroheterobicyclyl, C _5-12 spirobicyclyl C _1-6 aliphatic Family, C _5-12 spiro heterobicyclyl C _1-6 aliphatic, C _5-12 spiro heterobicyclyloxy C _1-6 alkoxy, C _5-12 spiro heterobicyclyl amino C _1-6 alkoxy Base, C _5-12 spirobicyclyl-C(=O)-, C _5-12 spirobicyclyl-C(=O)O-, C _5-12 spiroheterobicyclyl-C(=O)-, C _5-12 spiroheterobicyclyl-C(=O)O-, C _5-12 spirobicyclylamino-C(=O)-, C _5-12 spiroheterobicyclylamino-C(=O)-, C _5-12 spirobicyclyl-C(=O)NR ⁵ - or C _5-12 spiroheterobicyclyl-C(=O)NR ⁵ -.

In some other embodiments, ^{R is} independently selected from the following structural formulas:

wherein X ₄ and X ₄ ' are each independently selected from (CR ⁴ R ^4a ) _m , NR ⁵ , O, S, S=O or SO ₂ ; m and n each independently represent 0, 1 or 2; and t is 1, 2 or 3.

In some embodiments, R ² is independently selected from H, halogen, cyano, hydroxyl, R ^5a R ⁵ N-, -C(=O)NR ⁵ R ^5a , -OC(=O)NR ⁵ R ^5a , -OC(=O)OR ⁵ , -NR ⁵ C(=O)NR ⁵ R ^5a , -NR ⁵ C(=O)OR ^5a , -NR ⁵ C(=O)-R ^5a , R ⁵ R ^5a NO ₂ S-, R ⁵ O ₂ S-, R ⁵ O ₂ SR ^5a N-, R ^5a R ⁵ N-alkyl, R ⁵ S(=O)-alkyl, R ⁵ R ^5a NC(=O)- Alkyl, R ^5a R ⁵ N-alkoxy, R ⁵ S(=O)-alkoxy, R ⁵ R ^5a NC(=O)-alkoxy, aliphatic, alkoxy, hydroxyalkoxy , aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylaminohaloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy , arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy), carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), Aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy, azidoalkoxy, fused Bicyclyl, fused heterobicyclyl, fused bicyclylaliphatic, fused heterobicyclylaliphatic, fused bicyclyloxy, fused heterobicyclyloxy, fused bicyclylamino, fused heterobicyclyl Amino, fused bicyclyloxyalkoxy, fused heterobicyclyloxyalkoxy, fused bicyclylaminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(= O)-, fused bicyclyl-C(=O)O-, fused heterobicyclyl-C(=O)-, fused heterobicyclyl-C(=O)O-, fused bicyclylamino- C(=O)-, fused heterobicyclylamino-C(=O)-, fused bicyclyl-C(=O)NR ⁵ -, fused heterobicyclyl-C(=O)NR ⁵ -, Spirobicyclyl, spiroheterobicyclyl, spirobicyclylaliphatic, spiroheterobicyclylaliphatic, spirobicyclyloxy, spiroheterobicyclyloxy, spirobicyclylamino, spiroheterobicyclylamino, spirobicyclyloxy Alkoxy, spirobicyclyloxyalkoxy, spirobicyclylaminoalkoxy, spirobicyclylaminoalkoxy, spirobicyclyl-C(=O)-, spirobicyclyl-C(= O) O-, spiroheterobicyclyl-C(=O)-, spiroheterobicyclyl-C(=O)O-, spirobicyclylamino-C(=O)-, spiroheterobicyclylamino-C( =O)-, spirobicyclyl-C(=O)NR ⁵ -, spiroheterobicyclyl-C(=O)NR ⁵ -, aryl, heteroaryl, arylaliphatic or heteroarylaliphatic, Wherein, each of the alkoxy and alkylamino moieties mentioned above may be independently substituted with one or more hydroxyl groups, amino groups or substituted amino groups.

In other embodiments, R ² is independently selected from hydrogen, halogen, cyano, R ^5a R ⁵ N C _1-6 alkoxy, optionally substituted C _1-6 alkoxy, C _1-6 hydroxyalkoxy C _1-6 aminoalkoxy, C _1-6 hydroxy substituted aminoalkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino C _1-6 alkoxy, C _1-6 alkoxy Oxygen C _1-6 alkoxy, C _4-10 heterocyclyl oxy C _1-6 alkoxy, C _5-12 fused bicyclic, C _5-12 fused bicyclic C _1-6 aliphatic , C _5-12 fused heterobicyclyl C _1-6 aliphatic, C _5-12 fused bicyclyloxy, C _5-12 fused bicyclylamino, C _5-12 fused bicyclyloxy C _{1 -6} alkoxy, C _5-12 fused bicyclyl amino C _1-6 alkoxy, C _5-12 fused bicyclyl-C(=O)-, C _5-12 fused bicyclyl-C( =O)O-, C _5-12 fused heterobicyclyl-C(=O)-, C _5-12 fused heterobicyclyl-C(=O)O-, C _5-12 fused bicyclylamino -C(=O)-, C _5-12 fused heterobicyclylamino-C(=O)-, C _5-12 fused bicyclyl-C(=O)NR ⁵ -, C _5-12 fused Heterobicyclyl-C(=O)NR ⁵ -, C _5-12 spirobicyclyl, C _5-12 spirobicyclyloxy, C _5-12 spirobicyclylamino, C _5-12 spirobicyclyloxy C _1-6 alkoxy, C _5-12 spirobicyclyl amino C _1-6 alkoxy, C _5-12 fused heterobicyclyl, C _5-12 fused heterobicyclyloxy, C _5-12 fused Heterobicyclylamino, C _5-12 fused heterobicyclyloxy C _1-6 alkoxy, C _5-12 fused heterobicyclylamino C _1-6 alkoxy, C _5-12 spiro heterobicyclic Base, C _5-12 spiro bicyclyl C _1-6 aliphatic, C _5-12 spiro heterobicyclyl C _1-6 aliphatic, C _5-12 spiro heterobicyclyl oxy C _1-6 alkoxy, C _5-12 spiro heterobicyclylamino C _1-6 alkoxy, C _5-12 spirobicyclyl-C(=O)-, C _5-12 spirobicyclyl-C(=O)O-, C _{5- 12} spiro heterobicyclyl-C(=O)-, C _5-12 spiro heterobicyclyl-C(=O)O-, C _5-12 spirobicyclylamino-C(=O)-, C _5-12 Spiroheterobicyclylamino-C(=O)-, C _5-12 spirobicyclyl-C(=O)NR ⁵ - and C _5-12 spiroheterobicyclyl-C(=O)NR ⁵ -, C _{6 -10} aryl, C _1-10 heteroaryl, C _6-10 aryl C _1-6 aliphatic or C _1-10 heteroaryl C _1-6 aliphatic.

In some embodiments, R ^and R ^{are each} independently selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, R ^5a R ⁵ N-, R ^5a R ⁵ N-aliphatic, hydroxyaliphatic , Aliphatic, Alkoxy, Alkoxyaliphatic, Haloalkyl, Heterocyclyl, Heterocyclylalkyl, Cycloalkyl, Cycloalkyloxyaliphatic, Heterocyclyloxyaliphatic, Cycloalkyl Alkoxy, heterocyclylalkoxy, aryloxyalkyl, heteroaryloxyaliphatic, arylaliphatic, heteroarylaliphatic, aryl or heteroaryl. Some other embodiments are that R ³ and R ^3a are each independently selected from H, F, Cl, Br, -CN, R ^5a R ⁵ NC _1-3 aliphatic, C _1-3 aliphatic, C _1-3 alkane Oxygen C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, cycloalkyloxy C _1-3 aliphatic or heterocyclyloxy C _1-3 aliphatic.

In some of these embodiments, _U1 and _U2 are each independently selected from ^CR4 or N.

In some of these embodiments, V is selected from ^NR5R5a , ^OR5 , aliphatic, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylaliphatic ^, or heteroarylaliphatic.

In some embodiments, V ₁ is selected from O or NR ⁵ .

In some of these embodiments, V ₂ , V ₃ and V ₄ are each independently selected from CR ⁴ R ^4a , NR ⁵ , CR ⁴ or N, provided that only one of V ₂ , V ₃ and V ₄ can be selected from NR ⁵ or N, or V ₂ and V ₃ or V ₃ and V ₄ can be combined in the form of CR ⁴ R ^4a , NR ⁵ , O, CR ⁴ or N, provided that the final formula is a chemically stable formula.

In some embodiments, W ₁ , W ₂ , W ₃ and W ₄ are each independently selected from CR ⁴ R ^4a , NR ⁵ , CR ⁴ or N, or W ₁ and W ₂ or W ₃ and W ₄ can be combined to form CR ⁴ R ^4a , NR ⁵ , O or S form.

In some of these embodiments, X ₁ is selected from (CR ⁴ R ^4a ) _m , NR ⁵ , O, S, S═O, or SO ₂ ; and m is 0, 1, or 2. In some other embodiments, X ₁ is selected from O or NR ⁵ .

In some embodiments, each of X ₂ and X ₃ is independently selected from O, S or NR ⁵ .

In some embodiments, Z is selected from -NR ⁵ C(=O)-(CR ⁴ R ^4a ) _p -, -NR ⁵ C(=S)-(CR ⁴ R ^4a ) _p -, -NR ^5a (CR ⁴ R ^4a ) _p -, -NR ⁵ (CR ⁴ R ^4a ) _p C(=O)-, -NR ⁵ (CR ⁴ R ^4a ) _p C(=S)-, -NR ⁵ S(=O) _r -, -NR ⁵ S(=O) _r (CR ⁴ R ^4a ) _p -, -C(=O)NR ⁵ (CR ⁴ R ^4a ) _p -or -NR ⁵ -(CR ⁴ R ^4a ) _p S( =0) _r -, wherein p is 0, 1, 2 or 3; and r is 1 or 2. In some other embodiments, Z is selected from -NHC(=O)-.

In some embodiments, Z ₁ and Z ₂ are each independently selected from NR ⁵ or CR ⁴ R ^4a .

In some embodiments, Z in formula (IIa) is -NHC(=O)-; Z ₁ in formula (IIb) is NH; X ₁ , U ₁ and R ³ in formula (I) collectively define The substructure of is selected from:

In some embodiments, R ⁴ and R ^4a are each independently selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, -NR ^5a R ⁵ , alkoxy, cycloalkyloxy, heterocyclyl Alkoxy, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, naphthenic Aliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl A group, a heterocyclic group or a carbocyclic group; wherein, when R ⁴ and R ^4a are connected to the same carbon atom, R ⁴ , R ^4a and the carbon atom can be arbitrarily substituted or unsubstituted 3-8 carbon atoms ring or heterocycle.

In some embodiments, R ⁵ and R ^5a are each independently selected from hydrogen, R ⁶ R ^6a NC(=O)-, R ⁶ OC(=O)-, R ⁶ C(=O)-, R ⁶ R ^6a NS(=O)-, R ⁶ OS(=O)-, R ⁶ S(=O)-, R ⁶ R ^6a NSO ₂ -, R ⁶ OSO ₂ -, R ⁶ SO ₂ -, aliphatic, halogen Substituted aliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic aliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclic group; when R ⁵ and R ^5a are connected to the same nitrogen atom, R ⁵ , R ^5a and the nitrogen atom can optionally form a substituted or unsubstituted 3-8 membered ring, including a spiro bicyclic ring and a fused bicyclic ring.

In some embodiments, R ^and R ^are each independently selected from the group consisting of H, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic , Arylaliphatic, Heterocyclylaliphatic, Cycloalkylaliphatic, Aryloxyaliphatic, Heterocyclyloxyaliphatic, Cycloalkyloxyaliphatic, Araminoaliphatic, Heterocyclylaminoaliphatic aliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl.

In some embodiments, the substructure jointly defined by X ₁ , U ₁ and R ³ in formula (I) is selected from the following structural formulas:

其中Ar为芳基；  Q ₁ stands for

Wherein Ar is aryl;

Q ₂ stands for

^R1 is Wherein X ₄ and X ₄ ' are each independently selected from O, and t is 3;

^R2 is hydrogen;

Z is -NHC(=O)-;

R ^3a is selected from aliphatic;

^R5 and ^R5a are each independently selected from H, aliphatic or aryl.

Each of the substituents such as: R ^5a R ⁵ N-, -C(=O)NR ⁵ R ^5a , -OC(=O)NR ⁵ R ^5a , -OC(=O)OR ⁵ , -NR ⁵ C( =O)NR ⁵ R ^5a , -NR ⁵ C(=O)OR ^5a , -NR ⁵ C(=O)-R ^5a , R ⁵ R ^5a NO ₂ S-, R ⁵ O ₂ S-, R ⁵ O ₂ SR ^5a N-, OR ⁵ , NR ⁵ , CR ⁴ R ^4a , CR ⁴ , (CR ⁴ R ^4a ) _m , -NR ⁵ C(O)-(CR ⁴ R ^4a ) _p -, -NR ⁵ C( =S)-(CR ⁴ R ^4a ) _p -, -NR ^5a -(CR ⁴ R ^4a ) _p -, -NR ⁵ -(CR ⁴ R ^4a ) _p C(=O)-, -NR ⁵ -(CR ⁴ R ^4a ) _p C(=S)-, -NR ⁵ S(O) _r -, -NR ⁵ S(=O)(CR ⁴ R ^4a ) _p -, -C(=O)NR ⁵ -(CR ⁴ R ^4a ) _p -, -NR ⁵ -(CR ⁴ R ^4a ) _p -S(=O) _r -, R ^5a R ⁵ N-alkyl, R ⁵ (S=O) _r -alkyl, R ⁵ R ^5a N-(C=O)-C _1-6 alkyl, R ^5a R ⁵ NC _1-6 alkoxy, R ⁵ (S=O)-alkoxy, R ⁵ R ^5a N-(C= O)-alkoxy, R ⁶ R ^6a NC(=O)-, R ⁶ OC(=O)-, R ⁶ C(=O)-, R ⁶ R ^6a NS(=O)-, R ⁶ OS (=O)-, R ⁶ S(=O)-, R ⁶ R ^6a NSO ₂ -, R ⁶ OSO ₂ -, R ⁶ SO ₂ -, hydroxy-substituted cyclopropylalkoxy, R ⁵ S(= O) ₂ O-substituted cyclopropylalkoxy, R ^5a R ⁵ N-aliphatic, haloalkyl, heterocyclylalkyl, cycloalkyl, cycloalkyloxyaliphatic, cycloalkylalkoxy , aryloxyalkyl, heteroaryloxyaliphatic, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, Alkylaminohaloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl ( hydroxyalkoxy), carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxy Alkoxy, heterocyclyloxy, cycloalkyloxy, azidoalkoxy, fused bicyclyl, fused heterobicyclyl, fused bicyclyl aliphatic, fused heterobicyclyl aliphatic Aliphatic, fused bicyclyloxy, fused heterobicyclyloxy, fused bicyclylamino, fused heterobicyclylamino, fused bicyclyloxyalkoxy, fused heterobicyclyloxyalkoxy Base, fused bicyclylaminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(=O)-, fused bicyclyl-C(=O)O-, fused heterobicyclyl Base-C(=O)-, fused heterobicyclyl-C(=O)O-, fused bicyclylamino-C(=O)-, fused heterobicyclylamino-C(=O)-, Fused bicyclyl-C(=O)NR ⁵ -, fused heterobicyclyl-C(=O)NR ^5- , spirobicyclyl, spiroheterobicyclyl, spirobicyclylaliphatic, spiroheterobicyclylaliphatic , spirobicyclyloxy, spiroheterobicyclyloxy, spirobicyclylamino, spiroheterobicyclylamino, spirobicyclyloxyalkoxy, spiroheterobicyclyloxyalkoxy, spirobicyclylaminoalkoxy Base, spiroheterobicyclylaminoalkoxy, spirobicyclyl-C(=O)-, spirobicyclyl-C(=O)O-, spiroheterobicyclyl-C(=O)-, spiroheterobicyclyl -C(=O)O-, spirobicyclylamino-C(=O)-, spiroheterobicyclylamino-C(=O)-, spirobicyclyl-C(=O)NR ⁵ -, or spirohetero Bicyclyl-C(=O)NR ⁵ -, aryl, heteroaryl, arylaliphatic, heteroarylaliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkane Aminoaliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, aromatic Aminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, heterocyclyl, and carbocyclyl groups can all be independently substituted or unsubstituted substituents.

One aspect of the present invention relates to pharmaceutical compositions, comprising the compounds of the present invention, or their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable Acceptable salts or their prodrugs, or optional pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or combinations thereof. In some embodiments, the compounds are inhibitors of protein tyrosine kinases, and in other embodiments, the compounds are inhibitors of VEGF receptor signaling, HGF receptor signaling, or IGF receptor signaling. the

In some embodiments, the pharmaceutical composition of the present invention further comprises additional therapeutic agents, these additional therapeutic agents are preferably chemotherapeutic drugs, antiproliferative agents, drugs for the treatment of atherosclerosis, drugs for the treatment of pulmonary fibrosis Chemicalized drugs, or combinations thereof. the

In some embodiments, the additional therapeutic agent of the present invention is Adriamycin, Rapamycin, Temsirolimus, Everolimus, Ixabepilone, Gemcitabine, Cyclophosphamide (Cyclophosphamide), Dexamethasone, Etoposide, Fluorouracil, Imatinib mesylate, Dasatinib, Nilotinib , Erlotinib, Lapatinib, Iressa, Sorafenib, Sunitinib, Interferon, Carboplatin ), Topotecan, Paclitaxel, Vinblastine, Vincristine, Temozolomide, Tositumomab, Trabedectin, Avastin (Bevacizumab), Herceptin (Trastuzumab), Western Cetuximab, Panitumumab, or a combination thereof. the

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

Another aspect of the present invention relates to a method of preventing, treating, treating or alleviating a proliferative disorder in a patient, said method comprising administering to the patient a pharmaceutically effective dose of a pharmaceutical composition comprising a compound of the present invention. the

Another aspect of the present invention relates to the use of a compound of the present invention to prepare a medicament for preventing, treating, treating or alleviating a proliferative disorder in a patient. the

Another aspect of the present invention relates to the use of a pharmaceutical composition comprising the compound of the present invention to prepare a medicament for preventing, treating, treating or alleviating proliferative disorders in a patient. the

In some of these embodiments, the proliferative disorder of the invention is metastatic cancer. In other embodiments, the proliferative disorder of the present invention is colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, brain tumor, neck cancer, prostate cancer, pancreatic cancer, CNS (central nervous system), malignant glioma, or myeloproliferative disease. In other embodiments, the proliferative disorder of the invention is atherosclerosis or pulmonary fibrosis. the

Another aspect of the invention relates to a method of inhibiting or modulating protein kinase activity in a biological sample, said method comprising contacting said biological sample with a compound of the invention. the

Another aspect of the present invention relates to a method of inhibiting or modulating protein kinase activity in a biological sample, said method comprising contacting said biological sample with a pharmaceutical composition comprising a compound of the invention. the

In some embodiments, the protein kinase of the present invention is a receptor tyrosine kinase, and in other embodiments, the receptor tyrosine kinase is KDR, c-Met or IGF1R. the

Another aspect of the invention relates to a method of inhibiting a protein tyrosine kinase comprising contacting the kinase with a compound or composition of the invention. In particular, the invention relates to a method of inhibiting VEGF receptor signaling, HGF receptor signaling or IGF receptor signaling comprising contacting the receptor with a compound or composition of the invention. Inhibition of receptor protein kinase activity, particularly VEGF, HGF or IGF receptor signaling responses, can be performed in unicellular or multicellular organisms. If present in a multicellular organism, the methods described herein comprise administering to the organism a compound or composition of the invention. In some embodiments, the organism is a mammal, and in other embodiments, the organism is a human. In other embodiments, the method further comprises contacting the kinase with an additional therapeutic agent. the

Another aspect of the present invention relates to a method of inhibiting the proliferative activity of cells, the method comprising contacting cells with an amount of the compound or composition of the present invention effective to inhibit cell proliferation. In other embodiments, the method further comprises contacting the cells with an additional therapeutic agent. the

Another aspect of the present invention relates to the treatment of a cell proliferative disease in a patient, the method comprising administering to the patient a dose of a compound or composition thereof of the present invention required for effective treatment. In some other embodiments, the method further comprises the administration of an additional therapeutic agent. the

Another aspect of the present invention relates to a method of inhibiting tumor growth in a patient, the method comprising administering to the patient a dose of a compound of the present invention or a composition thereof required for effective treatment. In some other embodiments, the method further comprises the administration of an additional therapeutic agent. the

Another aspect of the present invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I), (IV) or (V). the

The preceding description merely outlines certain aspects of the invention, but is not intended to be limiting. These and other aspects will be described in more detail and more fully below. the

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 embodiments are accompanied by diagrams 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, the usage of terms, the techniques described, or the scope governed by the present application. the

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, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, so all The contents are incorporated with 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, 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", means that one or more hydrogen atoms in a given structure are 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 described therein can be, but are not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro group, aryloxy group, etc. the

The term "aliphatic" or "aliphatic group", as used herein, means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more degrees of unsaturation . Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms, in some embodiments, aliphatic groups contain 1-10 carbon atoms, in other embodiments, aliphatic groups contain 1-8 Carbon atoms, in still other embodiments, aliphatic groups contain 1-6 carbon atoms, in still other embodiments, aliphatic groups contain 1-4 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups such as methyl, ethyl, propyl, vinyl and the like. the

The term "halogenated aliphatic" used in the present invention means that the aliphatic group is substituted by one or more identical or different halogen atoms, wherein the aliphatic group has the meaning as described in the present invention, and the halogen atom is fluorine, chlorine , bromine or iodine, examples of which include, but are not limited to, trifluoromethyl, trifluoroethyl, and the like. the

As used herein, the term "hydroxyaliphatic" means that an aliphatic group is substituted by one or more hydroxyl groups, wherein the aliphatic group has the meaning described herein, examples of which include, but are not limited to, hydroxy Ethyl, 2-hydroxypropyl, hydroxymethyl, etc. the

The term "aminoaliphatic" used in the present invention means that an aliphatic group is substituted by one or more amino groups, wherein the aliphatic group has the meaning as described in the present invention, such examples include, but are not limited to amino Methyl, 2-aminoethyl, 2-aminoisopropyl, etc. the

The term "alkyl" used in the present invention includes 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms saturated linear or branched monovalent hydrocarbon groups, wherein the alkyl groups can be independently optionally Substituted by one or more substituents described herein. Further examples of aliphatic groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH(CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl ( -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2- Methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl- 1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ) ), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl and the like. The term "alkyl" and its prefix "alk" are used herein to include straight and branched saturated carbon chains. The term "alkylene" is used herein to denote a saturated divalent hydrocarbon radical obtained by elimination of two hydrogen atoms from a linear or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylene , Hypoisopropyl and so on.

The term "alkenyl" means 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms linear or branched monovalent hydrocarbon groups, at least one The position is in an unsaturated state, that is, one CC is a sp ² double bond, and the alkenyl group can be independently and optionally replaced by one or more substituents described in the present invention, including groups with "anti"" Orientation of "normal" or "E""Z", where specific examples include, but are not limited to, vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ) and the like.

The term "alkynyl" means 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms straight-chain or branched monovalent hydrocarbon group, wherein at least one position It is an unsaturated state, that is, one CC is a sp triple bond, wherein the alkynyl group can be independently and optionally replaced by one or more substituents described in the present invention, specific examples include, but are not limited to, ethynyl (-CtriCH), propargyl ( _-CH2CtriCH ), and so on.

The term "cycloaliphatic" (or "carbocycle", "carbocyclyl", "cycloalkyl") refers to a monovalent or multivalent, non-aromatic, saturated or partially unsaturated ring comprising 3-12 A monocyclic ring of carbon atoms or a bicyclic ring of 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. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. 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, and the like. And the cycloaliphatic" (or "carbocycle", "carbocyclyl", "cycloalkyl") can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydroxyl, amino, Halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, etc.

The term "carbocyclyl(hydroxyalkoxy)" means that a hydroxyalkoxy group is substituted by one or more carbocyclyl groups, wherein the carbocyclyl group and hydroxyalkoxy have the Meaning, such examples include, but are not limited to, cyclopropyl hydroxymethyl, cyclopropyl hydroxyethyl, cyclopropyl hydroxypropyl, cyclohexyl hydroxypropyl, cyclohexyl hydroxymethyl, and the like. the

The term "cycloalkyloxy" ("carbocyclyloxy") includes optionally substituted cycloalkyl groups, as defined herein, attached to and through the oxygen atom to the remainder of the molecule such that Examples include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy, and the like. the

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, hydroxyl-substituted cyclopropylamino, dicyclohexylamino, dicyclopropylamino, etc. the

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, etc. the

The term "cycloalkyloxyaliphatic" means that an aliphatic group is substituted by one or more cycloalkyloxy groups, wherein the aliphatic group and the cycloalkyloxy group have meaning, such examples include, but are not limited to, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxyethyl, Halocyclopropyloxyethyl etc. the

The term "cycloalkylaminoaliphatic" means that an aliphatic group is substituted by one or more cycloalkylamino groups, wherein the aliphatic group and cycloalkylamino group have the meanings as described in the present invention, such that Examples include, but are not limited to, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopentylaminomethyl, cyclopentylaminoethyl, cyclohexylaminoethyl, halocyclopropylaminoethyl wait. the

The term "cycloalkylaliphatic" means that an aliphatic group may be substituted by one or more cycloalkyl groups, wherein cycloalkyl and aliphatic groups have the meanings described herein, examples of which include, However, it is not limited to cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopentylmethyl, cyclohexylethyl and the like. the

The term "cycloalkylalkoxy" ("carbocyclylalkoxy") denotes an alkoxy group substituted by one or more cycloalkyl groups, wherein the cycloalkyl group and the alkoxy group Having the meaning as described in the present invention, such examples include, but are not limited to, cyclopropylmethoxy, cyclopropylethoxy, cyclopentylethoxy, cyclohexylethoxy, cyclohexylmethoxy , Cyclopropylpropoxy, etc. the

The term "cyclopropylalkoxy" means that an alkoxy group is substituted by one or more cyclopropyl groups, wherein the alkoxy group has the meaning as described in the present invention, examples of which include, but are not It is not limited to cyclopropylmethoxy, cyclopropylethoxy, cyclopropylpropoxy, cyclopropylbutoxy and the like. the

The term "hydroxyl-substituted cyclopropylalkoxy" means that a cyclopropylalkoxy group is substituted with one or more hydroxyl groups, where the hydroxyl group can be substituted at any substitutable position of the cyclopropylalkoxy group , can be a cyclopropyl moiety or an alkoxy moiety, wherein cyclopropylalkoxy has the meaning as described in the present invention, examples of which include, but are not limited to, 1-(1-hydroxycyclopropyl )methoxy, 2-(1-hydroxycyclopropyl)ethoxy, 3-(1-hydroxycyclopropyl)propoxy, 4-(1-hydroxycyclopropyl)butoxy, 3-cyclopropyl Propyl-2-hydroxypropoxy, 3-cyclopropyl-3-hydroxypropoxy, 4-cyclopropyl-3-hydroxybutoxy and the like. And the cyclopropyl group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl , Alkynyl, heterocyclyl, mercapto, nitro, aryloxy, etc. the

The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein to refer to monocyclic, bicyclic, or tricyclic ring systems in which one or more atoms on the ring Independently and optionally heteroatom substituted, the rings may be fully saturated or contain one or more degrees of unsaturation, but are never aromatic, and have only one point of attachment to other molecules. One or more ring hydrogen atoms are independently optionally substituted with one or more substituents described herein. In some embodiments, a "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and selected from N, 1-3 heteroatoms of 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 , when the ring When it is a three-membered ring, there is only one heteroatom), or a 7-10-membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P Optional substitution by one or more oxygen atoms gives groups like SO, _SO2 , PO, _PO2 ).

