TW201331206A - Novel fused heterocyclic derivative useful as c-Met inhibitor - Google Patents

Abstract

This invention relates to a novel fused quinazoline derivative (represented by the formula I) useful as a c-Met inhibitor, its synthesis and application for treating c-Met mediated disorders. In particular, this invention relates to a fused heterocyclic derivative useful as a c-Met inhibitor, its synthesis and application for treating c-Met mediated disorders.

Description

Novel fused ring heterocyclic derivatives as c-Met inhibitors

The present invention relates to a novel series of fused ring quinazoline derivatives as c-Met inhibitors, a process for their preparation and their use for the treatment of c-Met dysregulation. In particular, the invention relates to fused ring heterocyclic derivatives as c-Met inhibitors, to processes for their preparation and to the use thereof for the treatment of c-Met dysregulation.

Because of the potential benefits of new molecular targeting agents for the treatment of diseases associated with signal transduction pathways, there is considerable interest in the study of these pathways in both normal and pathological states. Receptor tyrosine kinases (RTKs) are key enzymes that catalyze the autophosphorylation of tyrosine residues in the cytoplasm and the signal transduction pathway of the C-terminal protein domain. This will result in a binding site for the recruitment of downstream proteins and subsequent signalling involving a large number of cellular activities including growth, proliferation and survival. The more general mediated immune kinase signals are diverse pathological conditions, including immunology, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases. Known receptor tyrosine kinases include 20 families, and many receptor tyrosine kinases are associated with cancer (Blume-Jensen P et al, 2001. Nature 411 355-365). c-Met is a subfamily of receptor tyrosine kinases (RTKs) including the macrophage stimulating protein receptor (Ron)-associated protein and its chicken cognate receptor (Sea). The endogenous ligand is the growth and motor genetic hepatocyte growth factor (HGF, also known as the diffusion factor). The expression of C-Met and HGF are interrelated, although their expression is usually limited to epithelial cells and mesenchymal origin. In contrast, tumor cells are often expressed in activated c-Met. Now, there is a growing body of convincing evidence from animal studies and cancer patients that HGF-Met signaling plays an important role in the development and progression of malignant tumors and is particularly relevant to invasive malignancies. . In many cancer patients, c-Met and HGF are highly expressed relative to surrounding tissues, and their expression is associated with poor prognosis in patients (Jiang, W et al. 1999 Crit. Rev. Oncol.-hematol., 29, 209-248). .)

The initiation site mutation of the c-Met kinase domain is involved in the sporadic and hereditary milky kidney cancer family (Danilkovitch-Miagkova, A et al 2002. 1 J. Clin. Invest. 109, 863-867). c-Met is Markers of cancer and malignancy, and c-Met-HGF signaling inhibitors may improve disease progression in related cancers.

A novel fused ring quinazoline derivative is known to be a potent inhibitor of c-Met, and it is an object of the present invention to provide a novel compound capable of inhibiting c-Met activity. The structural formula of the compound is as shown in formula (I):

Or their pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein, A is a 5-18 membered ring; R ₁ is independently selected from hydrogen, halo, a substituted or unsubstituted C _1-8 alkyl A substituted or unsubstituted C _2-8 alkenyl group, a substituted or unsubstituted C _2-8 alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic aryl group, a substituted or unsubstituted hetero Cycloalkyl, C _1-8 alkyl fluorenyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkyl sulfonyl, aryl sulfonyl, cyano , nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio , N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _3-8 alkynylamino, N-(C _1-8 alkyl)aminosulfinyl or N,N-di(C _1-8 alkyl)aminosulfinyl; m is an integer from 0 to 3; A ₁ and A _{2 are} independently selected from: =N- or =C(R ₂ )-; R _{2 is} selected from -H, halogen, trichloromethyl, -CN, -NO ₂ , -NH ₂ , -OR ₅ , -NR ₅ R ₆ , -S(O) _0-2 R ₅ , -SO ₂ NR ₅ R ₆ , -CO ₂ R ₅ , -C(O)NR ₅ R ₆ , -N(R ₃ )SO ₂ R ₅ , -N(R ₅ )C(O)R ₆ , -N(R ₅ )CO ₂ R ₆ , -C(O)R ₅ or a substituted or unsubstituted lower An alkyl group; wherein R ₅ and R _{6 are} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _{2 - 8} alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _{1- 8} alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _{1-8 alkylheteroaryl} or substituted or unsubstituted C _1-8 alkane a heterocycloalkyl group; n is an integer from 0 to 4; A _{3 is} selected from: =N-, =C(H)- or =C(CN)-; X is selected from NR ₂₀ , CHR ₂₁ , O or S; The R ₂₀ and R _{21 are} independently selected from H or C _1-8 alkyl; Z is selected from the group consisting of NR ₃ R ₄ or formula (II):

R _{3 is} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted C _1-8 alkanoyl, substituted or unsubstituted C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkylsulfonyl, arylsulfonyl, cyano , nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio , N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _3-8 alkynylamino, N-(C _1-8 alkyl)aminosulfonyl or N,N-di(C _1-8 alkyl)aminosulfonyl; R ₉ and R _{10 are} independently selected Self-substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted Heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinyl, C _1-8 alkyl sulfonate sulfo acyl or aryl acyl group; R ₄ is selected from formula (III), formula (IV), formula (V), formula (VI) Of formula (VII) represented by the group:

Where B ₁ is

Q ₁ is C(R ₅ ) ₂ ; B ₂ is NHQ ₂ ; Q _{2 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, substituted or Unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _{1-8 alkylheteroaryl} or substituted or unsubstituted C _1-8 alkylheterocycloalkyl; or, B ₁ and B ₂ together form a 5-10 membered substituted or unsubstituted heterocyclic aryl or substituted or unsubstituted heterocycloalkyl; Q _{3 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted Or unsubstituted heterocycloalkyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _{1-8 alkylheteroaryl} or substituted or unsubstituted C _1-8 alkyl Heterocycloalkyl; X _{1 is} selected from NR ₈ or CR ₇ R ₈ ; R ₇ , R ₈ and R _{11 are} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _{1- 8} -alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkylsulfinyl, C _1-8 alkylsulfonate , N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, arylsulfonyl, cyano , nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio , C _1-8 alkanoguanamine, C _3-8 alkynylamino, N-(C _1-8 alkyl)aminosulfonyl, N,N-di(C _1-8 alkyl)aminosulfonate A substituted or unsubstituted C _1-8 alkylaryl group, a substituted or unsubstituted C _1-8 alkylheteroaryl group or a substituted or unsubstituted C _1-8 alkylheterocycloalkyl group.

In another embodiment, R _{4 is} selected from the group of formula (III):

B ₁ is

Q ₁ is C(R ₅ ) ₂ ; B ₂ is NHQ ₂ ; Q _{2 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, substituted or Unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _{1-8 alkylheteroaryl} or substituted or unsubstituted C _1-8 -heterocycloalkyl; B ₁ and B _{2 are taken} together a 5-10 membered substituted or unsubstituted heterocyclic aryl group or a substituted or unsubstituted heterocycloalkyl group; R ₅ and R _{6 are} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted Substituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkyl fluorenyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkyl sulfonyl, aryl sulfonyl, cyano, nitro, hydroxy , amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _1-8 alkyl Polycyclic aryl group or a substituted or unsubstituted heterocycloalkyl C _1-8 alkyl, and pharmaceutically acceptable salts thereof; Jiaoyou another embodiment, A ring further comprising 0-6 heteroatoms selected from O, S or N hetero atom.

In a preferred embodiment, R _{1 is} selected from the group consisting of hydrogen, halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heterocyclic aryl, heterocycloyl (heterocyclyl) , (halogen) _1-3 (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkyl, C _1-4 alkoxy (C _1-8 ) alkyl, cyano (C _1-8 ) Alkyl, amino (C _1-8 ) alkyl, aryl (C _1-8 ) alkyl, heteroaryl (C _1-8 ) alkyl, heterocycloalkyl (C _1-8 ) alkyl , (halogen) _1-3 (C _2-8 ) alkenyl, hydroxy (C _2-8 ) alkenyl, C _1-4 alkoxy (C _2-8 ) alkenyl, cyano (C _2-8 ) Alkenyl, amino (C _2-8 ) alkenyl, aryl (C _2-8 ) alkenyl, heterocyclic aryl (C _2-8 ) alkenyl, heterocycloalkyl (C _2-8 ) alkenyl , (halogen) _1-3 (C _2-8 ) alkynyl, hydroxy (C _2-8 ) alkynyl, C _1-4 alkoxy (C _2-8 ) alkynyl, cyano (C _2-8 ) Alkynyl, amino (C _2-8 ) alkynyl, aryl (C _2-8 ) alkynyl, heterocyclic aryl (C _2-8 ) alkynyl, heterocycloalkyl (C _2-8 ) alkynyl , C _1-8 alkyl fluorenyl, aryl (C _1-8 ) alkyl fluorenyl, heterocyclic aryl (C _1-8 ) alkyl fluorenyl, heterocycloalkyl (C _1-8 ) alkyl fluorenyl, C _1-8 alkoxycarbonyl, aryl (C _1-8) alkoxycarbonyl group, heterocyclic aryl (C _1-8) alkoxycarbonyl group, a heterocyclic group _(1-8 C) Oxycarbonyl group, C _1-8 alkylsulfinyl acyl, C _1-8 alkylsulfonyl group, a sulfo group aryl acyl, aryl (C _1-8) alkylsulfonyl group, a heterocyclic aromatic group ( C _1-8 )alkylsulfonyl, heterocycloalkyl (C _1-8 )alkylsulfonyl, aryl, heterocyclic aryl, heterocycloalkyl, cyano, nitro, hydroxy, amine ,carboxy, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 Alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _3-8 alkynylamino N-(C _1-8 alkyl)aminosulfonyl and N,N-di(C _1-8 alkyl)aminosulfinyl.

In another preferred embodiment, the above amine group, amine (C _1-8 ) alkyl group, amine group (C _2-8 ) alkenyl group or amine group (C _2-8 ) alkynyl group on R ₁ is Substituents independently selected from hydrogen, C _1-8 alkyl, C _2-8 alkenyl or C _2-8 alkynyl.

In another preferred embodiment, any of the above aryl, heterocyclic aryl or heterocycloalkyl groups on R ₁ may be optionally 1-3 independently selected from the group consisting of halogen, trifluoromethyl, cyano, nitro, a substituent of a hydroxyl group, an amine group, a carboxyl group, an amino group, a (C _1-8 ) alkyl group, a (C _2-8 ) alkenyl group, a (C _2-8 ) alkynyl group or a (C _1-8 ) alkoxy group Replace.

In another preferred embodiment, R _{3 is} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl , C _1-8 alkyl fluorenyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkyl sulfonyl, aryl sulfonyl, cyano, nitro , hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N- (C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _{3 - 8} alkynylamino, N-(C _1-8 alkyl)aminosulfonyl and N,N-di(C _1-8 alkyl)aminosulfinyl.

In another preferred embodiment, R _{4 is} selected from the group consisting of compounds of formula (IV):

Wherein Q _{3 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or Unsubstituted C _{1-8 alkylheteroaryl} , substituted or unsubstituted C _1-8 alkylheterocycloalkyl.

In another preferred embodiment, R ₇ and R _{8 are} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl , C _1-8 alkyl sulfinylene, C _1-8 alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 alkyl)aminoindenyl, N,N-di (C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoylamino, C _3-8 alkynylamino, N-(C _1-8 alkyl)amino Sulfonyl and N,N-di(C _1-8 alkyl)aminosulfonyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _1-8 alkyl heterocyclic A substituted, unsubstituted or substituted C _1-8 alkylheterocycloalkyl group.

In another preferred embodiment, R _{3 is} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl , C _1-8 alkyl fluorenyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkyl sulfonyl, aryl sulfo, cyano, nitro, Hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-( C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _3-8 An alkynylamino group, an N-(C _1-8 alkyl)aminosulfonyl group and an N,N-di(C _1-8 alkyl)aminosulfinyl group.

In another preferred embodiment, R _{4 is} selected from the group consisting of compounds of formula (V):

Wherein Q _{3 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or Unsubstituted C _{1-8 alkylheteroaryl} , substituted or unsubstituted C _1-8 alkylheterocycloalkyl.

X _{1 is} selected from NR ₈ or CR ₇ R ₈ .

R ₇ and R _{8 are} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted Or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl Thionylene, C _1-8 alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl Aminoguanidino, C _1-8 alkanoate group, C _1-8 alkanoguanamine group, C _3-8 alkynylamino group, N-(C _1-8 alkyl)aminosulfonyl group and N,N -di(C _1-8 alkyl)aminosulfonyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _{1-8 alkylheteroaryl} , substituted or unsubstituted C _1-8 alkylheterocycloalkyl.

In another preferred embodiment, R _{3 is} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl , C _1-8 alkyl fluorenyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkyl sulfonyl, aryl sulfonyl, cyano, nitro , hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N- (C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _{3 - 8} alkynylamino, N-(C _1-8 alkyl)aminosulfonyl and N,N-di(C _1-8 alkyl)aminosulfinyl.

In another preferred embodiment, R _{4 is} selected from the group consisting of compounds of formula (VI):

Wherein Q _{3 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or Unsubstituted C _{1-8 alkylheteroaryl} , substituted or unsubstituted C _1-8 alkylheterocycloalkyl.