A heterocyclic group may be a carbon group or a heteroatom group. "Heterocyclyl" also includes radicals formed by the fusion of a heterocyclic radical with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl Base, azepanyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, Indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl, pyrazolinyl, dithianyl, dithianyl, dithianyl Hydrothienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1 .0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl and N-pyridylurea. Examples of the heterocyclic group also include 1,1-dioxothiomorpholinyl, and a pyrimidinedione group in which two ring carbon atoms are replaced by oxygen atoms. And the heterocyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl , Alkynyl, heterocyclyl, mercapto, nitro, aryloxy, etc. the

The term "heterocyclylalkyl" includes heterocyclyl-substituted alkyl; the term "heterocyclylalkoxy" includes heterocyclyl-substituted alkoxy wherein the oxygen atom is attached to the rest of the molecule; the term "heterocyclyl "Alkylamino" includes heterocyclyl-substituted alkylamino groups in which the nitrogen atom is attached to the rest of the molecule. Where heterocyclyl, alkyl, alkoxy and alkylamino have the meanings described herein, such examples include, but are not limited to, pyrrol-2-ylmethyl, morpholin-4-ylethyl, morpholin-4-ylethyl, Lin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino and the like. the

The term "heterocyclylaliphatic" means a heterocyclyl-substituted aliphatic group, wherein the heterocyclyl and aliphatic groups have the meanings described herein, examples of which include, but are not limited to, pyrrole-2- Methyl, piperidine-2-ethyl, piperazine-2-ethyl, piperidine-2-methyl, etc. the

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

The term "heterocyclylamino" means that the amino group is substituted by one or two heterocyclyl groups, wherein the nitrogen atom is attached to the rest of the molecule, and the heterocyclyl has the meaning as described in the present invention, such examples Including, but not limited to, pyrrole-2-amino, pyrrole-3-amino, piperidine-2-amino, piperidine-3-amino, piperidine-4-amino, piperazine-2-amino, dipyrrole-2 -Amino etc. the

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 base, piperazin-2-oxymethoxy, piperidine-4-oxyethoxy, etc. the

The term "heterocyclyloxyaliphatic" means that an aliphatic group is substituted by one or more heterocyclyloxy groups, wherein the aliphatic group and the heterocyclyloxy group have Meaning, such examples include, but are not limited to, pyrrole-2-oxymethyl, piperazine-3-oxyethyl, piperazine-2-oxyethyl, morpholine-2-oxymethyl, Piperidine-2-oxyethyl etc. the

The term "heterocyclylaminoaliphatic" means that the aliphatic group is substituted by one or more heterocyclylamino groups, wherein the aliphatic group and the heterocyclylamino group have the meanings as described in the present invention, such that Examples include, but are not limited to, pyrrole-2-aminomethyl, piperazine-3-aminoethyl, piperazine-2-aminoethyl, piperidine-2-aminoethyl, morpholine-2-aminomethyl Base etc. the

The term "heterocyclyl(hydroxyalkoxy)" means that a hydroxyalkoxy group is substituted by one or more heterocyclyl groups, wherein the heterocyclyl group and the hydroxyalkoxy group have the Meaning, such examples include, but are not limited to, pyrrol-2-ylhydroxymethoxy, morpholin-4-ylhydroxymethoxy, and the like. the

The term "heteroatom" means one or more of O, S, N, P, and Si, including forms in any oxidation state of N, S, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or nitrogen in heterocycles The form in which the hydrogen on the atom is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrole NR in the alkyl). the

The term "halogen" refers to F, Cl, Br or I. the

As used herein, the term "unsaturated" means that a moiety contains one or more degrees of unsaturation. the

The term "alkoxy", as used herein, refers to an alkyl group, as defined herein, attached to the main carbon chain through an oxygen atom ("alkoxy"), examples of which include, but do not It is not limited to methoxy, ethoxy, propoxy, butoxy and the like. And the aryl group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro etc. the

The term "hydroxyalkoxy" means that an alkoxy group is substituted by one or more hydroxy groups, where alkoxy has the meaning described herein, examples of which include, but are not limited to, hydroxymethoxy , 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxyisopropoxy, etc. the

The term "aminoalkoxy" means that an alkoxy group is substituted by one or more amino groups, where alkoxy has a meaning as described herein, examples of which include, but are not limited to, aminomethoxy , 2-aminoethoxy, 2-aminopropoxy, 2-aminoisopropoxy, etc. the

The term "azidoalkoxy" means that an alkoxy group is substituted by one or more azido groups, wherein the alkoxy group has the meaning as described in the present invention, such examples include, but are not limited to 2- Azidoethoxy, 3-azidopropoxy, 2-azidopropoxy and the like. the

The term "alkoxyalkoxy" means that an alkoxy group is substituted by one or more alkoxy groups, wherein the alkoxy group has the meaning as described in the present invention, such examples include, but are not It is not limited to methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy and the like. the

The term "alkoxyaliphatic" used in the present invention means that an aliphatic group is substituted by one or more alkoxy groups, wherein the aliphatic group and alkoxy group have the meanings as described in the present invention , such examples include, but are not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, ethoxypropenyl, and the like. the

The term "alkylaminoaliphatic" used in the present invention means that the aliphatic group is substituted by one or more alkylamino groups, wherein the aliphatic group and the alkylamino group have the meanings as described in the present invention, such Examples include, but are not limited to, dimethylaminoethyl, methylaminoethyl, diethylaminomethyl, diethylaminoethyl, and the like. the

The term "alkylthioaliphatic" as used herein means that an aliphatic group is substituted by one or more alkylthio groups, wherein the aliphatic group and the alkylthio group have the meanings described herein , such examples include, but are not limited to, methylthioethyl, methylthiopropyl, ethylthioethyl, methylthiopropenyl, and the like. the

The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" denote an alkyl, alkenyl or alkoxy group which may be substituted with one or more halogen atoms, examples of which include, but are not limited to, three Fluoromethyl, 2-chloro-vinyl, trifluoromethoxy and the like. the

The term "amino-substituted haloalkoxy" means that haloalkoxy is substituted by one or more amino groups, wherein haloalkoxy has the meaning as described in the present invention, such examples include, but are not limited to, 3-amino- 2-chloropropoxy, etc. the

The term "hydroxyl-substituted haloalkoxy" means that a haloalkoxy group is substituted by one or more hydroxy groups, wherein the haloalkoxy group has the meaning as described herein, examples of which include, but are not limited to, 3-hydroxy- 2-fluoropropoxy, hydroxymethyltrifluoromethoxy, etc. the

The term "aryl" can be used alone or as a part of "aralkyl", "aralkoxy" or "aryloxyalkyl" and represents monocyclic, bicyclic, and tricyclic rings containing 6-14 ring members in total. Ring carbocyclic ring systems, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 membered rings, and has only one point of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g. 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, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, Alkynyl, heterocyclyl, mercapto, nitro, aryloxy, etc. the

The term "arylaliphatic" means an aliphatic group substituted by one or more aryl groups, wherein aliphatic and aryl groups have the meanings described herein, examples of which include, but do not It is not limited to phenethyl, benzyl, p-tolyl, styryl and the like. the

The term "aryloxy" includes an optionally substituted aryl group, as defined herein, attached to an oxygen atom, and through the oxygen atom, to the remainder of the molecule, wherein the aryl group has a meaning as defined herein , such examples include, but are not limited to, phenoxy, tolyloxy, ethylphenoxy, and the like. the

The term "arylamino" means that the amino group is substituted by one or two aryl groups, wherein aryl has the meaning as described in the present invention, such examples include, but are not limited to, phenylamino, diphenylamino , Xylylamino, etc. the

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, However, it is not limited to phenoxymethoxy, phenoxyethoxy, phenoxypropoxy and the like. the

The term "aryloxyaliphatic" means that an aliphatic group is substituted by one or more aryloxy groups, wherein aryloxy and aliphatic groups have the meanings described herein, examples of which include, but It is not limited to phenoxymethyl, phenoxyethyl, tolyloxyethyl, phenoxypropyl and the like. the

The term "arylaminoaliphatic" means that an aliphatic group is substituted by one or more arylamino groups, wherein arylamino and aliphatic groups have the meanings described in the present invention, such examples include, but do not It is limited to anilinomethyl, anilinoethyl, tolylaminoethyl, anilinopropyl, anilinoallyl and the like. the

The term "aryl(hydroxyalkoxy)" means that a hydroxyalkoxy group is substituted by one or more aryl groups, wherein the aryl group and the hydroxyalkoxy group have the meanings as described in the present invention, such examples Including, but not limited to, phenylhydroxymethyl, phenylhydroxyethyl, p-tolylhydroxyethyl and the like. the

The term "heteroaryl" may be used alone or as part of "heteroarylalkyl" or "heteroarylalkoxy" to denote monocyclic, bicyclic, and tricyclic ring systems containing a total of 5-14 ring members , wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 membered rings and there is only one point of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". And the heteroaryl can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl , Alkynyl, heterocyclyl, mercapto, nitro, aryloxy, etc. the

In some other embodiments, aromatic heterocycles include, but are not limited to, the following monocycles: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrole Base, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2 -thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3 -Thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl Azolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyr Azinyl, 1,3,5-triazinyl; also include, but are by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuryl, benzothienyl, indolyl (such as 2-indole base), purinyl, quinolinyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolinyl). the

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 In the stated meaning, such examples include, but are not limited to, pyridin-2-oxyl, thiazole-2-oxyl, imidazol-2-oxyl, pyrimidin-2-oxyl, and the like. the

The term "heteroaryloxyaliphatic" means that an aliphatic group is substituted by one or more heteroaryloxy groups, wherein the aliphatic group and the heteroaryloxy group have meaning, such examples include, but are not limited to, pyridine-2-oxyethyl, thiazole-2-oxymethyl, imidazole-2-oxyethyl, pyrimidine-2-oxypropyl, and the like. The term "sulfonyl", whether used alone or in combination with other terms like "alkylsulfonyl", denotes the divalent group _-SO2- , respectively. _The term "alkylsulfonyl" refers to an alkyl substituted sulfonyl group, forming an alkylsulfonyl group ( _-SO2CH3 ).

The terms "sulfamoyl", "aminosulfamoyl" and "sulfamoyl" denote a sulfonyl group substituted with an amino group, forming a sulfamoyl group ( _{-SO2NH2 )} .

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", means -CO ₂ H; the term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or ""Acyloxy" means -(C=O)-.

The term "aralkyl" includes aryl-substituted alkyl groups. In some of these embodiments, an aralkyl group refers to a "lower aralkyl" group, ie, an aryl group attached to a C _1-6 alkyl group. In some other embodiments, an aralkyl group refers to a "phenylene" group containing a C _1-3 alkyl group. Specific examples thereof include benzyl, diphenylmethyl, and phenethyl. The aryl group on the aralkyl group may be further substituted by halogen, alkyl, alkoxy, haloalkyl and haloalkoxy.

The term "alkylthio" includes a C _1-10 straight or branched chain alkyl attached to a divalent sulfur atom. In some embodiments, the alkylthio group is a lower C _1-3 alkylthio group, examples of which include, but are not limited to, methylthio (CH ₃ S—).

The term "haloalkylthio" includes a C _1-10 haloalkyl group attached to a divalent sulfur atom. In some embodiments, the haloalkylthio is a lower _C1-3 haloalkylthio, examples of which include, but are not limited to, trifluoromethylthio.

The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group 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 "alkylaminohaloalkoxy" means that a haloalkoxy group is substituted by one or more alkylamino groups, wherein the haloalkoxy and alkylamino groups have the meanings described herein, examples of which include, but are not It is limited to methylaminodifluoromethoxy, ethylaminotrifluoromethoxy and the like. the

The term "arylamino" means that an amino group is substituted by one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some of these embodiments, the aromatic ring on the arylamino group can be further substituted. the

The term "heteroarylamino" means that an amino group is substituted by one or two heteroaryl groups, examples of which include, but are not limited to, N-thienylamino. In some of these embodiments, the heteroaryl ring on the heteroarylamino group can be further substituted. the

The term "aminoalkyl" includes C _1-10 straight or branched chain alkyl groups substituted with one or more amino groups. In some embodiments, the aminoalkyl group is a C _1-6 "lower aminoalkyl" substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, amino Ethyl, aminopropyl, aminobutyl and aminohexyl.

The term "alkylaminoalkyl" includes alkyl groups substituted with alkylamino groups. In some of these embodiments, the alkylaminoalkyl is a C _1-6 lower alkylaminoalkyl. In some other embodiments, the alkylaminoalkyl is a C _1-3 lower alkylaminoalkyl. Suitable alkylaminoalkyl groups may be mono- or di-alkyl substituted, examples of which include, but are not limited to, N-methylaminomethyl, N,N-dimethylaminoethyl, N , N-diethylaminomethyl and so on.

The term "alkylaminoalkoxy" includes alkoxy groups substituted with alkylamino groups. Suitable alkylaminoalkoxy groups may be substituted with mono- or di-alkyl groups, examples of which include, but are not limited to, N-methylaminoethoxy, N,N-dimethylaminoethoxy, N , N-diethylaminoethoxy and the like. the

The term "alkylaminoalkoxyalkoxy" denotes an alkoxy group substituted with an alkylaminoalkoxy group. Suitable alkylaminoalkoxyalkoxy groups may be substituted with mono- or di-alkyl groups, examples of which include, but are not limited to, N-methylaminomethoxyethoxy, N-methylaminoethyl Oxyethoxy, N,N-dimethylaminoethoxyethoxy, N,N-diethylaminomethoxymethoxy, and the like. the

The term "carboxyalkyl" includes C _1-10 straight or branched chain alkyl groups which may be substituted with one or more carboxy groups, examples of which include, but are not limited to, carboxymethyl, carboxypropyl, and the like.

The term "aryloxy" includes optionally substituted aryl groups, as defined herein, attached to and through an oxygen atom to the rest of the molecule, examples of which include, but are not limited to, phenoxy, etc. . the

The term "heteroarylalkoxy" includes heteroarylalkyl groups containing an oxygen atom attached to other groups through an oxygen atom, wherein heteroarylalkyl has the meaning described herein, examples of which include , but not limited to pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, etc. . the

The term "cycloalkylalkyl" denotes a cycloalkyl substituted alkyl group, examples of which include, but are not limited to, cyclohexylmethyl. Said cycloalkyl group may be further substituted by halogen, alkyl, alkoxy and hydroxyl. the

The terms "fused bicyclic", "fused ring", "fused bicyclyl", "fused cycloyl" denote saturated or unsaturated fused ring systems and relate to non-aromatic bicyclic systems. 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-fluoro[3,2-b]furan, 2,3,3a,4, 7,7a-hexahydro-1H-indene, 7-azabicyclo[2.2.1]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, 1,2, 3, 4, 4a, 5, 8, 8a-octahydronaphthalene, these 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, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl radical, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, etc. the

The term "fused heterobicyclyl" denotes a saturated or unsaturated fused ring system, involving non-aromatic bicyclic ring systems. 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 a 3-7 membered ring, 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 give groups like SO, SO ₂ , PO, PO ₂ , examples of which include, but are not limited to, hexahydro-fluoro[3,2 -b]furan, 7-azabicyclo[2.2.1]heptane, etc. And the fused heterobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, Alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, etc.

The term "fused bicyclyl aliphatic" means that an aliphatic group is substituted by one or more fused bicyclyl groups, wherein the aliphatic group and the fused bicyclyl group have the meanings described herein, such that Examples include, but are not limited to, 1,2,3,4,4a,5,8,8a-octahydronaphthylethyl, 1,2,3,4,4a,5,8,8a-octahydronaphthalene 1,2,3,4,4a,5,8,8a-octahydronaphthylpropyl, fused bicyclo[3.3.0]octylmethyl, fused bicyclo[3.1.0]hexyl Alkyl ethyl etc. the

The term "fused heterobicyclylaliphatic" means that an aliphatic group is substituted by one or more fused heterobicyclyl groups, wherein the aliphatic group and the fused heterobicyclyl group have the Meaning, such examples include, but are not limited to, hexahydro-fluoro[3,2-b]furan-2-ylethyl, hexahydro-fluoro[3,2-b]furan-2-ylmethyl, 7 -Azabicyclo[2.2.1]heptane-2-ylmethyl, 7-azabicyclo[2.2.1]heptane-2-ylethyl, 7-azabicyclo[2.2.1]heptane- 4-ylmethyl etc. the

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]hexane -2-oxyl, etc. the

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-fluoro[3,2-b]furan-2-yloxy, 7-azabicyclo[2.2.1]heptan-2-yloxy, 7-azabicyclo[2.2.1 ] heptane-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, two (1,2,3,4,4a,5,8,8a-octahydronaphthyl)amino, fused bicyclic [3.3. 0]octylamino, fused bicyclo[3.1.0]hexylamino, etc. the

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-fluoro[3,2-b]furan-2-ylamino, 7-azabicyclo[2.2.1]heptane-2-ylamino, 7-azabicyclo[2.2.1]heptane-4 - Base amino and so on. the

The term "fused bicyclyloxyalkoxy" means that an alkoxy group is substituted by one or more fused bicyclyloxy groups, wherein the alkoxy and fused bicyclyloxy groups have meaning, such examples include, but are not limited to, 1,2,3,4,4a,5,8,8a-octahydronaphthyloxymethoxy, 1,2,3,4,4a,5,8 , 8a-octahydronaphthyloxyethoxy, fused bicyclo[3.3.0]octane-2-oxyethoxy, fused bicyclo[3.1.0]hexane-2-oxypropoxy wait. the

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 As stated, such examples include, but are not limited to, hexahydro-fluoro[3,2-b]furan-2-yloxypropoxy, 7-azabicyclo[2.2.1]heptane-2 -yloxyethoxy, 7-azabicyclo[2.2.1]heptane-4-yloxypropoxy, hexahydro-fluoro[3,2-b]furan-2-yloxyethoxy Base, 7-azabicyclo[2.2.1]heptane-2-yloxypropoxy, 7-azabicyclo[2.2.1]heptane-4-yloxyethoxy, etc. the

The term "fused bicyclylaminoalkoxy" means that an alkoxy group is substituted by one or more fused bicyclylamino groups, wherein alkoxy and fused bicyclylamino groups have the meanings described in the present invention, such examples Including, but not limited to, 1,2,3,4,4a,5,8,8a-octahydronaphthylaminoethoxy, 1,2,3,4,4a,5,8,8a-octahydronaphthalene Aminopropoxy, bis(1,2,3,4,4a,5,8,8a-octahydronaphthyl)aminopropoxy, fused bicyclo[3.3.0]octane-2-aminoethoxy base, fused bicyclo[3.1.0]hexane-2-aminopropoxy, etc. the

The term "fused heterobicyclylaminoalkoxy" means that an alkoxy group is substituted by one or more fused heterobicyclylamino groups, wherein alkoxy and fused heterobicyclylamino groups have the meanings described in the present invention, Such examples include, but are not limited to, 7-azabicyclo[2.2.1]heptan-2-ylaminoethoxy, 7-azabicyclo[2.2.1]heptan-4-ylaminopropoxy , Hexahydro-fluoro[3,2-b]furan-2-ylaminoethoxy, hexahydro-fluoro[3,2-b]furan-2-ylaminopropoxy, hexahydro-fluoro[3, 2-b] furan-2-ylaminomethoxy and the like. the

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]heptane-5-yl, etc. And the spiro bicyclyl can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl , Alkynyl, heterocyclyl, mercapto, nitro, aryloxy, etc. the

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 a 3-7 membered ring, 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 give groups like SO, SO ₂ , PO, PO ₂ , examples of which include, but are not limited to, 4-azaspiro[2.4] Heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, 7-hydroxy-5-azaspiro[2.4]heptane Alk-5-yl, etc. And the spiro heterobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl radical, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, etc.

The term "spirobicyclyl aliphatic" means that an aliphatic group is substituted by one or more spirobicyclyl groups, wherein the aliphatic group and the spirobicyclyl group have the meanings described herein, such examples include , but not limited to spiro[2.4]heptylmethyl, spiro[2.4]heptylethyl, spiro[2.4]heptylpropyl, spiro[4.4]nonylmethyl, spiro[4.4]nonanyl Alkylethyl, 4-azaspiro[2.4]heptane-5-ylmethyl, 4-azaspiro[2.4]heptane-5-ylethyl, 4-oxaspiro[2.4]heptane- 5-ylethyl, 5-azaspiro[2.4]heptan-5-ylpropyl, 7-hydroxy-5-azaspiro[2.4]heptan-5-ylpropyl and the like. the

The term "spiroheterobicyclylaliphatic" means that the aliphatic group is substituted by one or more spiroheterobicyclyl groups, wherein the aliphatic group and the spiroheterobicyclyl group have the meanings as described in the present invention, such that Examples include, but are not limited to, 4-azaspiro[2.4]heptan-5-ylmethyl, 4-azaspiro[2.4]heptan-5-ylethyl, 4-oxaspiro[2.4] Heptane-5-ylethyl, 5-azaspiro[2.4]heptan-5-ylpropyl, 7-hydroxy-5-azaspiro[2.4]heptan-5-ylpropyl and the like. the

The term "spirobicyclyloxy" includes optionally substituted spirobicyclyl groups, as defined herein, attached to and through an oxygen atom to the rest of the molecule, examples of which include, but are not limited to, spirobicyclyl [2.4]heptane-2-oxyl, spiro[2.4]heptane-3-oxyl, spiro[2.4]heptane-4-oxyl, spiro[4.4]nonane-2-oxyl, spiro[4.4 ]nonane-4-oxyl, 4-azaspiro[2.4]heptane-5-oxyl and the like. the

The term "spiroheterobicyclyloxy" includes optionally substituted spiroheterobicyclyl groups, as defined herein, attached to and through an oxygen atom to the rest of the molecule, examples of which include, but do not Limited to 4-azaspiro[2.4]heptan-5-yloxy, 4-oxaspiro[2.4]heptan-5-yloxy, 5-azaspiro[2.4]heptan-5-yloxy Base etc. the

The term "spirobicyclylamino" means that the amino group is substituted by one or two spirobicyclyl groups, wherein spirobicyclyl has the meaning as described in the present invention, such examples include, but are not limited to spiro[2.4] Heptane-2-amino, spiro[2.4]heptane-3-amino, spiro[2.4]heptane-4-amino, spiro[4.4]nonane-2-amino, spiro[4.4]nonane-4-amino , 4-azaspiro[2.4]heptane-5-amino, etc. the

The term "spiroheterobicyclylamino" means that the amino group is substituted by one or two spiroheterobicyclyl groups, wherein the spiroheterobicyclyl has the meaning as described in the present invention, such examples include, but are not limited to 4 -Azaspiro[2.4]heptane-5-ylamino, 4-azaspiro[2.4]heptane-2-ylamino, 4-oxaspiro[2.4]heptane-5-ylamino, 5-azaspiro[2.4]heptane-5-ylamino, Heterospiro[2.4]heptan-5-ylamino, etc. the

The term "spirobicyclyloxyalkoxy" means that an alkoxy group is substituted by one or more spirobicyclyloxy groups, wherein the spirobicyclyloxy and alkoxy groups have the meanings described herein , such examples include, but are not limited to, spiro[2.4]heptane-2-oxyethoxy, spiro[2.4]heptane-3-oxypropoxy, spiro[2.4]heptane-4-oxy ylpropoxy, spiro[4.4]nonane-2-oxyethoxy, spiro[4.4]nonane-4-oxypropoxy, 4-azaspiro[2.4]heptane-5-oxyl Propoxy etc. the

The term "spiroheterobicyclyloxyalkoxy" means that an alkoxy group is substituted by one or more spiroheterobicyclyloxy groups, wherein the spiroheterobicyclyloxy and alkoxy groups have Such examples include, but are not limited to, 4-azaspiro[2.4]heptane-5-yloxyethoxy, 4-oxaspiro[2.4]heptane-5-yloxyethoxy Oxygen, 5-azaspiro[2.4]heptane-5-yloxyethoxy, 4-azaspiro[2.4]heptane-5-yloxypropoxy, 4-oxaspiro[2.4 ]heptan-5-yloxypropoxy, 5-azaspiro[2.4]heptan-5-yloxypropoxy and the like. the

The term "spirobicyclylaminoalkoxy" means that an alkoxy group is substituted by one or more spirobicyclylamino groups, wherein alkoxy and spirobicyclylamino groups have the meanings described herein, examples of which include, but Not limited to spiro[2.4]heptane-2-aminoethoxy, spiro[2.4]heptane-3-aminopropoxy, spiro[2.4]heptane-4-aminoethoxy, spiro[4.4]nonane Alkane-2-aminoethoxy, spiro[4.4]nonane-4-aminopropoxy, 4-azaspiro[2.4]heptane-5-aminopropoxy and the like. the

The term "spiroheterobicyclylaminoalkoxy" means that an alkoxy group is substituted by one or more spiroheterobicyclylamino groups, wherein alkoxy group and spiroheterobicyclylamino group have the meanings as described in the present invention, such examples Including, but not limited to, 4-azaspiro[2.4]heptan-5-ylaminoethoxy, 4-azaspiro[2.4]heptan-2-ylaminopropoxy, 4-oxaspiro[ 2.4] Heptan-5-ylaminoethoxy, 5-azaspiro[2.4]heptan-5-ylaminopropoxy, etc. the

As described in the present invention, substituents drawing a bond to the central ring to form a ring system (shown below) means that substituents can be substituted at any substitutable position on the ring. For example, a represents any possible substitution position on the B ring, as shown in b. the

As described herein, a dotted bond in a ring system represents a double bond or a single bond. For example, the structure of c represents any structure selected from d. the

Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R, S configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures thereof as enantiomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention. the

The term "prodrug" used in the present invention represents the conversion of a compound into compounds represented by formulas (I), (IV) and (V) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissues 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, including 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: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, the ACSSymposium Series, Vol 14; Ed. Edward B. Roche, 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, 2328-2345 .

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. the

"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. the

Definitions of stereochemistry and usage of conventions in the present invention are generally referred to in: 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 as 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

The term "tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. For example, proton tautomers (ie, prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Atomic (valency) tautomers include interconversions of rearranged bonding electrons. the

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, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, 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 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, _{C1 -8} sulfonates and aromatic sulfonates.

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. The term "hydrate" refers to an association of solvent molecules with water. the

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 the carboxyl group used to block or protect the functionality of the carboxyl group. The general carboxyl protecting group includes -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 see: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

Description of the compounds of the invention

The compounds and their pharmaceutical preparations involved in the present invention have potential applications in the treatment of diseases or conditions regulated by tyrosine kinase receptors, especially KDR, c-Met receptors or IGF receptors. In particular, the present invention relates to a compound as shown in formula (I):

or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, wherein R ³ , U ₁ , X ₁ , _Q1 and _Q2 are defined as follows.

In some of these embodiments, _Q represents formula (IIa) or (IIb):

wherein V, V ₁ , V ₂ , V ₃ , V ₄ , X ₂ , X ₃ , Z, Z ₁ and Z ₂ are defined as follows; and Q ₂ represents formula (III):

The definitions of R ¹ , R ² , W ₁ , W ₂ , W ₃ , W ₄ and U ₂ are as follows.

In some of these embodiments, the present invention also relates to a compound as shown in formula (IV) or (V):

or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, wherein R ³ , U ₁ , V , V ₁ , V ₂ , V ₃ , V ₄ , X ₁ , X ₂ , X ₃ , Z, Z ₁ , Z ₂ and Q ₂ are defined as follows, where:

R ¹ and R ² are each independently selected from hydrogen, halogen, cyano, hydroxyl, R ^5a R ⁵ N-, -C(=O)NR ⁵ R ^5a , -OC(=O)NR ⁵ R ^5a , -OC (=O)OR ⁵ , -NR ⁵ C(=O)NR ⁵ R ^5a , -NR ⁵ C(=O)OR ^5a , -NR ⁵ C(=O)R ^5a , R ⁵ R ^5a NO ₂ S- , R ⁵ O ₂ S-, R ⁵ O ₂ SR ^5a N-, R ^5a R ⁵ N-alkyl, R ⁵ S(=O) _r -alkyl, R ⁵ R ^5a N-(C=O)- Alkyl, R ^5a R ⁵ N-alkoxy, R ⁵ S(=O) _r -alkoxy, R ⁵ R ^5a N-(C=O)-alkoxy, aliphatic, alkoxy, hydroxyl Alkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylaminohaloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxy Alkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy), carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy radical), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy, azidoalkoxy , fused bicyclyl, fused heterobicyclyl, fused bicyclylaliphatic, fused heterobicyclylaliphatic, fused bicyclyloxy, fused heterobicyclyloxy, fused bicyclylamino, fused Heterobicyclylamino, fused bicyclyloxyalkoxy, fused heterobicyclyloxyalkoxy, fused bicyclylaminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl- C(=O)-, Fused Bicyclyl-C(=O)O-, Fused Heterobicyclyl-C(=O)-, Fused Heterobicyclyl-C(=O)O-, Fused Bicyclyl Amino-C(=O)-, fused heterobicyclylamino-C(=O)-, fused bicyclyl-C(=O)NR ⁵ -, fused heterobicyclyl-C(=O)NR ⁵ -, spirobicyclyl, spiroheterobicyclyl, spirobicyclylaliphatic, spiroheterobicyclylaliphatic, spirobicyclyloxy, spiroheterobicyclyloxy, spirobicyclylamino, spiroheterobicyclylamino, spiro Bicyclyloxyalkoxy, spiroheterobicyclyloxyalkoxy, spirobicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spirobicyclyl-C(=O)-, spirobicyclyl- C(=O)O-, spiroheterobicyclyl-C(=O)-, spiroheterobicyclyl-C(=O)O-, spirobicyclylamino-C(=O)-, spiroheterobicyclylamino -C(=O)-, spirobicyclyl-C(=O)NR ⁵ -, spiroheterobicyclyl-C(=O)NR ⁵ -, aryl, heteroaryl, arylaliphatic or heteroaryl Aliphatic, wherein r is 0, 1 or 2, and each of the alkoxy and alkylamino moieties mentioned above may be independently substituted with one or more hydroxyl groups, amino groups or amino groups Substituted by a group;

R ³ and R ^3a are each independently selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, R ^5a R ⁵ N-, R ^5a R ⁵ N-aliphatic, hydroxyaliphatic, aliphatic, alkoxy radical, alkoxyaliphatic, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkyloxyaliphatic, heterocyclyloxyaliphatic, cycloalkylalkoxy, heterocyclic alkoxy, aryloxyalkyl, heteroaryloxyaliphatic, arylaliphatic, heteroarylaliphatic, aryl, or heteroaryl; in some embodiments, each of R ³ and R ^3a is independently Selected from H, F, Cl, Br, -CN, R ^5a R ⁵ NC _1-3 aliphatic, C _1-3 aliphatic, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkane Oxygen, C _1-3 haloalkyl, cycloalkyloxy C _1-3 aliphatic or heterocyclyloxy C _1-3 aliphatic;

U ₁ and U ₂ are each independently selected from CR ⁴ or N;

V is selected from NR ⁵ R ^5a , OR ⁵ , aliphatic, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylaliphatic or heteroarylaliphatic;

V ₁ is selected from O or NR ⁵ ;

V ₂ , V ₃ and V ₄ are each independently selected from CR ⁴ R ^4a , NR ⁵ , CR ⁴ or N, provided that only one of V ₂ , V ₃ , and V ₄ can be selected from NR ⁵ or N, or V ₂ and V ₃ or V ₃ and V ₄ can be combined into the form of CR ⁴ R ^4a , NR ⁵ , O, CR ⁴ or N, provided that the final structural formula is a chemically stable structural formula;

W ₁ , W ₂ , W ₃ and W ₄ are each independently selected from CR ⁴ R ^4a , NR ⁵ , CR ⁴ or N, or W ₁ and W ₂ or W ₃ and W ₄ can be combined into CR ⁴ R ^4a , NR ^5. In the form of O or S;

X ₁ is selected from (CR ⁴ R ^4a ) _m , NR ⁵ , O, S, S═O or SO ₂ ; and m is 0, 1 or 2;

X ₂ and X ₃ are each independently selected from O, S or NR ⁵ ;

Z is selected from -NR ⁵ C(=O)(CR ⁴ R ^4a ) _p -, -NR ⁵ C(=S)-(CR ⁴ R ^4a ) _p -, -NR ^5a -(CR ⁴ R ^4a ) _p - , -NR ⁵ (CR ⁴ R ^4a ) _p C(=O)-, -NR ⁵ (CR ⁴ R ^4a ) _p C(=S)-, -NR ⁵ S(=O) _r -, -NR ⁵ S (=O) _r (CR ⁴ R ^4a ) _p -, -C(=O)NR ⁵ (CR ⁴ R ^4a ) _p - or -NR ⁵ (CR ⁴ R ^4a ) _p S(=O) _r -, where p is 0, 1 or 2 or 3; and r is 1 or 2;

Z ₁ and Z ₂ are each independently selected from NR ⁵ or CR ⁴ R ^4a ;

R ⁴ and R ^4a are each independently selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, -NR ^5a R ⁵ , alkoxy, cycloalkyloxy, heterocyclylalkoxy, aliphatic , Halogenated aliphatic, hydroxy aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, aryl aliphatic, heterocyclyl aliphatic, cycloalkyl aliphatic, aryl oxygen aliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or Carbocyclyl; when R ⁴ and R ^4a are connected to the same carbon atom, R ⁴ , R ^4a and the carbon atom can optionally form a substituted or unsubstituted carbocyclic or heterocyclic ring with 3-8 atoms;

R ⁵ and R ^5a are each independently selected from hydrogen, R ⁶ R ^6a NC(=O)-, R ⁶ OC(=O)-, R ⁶ C(=O)-, R ⁶ R ^6a NS(=O) -, R ⁶ OS(=O)-, R ⁶ S(=O)-, R ⁶ R ^6a NSO ₂ -, R ⁶ OSO ₂ -, R ⁶ SO ₂ -, aliphatic, halogenated aliphatic, hydroxyaliphatic Aliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxy aliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl; when ^R5 and R ^5a is connected to the same nitrogen atom, and R ⁵ , R ^5a and the nitrogen atom can optionally form a substituted or unsubstituted ring of 3-8 atoms, including spiro bicyclic rings and fused bicyclic rings;

R ^and R ^are each independently selected from the group consisting of H, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, Heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylamino aliphatic, aryl, heteroaryl, heterocyclyl, or carbocyclyl; and

Wherein each substituent mentioned in the present invention is such as: R ^5a R ⁵ N-, -C(=O)NR ⁵ R ^5a , -OC(=O)NR ⁵ R ^5a , -OC(=O)OR ⁵ , -NR ⁵ C(=O)NR ⁵ R ^5a , -NR ⁵ C(=O)OR ^5a , -NR ⁵ C(=O)-R ^5a , R ⁵ R ^5a NO ₂ S-, R ⁵ O ₂ S-, R ⁵ O ₂ SR ^5a N-, OR ⁵ , NR ⁵ , CR ⁴ R ^4a , CR ⁴ , (CR ⁴ R ^4a ) _m , -NR ⁵ C(O)-(CR ⁴ R ^4a ) _p - , -NR ⁵ C(=S)-(CR ⁴ R ^4a ) _p -, -NR ^5a -(CR ⁴ R ^4a ) _p -, -NR ⁵ -(CR ⁴ R ^4a ) _p C(=O)-, -NR ⁵ -(CR ⁴ R ^4a ) _p C(=S)-, -NR ⁵ S(O) _r -, -NR ⁵ S(=O)(CR ⁴ R ^4a ) _p -, -C(=O )NR ⁵ -(CR ⁴ R ^4a ) _p -, -NR ⁵ -(CR ⁴ R ^4a ) _p -S(=O) _r -, R ^5a R ⁵ N-alkyl, R ⁵ (S=O) _r -alkyl, R ⁵ R ^5a N-(C=O)-C _1-6 alkyl, R ^5a R ⁵ NC _1-6 alkoxy, R ⁵ (S=O) _r -alkoxy, R ⁵ R ^5a N-(C=O)-alkoxy, R ⁶ R ^6a NC(=O)-, R ⁶ OC(=O)-, R ⁶ C(=O)-, R ⁶ R ^6a NS(= O)-, R ⁶ OS(=O)-, R ⁶ S(=O)-, R ⁶ R ^6a NSO ₂ -, R ⁶ OSO ₂ -, R ⁶ SO ₂ -, R ^5a R ⁵ N-aliphatic , haloalkyl, heterocyclylalkyl, cycloalkyl, cycloalkyloxyaliphatic, cycloalkylalkoxy, aryloxyalkyl, heteroaryloxyaliphatic, aliphatic, alkoxy, hydroxy Alkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylaminohaloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxy Alkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy), carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy radical), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy, azidoalkoxy , Fused bicyclyl, Fused heterobicyclyl, Fused bicyclyl aliphatic, Fused heterobicyclyl aliphatic, Fused bicyclyloxy, Fused heterobicyclyloxy, Fused bicyclylamino Base, fused heterobicyclylamino, fused bicyclyloxyalkoxy, fused heterobicyclyloxyalkoxy, fused bicyclylaminoalkoxy, fused heterobicyclylaminoalkoxy, fused Fused bicyclyl-C(=O)-, fused bicyclyl-C(=O)O-, fused heterobicyclyl-C(=O)-, fused heterobicyclyl-C(=O)O- , Fused bicyclylamino-C(=O)-, Fused heterobicyclylamino-C(=O)-, Fused bicyclyl-C(=O)NR ⁵ -, Fused heterobicyclyl-C( =O)NR ⁵ -, spirobicyclyl, spiroheterobicyclyl, spirobicyclylaliphatic, spiroheterobicyclylaliphatic, spirobicyclyloxy, spiroheterobicyclyloxy, spirobicyclylamino, spiroheterobicyclo Baseamino, spirobicyclyloxyalkoxy, spiroheterobicyclyloxyalkoxy, spirobicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spirobicyclyl-C(=O)-, Spirobicyclyl-C(=O)O-, spiroheterobicyclyl-C(=O)-, spiroheterobicyclyl-C(=O)O-, spirobicyclylamino-C(=O)-, spiro Heterobicyclylamino-C(=O)-, spirobicyclyl-C(=O)NR ⁵ -, or spiroheterobicyclyl-C(=O)NR ⁵ -, aryl, heteroaryl, aryl aliphatic aliphatic, heteroaryl aliphatic, halogenated aliphatic, hydroxy aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, heterocyclyl aliphatic, cycloalkyl aliphatic, Aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, heterocyclyl and carbocyclyl are all acceptable are independently substituted or unsubstituted substituents.

Some other embodiments are compounds as shown in formula (I), wherein,

R ¹ and R ² are each independently selected from hydrogen, halogen, cyano, hydroxyl, R ^5a R ⁵ N-, -C(=O)NR ⁵ R ^5a , -OC(=O)NR ⁵ R ^5a , -OC (=O)OR ⁵ , -NR ⁵ C(=O)NR ⁵ R ^5a , -NR ⁵ C(=O)OR ^5a , -NR ⁵ C(=O)-R ^5a , R ⁵ R ^5a NO ₂ S -, R ⁵ O ₂ S-, R ⁵ O ₂ SR ^5a N-, R ^5a R ⁵ NC _1-6 alkyl, R ⁵ S(=O) _r -C _1-6 alkyl, R ⁵ R ^5a NC (=O)-C _1-6 alkyl, R ^5a R ⁵ NC _1-6 alkoxy, R ⁵ S(=O) _r -alkoxy, R ⁵ R ^5a N-(C=O)-alk Oxygen, C _1-6 aliphatic, C 1-6 alkylamino- _{C 1-6} alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _3-10 heterocyclyl-C _{1- 6} alkyl, C _1-6 alkoxy-C 1-6 alkoxy, C _1-6 alkylthio-C _1-3 alkoxy, -C _1-6 alkoxy- _NR ^5a -C( =O)-OR ⁵ , -C _1-3 alkoxy-NR ^5a -C(=O)-R ⁵ , -C _1-3 alkoxy-C(=O)-C _1-3 alkyl, C _1-6 alkoxy, hydroxy-C _1-6 alkoxy, amino-C _1-6 alkoxy, hydroxy-substituted amino-C _1-6 alkoxy, C _1-6 haloalkoxy, amino Substituted -C _1-6 haloalkoxy, C _1-6 alkylamino-C _1-6 haloalkoxy, hydroxy substituted -C _1-6 haloalkoxy, C _1-6 alkylamino-C _1-6 alkane Oxygen, aryl-C _1-6 alkoxy, C _4-10 heterocyclyl-C _1-6 alkoxy, C _3-10 cycloalkyl-C _1-6 alkoxy, C _4-10 Heterocyclyl (hydroxy-C _1-6 alkoxy), C _3-10 cycloalkyl (hydroxy-C _1-6 alkoxy), aryl (hydroxy-C _1-6 alkoxy), aryloxy Base-C _1-6 alkoxy, C _4-10 heterocyclyloxy-C _1-6 alkoxy, C _3-10 cycloalkyloxy-C _1-6 alkoxy, C _6-10 Aryloxy, C _4-10 heterocyclyloxy, C _3-10 cycloalkyloxy, halo-C _1-6 alkoxy, azido-C _1-6 alkoxy, aryl- C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyloxy, C _4-10 heterocyclyl alkoxy, C _1-10 heteroaryl alkoxy, C _{5 -12} fused bicyclyl, C _5-12 fused heterobicyclyl, C _5-12 fused bicyclyl C _1-3 aliphatic, C _5-12 fused heterobicyclyl C _1-3 aliphatic, C _{5 -12} fused bicyclyloxy group, C _5-12 fused bicyclylamino, C _5-12 fused bicyclyloxy C _1-6 alkoxy, C _5-12 fused bicyclylamino C _1-6 alkoxy, C _5-12 fused bicyclyl-C(=O)-, C _5-12 fused bicyclyl-C(=O)O-, C _5-12 fused heterobicyclyl-C(=O)-, C _5-12 fused heterobicyclyl-C(=O)O -, C _5-12 fused bicyclylamino-C(=O)-, C _5-12 fused heterobicyclylamino-C(=O)-, C _5-12 fused bicyclyl-C(=O )NR ⁵ -, C _5-12 fused heterobicyclyl-C(=O)NR ⁵ -, C _5-12 spirobicyclyl, C _5-12 spiroheterobicyclyl, C _5-12 spirobicyclyl C _{1 -3} aliphatic, C _5-12 spiro heterobicyclyl C _1-3 aliphatic, C _5-12 spiro bicyclyloxy C _1-6 alkoxy, C _5-12 spiro bicyclyl amino C _1-6 alkane Oxygen, C _5-12 spirobicyclyloxy, C _5-12 spirobicyclylamino, C _5-12 fused heterobicyclyloxy, C _5-12 fused heterobicyclylamino, C _5-12 fused Heterobicyclyloxy C _1-6 alkoxy, C _5-12 fused heterobicyclylamino C _1-6 alkoxy, C _5-12 spiro heterobicyclyl oxy C _1-6 alkoxy, C _5-12 spiro heterobicyclyl amino C _1-6 alkoxy, C _5-12 spiro heterobicyclyl oxy, C _5-12 spiro heterobicyclyl amino, C _5-12 spiro bicyclyl-C(=O )-, C _5-12 spirobicyclyl-C(=O)O-, C _5-12 spiroheterobicyclyl-C(=O)-, C _5-12 spiroheterobicyclyl-C(=O)O -, C _5-12 spirobicyclylamino-C(=O)-, C _5-12 spiroheterobicyclylamino-C(=O)-, C _5-12 spirobicyclyl-C(=O)NR ⁵ -, C _5-12 spiro heterobicyclyl-C(=O)NR ⁵ -, C _6-10 aryl, C _1-10 heteroaryl, C _6-10 aryl C _1-6 aliphatic or C _{1 -10} Heteroaryl C _1-6 aliphatic; wherein, r is 0, 1 or 2, and each of the alkoxy and alkylamino moieties mentioned above can be independently replaced by one or more hydroxyl groups, amino groups or substituted amino groups;

R ³ and R ^3a are each independently selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, R ^5a R ⁵ N-, R ^5a R ⁵ N-C1-3 aliphatic, hydroxyl C1-3 aliphatic , C _1-3 aliphatic, C _{1-3 alkoxy, C 1-3 alkoxy C 1-3 aliphatic, C 1-3 haloalkyl, C 3-6 heterocyclyl , C 3-6 hetero} Cyclic C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy C _1-3 aliphatic, C _3-6 heterocyclyloxy C _1-3 aliphatic, C _3-6 cycloalkyl C _1-3 alkoxy, C _3-6 heterocyclyl C _1-3 alkoxy, C _6-10 aryloxy C _1-3 alkyl, C _1-10 heteroaryloxy C _1-3 aliphatic, C _6-10 aryl C _1-3 aliphatic, C _1-10 heteroaryl C _1-3 aliphatic, C _6-10 aryl or C _1-10 heteroaryl;

U ₁ and U ₂ are each independently selected from CR ⁴ or N; and

V is selected from NR ⁵ R ^5a , C _1-6 aliphatic, C _6-10 aryl, C _1-10 heteroaryl, C _6-10 aryl C _1-6 aliphatic or C _1-10 heteroaryl C _1-6 aliphatic.

Some other embodiments are compounds as shown in formula (I), wherein, formula (IIa) is selected from the following substructural formulas:

Wherein R ^3a , R ⁵ and R ^5a are as defined above.

Some other embodiments are compounds as shown in formula (I), wherein _Q is selected from the following substructural formulas:

Wherein R ¹ , R ² and R ⁵ are as defined above.

Some other embodiments are compounds as shown in formula (I), wherein,

X ₁ is selected from O or NR ⁵ ;

Z is selected from -NH-C(=O)-; and

Z ₁ and Z ₂ are each independently selected from NR ⁵ or CR ⁴ R ^4a , provided that, when R ⁴ and R ^4a are connected to the same carbon atom, R ⁴ , R ^4a and the carbon atom can optionally be substituted or non-substituted. Substituted carbocyclic or heterocyclic rings of 3-8 atoms.

Some other embodiments are compounds as shown in formula (I), wherein the substructures jointly defined by X ₁ , Z, U ₁ and R ₃ are selected from the following structural formulas:

Some other embodiments are compounds as shown in formula (I), wherein, formula (IIb) is selected from the following structural formulas:

wherein, Ar represents a substituted or unsubstituted aryl or heteroaryl group; and s is 0 or 1. the

Some other embodiments are compounds as shown in formula (I), wherein ^R is selected from the following structural formulas:

wherein, X ₄ and X ₄ ' are each independently selected from (CR ⁴ R ^4a ) _m , NR ⁵ , O, S, S=O or SO ₂ ; m and n are independently selected from 0, 1 or 2; and t is 1, 2 or 3.

In other embodiments, the present invention relates to one of the following compounds and pharmaceutically acceptable salts and solvates thereof, but are by no means limited to these compounds:

The present invention also encompasses the use of the compounds of the present invention and their pharmaceutically acceptable salts for the manufacture of medicinal products for the treatment of acute and chronic angiogenesis-mediated diseases, including those described herein. The application of the compound of the present invention in the production of anticancer drugs. The compounds of the present invention are also useful in the manufacture of a medicament for alleviating, preventing, controlling or treating disorders mediated by KDR, c-Met or IGF1R. The present invention includes a pharmaceutical composition comprising a compound represented by formula (I), (IV) or (V) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent required for effective treatment Dosage. the

The present invention also encompasses methods of treating an angiogenesis-mediated disease in a patient, or being susceptible to it, comprising treating the patient with a therapeutically effective amount of a compound represented by formula (I), (IV) or (V). the

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. the

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. the

The salts of the compounds of the present invention also include intermediates used in the preparation or purification of compounds represented by formula (I), (IV) or (V) or isolated compounds of compounds represented by formula (I), (IV) or (V) Salts of enantiomers, but not necessarily pharmaceutically acceptable salts. the

If the compound of the present invention is basic, the desired salts 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. Alternatively organic acids such as acetic, maleic, succinic, mandelic, fumaric, malonic, pyruvic, oxalic, glycolic and salicylic; pyranonic acids such as glucuronic and galactose Alkyd acids; α-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, ethanesulfonic acid, etc. the

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 or 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, and cyclic ammonia such as piperidine, morpholine and piperazine etc., and inorganic salts obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. the

Compositions, Formulations and Administration of Compounds of the Invention

According to another aspect, the characteristics of the pharmaceutical composition of the present invention include a compound of formula (I), (IV) or (V), a compound listed in the present invention, or a compound of Examples 1-28, and a pharmaceutically acceptable acceptable carrier, adjuvant, or vehicle. The amount of compound in the compositions of the invention is effective to detectably inhibit a protein kinase in a biological specimen or patient. the

The compounds of the present invention exist in free form, or suitably, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other compounds that can be administered directly or indirectly according to the needs of patients. Adducts or derivatives, compounds described in other aspects of the present invention, their metabolites or their residues. the

As described in the present invention, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used in the present invention, includes any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, etc., are suitable for the particular intended dosage form. As described in: In Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, edited by D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988-1999 , Marcel Dekker, New York, synthesized the contents of the literature herein, showing that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except to the extent that any conventional carrier media is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions in a deleterious manner with any other components of the pharmaceutically acceptable composition, they The purposes of the present invention are also considered scope. the

Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid, Potassium phosphate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, 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 such as carboxymethyl sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive, corn, and soybean oils; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffered solution, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coatings, sweeteners, flavors and fragrances, preservatives and antioxidants. the

The compositions of the present invention may be administered orally, by injection, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable kit . The term "injectable" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial (cavity), intrasternal, intrathecal, intraocular, intrahepatic, Intralesional, and intracranial injection or infusion techniques. Preferred compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oleaginous suspensions. These suspensions may be formulated according to the known art using suitable dispersing agents, wetting agents and suspending agents. Sterile injections can be sterile injection solutions or suspensions, which are non-toxic acceptable diluents or solvents for injection, such as 1,3-butanediol solution. Among the acceptable vehicles and solvents are water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile, fixed oils are conventionally employed as a solvent or suspending medium. the

For this purpose any bland fixed oil may be a synthetic mono- or diglyceride. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene derivatives. These oil solutions or suspensions may contain a long-chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersing agents, commonly used in pharmaceutical formulations of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifiers or enhancers of bioavailability, are generally used in pharmaceutically acceptable solid, liquid, or other dosage forms, and can be applied to target pharmaceutical preparations preparation. the

The pharmaceutically acceptable compositions of this invention may be orally administered in any acceptable oral dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For tablets for oral use, carriers generally include lactose and corn starch. Lubricants, such as magnesium stearate, are typically added. For oral administration in capsules, suitable diluents include lactose and dried cornstarch. When administered orally as an aqueous suspension, the active ingredient consists of emulsifying and suspending agents. Certain sweetening, flavoring or coloring agents may also be added if desired in these dosage forms. the

Additionally, the pharmaceutically acceptable compositions of this invention may be administered rectally in the form of suppositories. These can be prepared by mixing the agent with a suitable non-infusing excipient which is solid at room temperature but liquid at rectal temperature, where it melts and releases the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols. The pharmaceutically acceptable compositions of the present invention may be administered topically, especially when topical administration involves areas or organs where the therapeutic target is easily accessible, such as diseases of the eyes, skin or lower intestinal tract. Suitable topical formulations can be prepared and applied to these areas or organs. the

Rectal suppositories (see above) or suitable enemas can be applied topically in the lower intestinal tract. Local skin spots can also be used in this way. For topical use, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carrier compounds for topical administration of this invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions may be prepared in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, Span-60 (sorbitan monostearate), Tween 60 (polysorbate 60), cetyl esters wax, cetyl alcohol, 2- Octyldodecanol, Benzyl Alcohol and Water. the

For ophthalmic use, the pharmaceutically acceptable composition can be prepared as a formulation, such as isotonic micronized suspension, pH-adjusted sterile saline or other aqueous solution, preferably, isotonic solution and pH-adjusted sterile saline or For other aqueous solutions, disinfectant preservatives such as benzalkonium chloride can be added. In addition, for ophthalmic use, the pharmaceutically acceptable composition can be formulated into an ointment such as petrolatum. The pharmaceutically acceptable compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to known techniques of formulation formulation, or may be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption enhancers, fluorocarbons or other conventional solubilizing or dispersing agents to enhance bioavailability Spend. the

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may contain, in addition to the active compound, generally known inert diluents, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl esters, propylene glycol, 1,3-butanediol, dimethylformamide, oils and fats (especially cottonseed, groundnut, corn, microbial, olive, castor and sesame oils), glycerin, 2-tetrahydrofurfurylmethanol, polyethylene glycol , sorbitan fatty acid esters, and mixtures thereof. Besides inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying or suspending agents, sweetening, flavoring, and perfuming agents. the

Injections, such as sterile injections or oily suspensions, can be prepared according to known techniques using suitable dispersing agents, wetting agents and suspending agents according to formulations. Sterile injectable preparations can be sterile injectable solutions, suspensions or emulsions prepared with non-toxic injectable acceptable diluents or solvents, for example, 1,3-butanediol solution. Among the acceptable vehicles and solvents are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be used for this purpose including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in injectables. the

The injection can be sterile, such as filtered through a bacteria-defense filter, or incorporated in the form of a sterile solid composition with a sterilizing agent that can be dissolved or dispersed in sterile water or other sterile injectable media before use middle. In order to prolong the effect of the compounds of the invention, it is usually necessary to slow the absorption of the compounds by subcutaneous or intramuscular injection. In this way, the liquid suspension can be used to solve the problem of poor water solubility of crystalline or amorphous substances. The rate of absorption of a compound depends upon its rate of dissolution, which in turn depends on crystal size and crystalline shape. Additionally, delayed absorption of the compound administered by injection can be accomplished by dissolving or dispersing the compound in an oil vehicle. the

Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The rate at which the compound is released depends on the rate at which the compound forms the polymer and the nature of the particular polymer. Other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot forms are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues. the

In some embodiments, the composition for rectal or vaginal administration is a suppository, which can be prepared by mixing the compound of the present invention with a suitable non-infusion adjuvant or carrier, such as cocoa butter, polyethylene glycol, or Suppositories are waxy substances that are solid at room temperature but liquid at body temperature and therefore melt in the vaginal or thecal cavity to release the active compound. the

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or fillers or a) fillers such as starch, lactose, sucrose, glucose, mannitol and Silicic acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar, calcium carbonate, potatoes Starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) blocker solutions such as paraffin, f) absorption enhancers such as quaternary ammonium compounds, g) humectants such as cetyl alcohol and glycerol monostearate Esters, h) absorbents such as kaolin and bentonite, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. As with capsules, tablets and pills, these dosage forms may contain buffering agents. the

A similar type of solid composition can be a soft or hard capsule filled with fillers, and the used excipients include lactose and macromolecular polyethylene glycol and the like. Solid dosage forms like tablets, lozenges, capsules, pills and granules can be prepared by coating, shelling such as enteric coating and other known coating methods for pharmaceutical preparations. They may optionally contain opacifying agents or, preferably, release the only active ingredient in the composition in a certain part of the intestinal tract, optionally in a delayed manner. For example implant compositions may comprise polymeric substances and waxes. the

The active compounds can be in microencapsulated dosage form with one or more excipients as described herein. Solid dosage forms like tablets, lozenges, capsules, pills and granules can be coated or shelled, such as enteric coating, release-controlling coating and other well-known methods of pharmaceutical formulation. In these solid dosage forms, the active compound may be admixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain, as usual, additional substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. As with capsules, tablets and pills, these dosage forms may contain buffering agents. They may optionally contain a sedative or, preferably, release the only active ingredient of the composition in a certain part of the intestinal tract, with any delay. Applicable implant compositions may include, but are not limited to, polymers and waxes. the

Dosage forms for topical or dermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or necessary buffers. Ophthalmic pharmaceutical formulations, ear drops and eye drops are all contemplated by the present invention. In addition, the present invention also contemplates the application of transdermal patches, which have more advantages in controlling the delivery of the compound into the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can increase the flux of the compound across the skin, controlling the rate either by rate controlling films or by dispersing the compound in a polymer matrix or gelatin. the

The compounds of the present invention are preferably formulated in dosage unit form to ease administration and uniformity of dosage. The term "dosage unit form" as used herein refers to a physically discrete unit of drug required to adequately treat a patient. It is to be understood, however, that the total daily usage of the compounds or compositions of the present invention will be determined by the attending physician based on sound medically sound judgment. The particular effective dosage level for any particular patient or organism will depend on many factors including the condition being treated and the severity of the condition, the activity of the particular compound, the particular composition employed, the age, weight, health, sex of the patient and dietary habits, timing of administration, route of administration and rate of excretion of the particular compound employed, duration of treatment, use of the drug in combination or with specific compounds, and other factors well known in the art of pharmacy. the

The amount of a compound of the invention which may be combined with a carrier material to produce a single dosage composition will vary depending upon the indication and the particular mode of administration. In some embodiments, the composition can be prepared according to the formulation method into an inhibitor with a dose of 0.01-200 mg/kg body weight/day, and the administration is performed according to the amount of the composition accepted by the patient. the

The compounds of the present invention may be administered as the sole pharmaceutical agent or in combination with one or more other additional therapeutic (pharmaceutical) agents, where the combination causes acceptable adverse reactions, which has implications for the treatment of hyperproliferative diseases such as cancer special meaning. In such cases, the compounds of the invention may be combined with known cytotoxic agents, individual transduction inhibitors or other anticancer agents, as well as mixtures and combinations thereof. As used herein, an additional therapeutic agent normally administered to treat a particular disease is known as "appropriately treating a disease". "Additional therapeutic agents" as used in the present invention include chemotherapeutic drugs or other anti-proliferative drugs that can be combined with the compounds of the present invention to treat proliferative diseases or cancer. the

Chemotherapeutic or other antiproliferative agents include histone deacetylase (HDAC) inhibitors, including but not limited to, SAHA, MS-275, MGO103, and those compounds described in the following patents: WO 2006/010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US 2005/0288282, WO 00/71703, WO 01/38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO2005/0302005, WO 2005/0302005 /092899, and demethylating agents including, but not limited to, 5-aza-2′-deoxycytidine (5-aza-dC), azacitidine (Vidaza), decitabine (Decitabine), and Compounds described in the following documents: US 6,268137, US 5,578,716, US 5,919,772, US 6,054,439, US 6,184,211, US 6,020,318, US 6,066,625, US 6,506,735, US 6,221,849, US 6,953,131/83, US 6,953,706,735, US 6,221,849, US 6,953,131/83, US 6,953,131/83.9 the

In other embodiments, chemotherapeutic or other anti-proliferative drugs may be combined with the compounds of the invention for the treatment of proliferative diseases and cancers. Known chemotherapeutic agents including, but not limited to, other therapies or anticancer agents may be combined with anticancer agents of the present invention including surgery, radiation therapy (a few examples are gamma radiation, neutron beam radiation therapy, electron beam radiation therapy , proton therapy, brachytherapy and systemic radioisotope therapy), endocrine therapy, taxanes (paclitaxel, docetaxel, etc.), platinum derivatives, biological response modifiers (interferon, interleukin, tumor necrosis factor (TNF, TRAIL receptor targeting and mediators), hyperthermia and cryotherapy, agents to dilute any adverse effects (such as antiemetics), and other approved chemotherapeutic agents including, but not limited to, alkanes Chemicals (nitrogen mustard, chlorambucil, cyclophosphamide, phenylalanine mustard, ifosfamide), antimetabolites (methotrexate, pemetrexed, etc.), purines Antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-fluorouracil, Cytarabile, Gemcitabine), spindle inhibitors (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllum Toxins (Etoposide, Irinotecan, Topotecan), Antibiotics (Doxorubicin, Bleomycin, Mitomycin), Nitroureas (Carmustine, Lomustine), inorganic ions (cisplatin, carboplatin), cell division cycle inhibitors (KSP via mitotic kinesin inhibitors, CENP-E and CDK inhibitors), enzymes (asparaginase), hormones (Tamoxifen, Leuprolide, Flutamide, Megestrol), Gleevec ( Gleevec), Adriamycin, Dexamethasone, and cyclophosphamide. Anti-angiogenic factors (Avastin and others), kinase inhibitors (Imatinib, Sunitinib (Sutent), Sorafenib (Nexavar), Cetuximab (Erbitux ), Herceptin, Tarceva, Iressa, and others). Drugs inhibit or activate cancer pathways such as mTOR, HIF (hypoxia-inducible factor) pathway and others. See http://www.nci.nih.ggov/ for a broader forum on cancer treatment, http://www.fda.ggov/cder/cancer/druglist-rame.htm for a list of FAD-approved oncology drugs, and Gram Handbook, Eighteenth Edition. 2006, all contents are incorporated by reference.

In other embodiments, the compounds of the invention may bind cytotoxic anticancer agents. Such anticancer agents can be found in the Thirteenth Edition of The Merck Index (2001). These anticancer agents include, but are not limited to, Asparaginase, Bleomycin, Carboplatin, Carmustine, Chlorambucil, Cisplatin, L-asparaginase (Colaspase), cyclophosphamide, cytarabine (Cytarabine), dacarbazine (Dacarbazine), actinomycin D (Dactinomycin), daunorubicin (Daunorubicin), doxorubicin ( Doxorubicin), Epirubicin, Etoposide, 5-Fluorouracil, Hexamethylmelamine, Hydroxyurea, Ifosfamide, Irinotecan, Leucovorin, Cyclohexamethylene Nitrourea, nitrogen mustard, 6-mercaptopurine, Mesna, Methotrexate, Mitomycin C, Mitoxantrone, Prednisolone , Prednisone, Procarbazine, Raloxifen, Streptozocin, Tamoxifen, Thioguanine, Topotecan , vinblastine, vincristine, vinblastine. the

Other suitable cytotoxic drugs for use in combination with the compounds of the present invention include, but are not limited to, those compounds that are recognized for use in the treatment of neoplastic diseases, as described in Goodman and Gilman's The Pharmacological Basis of Therapeutics (9th Edition, 1996, McGraw-Hill.); these anticancer agents include, but are by no means limited to, aminoglutethimide, L-asparaginase, azathioprine, 5-azocyto Glycosides, Cladribine, Busulfan, Diethylstilbestrol, 2′,2′-Difluorodeoxycytidine, Docetaxel, Erythrohydroxynonyladenine, Acetylene Estradiol, 5-fluorouracil deoxynucleoside, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, Idarubicin, Interferon, Medroxyprogesterone Acetate, Megestrol Acetate, Melphalan, Mitotane, Paclitaxel, Pentostatin, N-Phosphate Acetyl-L-Aspartic Acid (PALA), Plicamycin, Methylcyclohexylnitrosourea (Semustine), Teniposide, Testosterone Propionate, Thiotepa , trimethylmelamine, uridine and vinorelbine. the

Other suitable cytotoxic anticancer agents for use in combination with the compounds of the present invention include newly discovered cytotoxic substances, including, but not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), capecitabine (Capecitabine), macrolide antineoplastic drugs and their natural or synthetic derivatives, Temozolomide (Quinn et al., J.Clin.Oncology, 2003, 21(4), 646-651), Tosimo Monoclonal antibody (Bexxar), Trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3181), and kinesin spindle protein inhibitor Eg5 (Wood et al., Curr.Opin.Pharmacol.2001, 1, 370-377). the

In other embodiments, the compounds of the invention may be combined with other signal transduction inhibitors. Interestingly, signal transduction inhibitors target the EGFR family, such as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000, 60 (Suppl.l), 15-23; Harari et al., Oncogene, 2000, 19(53), 6102-6114) and their respective ligands. Such agents include, but are by no means limited to, antibody therapies such as Herceptin (Trastuzumab), Cetuximab (Erbitux), and Pertuzumab. Such therapies also include, but are by no means limited to, small molecule kinase inhibitors such as Iressa (Gefitinib), Tasaiva (Erlotinib), Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788 (Traxler et al., Cancer Research, 2004 , 64, 4931-4941). the

In other embodiments, the compounds of the invention target receptor kinases of the domain kinase domain family (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, etc.) in combination with other signal transduction inhibitors , and their respective ligands. Such agents include, but are not limited to, antibodies such as bevacizumab (Avastin). Such agents include, but are by no means limited to, small molecule inhibitors such as Gleevec/Imanitib, Sprycel (Dasatinib), Tasigna/Nilotinib, Nexavar (Vandetanib), Vatalanib (PTK787/ZK222584) (Wood et al., Cancer Res. 2000, 60( 8), 2178-2189), Telatinib/BAY-57-9352, BMS-690514, BMS-540215, Axitinib/AG-013736, Motesanib/AMG706, Sutent/Sunitinib/SU-11248, ZD-6474 (Hennequin et al., pp. 92nd AACR Meeting, New Orleans, 24-28, March 2001, Abstract 3152), KRN-951 (Taguchi et al., 95th AACR Meeting, Orlando, FIa, 2004, Abstract 2575), CP-547, 632( Beebe et al, Cancer Res.2003, 63, 7301-7309), CP-673, 451 (Roberts et al, Proceedings of the American Association of Cancer Research, 2004, 45, Abstract 3989), CHIR-258 (Lee et al, Proceedings of the American Association of Cancer Research, 2004, 45, Abstract 2130), MLN-518 (Shen et al., Blood, 2003, 102, 11, Abstract 476). the

In other embodiments, the compounds of the invention may bind to histone deacetylase inhibitors. Such reagents include, but are by no means limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, Abstract 3024), LBH-589 (Beck et al, Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3025), MS-275 (Ryan et al, Proceedings of the American Association of Cancer Research, 2004, 45, abstract 2452), FR-901228 (Piekarz et al, Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3028) and MGCDOI 03 (US 6,897,220). the

In other embodiments, the compounds of the invention may be combined with other anticancer agents such as proteasome inhibitors and m-TOR inhibitors. These include, but are by no means limited to, Bortezomib (Mackay et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, Abstract 3109) and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research, 2004, 45, Abstract 3849). The compounds of the invention may also be combined with other anticancer agents such as topoisomerase inhibitors, including but by no means limited to camptothecin. the

Those additional therapeutic agents may be administered separately from the composition comprising the compound of the invention as part of a multiple dosing regimen. Alternatively, those therapeutic agents may be part of a single dosage form, mixed together with the compounds of this invention to form a single composition. If administered as part of a multiple dosing regimen, the two active agents may be delivered to each other simultaneously, sequentially or over a period of time, such that the desired agent activity is achieved. the

The amount of the compound and the additional therapeutic agent (those compositions containing an additional therapeutic agent such as those described herein) that can be combined to produce a single dosage form will vary depending on the indication and the particular mode of administration. Normally, the amount of additional therapeutic agent in the compositions of the invention will not exceed the amount normally administered for a composition comprising the therapeutic agent as the only active agent. In another aspect, the disclosed compositions additional therapeutic agent in an amount ranging from about 50% to 100% of the normal amount of prior compositions, comprising the agent as the sole active therapeutic agent. In those compositions comprising an additional therapeutic agent, the additional therapeutic agent will act synergistically with the compound of the invention. the

Uses of the compounds and compositions of the present invention

The characteristics of the pharmaceutical composition of the present invention include the compound represented by formula (I), (IV) or (V) or the compounds listed in the present invention, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of compound in the compositions of the invention is effective to detectably inhibit the activity of protein kinases such as VEGFR/KDR, IGF/IGF1R or HGF/c-Met. The compounds of the present invention will find application as antineoplastic agents in the treatment or reduction of the deleterious effects of VEGF, IGF and HGF. the

The compounds of the present invention will be used in, but by no means limited to, administering to a patient an effective amount of the compound or composition of the present invention to prevent or treat a proliferative disease in a patient. Such diseases include cancer, especially metastatic cancer, atherosclerosis, and pulmonary fibrosis. the

The compound of the present invention will be applied to the treatment of tumors including cancer and metastatic cancer, further including but not limited to, cancer such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including small cell lung cancer), esophageal cancer, Cancer of the gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic neoplasms of the lymphoid system (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell leukemia and Burkitt's lymphoma); hematopoietic tumors of the bone marrow system (including acute and chronic myelogenous myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, such as soft tissue and cartilage); tumors of the central peripheral nervous system ( including astrocytoma, neuroblastoma, glioma, and schwannoma); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid lesion Tumor and Kaposi's sarcoma). the

The compounds of the present invention are also useful in the treatment of ophthalmic disorders such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection; diabetic retinopathy; retrolentic fibroplasia, and neovascularization glaucoma; retinal ischemia; vitreous haemorrhage; Systemic disorders such as endometriosis. These compounds are also useful in the treatment of edema and vascular hyperpermeability conditions. the

The compounds of the present invention are useful in the treatment of conditions associated with diabetes such as diabetic retinopathy and microangiopathy. The compounds of the invention are also useful in cases of reduced blood flow in cancer patients. The compounds of the present invention also have a beneficial effect on the reduction of tumor metastasis in patients. the

In addition to their therapeutic benefits in humans, the compounds of the present invention have utility in the veterinary treatment of pets, introduced breeds, and farm animals, including mammals, rodents, and the like. Examples of additional animals include horses, dogs and cats. Here, the compounds of the present invention include their pharmaceutically acceptable derivatives. the

Where the plural form is applied to a compound, salt, etc., it also means a single compound, salt, etc. the

A method of treatment comprising administration of a compound or composition of the present invention, further comprising administration of an additional therapeutic agent (combination therapy) to the patient, wherein the additional therapeutic agent is selected from: chemotherapy, anti-proliferative or anti-inflammatory agents, wherein the additional treatment The agent is appropriate for the condition being treated, and the additional therapeutic agent may be administered in combination with the compound or composition of the invention as a single dosage form, or as separate compounds or compositions as part of a multiple dosage form. Additional therapeutic agents may be administered at the same time or at different times as the compounds of the invention. In the latter case, the administration may be staggered for 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months. the

The invention also encompasses a method of inhibiting the growth of cells expressing VEGFR, IGF1R or c-Met, the method comprising contacting the cell with a compound or composition of the invention, thereby inhibiting the growth of the cell. Cells whose growth can be inhibited 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, hepatocellular carcinoma cells, bladder cancer cells, gastric cancer cells, head or neck squamous cell carcinoma cells, melanoma cells, and leukemia cells. the

The invention provides a method of inhibiting VEGFR, IGF1R or c-Met kinase activity in a biological sample, the method comprising contacting the biological sample with a compound or composition of the invention. The term "biological specimen" used in the present invention refers to specimens outside the living body, including but not limited to, cell culture or cell extraction; biopsy material obtained from mammals or their extracts; blood, saliva, urine, Feces, semen, tears, or other liquid substances of living tissue and their extracts. Inhibition of kinase activity in a biological sample, particularly VEGFR, IGF1R or c-Met kinase activity, can be used for a variety of purposes well known to those skilled in the art. Such uses include, but are by no means limited to, blood transfusion procedures, organ transplantation, biospecimen storage, and bioassays. the

An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present invention refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention. According to the methods of the present invention, the compounds and compositions may be administered in any amount and by any route of administration effective for treating or lessening the severity of a disease. The exact amount necessary will vary from patient to patient, depending on race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. A compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein. the

The compounds of the present invention or pharmaceutical compositions thereof can be applied to the coating of implantable medical devices, such as prostheses, artificial valves, artificial blood vessels, stems and urinary catheters. Vascular stems, for example, have been used to overcome restenosis (reconstriction of vessel walls after injury). However, patients using stems or other implantable devices will be at 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. the

Suitable coatings and general methods of preparation of coatings for implantable devices are described in documents US 6,099,562; US 5,886,026; and US 5,304,121, the coatings being typically biocompatible polymeric materials such as hydrogels Polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating can optionally be further covered with a suitable coating, such as fluorosimethicone, polysaccharase, polyethylene glycol, phospholipids, or a combination thereof, to exhibit the controlled-release characteristics of the composition. Another aspect of the invention includes implantable devices coated with a compound of the invention. The compounds of the present invention may also be coated on implantable medical devices, such as beads, or mixed with polymers or other molecules to provide "drug depots", thus allowing drug Release has a longer time period. the

General Synthesis Process

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), (IV) or (V). The following reaction schemes and embodiments serve to further illustrate the teachings of the invention. the

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. the

Embodiments described below, unless otherwise indicated, 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 Ocean Chemical Factory. the

Anhydrous tetrahydrofuran, dioxane, toluene, and ether are obtained by reflux drying with sodium metal. Anhydrous dichloromethane and chloroform were obtained by reflux 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

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

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 CDCl 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).