R ₇ and R _{8 are} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted Or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl Thionylene, C _1-8 alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl Aminoguanidino, C _1-8 alkanoate group, C _1-8 alkanoguanamine group, C _3-8 alkynylamino group, N-(C _1-8 alkyl)aminosulfonyl group and N,N - bis(C _1-8 alkyl)aminosulfonyl, C _1-8 alkanoate, C _1-8 alkanoamine, C _3-8 alkynylamino, N-(C _1-8 alkane Aminosulfonyl, N,N-di(C _1-8 alkyl)aminosulfonyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _1-8 alkyl Heterocyclic aryl, substituted or unsubstituted C _1-8 alkylheterocycloalkyl.

In another preferred embodiment, R _{4 is} selected from the group consisting of compounds of formula (VII):

Wherein Q _{3 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or Unsubstituted C _{1-8 alkylheteroaryl} , substituted or unsubstituted C _1-8 alkylheterocycloalkyl.

R ₇ , R ₈ and R _{11 are} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkyne Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _{1- 8} -alkyl sulfinyl, C _1-8 alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkane Oxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _{1- 8-} alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoylamino, C _3-8 alkynylamino, N-(C _1-8 alkyl)aminosulfonyl and N,N-di(C _1-8 alkyl)aminosulfonyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _{1-8 alkylheteroaryl} , substituted or Unsubstituted C _1-8 alkylheterocycloalkyl.

R ₉ and R _{10 are} independently selected from substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted Aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene (C _1-8 )alkylsulfonyl, arylsulfonyl.

Preferably, A is a 6-18 membered ring; preferably, A is a 5-8 membered ring; preferably, A is a 5 or 12 membered ring; preferably, A is a 12 membered heterocyclic ring; preferably, said 12 membered member The heterocyclic ring contains 1, 2, 3 or 4 oxygen atoms; preferably, the 12-membered heterocyclic ring contains 4 oxygen atoms; preferably, the A is Preferably, said R _{1 is} selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C _1-5 alkyl, substituted or unsubstituted C _2-5 alkenyl, substituted or unsubstituted C _2-5 alkynyl, C _1-5 alkyl fluorenyl, C _1-5 alkoxycarbonyl, C _1-5 alkyl sulfinylene, C _1-5 alkylsulfonyl, C _1-5 alkoxy, C _2-5 Alkenyloxy, C _2-5 alkynyloxy, C _1-5 alkylthio, N-(C _1-5 alkyl)aminosulfonyl, N,N-di(C _1-5 alkyl)aminosulfonate Mercapto, C _1-5 alkanoate group, C _1-5 alkanoylamino group, C _3-6 alkynylamino group, N-(C _1-5 alkyl)aminosulfonyl group or N,N-di (C _1-5 alkyl)aminosulfonyl; preferably, said R _{1 is} selected from hydrogen, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted hetero a cycloalkyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl, oxo or aminoguanidino group; preferably, said R _{1 is} selected from hydrogen or a halogen; preferably, said R ₁ is hydrogen; preferably, m is an integer of 0-2; preferably, m is 0; preferably, said A ₂ is =N-; preferably, said A ₁ is =C(R ₂₎ -, A ₂ is = N-; Advantageously, the A ₁ is = CH-, A ₂ is = N-; Advantageously, the A ₁ and A ₂ are = C (R ₂₎ -; Preferably, the A ₁ and A ₂ are = CH-; Preferably, said A _{3 is} selected from the group consisting of =N- or =C(H)-; preferably, said X is selected from NR ₂₀ or CHR ₂₁ , and R ₂₀ and R _{21 are} independently selected from H or C _1-3 alkane Preferably, the X is selected from NR ₂₀ or CHR ₂₁ , and R ₂₀ and R ₂₁ are both H; preferably, the X is selected from oxygen or sulfur; preferably, the X is oxygen; R _{2 is} selected from -H, halogen, trihalomethyl, -CN, -NO ₂ or -NH ₂ ; preferably, said R _{2 is} selected from -H or halogen; preferably, said R _{2 is} selected from fluorine Or hydrogen; preferably, the R _{2 is} selected from the group consisting of -OR ₅ , -NR ₅ R ₆ , -S(O) _0-2 R ₅ , -SO ₂ NR ₅ R ₆ , -CO ₂ R ₅ , -C( O) NR ₅ R ₆ , -N(R ₃ )SO ₂ R ₅ , -N(R ₅ )C(O)R ₆ , -N(R ₅ )CO ₂ R ₆ or -C(O)R ₅ ; Preferably, said R _{2 is} selected from substituted lower alkyl, -CN, -NO ₂ or -NH ₂ ; preferably, said R _{3 is} selected from substituted or unsubstituted C _1-5 alkyl, substituted or unsubstituted Substituted C _2-5 alkenyl, substituted or unsubstituted C _2-5 alkynyl, C _1-5 alkanoyl, substituted or unsubstituted C _1-5 Alkoxycarbonyl, C _1-5 alkyl sulfinylene, C _1-5 alkylsulfonyl, C _1-5 alkoxy, C _2-5 alkenyloxy, C _2-5 alkynyloxy, C _1-5 alkylthio, N-(C _1-5 alkyl)aminosulfonyl, N,N-di(C _1-5 alkyl)aminosulfonyl, C _1-5 alkanoate, C _1-5 alkanoguanamine, C _3-6 alkynylamino, N-(C _1-5 alkyl)aminosulfonyl or N,N-di(C _1-5 alkyl)aminosulfonyl Preferably, the R _{3 is} selected from a substituted or unsubstituted C _1-3 alkyl group, a substituted or unsubstituted C _2-3 alkenyl group, a substituted or unsubstituted C _2-3 alkynyl group, C _1-3 Alkyl, substituted or unsubstituted C _1-3 alkoxycarbonyl, C _1-3 alkyl sulfinylene, C _1-3 alkylsulfonyl, C _1-3 alkoxy, C _{2 - 3} alkenyloxy, C _2-3 alkynyloxy, C _1-3 alkylthio, N-(C _1-3 alkyl)aminosulfonyl, N,N-di(C _1-3 alkyl)amino Sulfonyl, C _1-3 alkanoate, C _1-3 alkanoyl, N-(C _1-3 alkyl)aminosulfonyl, C _4-6 alkynylamino or N,N- a bis(C _1-3 alkyl)aminosulfonyl group; preferably, the R _{3 is} selected from a substituted or unsubstituted C _1-3 alkoxycarbonyl group, a C _1-3 alkyl sulfinylene group, C _{1 -3} alkylsulfonyl, C _1-3 alkoxy, C _2-3 alkene An oxy group, a C _2-3 alkynyloxy group or a C _1-3 alkylthio group; preferably, said R ₃ is hydrogen; preferably, said Q ₁ is CH ₂ ; preferably, said Q ₂ is a substitution or Unsubstituted aryl, substituted or unsubstituted heterocyclic aryl or substituted or unsubstituted heterocycloalkyl; preferably, said Q _{2 is} selected from halophenyl; preferably, said Q ₂ is fluoro a phenyl group; preferably, the Q _{2 is} selected from a substituted or unsubstituted C _1-5 alkylaryl group, a substituted or unsubstituted C _1-5 alkylheteroaryl group or a substituted or unsubstituted C _{1- a 5} -alkylheterocycloalkyl group; preferably, the B ₁ and B ₂ together form a 5-10 membered substituted or unsubstituted heterocyclic aryl group, or a substituted or unsubstituted heterocycloalkyl group; preferably, said Q _{3 is} selected from a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic aryl group; preferably, said Q _{3 is} selected from a substituted or unsubstituted phenyl group; preferably, said Q _{3 is} selected from phenyl or halophenyl; Advantageously, said Q ₃ is selected from fluoro phenyl; Advantageously, said X ₁ is selected from NR _8; Advantageously, said X ₁ is selected from NC _1-6 alkyl ; Advantageously, said X ₁ is NCH _3; Are preferred, the R _7, R ₈ and R _{11 are} independently selected from hydrogen, halogen, or substituted or unsubstituted C _1-8 alkyl; Advantageously, the R _7, R ₈ and R ₁₁ are independently selected from Substituted or unsubstituted C _2-5 alkenyl, substituted or unsubstituted C _2-5 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkane a group, a C _1-5 alkanoyl group, a C _1-5 alkoxycarbonyl group, an N-(C _1-5 alkyl)aminofluorenyl group, an N,N-di(C _1-5 alkyl)aminofluorenyl group, C _1-5 alkanoate group, arylsulfonyl group, cyano group, nitro group, hydroxyl group, amine group, carboxyl group, oxo group, amino group, C _1-5 alkoxy group, C _2-5 olefin oxygen , C _2-5 alkynyloxy, C _1-5 alkylthio, C _1-5 alkanoylamino, C _3-5 alkynylamino, N-(C _1-5 alkyl)aminosulfonyl , N,N-di(C _1-5 alkyl)aminosulfonyl, substituted or unsubstituted C _1-5 alkylaryl, substituted or unsubstituted C _1-5 alkylheteroaryl, or a substituted or unsubstituted C _1-5 alkylheterocycloalkyl group; preferably, said R ₇ , R ₈ and R ₁₁ are hydrogen; preferably, said R ₇ is a C _1-6 alkyl group; preferably, the R ₇ is -CH _3; Advantageously, Said R ₇ is selected from phenyl or halophenyl; Advantageously, the R ₇ phenyl group is selected from fluoro; Advantageously, said R ₈ is hydrogen; Advantageously, the R ₅ and R ₆ are independently selected from From hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl or substituted or unsubstituted C _2-6 alkynyl; preferably, said R ₅ and R ₆ are Is hydrogen; preferably, R ₅ and R _{6 are} independently selected from C _1-5 alkyl fluorenyl, C _1-5 alkoxycarbonyl, C _1-5 alkyl sulfinylene or C _1-5 alkane Alkylsulfonyl; preferably, said R ₅ and R _{6 are} independently selected from cyano, nitro, hydroxy, amine, carboxyl, oxo or aminoguanidino; preferably, said R ₅ and R ₆ Independently selected from cyano, nitro, hydroxy or amine; preferably, said R ₉ and R _{10 are} independently selected from substituted or unsubstituted C _1-6 alkyl or substituted or unsubstituted C _6-12 Aryl; preferably, said R ₉ and R _{10 are} independently selected from halo C _6-12 aryl or unsubstituted C _1-6 alkyl; preferably, said R ₉ and R _{10 are} independently selected from Methyl or halophenyl; preferably, R ₉ and R _{10 are} independently selected from methyl or fluorophenyl.

The following compounds provided by the present invention can provide the reader with a better understanding of the compounds encompassed by the present invention;

5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-guanamine;

● 1-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-guanamine;

1-[2-(4-Fluoro-phenyl)-ethenyl]cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9, 12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-guanamine;

3-(4-Fluoro-phenyl)-2-oxo-imidazoline-1-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9 , 12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-guanamine;

2-(4-Fluoro-phenyl)-1.5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid [3-fluoro-4-(7,8) ,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododecane[b]naphthalene-4-oxy)-phenyl]- Guanamine

● 2-(4-Fluoro-phenylamino)-5-[5-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxy-1,3-di Aza-cyclododecane[b]naphthalene-4-oxy)-pyridin-2-yl]-3-methyl-3H-pyrimidin-4-one;

5-[5-([1,3]Diox[4,5-g]quinazolin-8-oxy)-pyridin-2-yl]-2-(4-fluoro-phenylamino)- 3-methyl-3H-pyrimidin-4-one;

5-[5-(2,2-Difluoro-[1,3]dioxo[4,5-g]quinazolin-8-oxy)-pyridin-2-yl]-2-(4- Fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one;

5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [4-([1,3]dioxo[4,5-g] quinazoline Lung-8-oxy)-3-fluoro-phenyl]-guanamine;

5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-guanamine;

● 1-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-guanamine;

● 2-(4-Fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid [3-fluoro-4-(7) ,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-indole amine;

1-[2-(4-Fluoro-phenyl)-ethenyl]cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9, 12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-guanamine;

3-(4-Fluoro-phenyl)-2-oxo-imidazoline-1-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9 ,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine

5-[5-(2,2-Difluoro-[1,3]dioxo[4,5-g]quinazolin-8-oxy)-pyridin-2-yl]-2-(2- Fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one;

5-[5-(2,2-Difluoro-[1,3]dioxo[4,5-g]quinazolin-8-oxy)-pyridin-2-yl]-2-(phenyl) Amino)-3-methyl-3H-pyrimidin-4-one;

5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro 6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-amino)-phenyl]-guanamine;

5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-indolyl)-phenyl]-guanamine;

3-3-methyl-2-phenylamino-5-[5-(2,5,7,10-tetraoxo-14,16-diaza-tricyclo[9.8.0.013,18]pentadecane- 1(11),12,14,16,18-pentenyl-17-oxy)-pyridin-2-yl]-3H-pyrimidin-4-one;

5-[5-([8,9]Dihydro-7H-6,10-dioxo-1,3-diaza-cycloheptane[b]naphthalene-4-oxy)-pyridine-2- 2-(4-fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one;

● 2-(4-Fluoro-phenylamino)-3-methyl-5-[5-(9-methyl-8,9,10,11-tetrahydro-7H-6,12-dioxo-1 , 3,9-triaza-cyclodecane [b]naphthalene-4-oxy)-pyridin-2-yl]-3H-pyrimidin-4-one;

● 2-(4-Fluoro-phenylamino)-3-methyl-5-[5-(7,8,10,11-tetrahydro-6,9,12-trioxy-1,3-diaza Hetero-cyclodecane [b]naphthalene-4-oxy)-pyridin-2-yl]-3H-pyrimidin-4-one;

5-[5-(8,9-Dihydro-7H-6,10-dioxo-1-aza-cycloheptane[b]naphthalen-4-yloxy)-pyridin-2-yl]-2 -(4-fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one;

● 2-(4-Fluoro-phenylamino)-3-methyl-5-[5-(9-methyl-8,9,10,11-tetrahydro-7H-6,12-dioxo-1 , 9-diaza-cyclodecane [b]naphthalene-4-oxy)-pyridin-2-yl]-3H-pyrimidin-4-one;

2-(4-Fluoro-phenylamino)-3-methyl-5-[5-(7,8,10,11-tetrahydro-6,9,12-trioxa-1-aza-cyclo Decane [b]naphthalene-4-oxy)-pyridin-2-yl]-3H-pyrimidin-4-one;

3-3-methyl-2-phenylamino-5-[5-(2,5,7,10-tetraoxo-14-aza-tricyclo[9.8.0.013,18]pentadecan-1(11 , 12,14,16,18-pentenyl-17-oxy)-pyridin-2-yl]-3H-pyrimidin-4-one;

5-[5-(2,2-Difluoro-[1,3]dioxo[4,5-g]quinazolin-8-oxy)-pyridin-2-yl]-2-(2- Fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one;

5-[5-(2,2-Difluoro-[1,3]dioxo[4,5-g]quinazolin-8-oxy)-pyridin-2-yl]-2-(phenyl) Amino)-3-methyl-3H-pyrimidin-4-one;

5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalene-4-amino)-phenyl]-guanamine;

5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalen-4-indolyl)-phenyl]-guanamine;

● 5-[5-(2,5,8,11,14,17-hexaoxy-21-aza-tricyclo[16.8.0.020,25]-hexadecane-1(18),19,21, 23,25-pentenyl-24-oxy)-pyridin-2-yl]-3-methyl-2-phenylamino-3H-pyrimidin-4-one.