The conditions for low-resolution mass spectrometry (MS) data are: Agilent 1200 Series LCMS (ZorbaxSB-C18, 2.1 × 30mm, 4 microns, 10min, flow rate is 0.6mL/min, 5-95% (0.1% dissolved in H ₂ O Formic acid) (0.1% formic acid in _CH3CN ) with UV detection at 210/254 nm in low response electrospray mode (ESI).

Pure compounds were characterized by: Agilent 1100 Series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm (Zorbax SB-C18, 2.1×30mm, 4 microns, 10min, flow rate 0.6mL/min, 5 to 95% (0.1% formic acid in _CH3CN ) in 5-95% (0.1% formic acid in _H2O ).The column was operated at 40°C.

The following abbreviations are used throughout this disclosure:

HOAc Acetic acid

MeCN, _CH3CN acetonitrile

NH ₃ ammonia

NH ₄ Cl Ammonium Chloride

HBTU Benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate

HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

PyBop Benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate

Pd ₂ (dba) ₃ Tris(dibenzylideneacetone)dipalladium

BINAP 2,2′-bis-(diphenylphosphino)-1,1′-binaphthalene

TEAC bis(tetraethylammonium) carbonate

BBr ₃ boron tribromide

BSA bovine serum albumin

Br ₂ Bromine

BOC, Boc tert-butoxycarbonyl

Cs ₂ CO ₃ cesium carbonate

CHCl ₃ Chloroform

CDCl ₃ deuterated chloroform

Cu Copper

CuI Cuprous Iodide

Et ₂ O diethyl ether

DBU 1,8-diazabicyclo[5,4,0]undec-7-ene

DIBAL Diisobutylaluminum hydride

DIAD Diisopropyl azodicarboxylate

DIEA N-Ethyldiisopropylamine

DEAD Diethyl Azodicarboxylate

DMF N,N-Dimethylformamide

DMAP 4-Dimethylaminopyridine

DMSO Dimethyl Sulfoxide

EDC, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Dppa Diphenyl Phosphate Azide

EtOAc ethyl acetate

FBS Fetal Bovine Serum

g grams

h hours

HBr hydrobromic acid

HCl hydrochloric acid

HOBt1-Hydroxybenzotriazole hydrate

H ₂ hydrogen

H ₂ O ₂ hydrogen peroxide

Fe iron

LiHMDS lithium hexamethyldisilazyl

LDA lithium diisopropylamide

MCPBA m-chloroperoxybenzoic acid

MgSO ₄ magnesium sulfate

MeOH, _CH3OH Methanol

MeI methyl iodide

_CH2Cl2 , DCM _{dichloromethane}

NMP N-Methylpyrrolidone

mL, ml milliliter

N ₂ Nitrogen

Pd/C Palladium/Carbon

Pd(OAc) ₂ palladium acetate

Pd(OH) ₂ palladium hydroxide

Pd(PPh ₃ ) _4tetrakis (triphenylphosphine)palladium

Pd(dppf)Cl ₂ 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride

PE petroleum ether (60-90℃)

PBS Phosphate Buffered Saline

POCl ₃ phosphorus oxychloride

_{K2CO3potassium carbonate}

KOH potassium hydroxide

RT rt room temperature

Rt retention time

NaHCO ₃ sodium bicarbonate

NaBH ₄ sodium borohydride

NaBH ₃ CN Sodium cyanoborohydride

NaOtBu Sodium tert-butoxide

NaOH sodium hydroxide

NaClO ₂ sodium chlorite

NaCl Sodium Chloride

NaH ₂ PO ₄ sodium dihydrogen phosphate

NaH sodium hydride

NaI Sodium iodide

Sodium Na ₂ SO ₄ Sulfate

TBTU O-benzotriazole-N, N, N', N'-tetramethylurea tetrafluoroborate

THF Tetrahydrofuran

_Et3N , TEA triethylamine

TFA trifluoroacetic acid

P(t-bu) ₃ tri(tert-butyl)phosphine

NBS N-Bromosuccinimide

TBAI Tetrabutylammonium iodide

_H2O water

Tris Tris hydroxymethyl aminomethane

ATP Adenosine triphosphate

DTT Dimercaptothreitol

MOPS 3-(N-Morpholino)propanesulfonic acid

EDTA ethylenediaminetetraacetic acid

Nonidet Nonidet Detergent

Reaction scheme 1

Substituted compound 7 can be prepared by the method of Reaction Scheme 1, wherein W1, W2, W3 and W4 are CH, _X1 is O; ^R1 (that is, EO-), ^R5 and PG are as defined above. Substituted aryl compound 1 is nitrated by a suitable nitrating agent such as HNO ₃ at a suitable temperature such as 0°C to obtain compound 2. _NO2 groups are reduced by a reducing agent such as Fe powder or Zn powder, or Pd/C catalyzed, and reduced under a hydrogen atmosphere. Aniline compound 3 is condensed with a formate compound such as ethyl formate under basic conditions to obtain substituted quinoline compound 4, and then compound 4 is coupled with a suitable aryl derivative to obtain substituted diaryl ether 5. Protecting group PG leaves to obtain compound 6, thereafter with EL (L = suitable leaving group such as OMs, Cl, Br or I; E = aliphatic, heterocyclyl aliphatic, fused heterobicyclyl aliphatic , spiroheterobicyclyl aliphatic, cycloaliphatic, fused bicyclyl aliphatic, spirobicyclyl aliphatic, heterobicyclyl, fused heterobicyclyl, spiroheterobicyclyl, cycloalkyl, fused bicyclyl, spirobicyclyl, etc.) condensation to obtain the target kinase inhibitor 7.

Reaction Scheme 2

Alternatively, substituted indole/azaindole analogs 11 can be synthesized as described in Reaction Scheme 2. Wherein R ¹ , X ₁ , U ₂ and PG are as defined above, and R is selected from H, R ^5a R ⁵ N-, aliphatic, alkoxy, haloalkyl, heterocyclyl, heterocycloalkyl, cycloalkane radical, cycloalkylalkyl, cycloalkylalkoxy or heterocyclylalkoxy. Substituted 2-aminopyrazoles 8 are first converted to compounds 9 via a similar pathway to Scheme 1. The OH group is then replaced by a more easily leaving group L such as Cl, F or OMs. L is converted into kinase inhibitor 11 in compound 10 in an alkaline environment such as Cs ₂ CO ₃ , NaOH, DMAP, or lutidine in dioxane, toluene, or DMA, preferably under heating conditions.

Reaction Scheme 3

Alternatively, substituted kinase inhibitor 16 can be prepared by the method of Reaction Scheme 3. The definitions of W ₁ , W ₂ , W ₃ , W ₄ , R ¹ (that is, EO-), R ³ , U ₁ , U ₂ , X ₁ and PG are as above. Condensation of compound 12 with a nitro-substituted aryl derivative to give compound 13, followed by deprotection to give compound 14, followed by coupling with the E group, followed by reduction of the nitro group to give compound 15, and finally condensation of aniline compound 15 with an acid The target kinase inhibitor 16 is obtained, wherein the condensing agent used is EDCI or HATU and the like.

Reaction scheme 4

Alternatively, the kinase inhibitors of the present invention can be obtained by the method described in Reaction Scheme 4. Wherein R ¹ (that is, EO-), R ² and PG are defined as above. Compound 20 was obtained from 2-chloropyridine derivative 19 under Pd catalysis. Aniline compound 20 is condensed with acid, and the protective group is removed to obtain compound 22. Attachment of a suitable group such as a spiro or bicyclic moiety to the quinoline moiety affords compound 23. In the above structural formulas, R is the structural formula defined by V ₁ , V ₂ , V ₃ and V ₄ in formula (IIa) or the structural formula defined by Z ₁ , Z ₂ , X ₂ and X ₃ in formula (IIb).

Example

Example 1

N-(4-(7-((5S)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methoxyquinolin-4-yloxy)-3-fluorobenzene base)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

step 1:

(S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)pyrrolidin-2-one

(S)-5-hydroxymethylpyrrolidone (1.0g, 8.7mmol, Aldrich) and 3,4-dihydropyran (1.46g, 17.4mmol, Alfa) were dissolved in 20mL of dichloromethane, and then added to the reaction solution PPTS (0.437g, 1.74mmol, Aldrich) was slowly added to , and the reaction was stirred at room temperature for 4 hours. After the reaction was completed, 20 mL of saturated NaHCO ₃ solution was added to the reaction solution to quench the reaction, 25 mL of dichloromethane was extracted twice, the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel Purification by column chromatography (EtOAc) afforded the title compound as a colorless oil (0.9 g, 52%).

MS (ESI _, pos.ion) m/z: _199.9 (M+1); exact mass calculated for _C10H17NO3 : 199.1

¹ H NMR (400MHz, CDCl ₃ ): δ1.69-1.88(m, 6H), 2.25-2.28(m, 2H), 2.32-2.35(m, 2H), 3.23(m, 1H), 3.48-3.55( m, 2H), 3.78-3.85 (m, 2H), 4.58 (m, 1H).

Step 2:

(S)-1-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)pyrrolidin-2-one

Suspend NaH (0.48g, 12mmol, 60% mineral oil, Aldrich) in 15mL DMF, cool to -40°C, slowly add compound (S)-5-((tetrahydro-2H-pyran -2-yloxy)methyl)pyrrolidin-2-one (2g, 10mmol) in DMF solution 5mL, after reacting at -40°C for 1 hour, CH ₃ I (0.9mL, 12mmol, Shanghai Jingchun Reagent), after the dropwise addition, continue to react for 4 hours, keep the temperature at minus 40°C, then add 10mL saturated NaHSO ₃ solution to quench the reaction, extract the reaction mixture 3 times with 50mL ethyl acetate, combine the organic phases with It was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc) to obtain the title compound as a colorless oil (1.98 g, 92%).

MS (ESI, pos.ion) m/z: 214.0 (M+1); _Exact mass calculated for _C11H19NO3 : _213.1

¹ H NMR (400MHz, CDCl3): δ1.69-1.88(m, 6H), 1.93-2.17(m, 2H), 2.33-2.47(m, 2H), 2.90(3H, s), 3.40-3.52(m , 2H), 3.80-3.90 (m, 2H), 3.78 (m, 1H), 4.60 (m, 1H).

Step 3:

(5S)-4-Methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-azaspiro[2.4]heptane

Compound (S)-1-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)pyrrolidin-2-one (0.6 g, 2.82 mmol) was dissolved in 20 mL THF , under nitrogen protection, slowly added Ti(Oi-Pr) ₄ (2.56mL, 8.45mmol, d=0.937g/L, Ardrich) with a syringe, stirred at room temperature for 30min, and slowly added EtMgBr ( 5.63mL, 16.9mmol, 3M diethyl ether solution, Aldrich), react overnight at room temperature. Then slowly add 20mL of water and 30mL of ethyl acetate to quench the reaction under cooling in an ice-water bath, stir at room temperature for 20min, filter, the filtrate is extracted with ethyl acetate (30mL×3), and the combined organic phases are dried with anhydrous sodium sulfate. Filtration, concentration under reduced pressure, the residue was purified by silica gel column chromatography (50:1 (v/v) CH ₂ Cl ₂ /CH ₃ OH) to obtain (5S)-4-methyl-5-((tetrahydro-2H -pyran-2-yloxy)methyl)-4-azaspiro[2.4]heptane as pale yellow oil (64 mg, 10%).

MS (ESI _{, pos.ion} ) m/z: 226.0 (M+1); Exact mass calculated for _C13H23NO2 : 225.1

¹ H NMR (400MHz, CDCl ₃ ): δ0.23(m, 1H), 0.46(m, 1H), 0.63(m, 1H), 0.86(m, 1H), 1.58-1.90(m, 10H), 2.13 (s, 3H), 2.85 (m, 1H), 3.37-3.50 (m, 2H), 3.72-3.89 (m, 2H), 4.62 (m, 1H).

Step 4:

(5S)-4-Methyl-5-(hydroxymethyl)-4-azaspiro[2.4]heptane

Compound (5S)-4-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-azaspiro[2.4]heptane (64 mg, 0.284 mmol) was dissolved In 10 mL of methanol, 4-methylbenzenesulfonic acid (97.8 mg, 0.568 mmol, Aldrich) was slowly added, the reaction solution was stirred at 50°C overnight, and concentrated under reduced pressure to remove the solvent. Add 10 mL of saturated Na ₂ CO ₃ solution to the residue to adjust the pH value to about 8, extract with dichloromethane (20 mL×3), dry the combined organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the target compound as yellow Oil (32mg, 80%).

MS (ESI, pos.ion) m/ _z : 142.0 (M+1); exact mass calculated for _C8H15NO : 141.1

Step 5:

((5S)-4-Methyl-4-azaspiro[2.4]heptan-5-yl)methyl methanesulfonate

Compound (5S)-4-methyl-5-(hydroxymethyl)-4-azaspiro[2.4]heptane (0.2g, 1.42mmol) and triethylamine (0.287g, 2.84mmol, Shantou Xilong Chemical Plant) mixture was dissolved in 5 mL of dichloromethane, stirred at 0 ° C for 30 min. Under the protection of nitrogen, methanesulfonyl chloride (0.325 g, 2.84 mmol, Shanghai Haiqu Chemical) was slowly added dropwise to the reaction solution. After the dropwise addition, the reaction was continued to stir at 0° C. for 4 hours. Then 5 mL of saturated _Na2CO3 solution and 5 mL of water were added to _the reaction solution to quench the reaction, the mixture was extracted with dichloromethane (20 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain ((5S )-4-methyl-4-azaspiro[2.4]heptan-5-yl)methyl methanesulfonate was a yellow oil (150 mg, 48%), which was quickly used in the next reaction without purification.

Step 6:

N-(4-(7-((5S)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methoxyquinolin-4-yloxy)-3-fluorobenzene base)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

The compound ((5S)-4-methyl-4-azaspiro[2.4]heptan-5-yl)methyl methanesulfonate (150 mg, 0.685 mmol), N-(3-fluoro-4-( 7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (331.5mg, 0.685mmol) and cesium carbonate (893mg, 2.74mmol, Aladdin) were suspended in 8mL N,N-dimethylacetamide, stirred and reacted at 40°C for 3 days, the reaction mixture was concentrated under reduced pressure, and the residue Purification by silica gel column chromatography (50:1 (v/v) CH ₂ Cl ₂ /CH ₃ OH) gave the title compound as a pale yellow solid (25 mg, 6%).

MS (ESI, pos.ion) m/z: 304.5 [(M/2)+1]; _LC -MS Rt: _3.402 min; _Exact mass calculated for _C35H34FN5O4 : 607.2

¹ H NMR (400MHz, CDCl ₃ ): δ0.32(m, 1H), 0.52(m, 1H), 0.71(m, 1H), 0.92(m, 1H), 1.52(m, 2H), 1.85(m , 2H), 3.19(m, 1H), 2.26(s, 3H), 2.80(s, 3H), 3.37(s, 3H), 4.11(m, 1H), 4.22(m, 1H), 6.40(d, J=5.2Hz, 1H), 7.16(t, J=8.4Hz, 1H), 7.30(m, 1H), 7.36(m, 2H), 7.41(m, 1H), 7.48(m, 2H), 7.56( m, 2H), 7.91 (dd, J = 12Hz, 1H), 8.26 (d, J = 9Hz, 1H), 8.58 (d, J = 5Hz, 1H), 10.88 (s, 1H).

Example 2

N-(4-(7-((5R)-4-oxaspiro[2.4]heptane-5-yl)methoxy)quinolin-4-yloxy)-3-fluorophenyl)-2 , 3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

step 1:

(S)-5-Oxo-tetrahydrofuran-2-carboxylic acid

Dissolve glutamic acid (10.07g, 0.068mol, J & KCHEMICA) in 20mL concentrated hydrochloric acid and 40mL water, slowly add 20mL NaNO ₂ aqueous solution (5.1mol/L) dropwise at -5°C, and stir the reaction at room temperature 12 Hour. Concentrate under reduced pressure below 50°C, wash the residue with ethyl acetate, precipitate out, filter, combine the mother liquor and washing liquid, dry over anhydrous Na ₂ SO ₄ , filter, and concentrate under reduced pressure to obtain the target compound as a colorless oil (8.1 g, 91.6%).

MS ₍ ESI _, pos.ion) m/z: 130.9 (M+1); exact mass calculated for _C5H6O4 : 130.0

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.27-2.41 (m, 1H), 2.44-2.65 (m, 3H), 5.09 (m, 1H), 9.12-9.55 (m, 1H).

Step 2:

(S)-5-(Hydroxymethyl)-dihydrofuran-2(3H)-one

Compound (S)-5-oxo-tetrahydrofuran-2-carboxylic acid (0.6g, 0.0046mol) was dissolved in 10.8mL of THF solution, cooled to -20°C, and BH ₃ ·Me ₂ S solution was slowly added dropwise ( 2.76mL, 0.0055mol, 2M in THF, Aldrich), gradually raised to room temperature and stirred for 12 hours. Then, 5 mL of saturated NH ₄ Cl solution was added to the reaction mixture to quench the reaction, extracted with ethyl acetate until the aqueous phase was substantially free of the target compound, the combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure , the resulting crude product was purified by silica gel column chromatography (100:1 (v/v) _CHCl3 /MeOH) to afford (S)-5-(hydroxymethyl)-dihydrofuran-2(3H)-one as Colorless oil (0.253g, 47%).

MS ₍ ESI, pos.ion) m/z _: 116.9 (M+1); exact mass calculated for _C5H8O3 : 116.0

¹ H NMR (400MHz, CDCl ₃ ): δ2.11-2.15(m, 1H), 2.20-2.29(m, 1H), 2.46-2.51(m, 2H), 3.63(t, 2H), 3.83-3.86( d, J = 14.8 Hz, 1H), 4.58-4.63 (m, 1H).

Step 3:

(5S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-dihydrofuran-2(3H)-one

Compound (S)-5-(hydroxymethyl)-dihydrofuran-2(3H)-one (1.78g, 0.0153mol) and 3,4-dihydropyran (2.62g, 0.0312mol, Alfa) were dissolved In 40 mL of dichloromethane, PPTS (0.391 g, 0.00156 mol, Aldrich) was slowly added, and stirred overnight at room temperature. 5 mL of water was added to the reaction solution to quench the reaction, extracted with ethyl acetate (50 mL×3), the combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a light yellow oil. The oil was separated and purified by silica gel column chromatography (3:1 (v/v) petroleum ether/ethyl acetate) to obtain the title compound as a colorless oil (2.7 g, 88%).

MS ₍ ESI, pos.ion) m/z: 200.8 (M+1); exact mass calculated for _C10H16O4 : ₂₀₀

¹ H NMR (400MHz, CDCl ₃ ): δ1.41-1.62(m, 4H), 1.64-1.75(m, 2H), 2.11-2.19(m, 1H), 2.22-2.31(m, 1H), 2.39- 2.49(m, 1H), 2.51-2.62(m, 1H), 3.41-3.48(m, 1H), 3.58-3.62(dd, J ₁ =3.2Hz, J ₂ =14.6Hz, 1H), 3.74-3.79( m, 1H), 3.85-3.92 (dd, J ₁ =3.2 Hz, J ₂ =14.4 Hz, 1H), 4.55-4.72 (m, 2H).

Step 4:

1-((S)-3-Hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol

Ti(OiPr) ₄ (0.33mL, 0.001mol, Ardrich) and compound (5S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-dihydrofuran-2(3H )-ketone (1g, 0.005mol) was dissolved in 18.7mL of THF, at 15°C under nitrogen protection, EtMgBr (4.3mL, 0.0125mol, 3M ether solution Aldrich) was slowly added dropwise within 3 hours through a syringe pump, After the reaction was stirred for 1 hour, saturated NH ₄ Cl solution was added to the reaction liquid to quench the reaction, filtered, the filtrate was extracted with ethyl acetate (50 mL×2), the combined organic phases were dried with anhydrous Na ₂ SO ₄ , filtered, and reduced Concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (2:1 (v/v) n-hexane/ethyl acetate) to obtain the title compound as a colorless oil (0.853 g, 74%).

MS ₍ ESI, pos.ion) m/z: 253.0 (M+23); _exact mass calculated for _C12H22O4 : 230.1

¹ H NMR (400MHz, CDCl ₃ ): δ0.4-0.5(s, 1H), 0.67-0.87(m, 3H), 1.4-1.9(m, 12H), 3.38-3.44(m, 1H), 3.53- 3.60 (m, 1H), 3.75-3.78 (m, 1H), 3.87-3.96 (m, 1H), 4.57 (d, J=2.4Hz, 1H).

Step 5:

(5R)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-oxaspiro[2.4]heptane

Compound 1-((S)-3-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol (1.73g, 0.0075mol) and triphenylphosphine (2.95 g, 0.0113mol, Richjoint) was dissolved in 32mL of dry THF, and DEAD (1.96g, 0.0113mol, Aladdin) was slowly added dropwise through a syringe at room temperature under nitrogen protection, and the reaction mixture was reacted at 60°C for 12 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (8:1 (v/v) n-hexane/ethyl acetate) to obtain the title compound as a colorless oil (1.1 g, 64%). the

MS (ESI, pos.ion) m/z: 213.0 (M+1); _Exact mass calculated _{for C12H20O3} : 212.1;

¹ H NMR (400MHz, CDCl ₃ ): δ0.4-0.6(m, 2H), 0.75-0.95(s, 2H), 1.4-1.9(m, 10H), 3.45-3.52(m, 2H), 3.73- 3.79 (m, 1H), 3.80-3.90 (m, 1H), 4.23-4.28 (m, 1H), 4.63-4.69 (s, 1H).

Step 6:

(5R)-5-(Hydroxymethyl)-4-oxaspiro[2.4]heptane

The compound (5R)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-oxaspiro[2.4]heptane (101 mg, 0.48 mmol) was dissolved in 5 mL of methanol, PPTS (12.1 mg, 0.048 mol, Aldrich) was added at room temperature, and the reaction was stirred overnight at 40°C. The reaction mixture was concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography (CH ₂ Cl ₂ ) to afford (5S)-2-cyclopropyl-5-(hydroxymethyl)-dihydrofuran as a colorless oil (55 mg, 89%).

¹ H NMR (400MHz, CDCl ₃ ): δ0.4-0.6(m, 2H), 0.75-0.95(m, 2H), 1.84-1.91(m, 1H), 1.94-1.98(m, 2H), 2.07- 2.13 (m, 1H), 2.27 (s, 1H), 3.56-3.70 (m, 2H), 4.16-4.18 (m, 1H).

Step 7:

((5R)-4-Oxaspiro[2.4]heptan-5-yl)methyl mesylate

The compound (5R)-5-(hydroxymethyl)-4-oxaspiro[2.4]heptane (116mg, 0.9mmol) and triethylamine (183.8mg, 1.82mmol, Shantou Xilong Chemical Factory) were dissolved in 6mL In dry dichloromethane, the reaction solution was cooled to -10°C under the protection of nitrogen, and MsCl (203 mg, 1.4 mmol, Shanghai Haiqu Chemical) was slowly added dropwise with a syringe, and the reaction was continued for 2 hours after the addition was completed. Thereafter, 3 mL of ice water was added to the reaction solution to quench the reaction, the organic layer was separated, the aqueous phase was extracted with dichloromethane, the combined organic phase was dried over _anhydrous Na _SO , filtered, and concentrated under reduced pressure to obtain a light yellow oil , was used in the next reaction immediately without purification.

Step 8:

N-(4-(7-(((5R)-4-oxaspiro[2.4]heptane-5-yl)methoxy)quinolin-4-yloxy)-3-fluorophenyl)- 2,3-Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-di Hydrogen-1H-pyrazole-4-carboxamide (300mg, 0.62mmol), compound ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate (187.4mg, 0.91 mmol) and cesium carbonate (1.0 g, 3.1 mmol, Aladdin) were suspended in 4 mL of DMA and reacted at 40°C for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1:6 (v/v) n-hexane/ethyl acetate) to obtain the title compound as a white solid (220 mg, 60%). the

MS (ESI, pos.ion) m/z: 595.7 (M+1 _{) ;} LC-MS Rt: 4.17 min; _Exact mass calculated for _C34H31FN4O5 : 594.2

¹ H NMR (400MHz, CDCl ₃ ): δ0.63(m, 2H), 0.91(m, 2H), 2.03(d, J=5.2Hz, 3H), 2.29(m, 1H), 2.80(s, 3H ), 3.38(s, 3H), 4.17(dd, J ₁ =16Hz, J ₂ =2.4Hz, 2H), 4.49(m, 1H), 6.40(d, J=5.2Hz, 1H), 7.16(t, 1H), 7.26(d, J=5.2Hz, 1H), 7.29(d, J=2Hz, 1H), 7.38(m, 3H), 7.48(m, 1H), 7.56(t, 2H), 7.90(dd , J ₁ =14.8Hz, J ₂ =2.4Hz, 1H), 8.26(d, J=9.2Hz, 1H), 8.58(d, J=5.6Hz, 1H), 10.87(s, 1H).

Example 3

N-(5-(7-(((5R)-4-oxaspiro[2.4]heptane-5-yl)methoxy)quinolin-4-yloxy)pyridin-2-yl)-2 , 3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

The title compound was prepared as described in Example 2, using N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo- 2-Phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (280 mg, 0.69 mmol), cesium carbonate (1.17 g, 3.45 mmol, Aladdin), ((5R)-4-oxaspiro [2.4] Heptane-5-yl)methyl methanesulfonate (204mg, 0.99mmol) was suspended in 5mL DMA, purified by silica gel column chromatography (1:8 (v/v) n-hexane/ethyl acetate) to obtain The target compound was a white solid (110 mg, 27.6%). the

MS (ESI _{, pos.ion) m/z: 578.1 (M+1); LC-MS Rt: 4.11 min; Calcd exact mass for C33H31N5O5 : 577.2 ;}

¹ H NMR (400MHz, CDCl ₃ ): δ0.55(m, 2H), 0.92(m, 2H), 2.03(m, 3H), 2.31(m, 1H), 2.81(s, 3H), 3.38(s , 3H), 4.18(m, 2H), 4.52(m, 1H), 6.43(d, J=5.6Hz, 1H), 7.28(d, J=2.4Hz, 1H), 7.30(d, J=2.4Hz , 1H), 7.39(m, 3H), 7.51(m, 4H), 8.23(t, 1H), 8.38(d, J=8.8Hz, 1H), 8.60(d, J=5.6Hz, 1H), 11.25 (s, 1H).

Example 4

N-(3-fluoro-4-(7-(2-(1-hydroxycyclopropyl)ethoxy)quinolin-4-yloxy)phenyl)-1,5-dimethyl-3- Oxy-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

step 1:

3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid

Dissolve 3-hydroxypropionic acid (7.2g, 80mmol, TCI, TOKYO KASEI) and 3,4-dihydropyran (13.4g, _160mmol , Alfa) in a mixed solution of 100mL _CH2Cl2 and 100mL THF, room temperature PPTS (2 g, 8 mmol, Aldrich) was added in portions under stirring, and the reaction mixture was reacted overnight at room temperature. Then 50 mL of saturated NaHCO solution was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane (50 mL × 5), the combined organic phase was dried over anhydrous Na _{2 SO 4} , concentrated under reduced pressure, and the residue was passed through silica gel Purification by column chromatography (1:1 (v/v) petroleum ether/ethyl acetate) gave 3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid as a colorless oil (7.8 g, 56 %).

MS (ESI, pos.ion) m/z: 196.9 (M+ ₂₃ ); (ESI, nat.ion) m/ _{z: 172.8 (M-1); exact mass calculated for C8H14O4 :} 174.0

Step 2:

Benzyl 3-(tetrahydro-2H-pyran-2-yloxy)propionate

The compound 3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid (1g, 5.7mmol) and triethylamine (0.863g, 8.55mmol, Shantou Xilong Chemical Factory) were dissolved in 50mL CH ₂ Cl In ₂ , BnBr (0.98 g, 5.7 mmol, Aldrich) was slowly added dropwise with a syringe at 0°C, and then the reaction solution was gradually raised to room temperature for overnight reaction. Add 20 mL of water to the reaction solution to quench the reaction, separate the organic layer, extract the aqueous phase with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous Na ₂ SO ₄ , filter, concentrate under reduced pressure, and pass the residue through Purification by silica gel column chromatography (20:1 (v/v) petroleum ether/ethyl acetate) gave the title compound as a colorless oil (270 mg, 18.6%).

MS ₍ ESI, pos.ion) m/z: 287.0 (M+23); _exact mass calculated for _C15H20O4 : 264.1

¹ H NMR (400MHz, CDCl ₃ ): δ1.42-1.79 (m, 6H), 2.65-2.68 (t, 2H), 3.48-3.80 (dd, J=12.8Hz, 2H), 3.71-4.01 (dd, J=12Hz, 2H), 4.61(d, 1H), 5.15(s, 2H), 3.71-7.36(m, 5H).