In another aspect, the invention provides a pharmaceutical composition comprising at least one of the above compounds and a pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient" refers to any diluent, adjuvant, excipient or carrier that can be administered to at least one compound of the invention.

The invention also provides a preferred technical solution of the above technical solution:

The weight ratio of the compound to the excipient ranges from 0.0001 to 10:1.

The present invention further provides for the use of a pharmaceutical preparation of the above pharmaceutical composition and at least one compound of the formula (I).

The invention also provides a preferred technical solution for the above application:

The use of the medicament for the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, immune disorder or visual disturbance.

The use of the prepared medicament for delaying or preventing progression of cancer, cancer metastasis, cardiovascular disease, immune disorder or visual disorder.

The use of the medicament for the treatment or delay of progression or onset of cancer, cancer metastasis, cardiovascular disease, immune disorder or visual disorder.

The present invention provides the use of a compound of formula (I) for the treatment of cancer, prevention of cancer metastasis, treatment of cardiovascular diseases, immune disorders or visual disorders.

Preferably, at least one compound of formula (I) is used as a c-Met inhibitor.

The present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a condition modulating a protein kinase activity.

Preferably, the protein kinase is KDR, Tie-2, Flt3, FGFR3, AbI, Aurora A, c-Src, IGF-IR, ALK, c-MET, RON, PAK1, PAK2 or TAK1.

Preferably, the protein kinase activity modulating disorder is cancer.

Preferably, the cancer is solid tumor, sarcoma, fibrosarcoma, osteoma, malignant melanoma, retinoblastoma, rhabdomyosarcoma, glioblastoma, neuroblastoma, teratoma, hematopoietic malignancy or malignant ascites.

The present invention also provides the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof as a medicament.

Preferably, the medicament is for the treatment of cancer. The cancer is selected from the group consisting of lung cancer, breast cancer, colon cancer, kidney cancer, pancreatic cancer, head cancer, neck cancer, hereditary papillary renal cell carcinoma, childhood liver cancer, and gastric cancer.

Preferably, a mammal in need of such treatment is administered a therapeutically effective amount of at least one compound provided herein, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound for use in the treatment of a disorder in a c-Met tyrosine kinase regulatory disorder.

The term "halo" or "halogen", unless explicitly stated otherwise, means fluoro, chloro, bromo or iodo. More preferably, it refers to fluorine, chlorine and bromine.

As used herein, unless expressly stated otherwise, the term "alkyl" includes straight-chain, branched or cyclic saturated single-bond hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2 -Methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. The alkoxy group is derived from the oxygen ether form of the linear, branched or cyclic alkyl group described above. Similarly, alkenyl and alkynyl groups include straight chain, branched or cyclic olefins and alkynes.

The term "hydroxyalkyl" refers to a group of the formula HO-alkyl group attached to the terminal of the alkyl chain. The term "amino alkyl" refers to a substituted amine with one alkyl group (e.g., - alkyl -NH _2). The term "alkylamino" refers to an amine group (eg, -NH-alkyl) substituted with an alkyl group. The term "dialkylamino" refers to an amine group (eg, -N-(alkyl) ₂ ) substituted with two identical or different alkyl groups.

As used herein, the term "aryl", unless expressly defined otherwise, refers to unsubstituted or substituted aromatic groups such as phenyl, naphthyl and anthracenyl. The term "aryl" refers to -C(O)-aryl.

As used herein, the term "heterocyclyl", unless expressly defined otherwise, refers to an unsubstituted or substituted stable 3 to 8 membered ring system consisting of carbon atoms and 1 to 3 selected from N. The hetero atom of O or S may be composed, and the N or S hetero atom may also be oxidized, and the N hetero atom may also be a nitrogen of the quaternary ammonium salt. The heterocycloalkyl group can be attached to any heteroatom or carbon atom capable of producing a stable structure. For example, heterocycloalkyl, including, but not limited to, azetidinyl, pyrrolidinyl, acridinyl, pyridazinyl, oxoxazinyl, oxoacridinyl, oxooxazepine, Azafenyl, tetrahydrofuranyl, dioxopentyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholine Amidino, thiomorpholinium and oxadiazolyl.

As used herein, the term "heterocyclic aryl", unless expressly defined otherwise, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system, or unsubstituted or substituted 9- or 10-membered benzene. a fused ring heteroaromatic ring system or a bicyclic heteroaromatic ring system consisting of a carbon atom and 1 to 4 heteroatoms selected from N, O or S, And the N or S hetero atom can also be oxidized, and the N hetero atom can also be a nitrogen of the quaternary ammonium salt. The heterocyclic aryl group can be attached to any hetero atom or carbon atom capable of producing a stable structure. For example, heterocyclic aryl, including, but not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridine , pyridazinyl, fluorenyl, fluorenyl, oxazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyridyl An azolyl group, a benzothiazolyl group, a benzothiadiazolyl group, a benzotriazole adenine group, a quinolyl group or an isoquinolyl group.

The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups.

The term "arylalkenyl" or "arylalkynyl" includes alkenyl or alkynyl substituted by one or more aryl groups. Similarly, the term "heterocyclic arylalkyl", "heterocyclic arylalkenyl" or "heterocyclic arylalkynyl" refers to an alkyl, alkenyl or alkyne substituted with one or more heterocyclic aryl groups. "Heterocycloalkyl", "heterocyclenyl" or "heterocycloalkynyl" refers to an alkyl, alkenyl or alkynyl group substituted by one or more heterocycles.

The term "carbonyl" refers to C(O).

The term "aminoguanidino" refers to .

The term "alkanoate group" means Wherein R refers to any alkyl group.

The term "alkyl fluorenyl" means Wherein R refers to any alkyl group.

The terms "active ingredient", "therapeutic component", "effective component", unless otherwise expressly defined, refer to a compound and/or pharmaceutical composition provided herein.

Whenever the term "alkyl" or "aryl" or the first code root (eg, aralkyl, dialkylamino) present on a substituent, they are to be interpreted as "alkyl" and "aryl" as defined above. base". The specified number of carbon atoms (e.g., C ₁ -C ₆ , C _1-6 ) refers to the number of carbon atoms of the individual alkyl moiety or the number of carbon atoms of the alkyl moiety that appears as the first code root of the larger substituent.

As used herein, the term "composition" includes a product containing a particular quantity of a particular component, as well as any product that directly or indirectly contains a particular quantity of the particular component. Accordingly, the pharmaceutical composition includes the compound provided by the present invention as an active ingredient. The same method of preparing the compound is also part of the invention. Further, some of the crystalline forms of the compounds exist as polymorphs, and such polymorphs are also included within the scope of the present invention. In addition, some of the compounds form solvates with water (e.g., hydrates) or common organic solvents, and such solvates are also included in the scope of the present invention.

The compounds provided herein may also exist in the form of a pharmaceutically acceptable salt. In terms of pharmaceutical use, the salt of the compound provided by the present invention means a non-toxic pharmaceutically acceptable salt. The form of the pharmaceutically acceptable salt includes a pharmaceutically acceptable acid/anion or a guanidine/cationic salt. Pharmaceutically acceptable acid/anionic salts are generally present in the form of a protonated basic nitrogen with an inorganic or organic acid. Typical organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid. , tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfonic acid, salicylic acid , saccharin acid or trifluoroacetic acid. Pharmaceutically acceptable cesium/cationic salts including, but not limited to, aluminum salts, calcium salts, chloride salts, choline, diethanolamine salts, ethylenediamine salts, lithium salts, magnesium salts, potassium salts, sodium salts, and zinc salts .

Prodrugs of the compounds provided herein are included within the scope of the invention. Typically, the prodrug is a functional derivative of a compound provided herein that is readily converted in vivo to the desired compound. As used herein, the term "administering" as used in the present invention includes the use of a compound disclosed herein or a compound of the present invention which, although not disclosed, can be converted to a compound disclosed herein, can be used to treat the various disorders or disorders described herein. . Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in the book, for example, Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

As used herein, the definition of a variable at a particular position in any substituent or molecule is independent of the definition of the molecule in which it is located. It will be understood that in the present invention, one skilled in the art can select the substituents and substitutions of the compounds in view of chemical stability and ease of synthesis according to the methods of the prior art and the present invention.

The compounds of the invention may contain one or more asymmetric centers and may be derived/occurring isomers and optical isomers. The present invention includes all possible isomers and their racemic mixtures, disassembled simple enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

The above formula (I) does not exactly define the stereostructure of a certain position of the compound. The present invention includes all stereoisomers of the compound of formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. One of ordinary skill in the art will appreciate that the product produced by such a process may be a mixture of stereoisomers during the synthesis of such compounds, or during the use of racemization or epimerization.

When an isomer is present in the compound of formula (I), the invention includes any possible isomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise stated.

When a compound of formula (I) and a pharmaceutically acceptable salt thereof are present in a solvate or polymorph, the invention includes any possible solvate and polymorph unless specifically stated. The type of solvent forming the solvate is also not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic hydrazine or acid. When the compounds provided herein are acids, the corresponding salts can be prepared from pharmaceutically acceptable non-toxic hydrazines, including inorganic hydrazines and organic hydrazines. Salts derived from inorganic cerium include salts of aluminum, ammonium, calcium, copper (ic and ous), iron, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc. In particular, salts of ammonium, calcium, magnesium, potassium and sodium are preferred. Pharmaceutically acceptable non-toxic organic terpenes capable of derivatizing into salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents such as natural and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic hydrazines capable of forming salts, including ion exchange resins and arginine, beet mash, caffeine, choline, N', N'-dibenzylethylene diamine, diethylamine, 2- Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethyl acridine, glucosamine, glucosamine, histidine, hexamine, isopropylamine, Lai Amino acid, methyl glucosamine, morpholine, pyridazine, acridine, polyamine resin, procaine, guanidine, cocoa, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When the compound provided by the present invention is hydrazine, its corresponding salt can be obtained from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. More preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid. The use of the compound of formula (I) as a medicament, preferably, uses a purity such as a purity of at least 60%, a suitable purity of at least 75%, and a particularly suitable purity of at least 98% (% by weight).

The pharmaceutical composition provided by the present invention comprises the compound of the formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable excipient and other optional therapeutic components or adjuvants. While the most suitable mode of administration of the active ingredient will depend on the particular subject, the nature of the subject, and the severity of the condition, the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical, and parenteral (including subcutaneous administration, intramuscular injection, Intravenous administration) a pharmaceutical composition administered. The pharmaceutical compositions of this invention may conveniently be prepared in any dosage form known in the art and by any method known in the art.

In fact, according to the conventional drug mixing technique, the compound of the formula (I), or a prodrug, or a metabolite, or a pharmaceutically acceptable salt of the present invention can be used as an active ingredient and mixed with a pharmaceutical carrier into a pharmaceutical combination. Things. The pharmaceutical carrier can take a wide variety of forms depending on the mode of administration desired, for example, orally or by injection (including intravenous). Thus, the pharmaceutical compositions of the present invention may be present in any of the dosage forms predetermined for the active ingredient dosage, such as capsules, cachets or tablets. Further, the pharmaceutical composition of the present invention is in the form of a powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. Further, in addition to the above-mentioned common dosage forms, the compound of the formula (I) or a pharmaceutically acceptable salt thereof can also be administered by controlled release means and/or delivery means. The pharmaceutical compositions of the present invention can be prepared by any pharmaceutically suitable pharmaceutical method. In general, such methods include the step of bringing into association the active component with a carrier which comprises one or more of the necessary components. In general, the pharmaceutical compositions are prepared by intimate intimate mixing of the active component with a liquid carrier or a finely divided solid carrier or a mixture of both. In addition, the product can be conveniently prepared to the desired appearance.

Accordingly, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound of the formula (I), or a pharmaceutically acceptable salt thereof. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutically active compounds is also included in the pharmaceutical composition of the present invention.

The pharmaceutical carrier employed in the present invention may be, for example, a solid carrier, a liquid carrier or a gas carrier. Solid carriers include, but are not limited to, lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid. Liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, and water. Gas carriers include, but are not limited to, carbon dioxide and nitrogen. When preparing a pharmaceutical oral preparation, any convenient pharmaceutically acceptable medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants and the like can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, saccharides, micro Crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrators and the like can be used for oral solid preparations such as powders, capsules and tablets. Tablets and capsules are preferred for oral formulations in view of ease of administration. Alternatively, the tablet coating can be carried out using standard aqueous or non-aqueous formulation techniques.

Tablets containing a compound or pharmaceutical composition of the invention may be compressed or molded, optionally together with one or more accessory ingredients or adjuvants to form a tablet. The active component is admixed in a free-flowing form such as a powder or granules with a lubricant, inert diluent, surface active or dispersing agent, and in a suitable machine, compressed sheets can be prepared by compression. The powdered compound or pharmaceutical composition is impregnated with an inert liquid diluent, and then the molded piece can be obtained by molding in a suitable machine. Preferably, each tablet contains from about 0.05 mg to 5 g of active ingredient, and each blister or capsule contains from about 0.05 mg to 5 g of active ingredient. For example, a human oral formulation may contain from about 0.5 mg to about 5 g of the active ingredient, complexed with a suitable and conveniently metered auxiliary material, which comprises from about 5% to 95% of the total amount of the pharmaceutical composition. Unit dosage forms will generally contain from about 1 mg to about 2 grams of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

The present invention provides a pharmaceutical composition suitable for parenteral administration. The active ingredient can be added to water to prepare an aqueous solution or suspension. A suitable surfactant such as hydroxypropylcellulose can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, the preservative can prevent the growth of harmful microorganisms and is therefore also included in the pharmaceutical composition of the present invention.

The pharmaceutical compositions provided herein are suitable for injectable use, including sterile aqueous solutions or dispersions. Further, the above sterile solution or dispersion may be prepared in the form of a sterile powder. In any event, the final form of injection must be sterile and must be easy to flow for ease of injection. Furthermore, the preparation and storage of the pharmaceutical composition must be stable. Therefore, it is best to be contaminated with microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical combinations provided herein can be used in a suitable typical dosage form, for example, an aerosol, emulsion, ointment, lotion, dusting, or other similar dosage form. Further, the pharmaceutical compositions provided by the present invention can be used in a suitable form in a transdermal delivery device. These preparations can be produced by a conventional processing method using the compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof. As an example, an emulsion or ointment is prepared by adding a hydrophilic material and water (the total amount of which is about 5 to 10% by weight of the compound) to prepare an emulsion or ointment having the desired consistency.

The pharmaceutical composition provided by the invention may be in the form of a solid carrier and suitable for rectal administration, and a unit dosage suppository is the most typical dosage form. Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, followed by cooling and molding.

In addition to the excipient components mentioned above, the above formulation may also include, suitably, one or more additional excipient components such as diluents, buffers, flavoring agents, binders, surfactants, thickening Agents, lubricants, preservatives (including antioxidants), etc. Further, other adjuvants may also include a penetration enhancer that modulates the osmolality of the drug and blood. A pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, may be prepared in the form of a powder or a concentrate.

In general, for the conditions or discomforts indicated above, the dosage level of the drug is from about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or from 0.5 mg to 7 g per patient per day. For example, inflammation, tumors, psoriasis, allergies/asthma, diseases and discomforts of the immune system, diseases and discomforts of the central nervous system (CNS), effective doses of drugs ranging from 0.01 mg/kg body weight to 50 mg/kg body weight per day, or Each patient is 0.5 mg to 3.5 g per day.

However, it is understood that the specific dosage level for any particular patient will depend on a number of factors, including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination of medication, and treatment. The severity of a particular disease.

Unless otherwise indicated, the quantities used herein to refer to the various components, the reaction conditions, and the numbers recited in the specification and claims are to be construed as "about, broad" in all instances. Correspondingly, the numerical parameters quoted in the specification and the scope of the patent application are approximate parameters except for the specific reference. Under the respective experimental conditions, different digital parameters may be obtained due to different standard errors.

In this paper, when a variable parameter is referenced more than once in a chemical formula, the definition of each reference is independent of the definition of any other reference. The compounds described herein may contain one or more chiral centers and/or double bonds and the like, as well as stereoisomers such as double bond stereoisomers (eg geometric isomers), optical isomerism Bulk or diastereomer. Accordingly, any chemical structure within the scope of the description herein, whether in its entirety or in part, encompasses all of the possible enantiomers and diastereomers of the compound, including Any simple stereoisomer (such as a simple geometric isomer, a simple enantiomer or a simple diastereomer), a corresponding isomer, and any mixture of these isomers. Mixtures of racemic isomers and stereoisomers can be further resolved into enantiomers or stereoisomers by those skilled in the art using well-known separation techniques or chiral synthesis methods.

In order to make the above content clearer and clearer, the present invention will be further explained below.

The present invention provides a novel compound for use as an inhibitor of c-Met activity. The structural formula of the compound provided by the present invention is as shown in formula (I):

Wherein A is a 5-18 membered ring; R _{1 is} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl , C _1-8 alkyl sulfinylene, C _1-8 alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 alkyl)aminoindenyl, N,N-di (C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoylamino, C _3-8 alkynylamino, N-(C _1-8 alkyl)amino Sulfhydryl or N,N-di(C _1-8 alkyl)aminosulfonyl; m is an integer from 0 to 3; A ₁ and A _{2 are} independently selected from: =N- or =C(R ₂ ) - A _{3 is} selected from: =N-, =C(H)- or =C(CN)-; X is selected from NR ₂₀ , CHR ₂₁ , O or S; and R ₂₀ and R _{21 are} independently selected from H Or C _1-8 alkyl; R _{2 is} selected from -H, halogen, trihalomethyl, -CN, -NO ₂ , -NH ₂ , -OR ₅ , -NR ₅ R ₆ , -S(O) ₀ - ₂ R ₅ , -SO ₂ NR ₅ R ₆ , -CO ₂ R ₅ , -C(O)NR ₅ R ₆ , -N(R ₃ )SO ₂ R ₅ , -N(R ₅ )C(O)R ₆ , -N(R ₅ ) CO ₂ R ₆ , -C(O)R ₅ or an optionally substituted lower alkyl; n is an integer from 0 to 4; Z is selected from the group consisting of NR ₃ R ₄ or formula (II):

R _{3 is} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, C _1-8 alkane , C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl , oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 alkyl Aminoguanidino, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _3-8 alkynylamino, N -(C _1-8 alkyl)aminosulfonyl or N,N-di(C _1-8 alkyl)aminosulfinyl; R _{4 is} selected from the group of formula (III):

B ₁ is

Q ₁ is C(R ₅ ) ₂ ; B ₂ is NHQ ₂ ; Q _{2 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, substituted or Unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _{1-8 alkylheteroaryl} or substituted or unsubstituted C _1-8 alkylheterocycloalkyl; or, B ₁ and B ₂ together form a 5-10 membered substituted or unsubstituted heterocyclic aryl or substituted or unsubstituted heterocycloalkyl; R ₅ and R _{6 are} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkane A substituted or unsubstituted C _2-8 alkenyl group, a substituted or unsubstituted C _2-8 alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic aryl group, a substituted or unsubstituted hetero Cycloalkyl, C _1-8 alkyl fluorenyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkyl sulfonyl, aryl sulfonyl, cyano , nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio , N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _3-8 alkynyl XI Group, N-(C _1-8 alkyl) aminosulfonyl acyl, N, N- two (C _1-8 alkyl) aminosulfonyl acyl, substituted or unsubstituted aryl C _1-8 alkyl group, a substituted Or an unsubstituted C _1-8 alkylheteroaryl group or a substituted or unsubstituted C _1-8 alkylheterocycloalkyl group, and pharmaceutically acceptable salts thereof.

In a preferred embodiment, the A ring further comprises from 0 to 6 heteroatoms selected from the group consisting of O, S and N.

In a preferred embodiment, R _{1 is} selected from the group consisting of hydrogen, halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heterocyclic aryl, heterocycloalkyl, ( Ring) _1-3 (C _1-8 )alkyl, hydroxy, (C _1-8 )alkyl, C _1-4 alkoxy (C _1-8 )alkyl, cyano (C _1-8 ) alkane , an amino (C _1-8 ) alkyl group, an aryl (C _1-8 ) alkyl group, a heterocyclic aryl (C _1-8 ) alkyl group, a heterocycloalkyl (C _1-8 ) alkyl group, (Cyclo) _1-3 (C _2-8 ) alkenyl, hydroxy (C _2-8 ) alkenyl, (C _1-4 ) alkoxy (C _2-8 ) alkenyl, cyano (C _2-8 Alkenyl, amino (C _2-8 ) alkenyl, aryl (C _2-8 ) alkenyl, heterocyclic aryl (C _2-8 ) alkenyl, heterocycloalkyl (C _2-8 ) alkene Base, (ring) _1-3 (C _2-8 ) alkynyl, hydroxy (C _2-8 ) alkynyl, (C _1-4 ) alkoxy (C _2-8 ) alkynyl, cyano (C _{2 -8} ) alkynyl, amino (C _2-8 ) alkynyl, aryl (C _2-8 ) alkynyl, heterocyclic aryl (C _2-8 ) alkynyl, heterocycloalkyl (C _2-8 Alkynyl, C _1-8 alkanoyl, aryl (C _1-8 )(C _1-8 )alkylhydrazine, heterocyclic aryl (C _1-8 )alkylhydrazine, heterocycloalkyl (C _1-8 ) alkano group, C _1-8 alkoxycarbonyl group, aryl (C _1-8 ) alkoxycarbonyl group, heterocyclic aryl (C _1-8 ) alkoxycarbonyl group, heterocycloalkyl group ( C _1-8) Oxycarbonyl group, C _1-8 alkylsulfinyl acyl, C _1-8 alkylsulfonyl group, a sulfo group aryl acyl, aryl (C _1-8) acyl arylsulfonyl, heterocyclic aryl ( C _1-8 ) arylsulfonyl, heterocycloalkyl (C _1-8 ) arylsulfonyl, aryl, heterocyclic aryl, heterocycloalkyl, cyano, nitro, hydroxy, amine ,carboxy, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 Alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _3-8 alkynylamino , N-(C _1-8 alkyl)aminosulfonyl or N,N-di(C _1-8 alkyl)aminosulfinyl; another preferred embodiment, the above amine group on R ₁ , An amino (C _1-8 ) alkyl, an amine (C _2-8 ) alkenyl or an amine (C _2-8 ) alkynyl group is independently selected from hydrogen, (C _1-8 )alkyl, (C _2-8 )alkenyl or (C _2-8 )alkynyl substituted.

In another preferred embodiment, any aryl, heterocyclic aryl or heterocycloalkyl group may optionally contain from 1 to 3 independently selected from the group consisting of halogen, trifluoromethyl, cyano, nitro, hydroxy, amine. a group, a carboxyl group, a fluorenylamino group, a (C _1-8 )alkyl group, a (C _2-8 )alkenyl group, a (C _2-8 )alkynyl group or a (C _1-8 )alkoxy group.

In another preferred embodiment, R _{3 is} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkyne , C _1-8 alkyl fluorenyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkyl sulfonyl, aryl sulfonyl, cyano, nitrate Base, hydroxyl, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N -(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _{3 -8} alkynylamino, N-(C _1-8 alkyl)aminosulfonyl or N,N-di(C _1-8 alkyl)aminosulfinyl; another preferred embodiment, R ₄ Selected from the group represented by formula (IV):

Wherein Q _{3 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted C _{a 1-8} alkylheteroaryl group or a substituted or unsubstituted C _1-8 alkylheterocycloalkyl group; R ₇ and R _{8 are} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl , substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocyclic ring Alkyl, C _1-8 alkyl fluorenyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkyl sulfonyl, aryl sulfonyl, cyano , nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio , N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _3-8 alkynylamino, N-(C _1-8 alkyl)aminosulfonyl, N,N-di(C _1-8 alkyl)aminosulfonyl, substituted or unsubstituted C _{1- 8} alkylaryl group, a substituted or unsubstituted The C _1-8 alkyl group or a substituted heteroaryl C _1-8 alkyl or unsubstituted heterocycloalkyl.

In another preferred embodiment, R _{3 is} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkyne , C _1-8 alkyl fluorenyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkyl sulfonyl, aryl sulfonyl, cyano, nitrate Base, hydroxyl, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N -(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _{3 -8} alkynylamino, N-(C _1-8 alkyl)aminosulfonyl or N,N-di(C _1-8 alkyl)aminosulfinyl; another preferred embodiment, R ₄ Selected from the group represented by formula (V):

Wherein Q _{3 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or An unsubstituted C _1-8 alkylheteroaryl group or a substituted or unsubstituted C _1-8 alkylheterocycloalkyl group; X _{1 is} selected from NR ₈ or CR ₇ R8; R ₇ and R _{8 are} independently selected from Hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted aryl, substituted or Unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 Alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 Alkanoate group, C _1-8 alkanoguanamine group, C _3-8 alkynylamino group, N-(C _1-8 alkyl) aminosulfonyl group, N,N-di(C _1-8 alkyl group ) sulfo amino acyl, substituted or unsubstituted C _1-8 Aryl group, a substituted or unsubstituted C _1-8 alkyl heterocycloalkyl C _1-8 alkyl group or a substituted or unsubstituted heterocyclic aromatic unsubstituted.