Step 3:

1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)cyclopropanol

The compound 3-(tetrahydro-2H-pyran-2-yloxy) benzyl propionate (150 mg, 0.568 mmol) was dissolved in 2 mL of tetrahydrofuran, and Ti(Oi -Pr) ₄ (0.18mL, 0.568mmol, d=0.955g/L, Ardrich), kept stirring at 18°C for 30 minutes, then slowly added EtMgBr (0.48mL, 1.42mmol, 3M ether solution, Aldrich), after the completion of the reaction (TLC monitoring), slowly add 5mL of water to quench the reaction, filter, the filtrate was extracted with ethyl acetate (30mL × 3), the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered , concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10:1 (v/v) petroleum ether/ethyl acetate) to obtain 1-(2-(tetrahydro-2H-pyran-2-yloxy) Ethyl)cyclopropanol as a colorless oil (60 mg, 57%).

¹ H NMR (400MHz, CDCl ₃ ): δ0.46(m, 2H), 0.75-0.88(d, 2H), 1.55-1.83(m, 6H), 1.87-1.90(m, 2H), 3.55(q, 1H), 3.69(q, 1H), 3.88(t, 1H), 4.06(t, 1H), 4.66(s, 1H).

Step 4:

1-(2-Hydroxyethyl)cyclopropanol

The compound 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)cyclopropanol (380mg, 2.04mmol) was dissolved in 20mL of methanol, and PPTS (51mg, 0.204mmol, Aldrich), the reaction mixture was warmed up to 40°C and stirred overnight. Then 10 mL of water was added, extracted with dichloromethane (20 mL×3), the combined organic phases were dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (10:1 (v/v) petroleum ether /ethyl acetate) to obtain the title compound as a colorless oil (170 mg, 81.7%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.55(t, 2H), 0.85(t, 2H), 1.85(t, 2H), 4.02(t, 2H).

Step 5:

2-(1-Hydroxycyclopropyl)ethyl methanesulfonate

Dissolve the compound 1-(2-hydroxyethyl)cyclopropanol (86mg, 0.843mmol) and triethylamine (136mg, 1.35mmol, Shantou Xilong Chemical Factory) in 10mL of dichloromethane, and stir the reaction at -10°C After 30 min, methanesulfonyl chloride (106 mg, 0.927 mmol, Shanghai Haiqu Chemical) was slowly added dropwise to the reaction solution, and the reaction was continued to stir at the same temperature for 1 hour, then 1 mL of ice water was added to quench the reaction, and the organic phase was separated , the aqueous layer was extracted with dichloromethane (20 mL×3), the combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the target compound as a colorless oil, which was directly used in the next step without purification.

Step 6:

N-(3-fluoro-4-(7-(2-(1-hydroxycyclopropyl)ethoxy)quinolin-4-yloxy)phenyl)-1,5-dimethyl-3- Oxy-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-di Hydrogen-1H-pyrazole-4-carboxamide (204mg, 0.421mmol), 2-(1-hydroxycyclopropyl) ethyl methanesulfonate (152mg, 0.843mmol), cesium carbonate (1.37g, 4.2mmol, Aladdin) was suspended in 8 mL DMA, stirred at 40°C for one day, concentrated under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography (50:1 (v/v) CH ₂ Cl ₂ /CH ₃ OH) to obtain the title compound As a white solid (60 mg, 25%).

MS (ESI, pos.ion) m/z: 569.1 (M+1); (ESI, nat. ion) m/z: 567.1 (M-1); LC-MS Rt: 3.948min; C ₃₂ H ₂₉ FN Calculated exact mass of ₄ O ₅ : 568.2

¹ H NMR (400MHz, CDCl ₃ ): δ0.57(d, J=8Hz, 2H), 0.86(d, J=8Hz, 2H), 2.14(t, 2H), 2.80(s, 3H), 3.37( s, 3H), 4.43(t, 2H), 6.41(d, J=4Hz, 1H), 7.14-7.23(m, 2H), 7.26-7.35(m, 1H), 7.37-7.38(m, 2H), 7.45-7.50(m, 2H), 7.50-7.58(m, 2H), 7.90-7.93(dd, J=2.4Hz, 1H), 8.27(d, J=8Hz, 1H), 8.58(d, J=8Hz , 1H), 10.89 (s, 1H).

Example 5

N-(3-fluoro-4-(7-((1-cyclopropyl-1-methanesulfonate-1-yl)methoxy)quinolin-4-yloxy)phenyl)-1, 5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

step 1:

2-(Tetrahydro-2H-pyran-2-yloxy)ethyl acetate

Ethyl 2-hydroxyacetate (2g, 20mmol, TCI) and 3,4-dihydropyran (3.2g, 40mmol, Alfa) were dissolved in 40mL of dichloromethane, and PPTS (500mg, 2mmol, Aldrich), continued to stir and react for 4 hours, the reaction solution was washed with brine, the organic phase obtained was dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (20:1 (v/v) petroleum ether /ethyl acetate) to obtain the title compound as a colorless oil (3.01 g, 81%).

¹ H NMR (400MHz, CDCl ₃ ): δ1.25-1.32(m, 3H), 1.55-1.63(m, 3H), 1.69-1.88(m, 3H), 3.50-3.53(m, 1H), 3.82- 3.88 (m, 1H), 4.18-4.23 (m, 4H), 4.73 (t, J=3.2Hz, 1H).

Step 2:

1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol

The compound ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (1 g, 5.3 mmol) and Ti(O-iPr) ₄ (1.06 mL, 3.5 mmol, Aldrich) were dissolved in 18 mL THF , under nitrogen protection, EtMgBr (4.5mL, 13.25mmol, 3M ether solution, Aldrich) was slowly added dropwise with a syringe pump within 2 hours, and the temperature was kept between 15-20°C. After 2 hours of reaction, the temperature was lowered to 0 ℃, add saturated NH ₄ Cl solution to quench the reaction, filter, the filtrate was extracted with ethyl acetate, the combined organic phase was dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (20:1 (v /v) petroleum ether/ethyl acetate) purification afforded 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol as a colorless oil (500 mg, 55%).

¹ H NMR (400MHz, CDCl ₃ ): δ0.51-0.67(m, 2H), 0.77-0.85(m, 2H), 1.55-1.65(m, 4H), 1.74-1.87(m, 2H), 3.50- 3.55 (m, 2H), 3.81 (d, J=11.6Hz, 1H), 3.93-3.98 (m, 2H), 4.64-4.66 (m, 1H).

Step 3:

1-(Hydroxymethyl)cyclopropanol

Compound 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol (420mg, 2.44mmol) was dissolved in 30mL methanol, and PPTS (61mg, 0.244mmol, Aldrich) was added at room temperature , reacted overnight. Methanol was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (1:2 (v/v) petroleum ether/ethyl acetate) to obtain 1-(hydroxymethyl)cyclopropanol as a colorless oil (209 mg, 99%). the

¹ H NMR (400MHz, CDCl ₃ ): δ0.56(t, J=5.6Hz, 2H), 0.82(t, J=6Hz, 2H), 3.62(s, 2H).

Step 4:

1-((methylsulfonyloxy)cyclopropyl)methyl mesylate

Compound 1-(hydroxymethyl)cyclopropanol (100mg, 1.14mmol) and triethylamine (202mg, 1.82mmol, Shantou Xilong Chemical Factory) were dissolved in 20mL of dry dichloromethane, under nitrogen protection, keep Methanesulfonyl chloride (156mg, 1.32mmol, Shanghai Haiqu Chemical) was slowly added dropwise at -10°C, and the reaction was continued for 4 hours at the same temperature. After the reaction was completed, ice water was added to the reaction mixture to quench the reaction, extracted with dichloromethane, and the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the target compound as a light yellow oil (139 mg, 50%).

Step 5:

N-(3-fluoro-4-(7-(1-((methylsulfonyloxy)cyclopropyl)methoxy)quinolin-4-yloxy)phenyl)-1,5-dimethyl Base-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-di Hydrogen-1H-pyrazole-4-carboxamide (306mg, 0.57mmol), 1-((methylsulfonyloxy)cyclopropyl)methyl mesylate (139mg, 0.57mmol) and cesium carbonate (926mg, 2.84mmol, Aladdin) was suspended in 3mL DMA, stirred at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5:1 (v/v) CH ₂ Cl ₂ /EtOAc) to obtain the title compound as a white solid (200 mg, 55%).

MS (ESI, pos.ion) m/z: 633.1 (M+1); (ESI, nat. ion) m/z: 631.1 (M-1); LC-MS Rt: 4.178min; C ₃₂ H ₂₉ FN Calculated exact mass _{of 4O7S :} 632.1

¹ H NMR (400MHz, CDCl ₃ ): δ1.09(t, J=7.2Hz, 2H), 1.54(t, J=6.8Hz, 2H), 2.80(s, 3H), 3.07(s, 3H), 3.38(s, 3H), 4.45(s, 2H), 6.43(d, J=4.2Hz, 2H), 7.17(t, J=8.8Hz, 1H), 7.27-7.32(m, 2H), 7.36-7.40 (dd, J=0.2Hz, 3H), 7.49(d, J=7.2Hz, 1H), 7.57(t, J=8Hz, 2H), 7.90-7.94(dd, J=2.4Hz, 1H), 8.31( d, J=4.2Hz, 1H), 8.60 (d, J=4.2Hz, 1H).

Example 6

N-(4-(7-(4-oxaspiro[2.4]heptane-6-yloxy)-6-methoxy-quinolin-4-yloxy)-3-fluorophenyl)- 2,3-Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

step 1:

4-(tetrahydro-2H-pyran-2-yloxy)-dihydrofuran-2(3H)-one

4-Hydroxydihydrofuran-2(3H)-one (10 g, 0.1 mol, Alfa) and 3,4-dihydropyran (12.5 g, 0.15 mol, Alfa) were dissolved in 250 mL of dry dichloromethane, PPTS (2.4 g, 0.01 mol, Aldrich) was added in portions, and the reaction was stirred overnight at room temperature. The reaction solution was washed with brine, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (100mL×3). The combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was passed through a silica gel column layer. Purification by analysis (3:1 (v/v) ethyl acetate/n-hexane) gave 4-(tetrahydro-2H-pyran-2-yloxy)-dihydrofuran-2(3H)-one as colorless Oil (15.6 g, 68%).

¹ H NMR (400MHz, CDCl ₃ ): δ1.63-1.84(m, 6H), 2.54-2.79(m, 2H), 3.52-3.55(dd, J=12Hz, 1H), 3.79-3.86(m, 1H ), 4.31-4.47 (m, 2H), 4.57-4.59 (t, J=4Hz, 2H).

Step 2:

1-(3-Hydroxy-2-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol

Compound 4-(tetrahydro-2H-pyran-2-yloxy)-dihydrofuran-2(3H)-one (2.23g, 12mmol) and Ti(Oi-Pr) ₄ (0.68g, 2.4mmol , Aldrich) was dissolved in 40 mL of dry tetrahydrofuran solution, and at 15°C under the protection of nitrogen, EtMgBr (30 mmol, 10 mL, 3M ether solution, Aldrich) was slowly added dropwise with a syringe pump within 2 hours, and the reaction was continued for 2 hours. The reaction was quenched by adding 30 mL of saturated NH ₄ Cl solution, filtered, and the filtrate was extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain crude material which was subjected to silica gel column chromatography (1:1 ( v/v) separation and purification of ethyl acetate/n-hexane) to obtain 1-(3-hydroxyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol as a yellow oil ( 1.92 g, 73%).

¹ H NMR (400MHz, CDCl ₃ ): δ0.40-0.53(m, 2H), 0.71-0.83(m, 2H), 1.53-1.67(m, 5H), 1.81-1.96(m, 3H), 3.49- 3.72 (m, 3H), 3.98-4.11 (m, 2H), 4.64-4.73 (m, 1H).

Step 3:

3-(1-Hydroxycyclopropyl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate

Compound 1-(3-hydroxyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol (1.0g, 4.63mmol) and triethylamine (1mL, 7.4mmol, Shantou Xilong Chemical Plant) was dissolved in 30 mL of dichloromethane, cooled to 0°C, methanesulfonyl chloride (1 mL, 7.4 mmol, Shanghai Haiqu Chemical) was slowly added dropwise, and the reaction was continued at the same temperature for 1 hour. After the reaction was completed, 5 mL of ice water was added to the reaction solution to quench the reaction, the organic layer was separated, the aqueous layer was extracted with dichloromethane (50 mL×3), the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, Concentration under reduced pressure gave a yellow oil, which will be used in the next reaction shortly.

Step 4:

6-(Tetrahydro-2H-pyran-2-yloxy)-4-oxaspiro[2.4]heptane

Compound 3-(1-hydroxycyclopropyl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate (1.3g, 4.63mmol) and NaH (0.15g, 6mmol , Aldrich) was suspended in 20 mL of tetrahydrofuran solution and stirred at room temperature for 4 hours. After the reaction was completed, 5 mL of methanol was added to the reaction liquid to quench the reaction, and the obtained mixture was washed with water, extracted with ethyl acetate (30 mL×3), and the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (1:10 (v/v) ethyl acetate/petroleum ether) to obtain the title compound as a colorless oil (380 mg, 42%).

¹ H NMR (400MHz, CDCl ₃ ): δ0.45-0.63 (dd, J=4.8Hz, 2H), 0.81-0.93 (dd, J=4.8Hz, 2H), 1.56-2.29 (m, 8H), 3.54 (s, 1H), 3.87-4.03 (m, 3H), 4.60-4.66 (m, 2H).

Step 5:

6-Hydroxy-4-oxaspiro[2.4]heptane

Compound 6-(tetrahydro-2H-pyran-2-yloxy)-4-oxaspiro[2.4]heptane (1.03g, 5.2mmol) and PPTS (0.26g, 1mmol, Aldrich) were dissolved in 40ml In methanol, the reaction was stirred at 40°C for 5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (1:5 (v/v) ethyl acetate/petroleum ether) to obtain the target compound as a colorless oil (570 mg, 97%). the

¹ H NMR (400MHz, CDCl ₃ ): δ0.47-0.65(m, 2H), 0.81-0.96(m, 2H), 1.89-2.35(m, 2H), 3.80-3.96(m, 2H), 4.59( s, 1H).

Step 6:

(4-Oxaspiro[2.4]heptan-6-yl)methanesulfonate

The compound 6-hydroxy-4-oxaspiro[2.4]heptane (100mg, 0.88mmol) and triethylamine (150mg, 1.5mmol, Shantou Xilong Chemical Factory) were dissolved in 5mL of dichloromethane, cooled to 0°C , Methanesulfonyl chloride (130mg, 1mmol, Shanghai Haiqu Chemical) was slowly added dropwise under the protection of nitrogen, and the reaction was continued for 1 hour at the same temperature. After the reaction was completed, 5 mL of ice water was added to the reaction solution to quench the reaction, and extracted with dichloromethane (20 mL×3), the combined organic phase was dried with anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain (4-oxaspiro [2.4] Heptan-6-yl) methanesulfonate was a colorless oily substance (168 mg).

Step 7:

N-(4-(7-(4-oxaspiro[2.4]heptane-6-yloxy)-6-methoxy-quinolin-4-yloxy)-3-fluorophenyl)- 2,3-Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

N-(3-fluoro-4-(6-methoxy-7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-Dihydro-1H-pyrazole-4-carboxamide (300mg, 0.584mmol), (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (168mg, 0.877mmol) and cesium carbonate (893mg, 2.74mmol, Aladdin) were suspended in 5mL DMA, stirred at room temperature for 4 hours, then heated to 40°C for 16 hours, concentrated under reduced pressure, removed solvent, and the residue was subjected to silica gel column chromatography (5:1 (v/v) ethyl acetate/n-hexane) to give the title compound as a white solid (65 mg, 18%). the

MS (ESI, pos.ion) m/z: _611.1 [ _{M+1]; LC-MS Rt: 4.10 min; Exact mass calculated for C34H31FN4O6 : 610.2}

¹ H NMR (400MHz, CDCl ₃ ): δ0.56-0.71(m, 2H), 0.81-1.02(m, 2H), 2.33(m, 1H), 2.55(m, 1H), 2.81(s, 3H) , 3.38(s, 3H), 4.03(s, 3H), 4.21(m, 2H), 5.24(t, J=4Hz, 1H), 6.43(d, J=4Hz, 1H), 7.15-7.60(m, 9H), 7.90-7.94 (m, 1H), 8.48 (d, J=4Hz, 1H), 10.89 (s, 1H).

Example 7

N-(4-(7-(4-oxaspiro[2.4]heptane-6-yloxy)quinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro- 1,5-Dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

The preparation process of the title compound is as shown in Example 6, using N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo Subo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300mg, 0.62mmol), (4-oxaspiro[2.4]heptan-6-yl) mesylate (220mg, 1.14mmol) and cesium carbonate (450mg, 2.4mmol, Aladdin) were suspended in 6mL DMA, purified by silica gel column chromatography (5:1 (v/v) ethyl acetate/n-hexane) to obtain the title compound as Colored solid (68 mg, 19%). the

MS (ESI, pos.ion) m/z: 581.1 [ _M +1] _; LC-MS Rt: 4.255 min; Exact mass calculated for _C33H29FN4O5 : _580.2

¹ H NMR (400MHz, CDCl ₃ ): δ0.54-0.72(m, 2H), 0.88-1.07(m, 2H), 2.29(m, 1H), 2.57(m, 1H), 2.84(s, 3H) , 3.42(s, 3H), 4.22(m, 2H), 5.26(m, 1H), 6.46(d, J=4Hz, 1H), 7.18-7.63(m, 9H), 7.96(m, 1H), 8.33 (d, J=8Hz, 1H), 8.62(d, J=4Hz, 1H), 10.92(s, 1H).

Example 8

N-(5-(7-(4-oxaspiro[2.4]heptane-6-yloxy)quinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1 , 5-Dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

The preparation process of the title compound is as shown in Example 6, using N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo -2-Phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.64 mmol), (4-oxaspiro[2.4]heptane-6-yl) methanesulfonate ( 220mg, 1.14mmol) and cesium carbonate (450mg, 2.4mmol, Aladdin) were suspended in 6mL DMA, purified by silica gel column chromatography (ethyl acetate) to give the title compound as a colorless solid (140mg, 39%). the

MS (ESI, pos.ion) m/z: 564.1 [M+1] _{; LC} -MS Rt: 4.007 min; Exact mass calculated for _C32H29N5O5 : _563.2

¹ H NMR (400MHz, CDCl ₃ ): δ0.59(m, 2H), 0.91(m, 2H), 2.25(d, J=14Hz, 1H), 2.53(m, 1H), 2.80(s, 3H) , 3.37(s, 3H), 4.18(m, 2H), 5.22(t, J=4Hz, 1H), 6.44(d, J=5Hz, 1H), 7.24-7.56(m, 9H), 8.25(m, 1H), 8.38(d, J=9Hz, 1H), 8.60(d, J=3Hz, 1H), 11.26(s, 1H).

Example 9

N-(3-fluoro-4-(7-(3-(1-hydroxycyclopropyl)propoxy)-quinolin-4-yloxy)phenyl)-1,5-dimethyl-3 -Oxy-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

step 1:

1-(3-Hydroxypropyl)cyclopropanol

Dihydrofuran-2(3H)-one (2.0 g, 23 mmol, Alfa) and Ti(Oi-Pr) ₄ (1.32 g, 4.6 mmol, Aldrich) were dissolved in 80 mL of dry THF solution, kept at 15 °C under nitrogen Under protection, EtMgBr (60mmol, 20mL, 3M ether solution, Aldrich) was slowly added dropwise with a syringe pump within 3 hours, the temperature was kept below 20°C, and the reaction was continued for 3 hours. Then 60 mL of saturated NH ₄ Cl solution was added to the reaction solution to quench the reaction, extracted with ethyl acetate (50 mL×3), the combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain an orange oil Purification by silica gel column chromatography (1:1 (v/v) ethyl acetate/n-hexane) gave 1-(3-hydroxypropyl)cyclopropanol as a yellow oil (2.5 g, 93%).

Step 2:

3-(1-Hydroxycyclopropyl)propyl methanesulfonate

The compound 1-(3-hydroxypropyl)cyclopropanol (140mg, 1.2mmol) and triethylamine (0.3mL, 2.1mmol, Shantou Xilong Chemical Factory) were dissolved in 8mL of dichloromethane, stirred at 0°C for 10min . Then methanesulfonyl chloride (180 mg, 1.6 mmol, Shanghai Haiqu Chemical) was slowly added dropwise to the reaction solution, and the reaction was continued for 1 hour at 0° C. After the reaction was completed, 2 mL of ice water was added to the reaction solution to quench the reaction, and the Extracted with dichloromethane (10 mL×3), the combined organic phases were dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to obtain the title compound as a yellow oil.

Step 3:

N-(3-fluoro-4-(7-(3-(1-hydroxycyclopropyl)propoxy)-quinolin-4-yloxy)phenyl)-1,5-dimethyl-3 -Oxy-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

Compound 3-(1-hydroxycyclopropyl)propyl methanesulfonate (240mg, 1.2mmol), N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl) -1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300mg, 0.62mmol), cesium carbonate (470mg, 2.4mmol, Aladdin) was suspended in 5 mL DMA, stirred at room temperature for 12 hours, and then heated to 40°C for 6 hours. Thereafter, 20 mL of water was added to the reaction solution to quench the reaction, extracted with ethyl acetate (40 mL×3), the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Purification (5:1 (v/v) ethyl acetate/n-hexane) afforded the title compound as a white solid (68 mg, 19%).

MS (ESI, pos.ion) m/z: 583.1 [ _M +1] _{; LC} -MS Rt: 4.129 min; Exact mass calculated for _C33H31FN4O5 : 582.2

¹ H NMR (400MHz, CDCl ₃ ): δ0.51(m, 2H), 0.79(m, 2H), 1.81(t, J=8Hz, 2H), 2.15(m, 2H), 2.81(s, 3H) , 3.38(s, 3H), 4.24(t, J=8Hz, 2H), 6.41(d, J=4Hz, 1H), 7.15-7.59(m, 9H), 7.91(m, 1H), 8.27(d, J=8Hz, 1H), 8.58(d, J=4Hz, 1H), 10.87(s, 1H).

At the same time, another product is obtained:

N-(3-fluoro-4-(7-(3-(1-cyclopropyl-1-methanesulfonate-1-yl)propoxy)-quinolin-4-yloxy)phenyl) -1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

MS (ESI, pos.ion) m/z: 661.1 [M+1] _{; LC} -MS Rt: _4.272 min; Exact mass calculated for _C34H33FN4O7S : 660.2

¹ H NMR (400MHz, CDCl ₃ ): δ0.787(m, 2H), 1.29(m, 2H), 2.11(m, 4H), 2.80(s, 3H), 3.01(s, 3H), 3.38(s , 3H), 4.22(t, J=6Hz, 2H), 6.41(d, J=5Hz, 1H), 7.14-7.59(m, 9H), 7.91(m, 1H), 8.27(d, J=9Hz, 1H), 8.58 (d, J = 5 Hz, 1H), 10.88 (s, 1H).

Example 10

N-(5-(7-(3-(1-hydroxycyclopropyl)propoxy)quinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo -2-Phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

The preparation process of the title compound is shown in Example 9, using N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo -2-Phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (277mg, 0.593mmol), 3-(1-hydroxycyclopropyl)propyl methanesulfonate (334mg, 1.724mmol ) and cesium carbonate (560 mg, 1.724 mmol, Aladdin) were suspended in 10 mL DMA, and subjected to silica gel column chromatography (67:30:1:2 (v/v) EtOAc/CH ₂ Cl ₂ /CH ₃ OH/Et ₃ N ) to afford the title compound as a white solid (210 mg, 62.6%).

MS (ESI, pos.ion) m _/ z: 566 [M+1]; LC-MS Rt: _3.846 min; Exact _mass calculated for _C32H31N5O5 : 565.2

¹ H NMR (400MHz, CDCl ₃ ): δ0.49-052(t, J=6Hz, 2H), 0.78-0.81(t, J=6Hz, 2H), 1.26(s, 2H), 1.79-1.83(t , J=7.2Hz, 2H), 2.13-2.16(t, J=7.2Hz, 2H), 2.81(s, 3H), 3.38(s, 3H), 4.23-4.26(t, J=6Hz, 2H), 6.42-6.44 (d, J=5.2Hz, 1H), 7.20-7.23 (q, J ₁ =9.2Hz, J ₂ =2.4Hz, 1H), 7.37-7.39 (d, J=7.6Hz, 1H), 7.42 (s, 1H), 7.44-7.57(m, 4H), 8.22-8.25(m, 2H), 8.37-8.39(d, J=9.2Hz, 1H), 8.59-8.60(d, J=5.2Hz, 1H ), 11.26(s, 1H).

Example 11

N-(5-(7-((4-oxaspiro[2.4]heptane-6-yl)aminopropoxy)quinolin-4-yloxy)pyridin-2-yl)-2,3- Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

step 1:

(4-Oxaspiro[2.4]heptan-6-yl)methanesulfonate

6-Hydroxy-4-oxaspiro[2.4]heptane (200 mg, 1.75 mmol, see Example 6) and triethylamine (530.3 mg, 5.25 mmol, Shantou Xilong Chemical Factory) were dissolved in 8 mL of dry dichloromethane Methanesulfonyl chloride (401.7mg, 3.5mmol, Shanghai Haiqu Chemical) was slowly added dropwise at -10°C under nitrogen protection, and the reaction was continued for 2 hours at the same temperature. Then 3 mL of ice water was added to the reaction solution to quench the reaction, extracted with dichloromethane (10 mL×2), the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the target compound as a light yellow oil .

Step 2:

(4-Oxaspiro[2.4]heptan-6-yl)aminopropanol

The compound (4-oxaspiro[2.4]heptane-6-yl) mesylate (336 mg, 1.75 mmol) was dissolved in 3 mL of dry THF solution, and 3-amino-1-propanol ( 656.3mg, 8.75mmol, TCI), the reaction mixture was refluxed overnight. After completion of the reaction, it was concentrated under reduced pressure, and the solvent was removed to obtain a gray crude product, which was then purified by silica gel column chromatography (8:1 (v/v) EtOAc/MeOH) to obtain (4-oxaspiro[2.4]heptane-6- base) aminopropanol as a pale yellow oil (280 mg, 93%). the

MS ₍ ESI, pos.ion) m/z: 172.0 (M+1); Exact mass calculated _{for C9H17NO2} : 171.1

¹ H NMR (400MHz, CDCl ₃ ): δ0.45(m, 1H), 0.54(m, 1H), 0.88(m, 2H), 1.75(m, 2H), 1.83(dd, J ₁ = 4Hz, J ₂ =16.8Hz, 1H), 2.22(dd, J ₁ =7.2Hz, J ₂ =20Hz, 1H), 2.40(s, 2H), 3.58(m, 1H), 3.72(m, 1H), 3.83(t , 2H), 3.96 (dd, J ₁ =14.8Hz, J ₂ =5.6Hz, 1H).

Step 3:

tert-Butyl N-(4-oxaspiro[2.4]heptan-6-yl)hydroxypropyl carbamate

The compound (4-oxaspiro[2.4]heptane-6-yl)aminopropanol (361.9mg, 2.12mmol) and triethylamine (535.3mg, 5.3mmol, Shantou Xilong Chemical Factory) were dissolved in 10mL dichloro In methane, (Boc) ₂ O (692 mg, 3.17 mmol, Shantou Xilong Chemical Plant) was slowly added dropwise at room temperature, and the reaction was stirred overnight. Then 5 mL of water was added to the reaction solution to quench the reaction, extracted with ethyl acetate (20 mL×3), the combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the target compound as a light yellow oil (555.8 mg, 97%).

MS (ESI _, pos.ion) m/z: 272.0 (M+1); Exact mass calculated for _C14H25NO4 : _271.1

¹ H NMR (400MHz, CDCl ₃ ): δ0.45(m, 1H), 0.61(m, 1H), 0.78(m, 1H), 0.93(m, 1H), 1.47(s, 9H), 1.75(m , 3H), 2.13(t, 2H), 3.42(s, 2H), 3.59(d, J=5.2Hz, 2H), 3.76(dd, J ₁ =5.6Hz, J ₂ =14.8Hz, 1H), 3.94 (dd, J ₁ =7.6 Hz, J ₂ =16.4 Hz, 1H), 4.71 (s, 1H).

Step 4:

(N-(4-oxaspiro[2.4]heptan-6-yl)-tert-butoxycarbonylamino)propyl methanesulfonate

The compound tert-butyl N-(4-oxaspiro[2.4]heptan-6-yl)hydroxypropyl carbamate (278 mg, 1.03 mmol) and triethylamine (260 mg, 2.58 mmol) were dissolved in 10 mL and dried In dichloromethane, at -10°C under the protection of nitrogen, slowly add methanesulfonyl chloride (234.8mg, 2.06mmol) dropwise, continue to react for 2 hours, then add 3mL ice water to the reaction solution to quench the reaction, dichloro Methane was extracted until the aqueous phase was substantially free of the target compound, and the combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain (N-(4-oxaspiro[2.4]heptane-6-yl)-tert Butoxycarbonylamino)propyl methanesulfonate is a pale yellow oil.

Step 5:

N-(5-(7-((N-(4-oxaspiro[2.4]heptane-6-yl)-tert-butoxycarbonylamino)propoxy)quinolin-4-yloxy)pyridine -2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro -1H-pyrazole-4-carboxamide (200.6mg, 0.44mmol), (N-(4-oxaspiro[2.4]heptane-6-yl)-tert-butoxycarbonylamino)propylmethanesulfonic acid Ester (220mg, 0.63mmol) and cesium carbonate (684.6mg, 2.1mmol, Aladdin) were suspended in 6mL of DMA, and stirred at 40°C for 2 days. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (1:4 (v/v) n-hexane/ethyl acetate) to obtain the title compound as a colorless solid (200 mg, 62.5%). the

MS (ESI, _pos.ion ) m/z: 721.2 ( _{M+1); LC-MS Rt: 4.669 min; Exact mass calculated for C40H44N6O7 : 720.3}

¹ H NMR (400MHz, CDCl ₃ ): δ0.55(m, 1H), 0.65(m, 1H), 0.78(m, 1H), 0.93(m, 1H), 1.49(s, 9H), 2.09(m , 2H), 2.18(m, 3H), 2.81(s, 3H), 3.38(s, 3H), 3.45(m, 2H), 3.78(dd, J ₁ =5.6Hz, J ₂ =14.8Hz, 1H) , 3.95(m, 1H), 4.16(t, 2H), 6.43(d, J=5.6Hz, 1H), 7.22(dd, J ₁ =2.4Hz, J ₂ =11.6Hz, 1H), 7.38(m, 3H), 7.51(m, 4H), 8.23(d, J=4.4Hz, 1H), 8.24(d, J=2Hz, 1H), 8.38(d, J=9.2Hz, 1H), 8.60(d, J =5.2Hz, 1H), 11.26(s, 1H).

Step 6:

N-(5-(7-((4-oxaspiro[2.4]heptane-6-yl)aminopropoxy)quinolin-4-yloxy)pyridin-2-yl)-2,3- Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

Compound N-(5-(7-((N-(4-oxaspiro[2.4]heptane-6-yl)-tert-butoxycarbonylamino)propoxy)quinolin-4-yloxy )pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (50mg, 0.069mmol) was dissolved in 2mL To the dry tetrahydrofuran solution, a mixed solution of 2M HCl/THF (8 mmol) was slowly added, and the reaction was stirred at room temperature for 4 hours. Then add 10mL saturated _NaHCO3 solution to the reaction solution to adjust the pH value to neutral, the aqueous phase is extracted with ethyl acetate, the combined organic phase is dried with _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure to obtain the crude product. Purification by column chromatography (5:1 (v/v) EtOAc/MeOH) afforded a white solid (30 mg, 69%).