In another preferred embodiment, R _{3 is} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkyne , C _1-8 alkyl fluorenyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkyl sulfonyl, aryl sulfonyl, cyano, nitrate Base, hydroxyl, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N -(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _{3 -8} alkynylamino, N-(C _1-8 alkyl)aminosulfonyl or N,N-di(C _1-8 alkyl)aminosulfinyl; another preferred embodiment, R ₄ Selected from the group represented by formula (VI):

Wherein Q _{3 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or Unsubstituted C _{1-8 alkylheteroaryl} , substituted or unsubstituted C _1-8 alkylheterocycloalkyl.

R ₇ and R _{8 are} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted Or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl Thionylene, C _1-8 alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl Aminoguanidino, C _1-8 alkanoate group, C _1-8 alkanoguanamine group, C _3-8 alkynylamino group, N-(C _1-8 alkyl) aminosulfonyl group, N, N - bis(C _1-8 alkyl)aminosulfonyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _{1-8 alkylheteroaryl} or substituted or unsubstituted C _1-8 alkylheterocycloalkyl.

In another preferred embodiment, R _{4 is} selected from the group consisting of formula (VII):

Wherein Q _{3 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or Unsubstituted C _{1-8 alkylheteroaryl} , substituted or unsubstituted C _1-8 alkylheterocycloalkyl. R ₇ , R ₈ and R _{11 are} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkyne Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _{1- 8} -alkyl sulfinyl, C _1-8 alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkane Oxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _{1- 8-} alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoylamino, C _3-8 alkynylamino, N-(C _1-8 alkyl)aminosulfonyl, N,N-di(C _1-8 alkyl)aminosulfonyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _{1-8 alkylheteroaryl} or substituted or Unsubstituted C _1-8 alkylheterocycloalkyl.

R ₉ and R _{10 are} independently selected from substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted Aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene a C _1-8 alkylsulfonyl or arylsulfonyl group; the compound of the formula (I) is an inhibitor of tyrosine kinase activity for use in mammals including humans, and they are useful for the treatment and/or prevention of various Disease and discomfort are useful. In particular, the disclosed compounds are kinase inhibitors, especially, but not limited to, c-Met, KDR, Tie-2, FLT3, FGFR3, AbI, Aurora A, c-Src, IGF-IR, ALK, RON, PAK1 , PAK2 and TAK1, and can be used to treat proliferative diseases such as, but not limited to, cancer. Since MET and RON kinases have been shown to play a role in the EMT process, the compounds of formula (I) are useful in the treatment and/or prevention of various diseases and disorders involving EMT, for example, treatment of discomfort caused by EMT irregularities. .

In particular, the compounds of formula (I) provided by the present invention are useful in the treatment of a variety of cancers, including, but not limited to, solid tumors, sarcomas, fibrosarcoma, osteoma, malignant melanoma, retinoblastoma. , rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, hematopoietic malignancy, malignant ascites. More specifically, cancer, including but not limited to, lung cancer, bladder cancer, pancreatic cancer, kidney cancer, stomach cancer, breast cancer, colon cancer, prostate cancer (including bone metastasis), hepatocellular carcinoma, ovarian cancer, esophageal squamous cells Cancer, melanoma, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, glioblastoma.

In another preferred embodiment, the pharmaceutical compositions provided herein comprise a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant. The invention also provides a method of treating a disorder of protein kinase activity comprising administering to a patient a therapeutically effective amount of the above-mentioned pharmaceutical composition.

As defined herein, the term "subject" refers to an animal, preferably a mammal, and preferably a human. This "subject" refers to an article that has been treated, observed, or tested. As used herein, the term "effective therapeutic dose" refers to an active compound or pharmaceutical composition sought by a researcher, veterinarian, medical doctor or other clinician for the biological or pharmaceutical response to an animal or human tissue system, including the disease being treated. Or the symptoms of discomfort are alleviated.

As defined herein, the term "substitued" or "substituent", includes a plurality of substituents (eg, phenylalaninyl, aryl, heterocycloalkyl, heteroaryl), It is usually 1 to 5 substituents, preferably 1 to 3 substituents, and most preferably 1 to 2 substituents.

The compounds of the invention may contain asymmetric carbon atoms. One of ordinary skill in the art appreciates that diastereomeric mixtures can be separated into a single diastereomer based on differences in their physicochemical properties, for example, chromatography or fractional crystallization. Enantiomers are separated by conversion with a suitable optically active compound such as ethanol to convert the mixture of enantiomers into a mixture of diastereomers, followed by separation of the mixture of diastereomers and conversion of the resulting single diastereomer ( For example, hydrolysis) is the corresponding pure enantiomer. All such isomers, including mixtures of diastereomers and pure enantiomers, are part of the present invention.

In general, the compounds provided herein can be synthesized according to the general synthetic route described in Scheme 1, but the compounds provided herein are not limited to synthesis using this route. More specifically, Scheme 1 describes a method for synthesizing a quinazoline compound or a quinoline compound. The following examples more specifically illustrate the general synthetic routes described so that one of ordinary skill in the art can prepare and use the quinazoline or quinoline compounds provided herein.

Scheme 1 summarizes the general synthetic route for the compounds provided herein, for example, Z in formula (I) is NR ₃ R ₄ .

4-Chloro-6,7-dimethoxy-quinazoline (1a) or 4-chloro-6,7-dimethoxy-quinoline (1b) is commercially available or used by one of ordinary skill in the art. Made by conventional methods. In "Step 1" of Scheme 1, nucleophilic substitution of 1a or 1b with aniline 2a, phenol 2b or thiophenol 2c, in the presence of a trialkylamine or an alkali carbonate (for example, triethylamine, potassium carbonate) Under the conditions, it can be done easily.

In "Step 2" of Scheme 1, the treatment with the appropriate reagents and procedures starting from "Step 1", the methyl protecting groups at positions 6 and 7 of Intermediate 3 can be removed. For example, it is treated with boron tribromide at 0 ° C for 1 hour and then at room temperature for 4 hours.

In "Step 3" of Scheme 1, a suitable reagent such as 5 (the leaving group R ₉ is a tosylate, a bromide or an iodide) in the presence of a trialkylamine or an alkali carbonate (for example, triethyl) Treatment of the diphenol intermediate 4 under the conditions of an amine or potassium carbonate can produce a fused ring heterocyclic compound. The choice of solvent and reaction temperature is important for high yields. A generally preferred solvent is DMF or DMSO.

In "Step 4" of Scheme 1, the nitro reduction is accomplished by hydrogenation using palladium on carbon as a catalyst. In addition, zinc powder or iron powder can also be used for the nitro reduction.

In the final step of Scheme 1, aniline 7 is coupled with a suitable acid or its corresponding mercapto chloride 8 under basic conditions such as triethylamine, diisopropylethylamine to give the final product, decylamine 9. The coupling of aniline with acid 8 requires the use of coupling reagents such as HOBt, DCC.

A synthetic route to replace key intermediate 7 is shown in Scheme 2. 10 is coupled with aniline 11a , phenol 11b or thiophenol 11c to produce the corresponding key intermediate 7 , fused ring compound 4-chloro-quinazoline ( 10a ), 4-chloro-quinoline ( 10b ), aniline 11a , The phenols 11b or thiophenols 11c are commercially available or can be conveniently prepared according to known literature or by various methods known to those skilled in the art.

Another alternative route for the preparation of the final product of formula (I) is as shown in Scheme 3, 10 coupling with aniline 12a , phenol 12b or thiophenol 12c to give the corresponding compound of formula (I). The fused ring compound 4-chloro-quinazoline ( 10a ), 4-chloro-quinoline ( 10b ), aniline 12a , phenol 12b or thiophenol 12c are commercially available or prepared according to known literature or techniques in the art. Personnel are conveniently prepared by various known methods

In order to prepare the pharmaceutical composition provided by the present invention, one or more compounds represented by the formula (I) or a salt thereof is used as an active ingredient, and a pharmaceutically acceptable carrier is mixed according to a conventional compounding technique in the field of medicine, and the carrier can be variously used. The various forms depend on the mode of administration of the drug being prepared (eg, orally or by injection). Pharmaceutically acceptable carriers are well known in the art, and the Handbook of Pharmaceutical Excipients, published by the American Medical Association and the British Medical Association, describes certain pharmaceutically acceptable carriers which may be useful for the compounds of the invention. A description of the preparation of the pharmaceutically acceptable carrier used is provided. It may be necessary and/or advantageous to protect sensitive or reactive groups in the molecular structure. Sensitive or reactive groups can be protected by conventional methods of protecting the protecting groups, such as "Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973" and "Organic Synthesis". It is described in TW Greene & PGM Wuts, John Wiley & Sons, 1991 that the protecting group can be conveniently removed in a subsequent step using techniques well known in the art.

Administration of the active compound can be accomplished using any method that delivers the compound to a target, such as a cancer cell. These methods include oral route, rectal administration route, duodenal administration route, parenteral injection (including intravenous injection, subcutaneous injection, intramuscular injection, vascular injection or infusion), topical administration, etc., of course, the application amount of the active compound depends on The subject being treated, the severity of the pain, the mode of administration, and the judgment of the prescribing physician. However, effective dosages range from about 0.001 mg to about 300 mg (preferably, from about 0.01 mg to about 100 mg; more preferably from about 0.1 mg to about 30 mg), and a possible dosage of about 0.001 mg. /kg/day to 300 mg/kg/day (better, from about 0.01 mg/kg/day to about 100 mg/kg/day; more preferably, from about 0.1 mg/kg/day to about 30 mg/day) Kilograms/day).

For example, the pharmaceutical composition is suitable for oral dosage forms such as tablets, capsules, pills, powders, sustained release dosage forms, solutions or suspensions; for parenteral injection forms, such as sterile solutions, suspensions or emulsions; or topical For pharmaceutical forms such as ointments or creams; or for rectal administration such as suppositories. The pharmaceutical compositions are suitable for single administration of precise dosages in unit dosage form. The pharmaceutical composition includes a conventional pharmaceutically acceptable carrier or excipient and a compound as an active ingredient provided by the present invention. In addition, other medical or pharmaceutical agents, carriers or adjuvants, and the like may also be included.

A typical parenteral administration form comprises a solution or suspension of the active compound in a sterile aqueous solution, such as aqueous propylene glycol or dextrose. If necessary, it can be made into a suitable buffer type.

Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents. The pharmaceutical composition may also contain additional ingredients such as perfumes, binders, excipients and the like, if desired. Oral tablets may contain various excipients such as citric acid in combination with various disintegrating agents such as starch, alginic acid and certain complex phthalates, and binding agents such as sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often beneficial for tableting.

Solid components of similar type may also be used for filling soft and hard capsules. Therefore, preferred materials include lactose or milk sugar and ultra high molecular weight polyethylene glycol. If necessary, an oral suspension or elixirs in which the active compound may be combined with various sweetening or flavoring agents, coloring agents or food coloring agents, and if desired, in combination with emulsifiers or suspending agents and dilutions Agents such as water, ethanol, propylene glycol, glycerin or combinations thereof.

The compounds provided herein may also be administered to mammals other than humans. The dosage administered to a mammal will depend on the animal species and the disease or disorder being treated. The compound may be administered to the animal in a capsule, pill, tablet or liquid soak or the like. The compound may also be administered to the animal by injection or implantation. The above formulations were prepared in a conventional manner according to standard veterinary practice. As an alternative therapeutic compound, it may be administered with animal feed. Therefore, in order to mix with normal animal feed, a concentrated feed additive or premix can be prepared.

An example of the use of the invention is: a subject in need of treatment for an epidermal growth factor receptor (EGFR) tyrosine kinase or a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase mediated disorder, the treatment comprising The subject is administered a therapeutically effective amount of any of the above compounds or pharmaceutical compositions. A preferred embodiment for treating cancer, such as brain cancer, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, pancreatic cancer, breast cancer, head cancer, neck cancer, esophageal cancer, prostate cancer, colorectal cancer, gynecology Cancer or thyroid cancer.

detailed description

The following examples are presented to better understand the present invention. Unless otherwise stated, all parts and percentages are by weight and all temperatures are in degrees Celsius.

The following abbreviations are used in the examples: ATP: adenosine triphosphate; DMF: N,N-dimethylformamide; DMSO: dimethyl hydrazine; EtOAc: ethyl acetate; GSR: glutathione-s-transfer Enzyme; Crk, CT10: chicken tumor virus 10; Min: minute; H: hour; Rt: room temperature; SDS: sodium lauryl sulfate; SDS-PAGE: sodium alkyl sulfate polyacrylamide electrophoresis gel; TLC :TLC.

Example 1

5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-tetraoxy-1,3-dioxa-dodecyclo[b]naphthalen-4-yloxy)-phenyl]-decylamine (9a)

Step 1: 4-(4-Amino-2-methyl-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxo-1,3- Diaza-cyclododecane [b]naphthalene

4-Amino-2-fluoro-phenol (1.53 g, 12.0 mmol) was dissolved in 60% NaH (774 mg, 19. Then, mix and stir at room temperature for a few minutes, and add 4-chloro-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclo-10 dioxane [b] naphthalene (2.08g, 6.7mmol) in DMF (40ml) suspension, the reaction mixture was stirred at room temperature for 1-2 h, then diluted with EtOAc and washed with saturated NaHCO ₃ solution and 3 times, washed once, 1 Sin brine, then dried over Na ₂ SO _4, the resulting concentrate was dried in vacuo to give crude product (2.68g, -100%), without purification, was used directly in the next reaction.

^{1 H-NMR (400MHz, DMSO} ): 8.58 (s, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.04 (t, 1H), 6.50 (dd, 2H), 5.40 (br s, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H).

LC / MS theoretical value (M ⁺ H) + 401.4, found 402.5.

Step 2: 5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13, 14-hexahydro-6,9,12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine

Add HATU (15.65 g, 41.2 mmol) and i-Pr ₂ NEt (18 mL, 104 mmol) to 5-(4-fluorophenyl)-4-oxo-1,4 under nitrogen and ice bath temperature a suspension of dihydropyridine-3-carboxylic acid 8d (J. Med. Chem. 2008, 51, 5330-5341) (8.0 g, 34.3 mmol) in anhydrous DMF (56 mL). The mixture became a clear solution and was stirred for another 5 minutes. Then slowly add 4-(4-amino-2-methyl-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxane to the solution. -1,3-diaza-cyclododecane[b]naphthalene 7a (7.9 g, 32.5 mmol). After stirring at room temperature for 3 hours, it was poured into an aqueous solution of 1 N HCl. After solid formation, it was filtered, washed with distilled water, and dried. The resulting crude product was silica gel chromatography, eluting with 1-5% methanol in dichloromethane to give a pale yellow solid 9a (5.9g, 40%), m.p. 188-190 ℃. Further purification by HPLC gave a product with a purity of 97%.

^{1 H NMR (400MHz, DMSO)} δ 13.13 (s, 1H), 12.68 (br s, 1H), 8.62 (m, 2H), 7.97-8.12 (m, 2H), 8.04-7.99 (m, 2H), 7.78 (m, 1H), 7.69 (m, 2H), 7.42 (d, 2H), 7.21 (m, 2H); 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H).

LC / MS theoretical value (M ⁺ H) + 617.6, found 617.5.

Example 2

1-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine

Instead of 5-(4-fluoro), 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (J. Med. Chem. 2008, 51, 5330-5341) was used. Phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid was obtained according to the same procedure and conditions as in Example 1.

LC / MS theoretical value (M ⁺ H) + 617.6, found 617.5.

Example 3

Cyclopropyl-1,1-dicarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxy-1,3-di) Aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-nonylamine (4-fluoro-phenyl)-guanamine

Instead of 5-(4-fluorophenyl)-4-oxo, 1-(4-fluoro-phenylaminoindenyl)-cyclopropylcarboxylic acid (J. Med. Chem. 2008, 51, 5330-5341) was used. -1,4-Dihydro-pyridine-3-carboxylic acid, the title compound was obtained according to the same procedure and conditions as in Example 1.

^{1 H NMR (400MHz, DMSO)} δ 10.33 (s, 1H), 10.08 (s, 1H), 8.56 (m, 1H), 7.82 (m, 2H), 7.69 (m, 2H), 7.28-7.51 (m, 3H), 7.19 (m, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H), 1.47 (s, 4H).

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Example 4

3-(4-Fluoro-phenyl)-2-oxo-imidazole-1-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12 ,15-tetraoxa-1,3-diaza-cyclododecane[b]naphthalene-4-oxy)-phenyl]-decylamine

3-(4-Fluoro-phenyl)-2-oxo-1-imidazole-1-carboxylic acid (J. Med. Chem. 2008, 51, 5330-5341) was used instead of 5-(4-fluorophenyl) 4-Oxo-1,4-dihydropyridine-3-carboxylic acid, the title compound was obtained according to the same procedure and conditions as in Example 3.

LC / MS theoretical value (M ⁺ H) + 608.6, found 608.8.

Example 5

2-(4-Fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid [3-fluoro-4-(7, 8,10,11,13,14-hexahydro-6,9,12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalene-4-oxy)-phenyl] - guanamine

2-(4-Fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (J. Med. Chem. 2008, 51, 5330-5341) Instead of 5-(4-fluorophenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid, the target compound was obtained according to the same procedures and conditions as in Example 2. .

^{1 H NMR (400MHz, DMSO)} δ 10.93 (s, 1H), 8.59 (s, 1H), 7.96 (d, 1H), 7.82 (s, 1H), 7.69 (m, 2H), 7.28-7.51 (m, 4H), 7.19 (m, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H), 3.47 (s, 3H), 2.71 (s, 3H).

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Example 6

2-(4-Fluoro-phenylamino)-5-[5-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxo-1,3-diazepine Hetero-cyclododecane[b]naphthalene-4-oxy)-pyridin-2-yl]-3-methyl-3H-pyrimidin-4-one

Dissolving 2-(4-fluoro-phenylamino)-5-(5-hydroxy-pyridin-2-yl)-3-methyl-3H-pyrimidin-4-one (2.18 g, 7 mmo1) in 60% NaH (774 mg, 19.3 mmol) in anhydrous dimethylformamide (30 mL). Then, mix and stir at room temperature for a few minutes, and add 4-chloro-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclo-10 dioxane [b] naphthalene (2.08g, 6.7mmol) in DMF suspension (40ml), the reaction mixture was stirred at room temperature for 1-2 h, then diluted with EtOAc and washed with saturated NaHCO ₃ solution and 3 times, washed once, 1 Sin brine, then dried over Na ₂ SO _4, the resulting solution was concentrated to dryness in vacuo to give crude product was further purified to give product (3.68g, 90%).

^{1 H-NMR (400MHz, DMSO} ): 9.18 (s, 1H), 8.60 (m, 3H), 8.45 (d, 1H), 7.84 (s, 1H), 7.82 (m, 1H), 7.55 (m, 3H ), 7.21 (m, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H).

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Example 7

5-[5-([1,3]Diox[4,5-g]quinazolin-8-oxy)-pyridin-2-yl]-2-(4-fluoro-phenylamino)-3 -methyl-3H-pyrimidin-4-one

Dissolving 2-(4-fluoro-phenylamino)-5-(5-hydroxy-pyridin-2-yl)-3-methyl-3H-pyrimidin-4-one (2.18 g, 7 mmol) in 60% NaH (774 mg, 19.3 mmol) in anhydrous dimethylformamide (30 mL). After stirring at room temperature for a few minutes, a suspension of dry 8-chloro-[1,3]dioxo[4,5-g]quinazoline (2.08 g, 6.7 mmol) in DMF (40 ml) was added. stirred for 1-2 hours at a temperature, then diluted with EtOAc and washed with saturated NaHCO ₃ solution and 3 times, washed once with brine Sin 1 times and then dried over Na ₂ SO _4, the resulting concentrate was dried in vacuo to give crude product was further purified , got the product (3.68g, 90%).

^{1 H-NMR (400MHz, DMSO} ): 9.18 (s, 1H), 8.60 (m, 3H), 8.45 (d, 1H), 7.84 (s, 1H), 7.82 (m, 1H), 7.55 (m, 3H ), 7.21 (m, 2H), 4.15 (s, 2H).

LC / MS theoretical value (M ⁺ H) + 485.4, found 485.9.

Example 8

5-[5-(2,2-Difluoro-([1,3]dioxo[4,5-g]quinazolin-8-oxy)-pyridin-2-yl]-2-(4- Fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one

Dissolving 2-(4-fluoro-phenylamino)-5-(5-hydroxy-pyridin-2-yl)-3-methyl-3H-pyrimidin-4-one (2.18 g, 7 mmol) in 60% NaH (774 mg, 19.3 mmol) in anhydrous dimethylformamide (30 mL). Then, mix and stir at room temperature for a few minutes, and add 4-chloro-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclo-10 dioxane [b] naphthalene (2.08g, 6.7mmol) in DMF (40ml) suspension of the reaction mixture was stirred at room temperature for 1-2 h, then diluted with EtOAc and washed with saturated NaHCO ₃ solution and 3 times, washed once with brine washed 1 times and then dried over Na ₂ SO _4, the resulting solution was concentrated to dryness in vacuo to give crude product was further purified to give product (3.68g, 90%).

¹ H-NMR (400 MHz, DMSO): 9.18 (s, 1H), 8.78 (m, 3H), 8.55 (d, 1H), 7.84 (s, 1H), 7.82 (m, 1H), 7.55 (m, 3H) ), 7.21 (m, 2H).

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Example 9

5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [4-([1,3]dioxo[4,5-g]quinazoline -8-oxy)-3-fluoro-phenyl]-decylamine

Dissolving 2-(4-fluoro-phenylamino)-5-(5-hydroxy-pyridin-2-yl)-3-methyl-3H-pyrimidin-4-one (2.18 g, 7 mmol) in 60% NaH (774 mg, 19.3 mmol) in anhydrous dimethylformamide (30 mL). Then, mix and stir at room temperature for a few minutes, and add 4-chloro-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclo-10 dioxane [b] naphthalene (2.08g, 6.7mmol) in DMF (40ml) suspension, the reaction mixture was stirred at room temperature for 1-2 h, then diluted with EtOAc and washed with saturated NaHCO ₃ solution and 3 times, washed once, 1 Sin brine, then dried over Na ₂ SO _4, the resulting solution was concentrated to dryness in vacuo to give crude product was further purified to give product (3.68g, 90%).

^{1 H NMR (400MHz, DMSO)} δ 13.43 (s, 1H), 12.98 (br s, 1H), 8.82 (m, 2H), 7.97-8.12 (m, 2H), 8.04-7.99 (m, 2H), 7.78 (m, 1H), 7.69 (m, 2H), 7.42 (d, 2H), 7.21. (m, 2H); 4.65 (s, 4H).

LC / MS theoretical value (M ⁺ H) + 515.4, found 515.5.

Example 10

5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine

Step 1: 1-(3-Nitro-6,7,9,10,12,13-hexahydro-5,8,11,14-tetraoxa-benzocyclododecan-2-yl)-B ketone

1-(6,7,9,10,12,13-hexahydro-5,8,11,14-tetraoxa-benzocyclododec-2-yl)-ethanone (200 mmol, 51.3 g) Dissolved in DCM (750 mL) and cooled to 0 °C. After 20 minutes, nitric acid (90%, 300 mmol, 14 ml) was added dropwise to the cooled reaction mixture. Then, sulfuric acid (96.2%, 300 mmol, 8.75 ml) was added dropwise to the reaction solution at 0 ° C for 40 minutes. Further, nitric acid (200 mmol, 9.4 ml) was added dropwise to the reaction solution for 20 minutes. The reaction mixture was diluted with 300 ml of water and washed with water (3×200 ml), then washed with NaHCO ₃ sat. (4×200 ml, or until neutral). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude mixture was recrystallized from DMF to give 22.5 g of nit. The DMF layer was concentrated and recrystallized from ethyl acetate to give 8.75 g. The ethyl acetate layer was concentrated and purified using a silica gel column eluting 20% EtOAc / hexanes to afford The total yield was 36 g, (about 60%).

^{1 H NMR (400MHz, DMSO)} δ 7.82 (s, 1H), 7.61 (s, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H), 2.71 (s, 3H) .

LC/MS theoretical value (M+H) ⁺ 312.3, found 312.5

Step 2: 1-(3-Amino-6,7,9,10,12,13-hexahydro-5,8,11,14-tetraoxa-benzocyclododec-2-yl)-ethanone

Iron powder (477 mmol, 27 g), ammonium acetate (500 mmol, 31 g), 1-(3-nitro-6,7,9,10,12,13-hexahydro-5,8,11,14-tetraoxy- A mixture of benzocyclododec-2-yl)-ethanone (120 mmol, 36 g), toluene (500 ml) and water (500 ml) was refluxed overnight or until the reaction was completed. The mixture was filtered through celite and washed with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of NaCl, and dried over Na ₂ SO ₄ and concentrated to give a product.

^{1 H NMR (400MHz, DMSO)} δ 7.82 (s, 1H), 7.61 (s, 1H), 5.45 (s, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H) , 2.71 (s, 3H).

LC / MS theoretical value (M ⁺ H) + 282.3, found 282.5.

Step 3: 7,8,10,11,13,14-hexahydro-1H-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-one

1-(3-Amino-6,7,9,10,12,13-hexahydro-5,8,11,14-tetraoxa-benzocyclododec-2-yl)-ethanone (108 mmol, To a solution of 29.3 g of DME (700 ml), sodium methoxide (432 mmol, 23.35 g) was added. The resulting mixture was stirred for 30 minutes. Ethyl formate (540 mmol, 44 ml) was added and the mixture was stirred overnight. (The reaction was monitored by LC/MS, and if it was not completely reacted, additional sodium methoxide was added). After completion of the reaction, the mixture was hydrated (40 ml) and acidified to neutral with 1M HCl. The precipitate was filtered and washed with water and dried in vacuo to give 22 g (72%) of 7,8,10,11,13,14-hexahydro-1H-6,9,12,15-tetraoxa-1-aza-cyclo- Alkane [b]naphthalene-4-one.

^{1 H NMR (400MHz, DMSO)} δ 8.58 (s, 1H), 7.52 (s, 1H), 7.22 (s, 1H), 7.12 (m, 1H), 4.35 (s, 4H), 3.87 (d, 4H) , 3.62 (s, 4H).

LC / MS theoretical value (M ⁺ H) + 292.3, found 292.5.