MS (ESI, pos.ion) m/z: 621.2 ( _M +1 _{); LC-MS Rt: 3.192 min; Exact mass calculated for C35H36N6O5 : 620.2}

¹ H NMR (400MHz, CDCl ₃ ): δ0.48(m, 1H), 0.57(m, 1H), 0.81(m, 1H), 0.89(m, 1H), 1.94(dd, J ₁ = 4Hz, J ₂ =12Hz, 1H), 2.12(m, 2H), 2.24(dd, J ₁ =7.2Hz, J ₂ =20Hz, 1H), 2.81(s, 3H), 2.91(t, 2H), 3.38(s, 3H), 3.63(d, J=6.4Hz, 1H), 3.75(dd, _J1 =3.6Hz, _J2 =12.4Hz, 1H), 4.00(dd, _J1 =6.0Hz, _J2 =14.8Hz, 1H), 4.24(t, 2H), 6.43(d, J=5.2Hz, 1H), 7.22(dd, J=2.4Hz, J=11.6Hz, 1H), 7.38(m, 3H), 7.51(m, 4H), 8.23(d, J=2.8Hz, 1H), 8.24(d, J=3.6Hz, 1H), 8.38(d, J=8.8Hz, 1H), 8.60(d, J=5.2Hz, 1H) , 11.26(s, 1H).

Example 12

N-(5-(7-(3-(7-Hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)quinolin-4-yloxy)pyridin-2-yl) -2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

step 1

Ethyl 1-acetylcyclopropanecarboxylate

Ethyl acetoacetate (26 g, 200 mmol) was dissolved in 500 mL of acetone, then potassium carbonate was added, and finally 1,2-dibromoethane (45.12 g, 240 mmol) was slowly added dropwise with stirring. After the dropwise addition, the reaction solution was refluxed for 24 hours, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (1:50 (v/v) ethyl acetate/n-hexane) to obtain the target compound As a colorless oil (18.7 g, 60%). the

MS (ESI, pos.ion) m/z _: 157 (M+1); Exact mass calculated for _C8H12O3 : _156.08

¹ H NMR (400 MHz, CDCl ₃ ): δ1.25-1.29 (t, J=7.2 Hz, 3H), 1.45 (s, 4H), 2.45 (s, 3H), 4.18-4.20 (q, 2H).

step 2

Ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate

Ethyl 1-acetylcyclopropanecarboxylate (15.6g, 100mmol) and NBS (21.36g, 120mmol) were placed in a 100mL round bottom flask, and p-toluenesulfonic acid (1.9g, 10mmol), after the dropwise addition, the reaction mixture was stirred and reacted at room temperature for 8 hours, then the reaction solution was extracted with ether (200mL×3), the combined organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (1:30 (v/v) ethyl acetate/n-hexane) to obtain the title compound as a colorless oil (16.68 g, 71%). the

MS ₍ ESI _, pos.ion) m/z: 235, 237 (M+1); Exact mass calculated for _C8H11BrO3 : 233.99

¹ H NMR (400MHz, CDCl ₃ ): δ1.27(t, J=7.2Hz, 3H), 1.59-1.64(m, 4H), 4.19-4.24(q, J ₁ =14.4Hz, J ₂ =7.2Hz , 2H), 4.49 (s, 2H).

step 3

5-((R)-α-methylbenzyl)-4,7-dioxo-5-azaspiro[2.4]heptane

Dissolve ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate (4.7g, 20mmol) in 60mL tetrahydrofuran, and slowly add (R)-α-methylbenzylamine (2.9g, 24mmol) and triethyl Amine (4.04 g, 40 mmol). The reaction mixture was stirred and reacted at room temperature for 3 days. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was extracted with ethyl acetate (50 mL×2), washed with water (30 mL), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound as a bright yellow solid (3.66 g, 80%). the

MS (ESI, pos.ion) m/z: 230 (M+1); _Exact mass calculated _{for C14H15NO2} : 229.11

¹ H NMR (400MHz, CDCl ₃ ): δ1.58-1.60 (m, 4H), 1.62-1.63 (d, J=5.6Hz, 3H), 3.49-3.53 (d, J=17.6Hz, 1H), 3.83 -3.88 (d, J = 17.6 Hz, 1H), 5.80-5.82 (q, 1H), 7.26-7.39 (m, 5H).

step 4

5-((R)-α-methylbenzyl)-7-hydroxy-5-azaspiro[2.4]heptane

LiAlH ₄ (0.995g, 26.2mmol) was suspended in 40mL THF, and then 5-((R)-α-methylbenzyl)-4,7-dioxo-5-azaspiro[2.4]heptane (3.0g, 13.1mmol) was dissolved in 10mL THF, and the mixed solution was slowly added dropwise to the flask at 0°C. After the dropwise addition, the reaction mixture was reacted at 0°C for 2 hours, and then heated to 50°C to continue The reaction was stirred for 6 hours, and after the reaction was completed, 10 mL of ethyl acetate and 10 mL of water were added to the reaction flask at 0° C., the obtained suspension was filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (1: 3 (v/v) 2-butanol/n-hexane) to obtain the title compound as a colorless oil (2.4 g, 85%).

MS (ESI, pos.ion) m/ _z : 218 (M+1); exact mass calculated for _C14H19NO : 217.15

step 5

7-Hydroxy-5-azaspiro[2.4]heptane

5-((R)-α-methylbenzyl)-7-hydroxy-5-azaspiro[2.4]heptane (2.4 g, 11.1 mmol) was dissolved in 30 mL of ethanol, to which a catalytic amount of Pd was added /C, the resulting suspension was stirred and reacted under H _atmosphere for 3 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound as a bright orange oil (1.23g, 98%), which was directly used in the next step without purification. One step reaction.

MS (ESI, pos.ion) m/z: 114 (M+1) _; exact mass calculated for _C6H11NO : 113.08

step 6

3-(7-Hydroxy-5-azaspiro[2.4]heptan-5-yl)propanol

7-Hydroxy-5-azaspiro[2.4]heptane (1.23 g, 11.0 mmol) was dissolved in 40 mL THF, then 3-bromopropanol (2.3 g, 16.65 mmol) and Et ₃ N (2.24 g , 22.2 mmol). The reaction mixture was stirred and reacted at room temperature for 12 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (100:50:2 (v/v/v) EtOAc/CH ₃ OH/Et ₃ N ) to obtain the target compound as an orange-yellow oil (1.14 g, 60%).

MS (ESI, pos.ion) m/z: 172 (M+1) _{; LC} -MS Rt: 0.178 min; Calcd exact mass for _C9H17NO2 : 171.13

¹ H NMR (400MHz, CDCl ₃ ): δ0.59(m, 1H), 0.62(m, 1H), 0.70-0.72(m, 1H), 0.87-0.92(m, 1H), 1.68-1.74(m, 2H), 2.39-2.41(d, J=9.2Hz, 1H), 2.70-2.74(m, 2H), 2.84-2.87(m, 2H), 2.88-2.92(dd, _J1 =10.4Hz, _J2 = 4.8Hz, 1H), 3.73-3.75(m, 1H), 3.77-3.80(t, J=5.2Hz, 2H).

step 7

3-(7-Hydroxy-5-azaspiro[2.4]heptan-5-yl)propyl methanesulfonate

3-(7-Hydroxy-5-azaspiro[2.4]heptan-5-yl)propanol (1.14 g, 6.67 mmol) and Et ₃ N (1.35 g, 13.34 mmol) were dissolved in 20 mL CH ₂ Cl ₂ , at 0°C, methanesulfonyl chloride (1.15g, 10mmol) was slowly added dropwise thereto via a syringe. After the dropwise addition, the reaction solution was stirred and reacted at 0°C for 3 hours, and the reaction mixture was washed with water (10mL) and separated into layers. , the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3-(7-hydroxyl-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate as orange yellow The oil was used immediately in the next step without purification.

step 8

N-(5-(7-(3-(7-Hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)quinolin-4-yloxy)pyridin-2-yl) -2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro- 1H-Pyrazole-4-carboxamide (300 mg, 0.642 mmol) was dissolved in 3 mL of DMA, to which 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propylmethyl was added successively Sulfonate (240mg, 0.963mmol) and Cs ₂ CO ₃ (417mg, 1.284mmol), the reaction mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure to remove the solvent, and then added 10mL saturated sodium bicarbonate solution and 30mL chloroform , layered, the obtained organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (100:15:1 (v/v/v) EtOAc/CH ₃ OH/ _Et3N ) purification afforded the title compound as a white solid (259 mg, 65%).

MS (ESI, pos.ion) m _/ z: 621 (M+1 _{) ;} LC-MS Rt: 3.209 min; Exact mass calculated for _C35H36N6O5 : 620.27

¹ H NMR (400MHz, CDCl ₃ ): δ0.63(m, 1H), 0.67(m, 1H), 0.76-0.79(m, 1H), 0.96-0.99(m, 1H), 2.11-2.14(m, 2H), 2.47-2.50(d, J=8.4Hz, 1H), 2.80(s, 3H), 3.00-3.03(d, J=9.6Hz, 1H), 3.06-3.08(d, J=10.4Hz, 1H ), 3.37(s, 5H), 3.76-3.77(d, J=3.6Hz, 1H), 4.23-4.24(m, 2H), 6.42-6.43(d, J=5.2Hz, 1H), 7.20-7.23( d, J=8.8Hz, 1H), 7.36-7.38(d, J=7.6Hz, 2H), 7.47-7.49(m, 5H), 7.53-7.57(m, 2H), 8.22-8.24(d, J= 8.4Hz, 2H), 8.37-8.39(d, J=9.2Hz, 1H), 8.58-8.59(d, J=4.8Hz, 1H), 11.25(s, 1H).

Example 13

N-(4-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)quinolin-4-yloxy)-3-fluorophenyl )-N-phenylcyclopropane-1,1-dicarboxamide

Dissolve N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide (240 mg, 0.525 mmol) in 3 mL DMA, to which was added 3-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)propyl methanesulfonate (261 mg, 1.05 mmol) and Cs ₂ CO ₃ (512 mg, 1.575 mmol ), the reaction mixture was stirred and reacted at room temperature for 24 hours, concentrated under reduced pressure to remove the solvent, then added 15mL of saturated sodium bicarbonate solution and 30mL of chloroform, layered, the organic phase obtained was dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced Concentrated under reduced pressure, the residue was purified by silica gel column chromatography (100:15:1 (v/v/v) EtOAc/CH ₃ OH/Et ₃ N) to obtain the title compound as a white solid (170 mg, 53%).

MS ( _{ESI ,} pos.ion) m/ _z : 611 (M+1); Exact mass calculated for _C35H35FN4O5 : 610.26

¹ H NMR (400MHz, CDCl ₃ ): δ0.59-0.60(m, 1H), 0.62-0.65(m, 1H), 0.73-0.78(m, 1H), 0.92-0.96(m, 1H), 1.58- 1.62(q, J1=8.0Hz, J2=4.4Hz, 2H), 1.81-1.84(m, 2H), 2.05-2.88(m, 2H), 2.38-2.40(d, J=8.4Hz, 1H), 2.68 -2.73 (m, 2H), 2.81-2.85 (dd, _J1 = 4.8Hz, _J2 = 4.4Hz, 1H), 2.90-2.92 (d, J = 8.8Hz, 1H), 2.96-2.98 (d, J =9.2Hz, 1H), 3.74-3.73(d, J=3.6Hz, 1H), 4.21-4.26(m, 2H), 6.36-6.38(d, J=5.2Hz, 1H), 7.18-7.24(m, 2H), 7.26-7.29(d, J=10.4Hz, 1H), 7.36-7.40(t, J=8Hz, 2H), 7.48-7.51(m, 2H), 7.75-7.79(dd, _J1 =2Hz, J ₂ =2.4Hz, 1H), 8.05(s, 1H), 8.24-8.26(d, J=9.2Hz, 1H), 8.56-8.58(d, J=5.2Hz, 1H), 10.19(s, 1H) .

Example 14

N-(4-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)quinolin-4-yloxy)-3-fluorophenyl )-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro -1H-pyrazole-4-carboxamide (154 mg, 0.619 mmol) was dissolved in 3 mL of DMA, to which 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propane was slowly added Methanesulfonate (261mg, 1.05mmol) and Cs ₂ CO ₃ (268mg, 0.826mmol), the reaction mixture was stirred at room temperature for 40 hours, concentrated under reduced pressure to remove the solvent, and then added 10mL of saturated sodium bicarbonate solution and 25 mL of chloroform was separated, the obtained organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (100:15:1 (v/v/v) EtOAc/CH ₃ OH/ Et ₃ N) purification afforded the title compound as a pale yellow solid (192 mg, 73%).

MS (ESI, pos.ion) m/z: 638 (M+1); _LC -MS Rt: 3.140 min; _{Exact mass} calculated for _C36H36FN5O5 : 637.27

¹ H NMR (400MHz, CDCl ₃ ): δ0.63-0.65(m, 1H), 0.67-0.69(m, 1H), 0.76-0.81(m, 1H), 0.98-1.02(m, 1H), 2.08- 2.17(m, 2H), 2.54-2.57(d, J=9.2Hz, 1H), 2.80(s, 3H), 2.81(m, 2H), 2.98-3.02(dd, J ₁ =4.8Hz, J ₂ = 4.4Hz, 1H), 3.08-3.10(d, J=9.2Hz, 1H), 3.12-3.14(d, J=9.6Hz, 1H), 3.38(s, 3H), 3.79-3.80(d, J=4.8 Hz, 1H), 4.21-4.25(m, 2H), 6.40-6.42(d, J=5.2Hz, 1H), 7.14-7.17(d, J=8.4Hz, 1H), 7.19-7.22(dd, J ₁ =9.6Hz, J ₂ =2.4Hz, 1H), 7.29-7.31(d, J=4.8Hz, 1H), 7.36-7.37(d, J=6Hz, 2H), 7.47-7.50(m, 2H), 7.55 -7.59 (q, J=7.6Hz, 2H), 7.90-7.94 (dd, _J1 =12.4Hz, _J2 =2.4Hz, 1H), 8.25-8.28 (d, J=9.2Hz, 1H), 8.57- 8.58 (d, J = 9.2 Hz, 1H), 10.883 (s, 1H).

Example 15

N-(4-(7-(3-(7-Hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)-6-methoxyquinolin-4-yloxy) -3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

N-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl- 2,3-Dihydro-1H-pyrazole-4-carboxamide (200 mg, 0.389 mmol) was dissolved in 2 mL of DMA, to which was added successively 3-(7-hydroxy-5-azaspiro[2.4]heptane- 5-yl) propyl methanesulfonate (193mg, 0.778mmol) and Cs ₂ CO ₃ (379mg, 1.167mmol), the reaction mixture was stirred at room temperature for 40 hours, concentrated under reduced pressure to remove the solvent, and 10mL of saturated Sodium bicarbonate solution and 30mL chloroform were separated, the obtained organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (100:15:1 (v/v/v) EtOAc / _CH3OH / _Et3N ) to obtain the title compound as a pale yellow solid (171 mg, 66%).

MS (ESI, pos.ion) m/z: 668 (M+1); _LC -MS Rt: 3.421 min; _{Exact mass} calculated for _C37H38FN5O6 : 667.28

¹ H NMR (400MHz, CDCl ₃ ): δ0.72-0.77(m, 2H), 0.82-0.85(m, 1H), 1.08-1.12(m, 1H), 2.35-2.38(m, 2H), 2.75( m, 2H), 2.80(s, 3H), 2.83-2.86(d, J=6Hz, 1H), 3.17-3.18(m, 1H), 3.38(s, 3H), 3.41-3.46(t, J=10Hz , 2H), 3.86-3.88(d, J=4.8Hz, 1H), 4.02(s, 3H), 4.30(m, 2H), 6.43-6.44(d, J=5.2Hz, 1H), 7.15-7.19( t, J=8.8Hz, 1H), 7.29-7.31(d, J=8.8Hz, 1H), 7.35-7.37(d, J=7.2Hz, 2H), 7.46-7.50(m, 2H), 7.55-7.59 (m, 3H), 7.90-7.94 (dd, _J1 = 8.8Hz, _J2 = 8.8Hz, 1H), 8.45-8.47 (d, J = 5.2Hz, 1H), 10.89 (s, 1H).

Example 16

N-(5-(7-(3-(7-Hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)quinolin-4-yloxy)pyridin-2-yl) -N-Phenylcyclopropane-1,1-dicarboxamide

Dissolve N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide (110 mg, 0.25 mmol) in 2 mL DMA , to which 3-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)propyl methanesulfonate (125 mg, 0.50 mmol) and Cs ₂ CO ₃ (243 mg, 0.75 mmol) were sequentially added ), the reaction mixture was stirred and reacted at room temperature for 24 hours, concentrated under reduced pressure to remove the solvent, then added 10mL of saturated sodium bicarbonate solution and 30mL of chloroform, layered, the organic phase obtained was dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced Concentrated under reduced pressure, the residue was purified by silica gel column chromatography (100:15:1 (v/v/v) EtOAc/CH ₃ OH/Et ₃ N) to obtain the title compound as a light yellow solid (110 mg, 75%).

MS ( _ESI , pos.ion) m _{/z: 594 (M+1); Exact mass calculated for C34H35N5O5 : 593.26}

¹ H NMR (400MHz, CDCl ₃ ): δ0.55(m, 1H), 0.62(m, 1H), 0.77(m, 1H), 0.92-0.96(m, 1H), 1.66-1.69(q, J ₁ =7.2Hz, J ₂ =8.4Hz, J ₃ =4.4Hz, J ₄ =5.6Hz, 2H), 1.78-1.81(q, J ₁ =7.2Hz, J ₂ =8.4Hz, J ₃ =4.4Hz, J ₄ =5.6Hz, 2H), 2.04-2.09(m, 2H), 2.36-2.38(d, J=8.8Hz, 1H), 2.66-2.72(m, 2H), 2.79-2.83(dd, J ₁ =J ₂ =10Hz, J ₃ =J ₄ =4.8Hz, 1H), 2.87-2.89(d, J=8.8Hz, 1H), 2.93-2.95(d, J=9.6Hz, 1H), 3.73-3.74(d, J=4.4Hz, 1H), 4.19-4.25(m, 2H), 6.38-6.40(d, J=5.2Hz, 1H), 7.11-7.15(t, _J1 =8.8Hz, _J2 =7.2Hz, 1H ), 7.21-7.24 (dd, J ₁ =J ₂ =9.2Hz, J ₃ =J ₄ =2.8Hz, 1H), 7.31-7.35 (t, J ₁ =J ₂ =7.2Hz, 2H), 7.50-7.51 (d, J=2.8Hz, 1H), 7.55-7.58(m, 3H), 8.18-8.21(d, J=9.2Hz, 1H), 8.23-8.23(d, J=2.4Hz, 1H), 8.27- 8.29 (d, J=9.2Hz, 1H), 8.58-8.59 (d, J=5.2Hz, 1H).

Example 17

N-(4-(7-(3-(7-Hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)-6-methoxy-4-yloxy)-3 -Fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

N-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide (260mg, 0.534mmol) was dissolved in 3mL DMA, and 3-(7-hydroxyl-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (266mg, 1.068mmol) and Cs were added successively thereto _. CO ₃ (520mg, 1.602mmol), the reaction mixture was stirred at room temperature for 2 days, concentrated under reduced pressure to remove the solvent, then added 15mL of saturated sodium bicarbonate solution and 30mL of chloroform, the layers were separated, and the obtained organic phase was washed with anhydrous sulfuric acid Sodium-dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (100:15:1 (v/v/v) EtOAc/CH ₃ OH/Et ₃ N) to obtain the title compound as a light yellow solid (264 mg , 77%).

MS (ESI, _pos.ion ) m/z: 641 ( _{M+1); LC-MS Rt: 3.439 min; Exact mass calculated for C36H37FN4O6 : 640.27}

¹ H NMR (400MHz, CDCl ₃ ): δ0.61(m, 2H), 0.75(m, 1H), 0.96(m, 1H), 1.59-1.62(q, J ₁ =7.2Hz, J ₂ =8Hz, J ₃ =4.4Hz, J ₄ =5.2Hz, 2H), 1.81-1.84(q, J ₁ =7.6Hz, J ₂ =8.4Hz, J ₃ =4.4Hz, J ₄ =5.2Hz, 2H), 2.07- 2.15(m, 2H), 2.36-2.38(d, J=8.8Hz, 1H), 2.64-2.73(m, 2H), 2.76-2.80(dd, _J1 =9.6Hz, _J2 =9.2Hz, _J3 =4.4Hz, J ₄ =4.8Hz, 1H), 2.92-2.94(d, J=8.8Hz, 1H), 2.99-3.02(d, J=10Hz, 1H), 3.73-3.74(d, J=3.6Hz , 1H), 4.041(s, 3H), 4.30-4.32(m, 2H), 6.38-6.39(d, J=5.2Hz, 1H), 7.19-7.23(t, J ₁ =8.8Hz, J ₂ =8Hz , 1H), 7.30-7.30 (d, J=6.4Hz, 1H), 7.36-7.40 (t, J ₁ =8.4Hz, J ₂ =7.6Hz, 2H), 7.48-7.50 (d, J=9.6Hz, 2H), 7.56(s, 1H), 7.70(s, 1H), 7.76-7.80(dd, J ₁ =J ₂ =12Hz, J ₃ =J ₄ =2.4Hz, 1H), 8.15(s, 1H), 8.45-8.46 (d, J=5.2Hz, 1H), 10.24 (s, 1H).

Example 18

N-(4-(7-(3-(7-Hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)-6-methoxyquinolin-4-yloxy) -3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-di Carboxamide (240 mg, 0.475 mmol) was dissolved in 3 mL of DMA, and 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (236 mg, 0.95 mmol) and Cs ₂ CO ₃ (463mg, 1.425mmol), the reaction mixture was stirred at room temperature for 2 days, concentrated under reduced pressure to remove the solvent, then added 15mL of saturated sodium bicarbonate solution and 30mL of chloroform, and separated the layers to obtain the organic The phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (100:15:1 (v/v/v) EtOAc/CH ₃ OH/Et ₃ N) to obtain the target compound as Pale yellow solid (250 mg, 80%).

MS _{( ESI} , pos.ion) m/ _z : 659 (M+1); _Exact mass calculated for _C36H36F2N4O6 : 658.26

¹ H NMR (400MHz, CDCl ₃ ): δ0.58-0.66(m, 2H), 0.74-0.78(m, 1H), 0.95-1.00(m, 1H), 1.62-1.65(q, J ₁ = 7.6Hz , J ₂ =8.4Hz, J ₃ =4.4Hz, J ₄ =5.2Hz, 2H), 1.79-1.82(q, J ₁ =7.2Hz, J ₂ =8.4Hz, J ₃ =4.4Hz, J ₄ =5.6 Hz, 2H), 2.05-2.16(m, 2H), 2.39-2.42(d, J=8.8Hz, 1H), 2.68-2.77(m, 2H), 2.80-2.83(dd, _J1 = _J2 =10Hz , J ₃ =J ₄ =4.8Hz, 1H), 2.96-2.98(d, J=8.8Hz, 1H), 3.03-3.05(d, J=10Hz, 1H), 3.74-3.75(d, J=3.6Hz , 1H), 4.04(s, 3H), 4.30-4.31(m, 2H), 6.38-6.39(d, J=5.6Hz, 1H), 7.05-7.08(d, J=6.4Hz, 2H), 7.19- 7.23 (t, _J1 = _J2 = 8.4Hz, 1H), 7.27-7.29 (d, J = 9.6Hz, 1H), 7.41-7.47 (q, _J1 = _J2 = 6.8Hz, _J3 = _J4 =4.8Hz, 1H), 7.56(s, 1H), 7.69(s, 1H), 7.75-7.78(dd, J ₁ =J ₂ =12Hz, J ₃ =J ₄ =2.4Hz, 1H), 8.38(s , 1H), 8.44-8.46 (d, J=5.6Hz, 1H).

Example 19

N-(5-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)-6-methoxyquinolin-4-yloxy) Pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

N-(5-(7-hydroxy-6-methoxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2 , 3-dihydro-1H-pyrazole-4-carboxamide (200mg, 0.402mmol) was dissolved in 4mL DMA, and 3-(7-hydroxy-5-azaspiro[2.4]heptane-5 -yl) propyl methanesulfonate (150mg, 0.603mmol) and Cs ₂ CO ₃ (261mg, 0.804mmol), the reaction mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure to remove the solvent, and then added 5mL of saturated carbonic acid Sodium hydrogen solution and 25mL chloroform were separated, the obtained organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (100:15:1 (v/v/v) EtOAc/ CH ₃ OH/Et ₃ N) purification afforded the title compound as a pale yellow solid (165 mg, 63%).

MS (ESI, pos.ion) m/z: 651 (M+1 ₎ ; _{LC-MS Rt: 3.296 min; Calcd exact mass for C36H38N6O6 : 650.29}

¹ H NMR (400MHz, CDCl ₃ ): δ0.78(m, 1H), 0.79(m, 1H), 0.86(m, 1H), 0.90(m, 1H), 1.10(s, 3H), 1.37(m , 2H), 1.40(s, 2H), 1.43(s, 2H), 2.80(d, 3H), 3.14(m, 2H), 3.38(s, 3H), 4.02(s, 3H), 4.29(s, 1H), 6.46(d, J=5.2Hz, 1H), 7.36-7.39(d, 2H), 7.46-7.57(m, 6H), 8.24(d, J=2.8Hz, 1H), 8.38(d, J =9.2Hz, 1H), 8.49(d, J=5.2Hz, 1H), 11.28(s, 1H).

Example 20

N-(5-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)-6-methoxyquinolin-4-yloxy) Pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide

N-(5-(7-hydroxy-6-methoxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2 , 3-dihydro-1H-pyrazole-4-carboxamide (300mg, 0.640mmol) was dissolved in 4mL DMA, and 3-(7-hydroxyl-5-azaspiro[2.4]heptane-5 -yl) propyl methanesulfonate (239mg, 0.960mmol) and Cs ₂ CO ₃ (416mg, 1.280mmol), the reaction mixture was stirred at room temperature for 48 hours, concentrated under reduced pressure to remove the solvent, and then added 5mL of saturated carbonic acid Sodium hydrogen solution and 25mL chloroform were separated, the obtained organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (100:15:1 (v/v/v) EtOAc/ CH ₃ OH/Et ₃ N) purification afforded the title compound as a pale yellow solid (240 mg, 60%).

MS (ESI, pos.ion) m _{/ z :} 624 (M+1); Exact mass calculated for _C35H37N5O6 : 623.27

¹ H NMR (400MHz, CDCl ₃ ): δ0.71(m, 2H), 0.85(m, 2H), 1.25(m, 2H), 1.42(m, 2H), 1.69(m, 2H), 1.79(m , 2H), 2.23(m, 2H), 3.12(dd, 1H), 3.25(m, 2H), 3.82(d, 1H), 4.03(s, 3H), 4.32(m, 2H), 6.42(d, J=5.2Hz, 1H), 7.15(t, _J1 =8.8Hz, _J2 =7.2Hz, 1H), 7.30(dd, _J1 = _J2 =9.2Hz, _J3 = _J4 =2.8Hz, 1H ), 7.37 (t, _J1 = _J2 = 7.2Hz, 2H), 7.52 (d, J = 2.8Hz, 1H), 7.56 (m, 4H), 8.30 (d, J = 9.2Hz, 1H), 8.49 -8.23 (d, J=2.4Hz, 1H), 9.41 (s, 1H).

Example 21

N-(4-(7-(4-oxaspiro[2.4]heptane-6-yloxy)quinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane- 1,1-diamide

step 1

Ethyl cyclopropane-1,1-dicarboxylate

Diethylmalonate (3.2g, 20mmol) was dissolved in 50mL DMF, anhydrous potassium carbonate powder (6.9g, 50mmol) was added, and 1,2-dibromoethane (4.136 g, 22 mmol), after reacting for 2 hours, a catalytic amount of TBAI (0.738 g, 2.0 mmol) was added thereto, stirred at room temperature for 8 hours, the reaction mixture was filtered, and the solid was washed 3 times with 20 mL of ether. The filtrate was diluted with 200 mL of water, then extracted with ether (75 mL×4), the organic layers were combined, then washed with saturated brine (70 mL), and finally the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by alumina column chromatography (1:10 (v/v) ethyl acetate/n-hexane) to obtain the title compound as a yellow oil (3.3 g, 88.7%). the

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.27 (m, J=6.8 Hz, 6H), 1.42 (m, 4H), 4.18 (m, 4H).

step 2

1-(Ethoxycarbonyl)cyclopropanecarboxylic acid

Diethylcyclopropane-1,1-dicarboxylate (4.77 g, 25.6 mmol) was dissolved in 40 mL of ethanol, and 8 mL of 18% KOH aqueous solution was slowly added with stirring. The reaction mixture was stirred overnight at room temperature, evaporated to dryness under reduced pressure, slowly added hydrochloric acid (6mL, 5mol/L) dropwise until the reaction solution was neutral, the reaction mixture was extracted with ethyl acetate (100mL×3), and the combined organic phases were washed over dry Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give the title compound as a white solid (3.58 g, 88.4%). the

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.27 (t, J=6.7 Hz, 3H), 1.83 (m, 2H), 1.86 (m, 2H), 4.25 (m, 2H).

step 3

Ethyl 1-(phenylcarbamoyl)cyclopropanecarboxylate

Dissolve 1-(ethoxycarbonyl)cyclopropanecarboxylic acid (7.4g, 46.84mmol) in dry dichloromethane (70mL), cool the reaction solution to 0°C, add HATU (35.62g, 93.67mmol), The reaction was stirred for 10 min, then a mixture of aniline (8.71 g, 93.67 mmol), triethylamine (9.48 g, 93.67 mmol) and dichloromethane (30 mL) was added dropwise to the reaction liquid, and reacted at 40° C. for 24 hours. After completion of the reaction, 30 mL of water was added to quench the reaction, extracted with dichloromethane (3 × 100 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (1:5( v/v) Ethyl acetate/n-Hexane) Purification afforded the title compound as a pale yellow solid (9.7 g, 89%). the

¹ H NMR (400MHz, CDCl ₃ ): δ1.27(t, J=6.8Hz, 3H), 1.76(m, 2H), 1.85(m, 2H), 4.20(m, 2H), 6.68-6.71(m , 1H), 7.32-7.35 (m, 2H), 7.57-7.60 (m, 2H), 10.88 (s, 1H).

step 4

1-(Phenylcarbamoyl)cyclopropanecarboxylic acid

Dissolve ethyl 1-(phenylcarbamoyl)cyclopropanecarboxylate (13g, 55.79mmol) in ethanol/tetrahydrofuran (1/1 (v/v), 100mL), slowly add 8mL KOH aqueous solution under stirring (58%), stirred overnight at room temperature, concentrated under reduced pressure to remove ethanol and tetrahydrofuran, then slowly added dropwise concentrated hydrochloric acid (5mol/L, 20mL) to neutralize the solution, extracted with ethyl acetate (3 × 150mL), The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a white solid (10.1 g, 88.6%). the

¹ H NMR (400MHz, CDCl ₃ ): δ1.77(m, 2H), 1.84(m, 2H), 7.10(m, 1H), 7.30-7.34(m, 2H), 7.53-7.55(m, 2H) , 10.61 (s, 1H).

step 5

N-(4-(7-(Benzyloxy)quinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

Dissolve 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (1.14g, 5.6mmol) in dry dichloromethane (8mL), slowly add HATU (2.11g, 5.6mmol) at 0°C, stir After reacting for 10 minutes, 4-(7-(benzyloxy)quinolin-4-yloxy)-3-fluoroaniline (1.0g, 2.8mmol) and triethylamine (0.7g, 6.9mmol) were dissolved in di Chloromethane (5mL), this mixture was slowly added dropwise to the reaction solution, stirred at 40°C for 24 hours, then added water (10mL) to quench the reaction, extracted with dichloromethane (3×30mL), and the combined organic The phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (1:1 (v/v) ethyl acetate/n-hexane) to obtain the title compound as a white solid (1.3 g , 85%). the

MS (ESI, pos.ion) m _/ z: 548 ( _{M+1); LC-MS Rt: 4.595 min; Exact mass calculated for C33H26FN3O4 : 547.19}

¹ H NMR (400MHz, CDCl ₃ ): δ1.60(m, 2H), 1.83(m, 2H), 5.25(s, 2H), 6.45(m, 1H), 7.28-7.29(m, 1H), 7.16 -7.24(m, 2H), 7.34-7.57(m, 10H), 7.78-7.81(m, 1H), 7.99(s, 1H), 8.30(d, J=9.2Hz, 1H), 8.60(d, J =6Hz, 1H), 10.29(s, 1H).

step 6

N-(4-(7-Hydroxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

N-(4-(7-(benzyloxy)quinolin-4-yloxy)-3-fluorophenyl)-N-phenyl-cyclopropane-1,1-dicarboxamide (0.7g, 1.28mmol) and Pd/C (0.8g) were placed in methanol (20mL), reacted at room temperature in a hydrogen atmosphere for 1.5 hours, filtered the reaction solution, washed three times with 10mL methanol, combined the methanol solution, and concentrated under reduced pressure to obtain the target compound As a white solid (0.53 g, 90.6%). the

MS (ESI, pos.ion) m/z: 457 (M+1 ₎ ; _{LC-MS Rt: 3.936 min; Exact mass calculated for C27H21FN2O4 : 456.15}

¹ H NMR (400MHz, MeOD): δ1.66(s, 1H), 6.81(d, J=6.4Hz, 1H), 7.14(t, J=7.6Hz, 1H), 7.33(m, 3H), 7.41 -7.48(m, 3H), 7.55(d, J=8Hz, 2H), 7.92(d, J=12.8Hz, 1H), 8.49(d, J=8.8Hz, 1H), 8.69(d, J=6Hz , 1H).

step 7

N-(4-(7-(4-oxaspiro[2.4]heptane-6-yloxy)quinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane- 1,1-Dicarboxamide

(4-Oxaspiro[2.4]heptan-6-yl)methanesulfonate (168mg, 0.877mmol) and N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluoro Phenyl)-N-phenylcyclopropane-1,1-dicarboxamide (300mg, 0.584 mmol) was dissolved in 5mL N,N-dimethylacetamide, cesium carbonate (893mg, 2.74mmol) was added, stirred at room temperature After 36 hours, the temperature was raised to 40°C for 8 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (1:1 (v/v) ethyl acetate/n-hexane) to obtain the target compound as a white solid (65 mg, 18%). the

MS (ESI, pos.ion) m/z: 554.1 ( _M +1) _{; LC} -MS Rt: 4.354 min; Exact mass calculated for _C32H28FN3O5 : 553.2

¹ H NMR (400MHz, CDCl ₃ ): δ0.53(m, 1H), 0.65(m, 1H), 0.89(m, 1H), 1.00(m, 1H), 1.60(m, 2H), 1.84(m , 2H), 2.25(m, 1H), 2.53(m, 1H), 4.20(m, 2H), 5.22(m, 1H), 6.39(d, J=5.2Hz, 1H), 7.19(m, 2H) , 7.28(m, 2H), 7.38(m, 2H), 7.48(m, 2H), 7.77(m, 1H), 7.59(s, 1H), 8.28(d, J=9.2Hz, 1H), 8.58( d, J=5.2Hz, 1H).

Example 22

N-(4-(7-(((5R)-4-oxaspiro[2.4]heptane-5-yl)methoxy)quinolin-4-yloxy)-3-fluorophenyl)- N-Phenylcyclopropane-1,1-dicarboxamide

((5R)-4-Oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate (181.2mg, 0.877mmol) and N-(4-(7-hydroxyquinolin-4-yl Oxygen)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide (300mg, 0.584mmol) was dissolved in 5mL N,N-dimethylacetamide, cesium carbonate (893mg , 2.74mmol), stirred at room temperature for 36 hours, then raised the temperature to 40°C for 8 hours, the reaction solution was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (1:1 (v/v) ethyl acetate/n-hexane) Purification afforded the title compound as a white solid (234 mg, 63%). the

MS (ESI, pos.ion) m/z: 568.2 (M+1 _{) ; LC} -MS Rt: 4.364 min; Exact mass calculated for _C33H30FN3O5 : 567.22

¹ H NMR (400MHz, CDCl ₃ ): δ0.56(m, 2H), 0.91(m, 2H), 1.60(m, 4H), 1.83(m, 2H), 2.03(m, 2H), 4.18(m , 2H), 4.52(s, 1H), 6.38(m, 1H), 7.20(m, 2H), 7.30(m, 1H), 7.38(m, 3H), 7.48(m, 2H), 7.76(m, 1H), 8.02(s, 1H), 8.25(d, J=9.2Hz, 1H), 8.58(d, J=5.2Hz, 1H), 10.18(s, 1H).

Example 23

N-(4-(7-(3-(1-hydroxycyclopropyl)propoxy)quinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1 -Dicarboxamide

Mix 3-(1-hydroxycyclopropyl)propyl methanesulfonate (170.7mg, 0.877mmol) and N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl) -N-phenylcyclopropane-1,1-dicarboxamide (300mg, 0.584mmol) was dissolved in 5mL N,N-dimethylacetamide, cesium carbonate (893mg, 2.74mmol) was added, stirred at room temperature for 36 hours, and then The temperature was raised to 40°C for 8 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (4:1 (v/v) ethyl acetate/n-hexane) to obtain the target compound as a white solid (364.1 mg, 74%). the

MS (ESI, pos.ion) m/z: 556.2 (M+1 _{) ; LC} -MS Rt: 4.110 min; Exact mass calculated for _C32H30FN3O5 : 555.22

¹ H NMR (400MHz, CDCl ₃ ): δ0.51(s, 2H), 0.79(s, 2H), 1.25(s, 2H), 1.81(m, 4H), 2.15(m, 2H), 3.38(s , 3H), 4.24(m, 2H), 6.38(d, J=4.8Hz, 1H), 7.25(m, 4H), 7.46(m, 1H), 7.77(d, J=12Hz, 1H), 7.97( s, 1H), 8.26 (d, J = 9.2Hz, 1H), 8.58 (d, J = 4.8Hz, 1H), 10.18 (s, 1H).

Example 24

N-(5-(7-(4-oxaspiro[2.4]heptane-6-yloxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1 , 1-Dicarboxamide

step 1

N-(5-(7-(Benzyloxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide

Preparation of the title compound According to the synthetic method of step 5 of Example 21, using 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (1.14g, 5.6mmol), HATU (2.11g, 5.6mmol), 5-(7- (Benzyloxy)quinolin-4-yloxy)pyridin-2-amine (960 mg, 2.8 mmol) and DBU (868 mg, 7.0 mmol) were dissolved in dichloromethane (50 mL) to give the title compound as a white solid (1.22 g, 82%). the

MS (ESI, pos.ion) m/z: 531.1 ( _M +1) _; LC-MS Rt: 4.583 min; _Exact mass calculated for _C32H26N4O4 : 530.2

¹ H NMR (400MHz, CDCl ₃ ): δ1.67(m, 2H), 1.80(m, 2H), 5.24(s, 2H), 6.43(d, J=4.8Hz, 1H), 7.14(m, 1H ), 7.34(m, 4H), 7.41(m, 2H), 7.43(m, 3H), 7.51(m, 3H), 8.24(m, 2H), 8.30(d, J=8.8Hz, 1H), 8.61 (d, J=5.2Hz, 1H), 9.10(s, 1H), 9.44(s, 1H).

step 2

N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide

N-(5-(7-(Benzyloxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide (1.22g, 2.3 mmol) and Pd/C (1.2g) were placed in methanol (30mL), reacted at room temperature in a hydrogen atmosphere for 2 hours, the reaction solution was filtered, and washed three times with 10mL of methanol, the combined methanol solution was concentrated under reduced pressure to obtain the target The compound was a white solid (910.8 mg, 90%). the

MS (ESI, pos.ion) m/z: 441.2 ( _M +1) _{; LC} -MS Rt: 3.508 min; Exact mass calculated for _C25H20N4O4 : 440.15

¹ H NMR (400MHz, CD ₃ OD): δ1.69(m, 4H), 6.55(d, J=5.6Hz, 1H), 7.14(m, 1H), 7.30(m, 4H), 7.56(m, 2H), 7.74 (m, 1H), 8.29 (m, 3H), 8.55 (d, J = 5.6 Hz, 1H).

step 3

N-(5-(7-(4-oxaspiro[2.4]heptane-6-yloxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1 , 1-Dicarboxamide

(4-Oxaspiro[2.4]heptane-6-yl)methanesulfonate (168mg, 0.877mmol) and N-(5-(7-hydroxyquinolin-4-yloxy)pyridine-2 -yl)-N-phenylcyclopropane-1,1-dicarboxamide (300mg, 0.682mmol) was dissolved in 5mL N,N-dimethylacetamide, cesium carbonate (893mg, 2.74mmol) was added, stirred at room temperature After 36 hours, the temperature was raised to 40°C for 8 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (2:1 (v/v) ethyl acetate/n-hexane) to obtain the target compound as a white solid (73 mg, 20%). the

MS (ESI, pos.ion) m/z: 537.1 ( _M +1) _{; LC} -MS Rt: 4.429 min; Exact mass calculated for _C31H28N4O5 : 536.21

¹ H NMR (400MHz, CDCl ₃ ): δ0.60(m, 2H), 0.95(m, 2H), 1.70(m, 4H), 2.40(m, 1H), 2.54(m, 1H), 4.19(m , 2H), 5.23(m, 1H), 6.42(d, J=4.2Hz, 1H), 7.28(m, 3H), 7.34(m, 3H), 7.58(m, 3H), 8.24(m, 2H) , 8.62 (d, J=5.2Hz, 1H), 9.10 (s, 1H).

Example 25

N-(5-(7-(3-(1-hydroxycyclopropyl)propoxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenyl-cyclopropane-1,1 -Dicarboxamide

The title compound was prepared by the synthetic method of Example 9, using N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-di Carboxamide (300 mg, 0.682 mmol), 3-(1-hydroxycyclopropyl)propyl methanesulfonate (155 mg, 0.80 mmol), and Cs ₂ CO ₃ (668 mg, 2.05 mmol) were suspended in 3 mL of DMA. The residue was purified by silica gel column chromatography (3:1 (v/v) ethyl acetate/n-hexane) to obtain the title compound as a white solid (238.5 mg, 65%).

MS (ESI, _pos.ion ) m/z: 539.2 ( _M +1); _{LC-MS Rt: 4.156 min; Exact mass calculated for C31H30N4O5 :} 538.22

¹ H NMR (400MHz, CDCl ₃ ): δ0.51(m, 2H), 0.81(m, 2H), 1.69(m, 2H), 1.82(m, 4H), 2.15(m, 2H), 4.25(m , 2H), 6.42(d, J=5.2Hz, 1H), 7.16(m, 1H), 7.23(d, J=2.8Hz, 1H), 7.36(m, 2H), 7.44(d, J=2.4Hz , 1H), 7.58 (m, 3H), 8.24 (m, 2H), 8.31 (d, J=8.8Hz, 1H), 8.62 (d, J=5.2Hz, 1H).

Wherein also obtained another product N-(5-(7-(3-(1-cyclopropyl methanesulfonate-1-yl)propoxy)quinolin-4-yloxy)pyridine-2- base)-N-phenylcyclopropane-1,1-dicarboxamide as light yellow solid. the

MS (ESI, pos.ion) _m /z: 617.1 ( _M +1) _; LC-MS Rt: 4.491 min; Exact mass calculated for _C32H32N4O7S : 616.2

¹ H NMR (400MHz, CDCl ₃ ): δ0.78(m, 2H), 1.31(m, 2H), 1.67(m, 2H), 1.81(m, 2H), 2.14(m, 4H), 3.02(s , 3H), 4.23(m, 2H), 6.41(d, J=5.2Hz, 1H), 7.14(m, 1H), 7.22(m, 2H), 7.35(m, 2H), 7.41(d, J= 2.4Hz, 1H), 7.58(m, 3H), 8.22(m, 2H), 8.30(d, J=9.2Hz, 1H), 8.61(d, J=5.2Hz, 1H), 9.09(s, 1H) , 9.43 (s, 1H).

Example 26

N-(4-(7-(4-oxaspiro[2.4]heptane-6-yloxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N -Phenylcyclopropane-1,1-dicarboxamide

The title compound was prepared by the synthetic method of Example 24 using N-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenyl ring Propane-1,1-dicarboxamide (300mg, 0.616mmol), (4-oxaspiro[2.4]heptane-6-yl) methanesulfonate (138mg, 0.72mmol), and Cs ₂ CO ₃ (602.5 mg, 1.848mmol) was suspended in 3mL DMA. The residue was purified by silica gel column chromatography (2:1 (v/v) ethyl acetate/n-hexane) to obtain the title compound as a white solid (186.7 mg, 52%).

MS (ESI, pos.ion) m/z: 583.9 (M+1 _{) ; LC} -MS Rt: 4.432 min; Exact mass calculated for _C33H30FN3O6 : 583.2

¹ H NMR (400MHz, CDCl ₃ ): δ0.55(m, 1H), 0.65(m, 1H), 0.90(m, 1H), 1.05(m, 1H), 1.60(m, 2H), 1.85(m , 2H), 4.04(s, 3H), 4.24(m, 2H), 5.25(m, 1H), 6.41(d, J=4.4Hz, 1H), 7.20(m, 2H), 7.25(m, 1H) , 7.30(m, 2H), 7.40(m, 1H), 7.50(m, 2H), 7.60(s, 1H), 7.80(m, 2H), 7.95(m, 1H) 8.50(d, J=5.2Hz , 1H), 10.25(s, 1H).

Example 27

N-(4-(7-(3-(1-hydroxycyclopropyl)propoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenyl Cyclopropane-1,1-dicarboxamide

The title compound was prepared by the synthetic method of Example 9 using N-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenyl ring Propane-1,1-dicarboxamide (300mg, 0.616mmol), 3-(1-hydroxycyclopropyl)propyl methanesulfonate (155mg, 0.80mmol), and Cs ₂ CO ₃ (602.5mg, 1.848mmol ) was suspended in 3 mL DMA. The residue was purified by silica gel column chromatography (6:1 (v/v) ethyl acetate/n-hexane) to obtain the title compound as a white solid (263 mg, 73%).

MS (ESI, _pos.ion ) m/z: 586.2 (M+1 _{); LC-MS Rt: 4.244 min; Exact mass calculated for C33H32FN3O6 : 585.23}

¹ H NMR (400MHz, CDCl ₃ ): δ0.46(s, 2H), 0.76(m, 2H), 1.61(m, 2H), 1.84(m, 4H), 2.22(t, J=6.4Hz, 2H ), 4.03(s, 3H), 4.30(t, J=6Hz, 2H), 6.41(m, 1H), 7.21-7.58(m, 8H), 7.80(m, 1H), 7.95(s, 1H), 8.49 (d, J=5.2Hz, 1H), 10.24 (s, 1H).

Wherein another product N-(4-(7-(3-(1-cyclopropyl methanesulfonate-1-yl)propoxy)-6-methoxyquinolin-4-yloxy )-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide as pale yellow solid. the

MS (ESI, pos.ion) m/z: 664.2 (M+1) _{; LC} -MS Rt: _4.563 min; Exact mass calculated for _C34H34FN3O8S : 663.21

¹ H NMR (400MHz, CDCl ₃ ): δ0.78(m, 2H), 1.30(m, 2H), 1.60(m, 2H), 1.85(m, 2H), 2.11(m, 2H), 2.25(m , 2H), 3.06(s, 3H), 4.03(s, 3H), 4.28(m, 2H), 6.41(d, J=4.8Hz, 1H), 7.22(m, 2H), 7.27(m, 3H) , 7.39 (m, 2H), 7.49 (d, J=8Hz, 1H), 7.57 (s, 1H), 7.79 (d, J=12Hz, 1H), 7.94 (s, 1H).

Example 28

N-(4-(7-(3-(1-hydroxycyclopropyl)propoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4 -Fluorophenyl)cyclopropane-1,1-dicarboxamide

The title compound was prepared by the synthetic method of Example 9 using N-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4- Fluorophenyl)cyclopropane-1,1-dicarboxamide (300mg, 0.594mmol), 3-(1-hydroxycyclopropyl)propyl methanesulfonate (155mg, 0.80mmol), and Cs ₂ CO ₃ ( 581 mg, 1.782 mmol) was suspended in 3 mL DMA. The residue was purified by silica gel column chromatography (6:1 (v/v) ethyl acetate/n-hexane) to obtain the title compound as a white solid (247 mg, 69%).

MS (ESI, pos.ion) m/z: 604.2 (M+1); _LC - _{MS Rt} : 4.240 min; _Exact mass calculated for _C33H31F2N3O6 : 603.22

¹ H NMR (400MHz, CDCl ₃ ): δ0.46(m, 2H), 0.75(m, 2H), 1.64(m, 2H), 1.83(m, 4H), 2.22(m, 2H), 4.03(s , 3H), 4.31(m, 2H), 6.41(m, 1H), 7.08(m, 2H), 7.25(m, 1H), 7.46-7.79(m, 5H), 8.19(s, 1H), 8.49( d, J = 5.2 Hz, 1H), 10.00 (s, 1H).

Example 29

N-(3-fluoro-4-(7-(1-(1-hydroxycyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)phenyl)-N-(4 -Fluorophenyl)cyclopropane-1,1-dicarboxamide

The title compound was prepared by the synthesis method of Example 5 to obtain a white solid. the

MS (ESI, pos.ion) m/z: 576.2 (M+1); LC-MS Rt: 3.167min;

¹ H NMR (400MHz, CDCl ₃ ): δ0.767(m, 2H), 1.008(m, 2H), 1.637(m, 2H), 1.807(m, 2H), 4.040(s, 3H), 4.202(s , 2H), 6.397-6.409(d, J=4.8Hz, 1H), 7.047-7.088(d, J=4.8Hz, 2H), 7.222-7.243(d, J=4.8Hz, 1H), 7.410(s, 1H), 7.447-7.478(t, J=6Hz, 2H), 7.580(s, 1H), 7.761-.791(d, J=12Hz, 1H), 8.427(s, 1H), 8.474-8.487(d, J=5.2Hz, 1H), 10.119(s, 1H).

Example 30

N-(3-fluoro-4-(7-(1-(1-hydroxycyclopropyl)methoxy)quinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)ring Propane-1,1-dicarboxamide

The title compound was prepared by the synthesis method of Example 5 to obtain a white solid. the

MS (ESI, pos.ion) m/z: 566.2 (M+1); LC-MS Rt: 3.330min;

¹ H NMR (400MHz, d-DMSO): δ0.680(m, 2H), 0.718(m, 2H), 1.464(s, 4H), 4.138(s, 2H), 6.411-6.423(d, J=4.8 Hz, 1H), 7.118-7.162(t, J=8.8Hz, 2H), 7.319-7.342(d, J=9.2Hz, 1H), 7.391-7.436(t, J=9.2Hz, 2H), 7.494-7.517 (d, J = 9.2Hz, 1H), 7.612-7.644 (q, J ₁ = 7.6Hz, J ₂ = 5.2Hz, 2H), 7.871-7.904 (d, J = 13.2Hz, 1H), 8.202-8.225 ( d, J=9.2Hz, 1H), 8.580-8.596(d, J=6.4Hz, 1H), 9.990(s, 1H), 10.372(s, 1H).

Example 31

N-(3-fluoro-4-(7-(1-(1-hydroxycyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)phenyl)-1,5- Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbamoyl

The title compound was prepared by the synthesis method of Example 5 to obtain a white solid. the

MS (ESI, pos.ion) m/z: 585.3 (M+1); LC-MS Rt: 3.069min;

¹ H NMR (400MHz, CDCl ₃ ): δ0.764-0.795(t, J=6Hz, 2H), 1.007-1.039(t, J=6.4Hz, 2H), 2.829(s, 3H), 3.404(s, 3H), 4.069(s, 3H), 4.226(s, 2H), 6.455-6.468(d, J=5.2Hz, 1H), 7.181-7.224(t, J=8.4Hz, 2H), 7.324-7.352(d , J=11.2Hz, 1H), 7.383-7.421(m, 3H), 7.492-7.532(t, J=9.6Hz, 1H), 7.576-7.626(m, 3H), 7.930-7.967(dd, J ₁ = 12.4Hz, J ₂ =2.4Hz, 1H), 8.497-8.510(d, J=5.2Hz, 1H), 10.909(s, 1H).

Example 32

N-(3-fluoro-4-(7-(2-(1-hydroxycyclopropyl)ethoxy)-6-methoxyquinolin-4-yloxy)phenyl)-1,5- Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbamoyl

The title compound was prepared by the synthesis method of Example 4 to obtain a white solid. the

MS (ESI, pos.ion) m/z: 599.2 (M+1); LC-MS Rt: 3.283min;

¹ H NMR (400MHz, CDCl ₃ ): δ0.53(m, 2H), 0.60(m, 2H), 2.03(t, J=6.4Hz, 2H), 2.72(s, 3H), 3.41(s, 3H ), 3.95(s, 3H), 4.36(t, J=7.2Hz, 2H), 6.47(d, J=4.4Hz, 1H), 7.35-7.47(m, 5H), 7.53(m, 2H), 7.61 (t, J = 7.2Hz, 2H), 7.99 (dd, _J1 = 2.4Hz, _J2 = 13.2Hz, 1H), 8.48 (d, J = 5.2Hz, 1H), 10.99 (s, 1H).

Example 33

N-(3-fluoro-4-(7-(2-(1-hydroxycyclopropyl)ethoxy)-6-methoxyquinolin-4-yloxy)phenyl)-N-(4 -Fluorophenyl)cyclopropane-1,1-dicarboxamide

The title compound was prepared by the synthesis method of Example 4 to obtain a white solid. the

MS (ESI, pos.ion) m/z: 590.2 (M+1); LC-MS Rt: 3.280min;

¹ H NMR (400MHz, CDCl ₃ ): δ0.58(m, 2H), 0.85(m, 2H), 1.64(m, 2H), 1.82(m, 2H), 2.18(t, J=6.0Hz, 2H ), 4.03(s, 3H), 4.88(t, J=5.6Hz, 2H), 6.42(d, J=5.2Hz, 1H), 7.08(t, J=8.8Hz, 2H), 7.23(t, J =8.4Hz, 1H), 7.47(t, J=6.4Hz, 3H), 7.59(m, 1H), 7.77(dd, J ₁ =2.0Hz, J ₂ =12Hz, 1H), 8.37(s, 1H) , 8.49 (d, J=5.2Hz, 1H), 10.04 (s, 1H).

Example 34

N-(3-fluoro-4-(7-(2-(1-hydroxycyclopropyl)ethoxy)quinolin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1 -Dicarboxamide

The title compound was prepared by the synthesis method of Example 4 to obtain a white solid. the

MS (ESI, pos.ion) m/z: 542.2 (M+1); LC-MS Rt: 3.225min;

¹ H NMR (400MHz, CD ₃ OD): δ0.63(t, J=5.6Hz, 2H), 0.78(t, J=5.6Hz, 2H), 1.67(s, 4H), 2.15(t, J= 6.8Hz, 2H), 4.44(t, J=6.8Hz, 2H), 6.51(d, J=5.6Hz, 1H), 7.16(t, J=7.2Hz, 1H), 7.32-7.47(m, 6H) , 7.58(d, J=8.0Hz, 2H), 7.85(m, 1H), 8.32(d, J=9.2Hz, 1H), 8.56(d, J=5.2Hz, 1H).

Example 35

N-(3-fluoro-4-(7-(2-(1-hydroxycyclopropyl)ethoxy)quinolin-4-yloxy)phenyl)-1,5-dimethyl-3- Oxy-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

The title compound was prepared by the synthesis method of Example 5 to obtain a white solid. the

MS (ESI, pos.ion) m/z: 633.1 (M+1); (ESI, nat. ion) m/z: 631.1 (M-1); LC-MS Rt: 4.178min; C ₃₂ H ₂₉ FN Calculated exact mass _{of 4O7S :} 632.1

¹ H NMR (400MHz, CDCl ₃ ): δ1.09(t, J=7.2Hz, 2H), 1.54(t, J=6.8Hz, 2H), 2.80(s, 3H), 3.07(s, 3H), 4.45(s, 2H), 6.43(d, J=4.2Hz, 2H), 7.17(t, J=8.8Hz, 1H), 7.27-7.32(m, 2H), 7.36-7.40(dd, J=0.2Hz , 3H), 7.49(d, J=7.2Hz, 1H), 7.57(t, J=8Hz, 2H), 7.90-7.94(dd, J=2.4Hz, 1H), 8.31(d, J=4.2Hz, 1H), 8.60 (d, J = 4.2 Hz, 1H).

biological test

The following experiments are mainly used to confirm the efficacy of the compounds of the present invention as inhibitors of tyrosine kinase receptors such as c-Met, KDR and/or IGF1R-related activities and as antitumor drugs in xenograft animal models. the

MTT cell assay

Preparation instructions: MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)) is soluble in water (10mg/ml), ethanol (20mg /ml) and buffered saline solution and culture medium (5mg/ml). the

MTT solution: 5mg/ml MTT was added to PBS (phosphate buffered saline). The solution must be filter sterilized after addition of MTT. the

MTT solvent: a solution obtained by adding 4mM HCl, 0.1% Nonidet P-40 (NP40) to isopropanol. the

experiment procedure:

Short 96-well plate assay: At least three replicates or more for each data point. the

1. Day 1: Digest the cells with trypsin in a T-25 flask and add 5ml of complete medium to the digested cells. Place in a 15ml sterilized centrifuge tube and centrifuge at 500rpm (about 400×g) for 5 minutes using a swinging bucket rotor. the

2. Remove the culture medium, and then suspend the cells in 1.0ml of complete culture medium. the

3. Perform a cell count and record the number of cells per milliliter. Cells should be aseptically removed before reading.

4. Dilute the cell suspension (cv=cv) to 75,000 cells per milliliter with complete culture medium. the

5. Add 100 μl of cell suspension (7500 cells in total) to each well and incubate overnight. the

6. Day 2: The cells are treated with antagonists, inhibitors or drugs. the

- If the culture medium is removed, great care must be taken, otherwise the data will be greatly skewed. the

- The final volume should be 100 μl per well. the

7. The third day: Add 20 μl MTT (5 mg/ml) to each well, including a group of wells with MTT but no cells (blank control), all operations must be performed under sterile conditions. the

8. Incubate in an incubator at 37°C for 3.5 hours. the

9. Remove the culture medium very carefully, do not disturb the cells, and do not wash with PBS. the

10. Add 150 μl of MTT solvent. the

11. Cover with tin foil and shake the cells on an orbital shaker for 15 minutes. the

12. Read the absorbance at 590nm with a 620nm standard filter. the

Table 1 MTT assay results

Kinase activity assay

MET kinase activity assay

Met(h) was incubated with 8mM MOPS pH 7.0, 0.2mM EDTA, 250μM KKKSPGEYVNIEFG, 10mM magnesium acetate and [γ- ³³ P-ATP]P-ATP] (specific activity close to 500cpm/pmol, the concentration is the desired concentration). Add the MgATP mixture to start the reaction. After 40 minutes of incubation at room temperature, 3% phosphoric acid solution was added to stop the reaction. 10 μL of the reaction solution was added to the P30 detection plate, washed three times with 75 mM phosphoric acid and once with methanol before drying, and read by scintillation counting.

IGF-1R Kinase Activity Assay

IGF1R(h) was mixed with 50mM Tris pH 7.5, 0.1mM EDTA, 0.1mM Na ₃ VO ₄ , 0.1%-mercaptoethanol, 250μM KKKSPGEYVNIEFG, 10mM MnCl ₂ , 10mM magnesium acetate and [γ- ^33P -ATP] (the specific activity was close to 500cpm/pmol, the concentration is the desired concentration) and incubated together. Add the MgATP mixture to start the reaction. After 40 minutes of incubation at room temperature, 3% phosphoric acid solution was added to stop the reaction. 10 μL of the reaction solution was added to the P30 detection plate, washed three times with 75 mM phosphoric acid and once with methanol before drying, and read by scintillation counting.

KDR kinase activity assay

KDR(h) with 8mM MOPS pH 7.0, 0.2mM EDTA, 0.33mg/mL myelin basic protein, 10mM magnesium acetate and [γ- ^33P -ATP] (specific activity close to 500cpm/pmol, at the desired concentration) Co-incubate. Add the MgATP mixture to start the reaction. After 40 minutes of incubation at room temperature, 3% phosphoric acid solution was added to stop the reaction. 10 μL of the reaction solution was added to the P30 detection plate, washed three times with 75 mM phosphoric acid and once with methanol before drying, and read by scintillation counting.

The assay methods described above can be used to determine the _IC50 value or the inhibition constant _K1 of the inhibitory effect. The _IC50 value refers to the concentration of the compound required to inhibit 50% of the enzymatic activity under the conditions of the assay. The _IC50 value of the exemplary composition is, for example, less than 100 μM, less than 10 μM, less than 1 μM. Further examples include _IC50 Values are less than 100 nM, a further example is less than 10 nM.

Determination of certain kinase activities can be accomplished through commercial services, such as the KinaseProfiler ^™ /IC ₅₀ Profiler ^™ service of Millpore/upstate Corporation.

Table 2 Kinase inhibitory activity*

Example Met (IC ₅₀ , nM) KDR (IC ₅₀ , nM) IGF-1R (IC ₅₀ , nM) 2 9 9 2304 3 11 NT NT 4 4 5 1488 6 7 11 177 7 8 15 2321 8 8 NT NT 11 13 NT NT

13 3 8 479 14 7 6 145 15 6 5 57 17 8 15 NT 18 2 4 93 twenty one 10 13 NT twenty two 4 10 NT twenty three 4 8 NT twenty four 5 NT NT 27 6 10 NT 28 3 4 NT 29 8 61 NT 30 3 5 NT 31 8 6 205 32 18 13 341 33 5 6 NT 34 3 5 NT 35 8 7 862

*The kinase inhibitory activity in Table 2 was determined by commissioning the KinaseProfiler ^TM /IC ₅₀ Profiler ^TM service of Millpore/upstate Company, in which the ATP concentration was 10 μM; NT: indicates that the activity was not measured.

Tumor xenograft model

Human glioma tumor cells (U87MG cells, ATCC) were grown in culture, harvested and subcutaneously injected into 6-7-week-old female nude mice (BALB/cA-nude, Shanghai Slack Experimental Animal Co., Ltd.) (n=8). Then, the compound of the present invention was administered orally by gavage (10-100 mpk/dose), and after the tumor grew to 60-150 mm ³ , the animals were randomly divided into groups (d0). The tumor volume was measured 2-3 times a week, the mice were weighed, and the data was recorded.

Human lung cancer tumor cells (NCI-H441 cells) were grown in culture, harvested and injected subcutaneously into 6-7 week old female nude mice (BALB/cA-nude, Shanghai Slack Experimental Animal Co., Ltd.) (n= 8). Then, the compound of the present invention is carried out oral gavage (10-100mpk/dose) administration to it, and after the tumor grows to ^100-250mm , the animals are randomly divided into groups, and the tumor volume is measured 2-3 times a week, which is called Mouse weight, record data.

The formula for calculating the tumor volume (V) is:

V=1/2×a×b ²

T/C(%)＝(TT ₀ )/(CC ₀ )×100

Tumor inhibition rate (%TGI)＝100-T/C(%)

Wherein, a and b represent the length and width respectively; T and C are the tumor volumes at the end of the experiment; T ₀ and C ₀ are the tumor volumes at the beginning of the experiment.