Step 4: 4-(2-Fluoro-4-nitro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza -cyclododecane [b]naphthalene

A round bottom flask equipped with a magnetic stirrer was charged with 7,8,10,11,13,14-hexahydro-1H-6,9,12,15-tetraoxa-1-aza-cyclododecane [b Naphthyl-4-one (12.2 g, 43.3 mmol, 1.0 eq), acetonitrile (150 ml), DMF (150 ml) and EtOAc (28.2 g, 86.5 mmol, 2.0 eq). The resulting mixture was stirred at room temperature for 30 minutes and then, for 10 minutes, 1,2-fluoro-4-nitro-benzene (7.57 g, 47.6 mmol, 1.1 eq). After 2 hours, the reaction was completed 75%, acetonitrile and DMF were removed, then poured into ice water. The solid was filtered, dried, and further passed through a column (purchased from Biotage). The eluent was 1:3 ethyl acetate / n-hexane. The solvent was removed to give 4-(2-fluoro-4-nitro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxy- 1-Aza-cyclododecane [b]naphthalene (7.4 g, yield 41%).

^{1 H-NMR (400MHz, DMSO} ): 8.58 (s, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.04 (t, 1H), 6.88 (m, 1H), 6.50 (m, 2H ), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H).

LC / MS theoretical value (M ⁺ H) + 431.4, found 431.5.

Step 5: 4-(4-Amino-2-fluoro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza- Cyclododecane [b]naphthalene

4-(2-Fluoro-4-nitro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclo Dodecane[b]naphthalene (0.800g, 1.6mmol, 1.0eq.), DMF (50ml), EtoAc (50ml), MeOH (50ml), TEA (5ml) and 10% Pd/C (200mg) In a hydrogen reactor, hydrogenation was carried out overnight at 35 psi. The Pd was removed by filtration, and then the solvent was removed to give 4-(4-amino-2-fluoro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15- as a yellow solid. Tetraoxa-1-aza-cyclododecane [b]naphthalene (0.78 g, yield 99%).

^{1 H-NMR (400MHz, DMSO} ): 8.58 (s, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.04 (t, 1H), 6.88 (m, 1H), 6.50 (m, 2H ), 5.40 (br s, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H).

LC / MS theoretical value (M ⁺ H) + 401.4, found 401.5.

Step 6: 5-(4-Fluoro-phenyl 1)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13 ,14-hexahydrogen -6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine

5-(4-Fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid 8d (J. Med. Chem. 2008, 51, 5330-5341) (8.0 g, 34.3 mmol) A suspension was added to dry DMF (56 mL), then HATU (15.65 g, 41.2 mmol) and i-Pr ₂ NEt (18 mL, 104 mmol). After stirring for 5 minutes, the mixture became clear, and 4-(4-amino-2-fluoro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15 was slowly added. -Tetra-1-aza-cyclododecane[b]naphthalene 7a (7.9 g, 32.5 mmol). After the reaction mixture was stirred at room temperature for 3 hours, poured into 1N HCl. The formed solid was filtered, washed with distilled water and dried. The crude product was purified by silica gel chromatography, eluent 1-5% CH ₂ Cl ₂ MeOH solution to give a pale yellow solid 9a (5.9g, 40%), mp: 188-190 ℃. The purity after purification by HPLC was 97%.

^{1 H NMR (400MHz, DMSO)} δ 13.13 (s, 1H), 12.68 (br s, 1H), 8.62 (m, 2H), 7.97-8.12 (m, 2H), 8.04-7.99 (m, 2H), 7.78 (m, 1H), 7.69 (m, 2H), 7.42 (d, 2H), 7.21 (m, 2H); 6.89 (m, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 ( s, 4H).

<RTI ID=0.0></RTI>^<RTIID=0.0></RTI>

Example 11

1-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine

Substituting 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid for 5-(4-fluorophenyl)-4-oxo-1,4-dihydrogen -pyridine-3-carboxylic acid, the title compound was obtained according to the procedure and conditions described in Example 6.

<RTI ID=0.0></RTI>^<RTIID=0.0></RTI>

Example 12

2-(4-Fluoro-phenyl 1)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid [3-fluoro-4-(7, 8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine

Substituting 2-(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3 dihydro-1H-pyrazole-4-carboxylic acid for 5-(4-fluorophenyl) 4-Oxo-1,4-dihydro-pyridine-3-carboxylic acid, the title compound was obtained according to the procedure and conditions described in Example 6.

^{1 H NMR (400MHz, DMSO)} δ 10.93 (s, 1H), 8.59 (s, 1H), 7.96 (d, 1H), 7.82 (s, 1H), 7.69 (m, 2H), 7.28-7.51 (m, 4H), 7.19 (m, 1H), 6.46 (m, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H), 3.47 (s, 3H), 2.71 (s, 3H) ).

<RTI ID=0.0></RTI></RTI>^<RTIID=0.0></RTI>

Example 13

1-[2-(4-Fluoro-phenyl)-ethinyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12 ,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine

Substituting 1-(4-fluoro-phenylaminoindenyl)-cyclopropanecarboxylic acid for 5-(4-fluorophenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid according to the implementation The procedure and conditions described in Example 6 gave the target compound.

^{1 H NMR (400MHz, DMSO)} δ 10.33 (s, 1H), 10.08 (s, 1H), 8.56 (m, 1H), 7.82 (m, 2H), 7.69 (m, 2H), 7.28-7.51 (m, 3H), 7.19 (m, 2H), 6.88 (m, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H), 1.47 (s, 4H).

LC / MS theoretical value (M ⁺ H) + 606.6, found 606.7.

Example 14

3-(4-Fluoro-phenyl 1)-2-oxo-imidazolidine-1-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9 ,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine

Substituting 3-(4-fluoro-phenyl)-2-oxo-imidazolidine-1-carboxylic acid for 5-(4-fluorophenyl)-4-oxo-1,4-dihydro-pyridine-3 -carboxylic acid, the title compound was obtained according to the procedure and conditions described in Example 6.

<RTI ID=0.0></RTI></RTI>^<RTIID=0.0></RTI>

Pharmacological test

The following assays demonstrate that certain compounds of the invention potently inhibit intracellular c-Met phosphorylation and c-Met activity in vivo, exhibiting dose-related anti-tumor activity in certain xenograft models.

Biological testing

Cloning of the kinase domain of human c-Met (from glycine 966 to serine 1390, NCBI NM_000245) HT (Invitrogen, Carlsbad, CA) on the carrier. Use Bac-to- The system (Invitrogen) transcribes the His-c-Met kinase domain onto baculovirus DNA. SF9 cells are infected with recombinant baculovirus. The infected cells were centrifuged and collected and stored at -80 °C. Cells were lysed with buffer A (40 mM tris(hydroxymethyl)aminomethane (abbreviated as Tris), pH 7.5, 500 mM sodium chloride, 20% glycerol, and 10 mM imidazole). The cell lysate was homogenized and centrifuged. The supernatant was incubated with nickel-nitrogen triacetic acid (Ni-NTA) resin and applied to the column. The protein was eluted with buffer B (buffer A plus 0.3 M imidazole) and the eluate containing the c-Met fragment was pooled and loaded A 200 column (Amershan Bioscience, Piscataway, NJ) was stripped with buffer C (40 mM Tris, pH 7.5, 250 mM sodium chloride, 10% glycerol).

Hepatocyte growth factor (HGF) stimulated NCI-H460 Met (pY1349 mutation) cell level ELISA assay NCI-H460 cells (purchased from ATCC) in 10% fetal bovine serum (FBS) in RPMI 1640 medium (Invitrogen) Incubate and lay flat on a 96-well flat bottom plate (70% pre-fusion) at a density of 80 μL per well containing approximately 20,000 cells, then the cells are in a cell culture incubator (5% CO ₂ , 95% relative humidity (RH) Incubate overnight at 37 ° C and allow to adsorb onto the plate. The next morning, the cells were washed with 2 volumes of low serum culture (RSM) (RPMI 1640 medium supplemented with 0.5% fetal bovine serum (FBS)). After removing the final clearing solution, 80 μL of RSM was added to each well of the cell plate. The cell plates were incubated for 2.5 hours in a cell culture incubator and then a nominal dose of compound was added. The compound was first dissolved in 100% DMSO at a concentration of 10 mM and then diluted to 100 [mu]M with RSM containing 2% DMSO. Subsequently, serial dilutions (1:3) to a range of 100 μM to 0.005 μM. The cells were dosed, and 20 μL of the spare compound solution was added to give a final concentration of DMSO of 0.4%, and the final concentration of the compound was in the range of 20 to 0.001 μM. After each group of compounds was added, the cell plates were gently shaken and then placed in a cell culture incubator for 30 minutes. After the drug was administered, 20 μL of hepatocyte growth factor (HGF) was added to each well, and the final concentration was 100 ng/mL of low serum culture medium (except for negative control wells (MIN wells), which was stimulated with 20 μL of low serum culture medium). After incubating for 10 minutes in a cell culture incubator, the liquid was removed and 50 μL of ice-cold Meso Scale containing phosphatase I and II and protease inhibitors (Sigma, St. Louis, MO) was added. (MSD, Gaithersburg, Maryland) IX Lysis Buffer (IX Lysis Buffer, 150 mM NaCl, 20 mM Tris, pH 7.5, 1 mM EDTA, 1 mM ethylene glycol tetraacetic acid and 1%) X-100), lysing cells. After cleavage at room temperature for 30 min, transfer the cleavage product and utilize Multi-point 96-well plates capture signals.

Met phosphorylation 4 spot plates were blocked with BSA (30 mg/ml BlockA in IX Tris wash buffer) and then washed once with Tris wash buffer. After 2 hours of capture at room temperature, from The lysate was removed on the plate and the plate was washed with IX Tris wash buffer. 25 μL of 5 nM sulfur-labeled anti-total Met antibody after removal of stain (detection antibody Preparation: IX Tris wash buffer supplemented with 10 mg/mL BSA and 0.1% blocking agent DR ( )) join In the hole of the plate. After 1 hour of capture at room temperature, wash with IX Tris wash buffer Plate well, then add 150 μL of IX reading buffer T (with surfactant, ). Immediately after adding reading buffer, use SECTOR 6000 The microplate was analyzed by an Imager microplate reader. The four-parameter equation was fitted by the 10 dose points and the corresponding response values to the percentage of the "maximum" and "minimum" values, and the relative IC50 values were calculated using the MSD activity unit. The minimum Significant Ratio of the detection method is 2.06. All of the compounds tested had IC50 of less than 0.2 [mu]M (as shown in Table 1). For example, in Example 1, the average (N=6) IC50 value (50% inhibitory concentration) was 0.0352 μM, indicating that the compound is effective in inhibiting c-Met phosphorylation in cells.

c-Met in vivo targeted inhibition assay

SL14 cells (derived from PHS, overexpressing human hepatocyte growth factor (HGF) and human c-Met) were cultured and expanded in growth medium (Dulbecco's modified Eagle medium, supplement) containing 10% calf serum. The cells were collected and washed twice with phosphate buffer, 2X10 ⁶ cells with ^{BD Matrigel TM matrix (BD Bioscience,} Franklin, NJ) mixed in equal volumes, into the armpit of nude mice (athymic nude, from Harlan, Indianapolis, IN After 8 days, the compound (consisting of 10% gum arabic, or 1% carboxymethylcellulose/0.5% sodium lauryl sulfate/0.05% antifoaming agent, a suspension) is administered to the animal by intragastric administration. The dose was 50 mg/kg, the animals were sacrificed after 2 hours, tumors were collected and stored frozen.

Frozen tumors were crushed with motar-pastel. The comminuted tissue was transferred to contain Lysing Matrix D beads (MP Biomedicals, Solon, OH) and 600 μL of lysis buffer (RIPA buffer containing 50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1% NP-40, 0.5% oxygen). Sodium cholate, 0.1% SDS, from a test tube of Boston Bioproducts). use Cell Disrupter (MP Biomedicals) destroys tissue and lyses cells. Transfer the lysate to a clean tube with a 20 gauge needle. The protein concentration was determined by the Bradford method. Tumor lysate The phosphor-Met ELISA plate (fluorescent plate), the c-Met phosphorylation level determination method and the H460 cell level ELISA method. At a dose of 50 mg/kg, the SL14 in vivo inhibition rate of all of the assay compounds was equal to or greater than 50%. For example, the compound obtained in Example 1 is a potent inhibitor of c-Met phosphorylation, and the ED50 value (a dose of 2.9 mg/kg in which c-Met is inhibited by 50% in the tumor) indicates that it is a potent inhibitor of c-Met in vivo.

Transplanted tumor model

Human glioma cell line U87MG, human gastric cancer cell line MKN45, human non-small cell lung cancer cell line H441, and human renal cell carcinoma cell line Caki-1 were expanded, cultured, and subcutaneously injected into the lateral abdomen of the athymic nude mouse. Test compounds were prepared with appropriate excipients and administered intragastrically after tumor formation (after 7-21 days of implantation). During the course of treatment, tumor volume was measured twice a week to determine the tumor response. The tumor volume inhibition rate (%, growth inhibition) was determined by comparing the treatment group with the blank control group, and the body weight was measured as a general toxicity test. Among these models, the compound of Example 1 showed excellent dose-dependent antitumor activity. For example, at a dose of 30 mg/kg (oral (PO), twice daily (BID) x 35), the inhibition rate of the compound of Example 1 against U87MG tumor growth was 59%. At a dose of 60 mg/kg (PO, BID x 35), the inhibition rate of U87MG tumor growth was 82%. The dose of 120 mg / kg (PO, BID × 35), the inhibition rate of U87MG tumor growth is 92%

In the tumor xenograft model associated with c-Met, c-Met overexpression is a common feature of many human tumors, including lung cancer, breast cancer, colon cancer, gastric cancer, kidney cancer, pancreatic cancer, and head and neck cancer (1, 2). Mutations in the c-Met kinase domain are initiated as tumor inducers, such as hereditary papillary renal cell carcinoma, childhood liver cancer, and gastric cancer (3-7). Pfizer's c-Met inhibitors have shown therapeutic effects on many human tumors, including U87MG, GTL16, H441, Caki-1, and PC3 (8).