The evolution of tumor growth is tracked and measured by three-dimensional calipers and the results are reported in a time-recorded manner. The original statistical analysis was done by repeated measures analysis of variance (RMANOVA) followed by Scheffe's multiple post hoc comparisons. Vehicle alone (2% HPMC+1% Tween80, etc.) served as a negative control. In the tumor xenograft model of U87MG cells or NCI-H441 cells in Examples 13 and 14, after 21 days of administration at a dose of 30 mg/kg, the tumor inhibition rate (%TGI) was not less than 60%; Example 29 in MKN In the -45 cell tumor xenograft model, after 18 days of administration with a dosage of 30 mg/kg, its tumor inhibition rate (%TGI) was about 53%; in Example 35, in the MKN-45 cell tumor xenograft model, with After 21 days of administration at a dose of 20 mg/kg, the tumor inhibition rate (%TGI) is about 55%. the

Claims (39)

1. A compound as shown in formula I:

or its stereoisomers, geometric isomers, tautomers, nitrogen oxides or pharmaceutically acceptable salts thereof, wherein: _Q represents formula (IIa):

_Q represents formula (III):

R ¹ is selected from hydroxyl substituted cyclopropylalkoxy, R ⁵ S(=O) ₂ O-substituted cyclopropylalkoxy, spirobicyclyl, spiroheterobicyclyl, spirobicyclyl aliphatic, spirohetero Bicyclylaliphatic, spirobicyclyloxy, spirobicyclylamino, spirobicyclyloxyalkoxy, spiroheterobicyclyloxyalkoxy, spirobicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy Base, spirobicyclyl-C(=O)-, spirobicyclyl-C(=O)O-, spiroheterobicyclyl-C(=O)-, spiroheterobicyclyl-C(=O)O-, Spirobicyclylamino-C(=O)-, spiroheterobicyclylamino-C(=O)-, spirobicyclyl-C(=O)NR ⁵ - or spiroheterobicyclyl-C(=O)NR ⁵ -, or ^R is selected from the following structural formulas:

wherein X ₄ and X ₄ ' are each independently selected from (CR ⁴ R ^4a ) _m , NR ⁵ , O, S, S=O or SO ₂ ; m and n each independently represent 0, 1 or 2; and t represents 1, 2 or 3. R ² is selected from H, halogen, cyano, hydroxyl, R ^5a R ⁵ N-, -C(=O)NR ⁵ R ^5a , -OC(=O)NR ⁵ R ^5a , -OC(=O)OR ⁵ , -NR ⁵ C(=O)NR ⁵ R ^5a , -NR ⁵ C(=O)OR ^5a , -NR ⁵ C(=O)-R ^5a , R ⁵ R ^5a NO ₂ S-, R ⁵ O ₂ S-, R ⁵ O ₂ SR ^5a N-, R ^5a R ⁵ N-alkyl, R ⁵ (S=O)-alkyl, R ⁵ R ^5a N-(C=O)-alkyl, R ^5a R ⁵ N-alkoxy, R ⁵ (S=O)-alkoxy, R ⁵ R ^5a N-(C=O)-alkoxy, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy radical, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylaminohaloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkyl Oxy, Heterocyclylalkoxy, Carbocyclylalkoxy, Heterocyclyl(hydroxyalkoxy), Carbocyclyl(hydroxyalkoxy), Aryl(hydroxyalkoxy), Aryloxyalkoxy Oxygen, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy, azidoalkoxy, fused bicyclyl, fused Heterobicyclyl, fused bicyclylaliphatic, fused heterobicyclylaliphatic, fused bicyclyloxy, fused heterobicyclyloxy, fused bicyclylamino, fused heterobicyclylamino, fused Bicyclyloxyalkoxy, fused heterobicyclyloxyalkoxy, fused bicyclylaminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(=O)-, Fused bicyclyl-C(=O)O-, fused heterobicyclyl-C(=O)-, fused heterobicyclyl-C(=O)O-, fused bicyclylamino-C(=O )-, fused heterobicyclylamino-C(=O)-, fused bicyclyl-C(=O)NR ⁵ -, fused heterobicyclyl-C(=O)NR ^5- , spirobicyclyl, Spirobicyclyl, spirobicyclylaliphatic, spirobicyclylaliphatic, spirobicyclyloxy, spiroheterobicyclyloxy, spirobicyclylamino, spiroheterobicyclylamino, spirobicyclyloxyalkoxy , spirobicyclyloxyalkoxy, spirobicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spirobicyclyl-C(=O)-, spirobicyclyl-C(=O)O- , spiroheterobicyclyl-C(=O)-, spiroheterobicyclyl-C(=O)O-, spirobicyclylamino-C(=O)-, spiroheterobicyclylamino-C(=O)- , spirobicyclyl-C(=O)NR ⁵ -, spiroheterobicyclyl-C(=O)NR ^5- , aryl, heteroaryl, aryl aliphatic or heteroaryl aliphatic, wherein the above Each of the mentioned alkoxy and alkylamino moieties may be independently substituted with one or more hydroxyl, amino or substituted amino groups; ^R is selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, R ^5a R ⁵ N-, aliphatic, alkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, Cycloalkylaliphatic, cycloalkylalkoxy or heterocyclylalkoxy; U ₁ and U ₂ are each independently selected from CR ⁴ or N; V ₁ is selected from O or NR ⁵ ; V ₂ , V ₃ and V ₄ are each independently selected from CR ⁴ R ^4a , NR ⁵ , CR ⁴ or N; provided that only one of V ₂ , V ₃ and V ₄ can be selected from NR ⁵ or N, or V ₂ and V ₃ or V ₃ and V ₄ can be combined into the form of CR ⁴ R ^4a , NR ⁵ , O, CR ⁴ or N, provided that the final structural formula is a chemically stable structural formula; W ₁ , W ₂ , W ₃ and W ₄ are each independently selected from CR ⁴ R ^4a , NR ⁵ , CR ⁴ or N, or W ₁ and W ₂ or W ₃ and W ₄ can be combined into CR ⁴ R ^4a , NR ^5. In the form of O or S; X ₁ is selected from (CR ⁴ R ^4a ) _m , NR ⁵ , O, S, S═O or SO ₂ ; and m is 0, 1 or 2; X ₂ is selected from O, S or NR ⁵ ; Z is selected from -NR ⁵ C(=O)-(CR ⁴ R ^4a ) _p -, -NR ⁵ C(=S)-(CR ⁴ R ^4a ) _p -, -NR ^5a -(CR ⁴ R ^4a ) _p -, -NR ⁵ -(CR ⁴ R ^4a ) _p C(=O)-, -NR ⁵ -(CR ⁴ R ^4a ) _p C(=S)-, -NR ⁵ S(=O) _r --NR ⁵ S(=O) _r (CR ⁴ R ^4a ) _p -, -C(=O)NR ⁵ (CR ⁴ R ^4a ) _p -or -NR ⁵ -(CR ⁴ R ^4a ) _p S(=O) _r -, wherein p is 0, 1, 2 or 3; and r is 1 or 2; R ⁴ and R ^4a are each independently selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, -NR ^5a R ⁵ , alkoxy, cycloalkyloxy, heterocyclylalkoxy, aliphatic , Halogenated aliphatic, hydroxy aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, aryl aliphatic, heterocyclyl aliphatic, cycloalkyl aliphatic, aryl oxygen aliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or Carbocyclyl; wherein, when R ⁴ and R ^4a are connected to the same carbon atom, R ⁴ , R ^4a and the carbon atom can optionally form a substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ring; R ⁵ and R ^5a are each independently selected from hydrogen, R ⁶ R ^6a NC(=O)-, R ⁶ OC(=O)-, R ⁶ C(=O)-, R ⁶ R ^6a NS(=O) -, R ⁶ OS(=O)-, R ⁶ S(=O)-, R ⁶ R ^6a NSO ₂ -, R ⁶ OSO ₂ -, R ⁶ SO ₂ -, aliphatic, halogenated aliphatic, hydroxyaliphatic Aliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxy aliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl; when ^R5 and R ^5a is connected to the same nitrogen atom, and R ⁵ , R ^5a and the nitrogen atom can optionally form a substituted or unsubstituted 3-8 membered ring, including spirobicyclic and fused bicyclic rings; and R ^and R ^are each independently selected from the group consisting of H, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, Heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylamino Aliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl; Each of the substituents such as: R ^5a R ⁵ N-, -C(=O)NR ⁵ R ^5a , -OC(=O)NR ⁵ R ^5a , -OC(=O)OR ⁵ , -NR ⁵ C( =O)NR ⁵ R ^5a , -NR ⁵ C(=O)OR ^5a , -NR ⁵ C(=O)-R ^5a , R ⁵ R ^5a NO ₂ S-, R ⁵ O ₂ S-, R ⁵ O ₂ SR ^5a N-, OR ⁵ , NR ⁵ , CR ⁴ R ^4a , CR ⁴ , (CR ⁴ R ^4a ) _m , -NR ⁵ C(O)-(CR ⁴ R ^4a ) _p -, -NR ⁵ C( =S)-(CR ⁴ R ^4a ) _p -, -NR ^5a -(CR ⁴ R ^4a ) _p -, -NR ⁵ -(CR ⁴ R ^4a ) _p C(=O)-, -NR ⁵ -(CR ⁴ R ^4a ) _p C(=S)-, -NR ⁵ S(O) _r -, -NR ⁵ S(=O)(CR ⁴ R ^4a ) _p -, -C(=O)NR ⁵ -(CR ⁴ R ^4a ) _p -, -NR ⁵ -(CR ⁴ R ^4a ) _p -S(=O) _r -, R ^5a R ⁵ N-alkyl, R ⁵ (S=O) _r -alkyl, R ⁵ R ^5a N-(C=O)-C _1-6 alkyl, R ^5a R ⁵ NC _1-6 alkoxy, R ⁵ (S=O)-alkoxy, R ⁵ R ^5a N-(C= O)-alkoxy, R ⁶ R ^6a NC(=O)-, R ⁶ OC(=O)-, R ⁶ C(=O)-, R ⁶ R ^6a NS(=O)-, R ⁶ OS (=O)-, R ⁶ S(=O)-, R ⁶ R ^6a NSO ₂ -, R ⁶ OSO ₂ -, R ⁶ SO ₂ -, hydroxy-substituted cyclopropylalkoxy, R ⁵ S(= O) ₂ O-substituted cyclopropylalkoxy, R ^5a R ⁵ N-aliphatic, haloalkyl, heterocyclylalkyl, cycloalkyl, cycloalkyloxyaliphatic, cycloalkylalkoxy , aryloxyalkyl, heteroaryloxyaliphatic, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, Alkylaminohaloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl ( hydroxyalkoxy), carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxy Alkoxy, heterocyclyloxy, cycloalkyloxy, azidoalkoxy, fused bicyclyl, fused heterobicyclyl, fused bicyclylaliphatic, fused heterobicyclylaliphatic family, fused bicyclyloxy, fused heterobicyclyloxy, fused bicyclylamino, fused heterobicyclylamino, fused bicyclyloxyalkoxy, fused heterobicyclyloxyalkoxy , Fused bicyclylaminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(=O)-, fused bicyclyl-C(=O)O-, fused heterobicyclyl -C(=O)-, fused heterobicyclyl-C(=O)O-, fused bicyclylamino-C(=O)-, fused heterobicyclylamino-C(=O)-, fused Fused bicyclyl-C(=O)NR ⁵ -, fused heterobicyclyl-C(=O)NR ^5- , spirobicyclyl, spiroheterobicyclyl, spirobicyclyl aliphatic, spiroheterobicyclyl aliphatic, Spirobicyclyloxy, spiroheterobicyclyloxy, spirobicyclylamino, spiroheterobicyclylamino, spirobicyclyloxyalkoxy, spiroheterobicyclyloxyalkoxy, spirobicyclylaminoalkoxy , spiroheterobicyclylaminoalkoxy, spirobicyclyl-C(=O)-, spirobicyclyl-C(=O)O-, spiroheterobicyclyl-C(=O)-, spiroheterobicyclyl- C(=O)O-, spirobicyclylamino-C(=O)-, spiroheterobicyclylamino-C(=O)-, spirobicyclyl-C(=O)NR ⁵ -, or spiroheterobicyclo -C(=O)NR ⁵ -, aryl, heteroaryl, arylaliphatic, heteroarylaliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylamino Aliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylamino Aliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, heterocyclyl, and carbocyclyl groups can all be independently substituted or unsubstituted substituents. 2. The compound according to claim 1, wherein R ³ is selected from H, F, Cl, Br, -CN, C _1-3 aliphatic, C _1-3 alkoxy or C _1-3 haloalkyl. 3. The compound according to claim 1, wherein _Q is selected from the following substructural formulas:

wherein R ^3a is independently selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, R ^5a R ⁵ N-, R ^5a R ⁵ N-aliphatic, hydroxyaliphatic, aliphatic, alkoxy, alkane Oxyaliphatic, Haloalkyl, Heterocyclyl, Heterocyclylalkyl, Cycloalkyl, Cycloalkyloxyaliphatic, Heterocyclyloxyaliphatic, Cycloalkylalkoxy, Heterocyclylalkoxy radical, aryloxyalkyl, heteroaryloxyaliphatic, arylaliphatic, heteroarylaliphatic, aryl or heteroaryl. 4. The compound according to claim 1, wherein _Q is selected from the following substructural formulas:

5. The compound according to claim 1, wherein _X1 is selected from O or ^NR5 . 6. The compound according to claim 1, wherein Z in formula (IIa) is -NHC(=O)-; X ₁ , U ₁ and R ³ in formula (I) jointly define a substructure selected from The following structural formula:

7. The compound according to any one of claims 1-6, wherein: R ¹ is selected from hydroxyl substituted cyclopropyl C _1-6 alkoxy, R ⁵ S(=O) ₂ O-substituted cyclopropyl C _1-6 alkoxy, C _5-12 spiro bicyclyl, C _5-12 spiro heterobicyclyl, C _5-12 spiro bicyclyl C _1-6 aliphatic, C _5-12 spiro heterobicyclyl C _1-6 aliphatic, C _5-12 spiro heterobicyclyl oxy C _{1- 6} alkoxy, C _5-12 spiro heterobicyclylamino C _1-6 alkoxy, C _5-12 spiro bicyclyl-C(=O)-, C _5-12 spirobicyclyl-C(=O) O-, C _5-12 spiroheterobicyclyl-C(=O)-, C _5-12 spiroheterobicyclyl-C(=O)O-, C _5-12 spirobicyclylamino-C(=O) -, C _5-12 spiroheterobicyclylamino-C(=O)-, C _5-12 spirobicyclyl-C(=O)NR ⁵ - or C _5-12 spiroheterobicyclyl-C(=O) NR ⁵ -; and R ² is selected from hydrogen, halogen, cyano, R ^5a R ⁵ N C _1-6 alkoxy, optionally substituted C _1-6 alkoxy, C _1-6 hydroxyalkoxy, C _1-6 aminoalkane Oxygen, C _1-6 hydroxy substituted aminoalkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy radical, C _4-10 heterocyclyloxy C _1-6 alkoxy, C _5-12 fused bicyclyl, C _5-12 fused bicyclyl C _1-6 aliphatic, C _5-12 fused hetero Bicyclyl C _1-6 aliphatic, C _5-12 fused bicyclyloxy, C _5-12 fused bicyclylamino, C _5-12 fused bicyclyloxy C _1-6 alkoxy, C _{5 -12} fused bicyclylamino C _1-6 alkoxy, C _5-12 fused bicyclyl-C(=O)-, C _5-12 fused bicyclyl-C(=O)O-, C _{5 -12} fused heterobicyclyl-C(=O)-, C _5-12 fused heterobicyclyl-C(=O)O-, C _5-12 fused bicyclylamino-C(=O)-, C _5-12 fused heterobicyclylamino-C(=O)-, C _5-12 fused bicyclyl-C(=O)NR ⁵ -, C _5-12 fused heterobicyclyl-C(=O ) NR ⁵ -, C _5-12 spirobicyclyl, C _5-12 spirobicyclyloxy, C _5-12 spirobicyclylamino, C _5-12 spirobicyclyloxy C _1-6 alkoxy, C _5-12 spirobicyclyl amino C _1-6 alkoxy, C _5-12 fused heterobicyclyl, C _5-12 fused heterobicyclyloxy, C _5-12 fused heterobicyclylamino, C _{5 -12} fused heterobicyclyloxy C _1-6 alkoxy, C _5-12 fused heterobicyclylamino C _1-6 alkoxy, C _5-12 spiro heterobicyclyl, C _5-12 spirobicyclic Base C _1-6 aliphatic, C _5-12 spiro heterobicyclyl C _1-6 aliphatic, C _5-12 spiro heterobicyclyloxy C _1-6 alkoxy, C _5-12 spiro heterobicyclyl amino C _1-6 alkoxyl group, C _5-12 spirobicyclyl-C(=O)-, C _5-12 spirobicyclyl-C(=O)O-, C _5-12 spiroheterobicyclyl-C( =O)-, C _5-12 spiroheterobicyclyl-C(=O)O-, C _5-12 spirobicyclylamino-C(=O)-, C _5-12 spiroheterobicyclylamino-C( =O)-, C _5-12 spirobicyclyl-C(=O)NR ⁵ - and C _5-12 spiroheterobicyclyl-C(=O)NR ⁵ -, C _6-10 aryl, C _{1- 10} heteroaryl, C _6-10 aryl C _1-6 aliphatic or C _1-10 heteroaryl C _1-6 aliphatic. 8. The compound according to claim 1, wherein X ₁ , U ₁ and R ³ in formula (I) jointly define substructures selected from the following structural formulas:

Q ₁ stands for

Wherein Ar is a substituted or unsubstituted aryl group; Q ₂ stands for

^R1 is

Wherein X ₄ and X ₄ ' are each independently selected from O, and t is 3; ^R2 is hydrogen; Z is -NHC(=O)-; R ^3a is selected from aliphatic; and ^R5 and ^R5a are each independently selected from H, aliphatic or aryl. 9. The compound according to claim 1, comprising one of the following structures:

Or its stereoisomers, geometric isomers, tautomers, nitrogen oxides or pharmaceutically acceptable salts. 10. The compound according to claim 1, comprising one of the following structures:

Or its stereoisomers, geometric isomers, tautomers, nitrogen oxides or pharmaceutically acceptable salts. 11. A compound as shown in formula (V):

or its stereoisomers, geometric isomers, tautomers, nitrogen oxides or pharmaceutically acceptable salts thereof, wherein: _Q represents formula (III): R ¹ is selected from hydroxyl substituted cyclopropylalkoxy, R ⁵ S(=O) ₂ O-substituted cyclopropylalkoxy, spirobicyclyl, spiroheterobicyclyl, spirobicyclyl aliphatic, spirohetero Bicyclylaliphatic, spirobicyclyloxy, spirobicyclylamino, spirobicyclyloxyalkoxy, spiroheterobicyclyloxyalkoxy, spirobicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy Base, spirobicyclyl-C(=O)-, spirobicyclyl-C(=O)O-, spiroheterobicyclyl-C(=O)-, spiroheterobicyclyl-C(=O)O-, Spirobicyclylamino-C(=O)-, spiroheterobicyclylamino-C(=O)-, spirobicyclyl-C(=O)NR ⁵ - or spiroheterobicyclyl-C(=O)NR ⁵ -, or ^R is selected from the following structural formulas:

wherein X ₄ and X ₄ ' are each independently selected from (CR ⁴ R ^4a ) _m , NR ⁵ , O, S, S=O or SO ₂ ; m and n each independently represent 0, 1 or 2; and t represents 1, 2 or 3. R ² is selected from H, halogen, cyano, hydroxyl, R ^5a R ⁵ N-, -C(=O)NR ⁵ R ^5a , -OC(=O)NR ⁵ R ^5a , -OC(=O)OR ⁵ , -NR ⁵ C(=O)NR ⁵ R ^5a , -NR ⁵ C(=O)OR ^5a , -NR ⁵ C(=O)-R ^5a , R ⁵ R ^5a NO ₂ S-, R ⁵ O ₂ S-, R ⁵ O ₂ SR ^5a N-, R ^5a R ⁵ N-alkyl, R ⁵ S(=O)-alkyl, R ⁵ R ^5a NC(=O)-alkyl, R ^5a R ⁵ N -alkoxy, R ⁵ S(=O)-alkoxy, R ⁵ R ^5a NC(=O)-alkoxy, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substituted Aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylaminohaloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, hetero Cycloalkoxy, carbocyclylalkoxy, heterocyclyl (hydroxyalkoxy), carbocyclyl (hydroxyalkoxy), aryl (hydroxyalkoxy), aryloxyalkoxy, aryl Oxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy, azidoalkoxy, fused bicyclyl, fused heterobicyclyl , Fused Bicyclyl Aliphatic, Fused Heterobicyclyl Aliphatic, Fused Bicyclyloxy, Fused Heterobicyclyloxy, Fused Bicyclylamino, Fused Heterobicyclylamino, Fused Bicyclyloxy Alkoxy, fused heterobicyclyloxyalkoxy, fused bicyclylaminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(=O)-, fused bicyclyl -C(=O)O-, fused heterobicyclyl-C(=O)-, fused heterobicyclyl-C(=O)O-, fused bicyclylamino-C(=O)-, fused Heterobicyclylamino-C(=O)-, Fused Bicyclyl-C(=O)NR ⁵ -, Fused Heterobicyclyl-C(=O)NR ^5- , Spirobicyclyl, Spiroheterobicyclyl , spirobicyclylaliphatic, spiroheterobicyclylaliphatic, spirobicyclyloxy, spiroheterobicyclyloxy, spirobicyclylamino, spiroheterobicyclylamino, spirobicyclyloxyalkoxy, spiroheterobicyclo Baseoxyalkoxy, spirobicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spirobicyclyl-C(=O)-, spirobicyclyl-C(=O)O-, spiroheterobicyclyl Base-C(=O)-, spiroheterobicyclyl-C(=O)O-, spirobicyclylamino-C(=O)-, spiroheterobicyclylamino-C(=O)-, spirobicyclyl -C(=O)NR ⁵ -, spiroheterobicyclyl-C(=O)NR ⁵ -, aryl, heteroaryl, arylaliphatic or heteroarylaliphatic, wherein each of the above-mentioned An alkoxy and alkamino moiety may be independently substituted with one or more hydroxyl groups, amino groups or substituted amino groups; ^R is selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, R ^5a R ⁵ N-, aliphatic, alkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, Cycloalkylaliphatic, cycloalkylalkoxy or heterocyclylalkoxy; U ₁ and U ₂ are each independently selected from CR ⁴ or N; V is selected from NR ⁵ R ^5a , OR ⁵ , aliphatic, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylaliphatic or heteroarylaliphatic; W ₁ , W ₂ , W ₃ and W ₄ are each independently selected from CR ⁴ R ^4a , NR ⁵ , CR ⁴ or N, or W ₁ and W ₂ or W ₃ and W ₄ can be combined into CR ⁴ R ^4a , NR ^5. In the form of O or S; X ₁ is selected from (CR ⁴ R ^4a ) _m , NR ⁵ , O, S, S═O or SO ₂ ; and m is 0, 1 or 2; X ₂ and X ₃ are each independently selected from O, S or NR ⁵ ; Z ₁ and Z ₂ are each independently selected from NR ⁵ or CR ⁴ R ^4a ; R ⁴ and R ^4a are each independently selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, -NR ^5a R ⁵ , alkoxy, cycloalkyloxy, heterocyclylalkoxy, aliphatic , Halogenated aliphatic, hydroxy aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, aryl aliphatic, heterocyclyl aliphatic, cycloalkyl aliphatic, aryl oxygen aliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or Carbocyclyl; wherein, when R ⁴ and R ^4a are connected to the same carbon atom, R ⁴ , R ^4a and the carbon atom can optionally form a substituted or unsubstituted carbocyclic or heterocyclic ring with 3-8 atoms; R ⁵ and R ^5a are each independently selected from hydrogen, R ⁶ R ^6a NC(=O)-, R ⁶ OC(=O)-, R ⁶ C(=O)-, R ⁶ R ^6a NS(=O) -, R ⁶ OS(=O)-, R ⁶ S(=O)-, R ⁶ R ^6a NSO ₂ -, R ⁶ OSO ₂ -, R ⁶ SO ₂ -, aliphatic, halogenated aliphatic, hydroxyaliphatic Aliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxy aliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl; when ^R5 and R ^5a is connected to the same nitrogen atom, and R ⁵ , R ^5a and the nitrogen atom can optionally form a substituted or unsubstituted 3-8 membered ring, including spirobicyclic and fused bicyclic rings; and R ^and R ^are each independently selected from the group consisting of H, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, Heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylamino Aliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl; Each of the substituents such as: R ^5a R ⁵ N-, -C(=O)NR ⁵ R ^5a , -OC(=O)NR ⁵ R ^5a , -OC(=O)OR ⁵ , -NR ⁵ C( =O)NR ⁵ R ^5a , -NR ⁵ C(=O)OR ^5a , -NR ⁵ C(=O)-R ^5a , R ⁵ R ^5a NO ₂ S-, R ⁵ O ₂ S-, R ⁵ O ₂ SR ^5a N-, OR ⁵ , NR ⁵ , CR ⁴ R ^4a , CR ⁴ , (CR ⁴ R ^4a ) _m , -NR ⁵ C(O)-(CR ⁴ R ^4a ) _p -, -NR ⁵ C( =S)-(CR ⁴ R ^4a ) _p -, -NR ^5a -(CR ⁴ R ^4a ) _p -, -NR ⁵ -(CR ⁴ R ^4a ) _p C(=O)-, -NR ⁵ -(CR ⁴ R ^4a ) _p C(=S)-, -NR ⁵ S(O) _r -, -NR ⁵ S(=O)(CR ⁴ R ^4a ) _p -, -C(=O)NR ⁵ -(CR ⁴ R ^4a ) _p -, -NR ⁵ -(CR ⁴ R ^4a ) _p -S(=O) _r -, R ^5a R ⁵ N-alkyl, R ⁵ S(=O) _r -alkyl, R ⁵ R ^5a NC(=O)-C _1-6 alkyl, R ^5a R ⁵ NC _1-6 alkoxy, R ⁵ S(=O)-alkoxy, R ⁵ R ^5a NC(=O)-alk Oxygen, R ⁶ R ^6a NC(=O)-, R ⁶ OC(=O)-, R ⁶ C(=O)-, R ⁶ R ^6a NS(=O)-, R ⁶ OS(=O) -, R ⁶ S(=O)-, R ⁶ R ^6a NSO ₂ -, R ⁶ OSO ₂ -, R ⁶ SO ₂ -, hydroxy-substituted cyclopropylalkoxy, R ⁵ S(=O) ₂ O -Substituted cyclopropylalkoxy, R ^5a R ⁵ N-aliphatic, haloalkyl, heterocyclylalkyl, cycloalkyl, cycloalkyloxyaliphatic, cycloalkylalkoxy, aryloxy Alkyl, heteroaryloxyaliphatic, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylaminohaloalkoxy radical, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl (hydroxyalkoxy ), carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, Heterocyclyloxy, cycloalkyloxy, azidoalkoxy, fused bicyclyl, fused heterobicyclyl, fused bicyclyl aliphatic, fused heterobicyclyl aliphatic, Fused bicyclyloxy, fused heterobicyclyloxy, fused bicyclylamino, fused heterobicyclylamino, fused bicyclyloxyalkoxy, fused heterobicyclyloxyalkoxy, fused Condensed bicyclylaminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(=O)-, fused bicyclyl-C(=O)O-, fused heterobicyclyl-C (=O)-, fused heterobicyclyl-C(=O)O-, fused bicyclylamino-C(=O)-, fused heterobicyclylamino-C(=O)-, fused bicyclyl -C(=O)NR ⁵ -, fused heterobicyclyl-C(=O)NR ⁵ -, spirobicyclyl, spiroheterobicyclyl, spirobicyclylaliphatic, spiroheterobicyclylaliphatic, spirobicyclyl Baseoxy, spiroheterobicyclyloxyl, spirobicyclylamino, spiroheterobicyclylamino, spirobicyclyloxyalkoxy, spiroheterobicyclyloxyalkoxy, spirobicyclylaminoalkoxy, spirobicyclylaminoalkoxy, spirobicyclylaminoalkoxy Heterobicyclylaminoalkoxy, spirobicyclyl-C(=O)-, spirobicyclyl-C(=O)O-, spiroheterobicyclyl-C(=O)-, spiroheterobicyclyl-C( =O)O-, spirobicyclylamino-C(=O)-, spiroheterobicyclylamino-C(=O)-, spirobicyclyl-C(=O)NR ⁵ -, or spiroheterobicyclyl- C(=O)NR ⁵ -, aryl, heteroaryl, arylaliphatic, heteroarylaliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic , Alkylthioaliphatic, Arylaliphatic, Heterocyclylaliphatic, Cycloalkylaliphatic, Aryloxyaliphatic, Heterocyclyloxyaliphatic, Cycloalkyloxyaliphatic, Araminoaliphatic , heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, heterocyclyl, and carbocyclyl can all be independently substituted or unsubstituted substituents. 12. The compound according to claim 11, wherein R is ^selected from H, F, Cl, Br, -CN, C _1-3 aliphatic, C _1-3 alkoxy or C _1-3 haloalkyl. 13. The compound according to claim 11, wherein the substructures jointly defined by Z ₁ , Z ₂ , X ₂ , X ₃ and V in formula (V) are selected from the following structural formulas: wherein Ar represents substituted or unsubstituted aryl or heteroaryl; and s is 0 or 1. 14. The compound according to claim 11, wherein _Q is selected from the following structural formulas:

15. The compound according to claim 11, wherein _X1 is selected from O or ^NR5 . 16. The compound according to claim 11, wherein X ₁ , U ₁ and R ³ jointly define substructures selected from the following structural formulas:

17. The compound according to any one of claims 11-16, wherein ^R is selected from the following structural formulas:

wherein X ₄ and X ₄ ' are each independently selected from (CR ⁴ R ^4a ) _m , NR ⁵ , O, S, S=O or SO ₂ ; m and n each independently represent 0, 1 or 2; and t represents 1, 2 or 3. 18. The compound according to claim 11, wherein the substructure jointly defined by X ₁ , U ₁ and R ³ in formula (V) is selected from the following structural formulas:

Z ₁ , Z ₂ , X ₂ , X ₃ and V collectively define a substructure selected from Wherein Ar is a substituted or unsubstituted aryl group; Q ₂ stands for

^R1 is

Wherein X ₄ and X ₄ ' are each independently selected from O, and t is 3; ^R is hydrogen; and ^R5 and ^R5a are each independently selected from H, aliphatic or aryl. 19. The compound according to claim 11, comprising one of the following structures:

Or its stereoisomers, geometric isomers, tautomers, nitrogen oxides or pharmaceutically acceptable salts. 20. A pharmaceutical composition, comprising the compound according to claim 1, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof. 21. A pharmaceutical composition, comprising the compound according to claim 11, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof. 22. The pharmaceutical composition according to any one of claims 20-21, which further comprises additional therapeutic agents selected from chemotherapeutic drugs, antiproliferative agents, drugs for the treatment of atherosclerosis , a drug for treating pulmonary fibrosis, or a combination thereof. 23. The pharmaceutical composition according to claim 22, wherein said additional therapeutic agent is Adriamycin (Adriamycin), Rapamycin (Rapamycin), Temsirolimus, Everolimus (Everolimus), Ixabepilone, Gemcitabine ( Gemcitabin), Cyclophosphamide, Dexamethasone, Etoposide, Fluorouracil, Imatinib mesylate, Dasatinib, Ni Nilotinib, Erlotinib, Lapatinib, Iressa, Sorafenib, Sunitinib, Interferon ), Carboplatin, Topotecan, Paclitaxel, Vinblastine, Vincristine, Temozolomide, Tositumomab, Trabectedin, Bevacizumab, Hercep Trastuzumab, Cetuximab, Panitumumab, or a combination thereof. 24. A use of the compound of claim 1 to prepare medicines for preventing, treating, treating or alleviating proliferative diseases in patients. 25. A use of the compound of claim 11 to prepare medicines for preventing, treating, treating or alleviating proliferative diseases in patients. 26. The use according to any one of claims 24-25, wherein the proliferative disease is metastatic cancer. 27. The use according to any one of claims 24-25, wherein said proliferative disease is colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, brain tumor, neck cancer , prostate cancer, pancreatic cancer, cancer of the CNS (central nervous system), malignant glioma, or myeloproliferative disease. 28. The use according to any one of claims 24-25, wherein the proliferative disease is atherosclerosis or pulmonary fibrosis. 29. A use of the pharmaceutical composition according to any one of claims 20-21 to prepare medicines for preventing, treating, treating or alleviating proliferative diseases in patients. 30. The use according to claim 29, wherein said proliferative disease is metastatic cancer. 31. The use according to claim 29, wherein said proliferative disease is colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, brain tumor, neck cancer, prostate cancer, pancreatic cancer Cancer, cancer of the CNS (central nervous system), malignant glioma, or myeloproliferative disease. 32. The use according to claim 29, wherein said proliferative disease is atherosclerosis or pulmonary fibrosis. 33. A method for inhibiting or modulating protein kinase activity in a biological sample using the compound of claim 1, said method comprising contacting said biological sample with the compound of claim 1. 34. A method of inhibiting or modulating protein kinase activity in a biological sample using the compound of claim 11, said method comprising contacting said biological sample with the compound of claim 11. 35. The method of any one of claims 33-34, wherein the protein kinase is a receptor tyrosine kinase. 36. The method of claim 35, wherein the tyrosine kinase receptor is KDR, c-Met or IGF1R. 37. A method for inhibiting or adjusting protein kinase activity in a biological sample using the pharmaceutical composition of any one of claims 20-21, said method comprising using the pharmaceutical combination of any one of claims 20-21 The object is in contact with the biological specimen. 38. The method of claim 37, wherein the protein kinase is a receptor tyrosine kinase. 39. The method of claim 38, wherein the tyrosine kinase receptor is KDR, c-Met or IGF1R.