1. Christinsen, JG., Burrows, J., and Salgia, R. Cancer Letters 225: 1-26, 2005.

2. Birchmeier, C, Birchmeier, W., Gherardi, E., and Vande Woude, GF. Nat Rev MoI Cell Biol 4: 915-925, 2003.

3. Di Renzo, MF., Olivero, M., Martone, T. Et al. Oncogene 19: 1547-1555, 2000.

4. Lee, JH., Han, SU, Cho, H. et al. Oncogene 19: 4947-4953, 2000.

5. Ma, PC, Kijima, T., Maulik, G. et al. Cancer Res 63: 6272-6281, 2003. 6. Park, WS., Dong, SM., Kim, SY. et al. Cancer Res 59 :307-310,1999.

7. Schmidt, L., Duh, FM., Chen, F., et al. Nat Genet 16: 68-73, 1997.

8. Zou, HY., Li, Qiuhua., Lee, JH., et al. Cancer Res 67: 4408-4417, 2007.

The compounds provided herein are preferably administered as a pharmaceutical composition by a variety of means. Most preferably, the pharmaceutical composition is administered orally. Such pharmaceutical compositions and preparation processes are well known in the art, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, A. Gennaro, et al, eds., 19 ^th Ed., Mack Publishing Co., 1995). The compound of the formula (I) is effective over a relatively wide range of administration.

For example, the daily dose is usually from about 1 mg to about 200 mg (total total daily dose), preferably, the total daily dose is from 1 mg to 150 mg, more preferably, the total daily dose is from 1 mg to 50 mg. In some cases, a dose level below the lower end of the above range may still be sufficient, while in other cases, a large dose is still available. The above dosage ranges do not limit the scope of protection of the invention in any way. It is to be understood that the actual dosage of the compound provided by the present invention will be determined by the physician according to the circumstances, including the condition of the treatment, the choice of mode of administration, the compound and compound to be administered, the age, the weight, the response of the particular patient, and the patient. The severity of the symptoms.

Claims (83)

a compound having the activity of regulating c-Met kinase represented by the following formula (I), Or their pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein, A is a 5-18 membered ring; R ₁ is independently selected from hydrogen, halo, a substituted or unsubstituted C _1-8 alkyl A substituted or unsubstituted C _2-8 alkenyl group, a substituted or unsubstituted C _2-8 alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic aryl group, a substituted or unsubstituted hetero Cycloalkyl, C _1-8 alkyl fluorenyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkyl sulfonyl, aryl sulfonyl, cyano , nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio , N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _3-8 alkynylamino, N-(C _1-8 alkyl)aminosulfinyl or N,N-di(C _1-8 alkyl)aminosulfinyl; m is an integer from 0 to 3; A ₁ and A _{2 are} independently selected from: =N- or =C(R ₂ )-; R _{2 is} selected from -H, halogen, trichloromethyl, -CN, -NO ₂ , -NH ₂ , -OR ₅ , -NR ₅ R ₆ , -S(O) _0-2 R ₅ , -SO ₂ NR ₅ R ₆ , -CO ₂ R ₅ , -C(O)NR ₅ R ₆ , -N(R ₃ )SO ₂ R ₅ , -N(R ₅ )C(O)R ₆ , -N(R ₅ )CO ₂ R ₆ , -C(O)R ₅ or a substituted or unsubstituted lower An alkyl group; wherein R ₅ and R _{6 are} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _{2 - 8} alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _{1- 8} alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio, N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _{1-8 alkylheteroaryl} or substituted or unsubstituted C _1-8 alkane a heterocycloalkyl group; n is an integer from 0 to 4; A _{3 is} selected from: =N-, =C(H)- or =C(CN)-; X is selected from NR ₂₀ , CHR ₂₁ , O or S; The R ₂₀ and R _{21 are} independently selected from H or C _1-8 alkyl; Z is selected from the group consisting of NR ₃ R ₄ or formula (II): R _{3 is} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted C _1-8 alkanoyl, substituted or unsubstituted C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinylene, C _1-8 alkylsulfonyl, arylsulfonyl, cyano , nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio , N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, C _1-8 alkanoyl, C _3-8 alkynylamino, N-(C _1-8 alkyl)aminosulfonyl or N,N-di(C _1-8 alkyl)aminosulfonyl; R ₉ and R _{10 are} independently selected Self-substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted Heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl sulfinyl, C _1-8 alkyl sulfonate sulfo acyl or aryl acyl group; R ₄ is selected from formula (III), formula (IV), formula (V), formula (VI) Of formula (VII) represented by the group: Where B ₁ is Q ₁ is C(R ₅ ) ₂ ; B ₂ is NHQ ₂ ; Q _{2 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, substituted or Unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _{1-8 alkylheteroaryl} or substituted or unsubstituted C _1-8 alkylheterocycloalkyl; or, B ₁ and B ₂ together form a 5-10 membered substituted or unsubstituted heterocyclic aryl or substituted or unsubstituted heterocycloalkyl; Q _{3 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted Or unsubstituted heterocycloalkyl, substituted or unsubstituted C _1-8 alkylaryl, substituted or unsubstituted C _{1-8 alkylheteroaryl} or substituted or unsubstituted C _1-8 alkyl Heterocycloalkyl; X _{1 is} selected from NR ₈ or CR ₇ R ₈ ; R ₇ , R ₈ and R _{11 are} independently selected from hydrogen, halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _{1- 8} -alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkylsulfinyl, C _1-8 alkylsulfonate , N-(C _1-8 alkyl)aminoindenyl, N,N-di(C _1-8 alkyl)aminoindenyl, C _1-8 alkanoate, arylsulfonyl, cyano , nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-8 alkoxy, C _2-8 alkenyloxy, C _2-8 alkynyloxy, C _1-8 alkylthio , C _1-8 alkanoguanamine, C _3-8 alkynylamino, N-(C _1-8 alkyl)aminosulfonyl, N,N-di(C _1-8 alkyl)aminosulfonate A substituted or unsubstituted C _1-8 alkylaryl group, a substituted or unsubstituted C _1-8 alkylheteroaryl group or a substituted or unsubstituted C _1-8 alkylheterocycloalkyl group. The compound of claim 1, wherein A is a 6-18 membered ring. The compound according to claim 1, wherein A is a 5-8 membered ring. The compound of claim 1, wherein A is a 5 or 12 membered ring. The compound according to claim 1, wherein A is a 12-membered heterocyclic ring. The compound according to claim 5, wherein the 12-membered heterocyclic ring contains 1, 2, 3 or 4 oxygen atoms. The compound according to claim 5, wherein the 12-membered heterocyclic ring contains 4 oxygen atoms. The compound of claim 1, wherein the A is . The compound according to any one of claims 1 to 8, wherein the R _{1 is} selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C _1-5 alkyl, substituted or unsubstituted C _{2 -5} alkenyl, substituted or unsubstituted C _2-5 alkynyl, C _1-5 alkanoyl, C _1-5 alkoxycarbonyl, C _1-5 alkyl sulfinylene, C _1-5 alkane Sulfosyl, C _1-5 alkoxy, C _2-5 alkenyloxy, C _2-5 alkynyloxy, C _1-5 alkylthio, N-(C _1-5 alkyl)aminosulfonium , N,N-di(C _1-5 alkyl)aminosulfonyl, C _1-5 alkanoate, C _1-5 alkanoyl, C _3-6 alkynylamino, N-( C _1-5 alkyl)aminosulfonyl or N,N-di(C _1-5 alkyl)aminosulfonyl. The compound according to any one of claims 1 to 8, wherein the R _{1 is} selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted Or unsubstituted heterocycloalkyl, arylsulfonyl, cyano, nitro, hydroxy, amine, carboxyl, oxo or aminoguanidino. The compound according to any one of claims 1 to 8, wherein the R _{1 is} selected from hydrogen or halogen. The compound according to any one of claims 1 to 8, wherein the R ₁ is hydrogen. The compound according to any one of claims 1 to 8, wherein the m is an integer of 0-2. The compound according to any one of claims 1 to 8, wherein the m is 0. The compound according to any one of claims 1 to 8, wherein the A ₂ is =N-. The compound according to any one of claims 1 to 8, wherein A ₁ is =C(R ₂ )-, and A ₂ is =N-. The compound according to any one of claims 1 to 8, wherein A ₁ is =CH- and A ₂ is =N-. The compound according to any one of claims 1 to 8, wherein both A ₁ and A ₂ are =C(R ₂ )-. The compound according to any one of claims 1 to 8, wherein the A ₁ and A ₂ are both =CH-. The compound according to any one of claims 1 to 8, wherein the A _{3 is} selected from the group consisting of =N- or =C(H)-. The compound according to any one of claims 1 to 8, wherein X is selected from NR ₂₀ or CHR ₂₁ , and R ₂₀ and R _{21 are} independently selected from H or C _1-3 alkyl. The compound according to any one of claims 1 to 8, wherein X is selected from NR ₂₀ or CHR ₂₁ and R ₂₀ and R ₂₁ are both H. The compound of any one of claims 1-8, wherein the X is selected from the group consisting of oxygen or sulfur. The compound according to any one of claims 1 to 8, wherein the X is oxygen. The compound according to any one of claims 1 to 8, wherein the R _{2 is} selected from the group consisting of -H, halogen, trihalomethyl, -CN, -NO ₂ or -NH ₂ . The compound according to any one of claims 1 to 8, wherein the R _{2 is} selected from -H or halogen. The compound according to any one of claims 1 to 8, wherein the R _{2 is} selected from fluorine or hydrogen. The compound according to any one of claims 1 to 8, wherein the R _{2 is} selected from the group consisting of -OR ₅ , -NR ₅ R ₆ , -S(O) _0-2 R ₅ , -SO ₂ NR ₅ R ₆ , -CO ₂ R ₅ , -C(O)NR ₅ R ₆ , -N(R ₃ )SO ₂ R ₅ , -N(R ₅ )C(O)R ₆ , -N(R ₅ ) CO ₂ R ₆ or -C(O)R ₅ . The compound according to any one of claims 1 to 8, wherein the R _{2 is} selected from the group consisting of a substituted lower alkyl group, -CN, -NO ₂ or -NH ₂ . The compound according to any one of claims 1 to 8, wherein the R _{3 is} selected from a substituted or unsubstituted C _1-5 alkyl group, a substituted or unsubstituted C _2-5 alkenyl group. , substituted or unsubstituted C _2-5 alkynyl, C _1-5 alkyl fluorenyl, substituted or unsubstituted C _1-5 alkoxycarbonyl, C _1-5 alkyl sulfinylene, C _1-5 Alkylsulfonyl, C _1-5 alkoxy, C _2-5 alkenyloxy, C _2-5 alkynyloxy, C _1-5 alkylthio, N-(C _1-5 alkyl)aminosulfonate Mercapto, N,N-di(C _1-5 alkyl)aminosulfonyl, C _1-5 alkanoate, C _1-5 alkanoyl, C _3-6 alkynylamino, N- (C _1-5 alkyl)aminosulfonyl or N,N-di(C _1-5 alkyl)aminosulfinyl. The compound according to any one of claims 1 to 8, wherein the R _{3 is} selected from a substituted or unsubstituted C _1-3 alkyl group, a substituted or unsubstituted C _2-3 alkenyl group. , substituted or unsubstituted C _2-3 alkynyl, C _1-3 alkyl fluorenyl, substituted or unsubstituted C _1-3 alkoxycarbonyl, C _1-3 alkyl sulfinylene, C _1-3 Alkylsulfonyl, C _1-3 alkoxy, C _2-3 alkenyloxy, C _2-3 alkynyloxy, C _1-3 alkylthio, N-(C _1-3 alkyl)aminosulfonate Mercapto, N,N-di(C _1-3 alkyl)aminosulfonyl, C _1-3 alkanoate, C _1-3 alkanoyl, N-(C _1-3 alkyl)amino Sulfonyl, C _4-6 alkynylamino or N,N-di(C _1-3 alkyl)aminosulfinyl. The compound according to any one of claims 1 to 8, wherein the R _{3 is} selected from a substituted or unsubstituted C _1-3 alkoxycarbonyl group, a C _1-3 alkyl sulfoxide. a group, a C _1-3 alkylsulfonyl group, a C _1-3 alkoxy group, a C _2-3 alkenyloxy group, a C _2-3 alkynyloxy group or a C _1-3 alkylthio group. The compound according to any one of claims 1 to 8, wherein the R ₃ is hydrogen. The compound according to any one of claims 1 to 8, wherein the Q ₁ is CH ₂ . The compound according to any one of claims 1 to 8, wherein the Q ₂ is a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic aryl group or a substituted or unsubstituted hetero atom. Cycloalkyl. The compound of any one of claims 1-8, wherein the Q _{2 is} selected from the group consisting of halophenyl. The compound of any one of claims 1 to 8, wherein the Q ₂ is a fluorophenyl group. The compound according to any one of claims 1 to 8, wherein the Q _{2 is} selected from a substituted or unsubstituted C _1-5 alkylaryl group, a substituted or unsubstituted C _1-5 Alkylheteroaryl or substituted or unsubstituted C _1-5 alkylheterocycloalkyl. The compound according to any one of claims 1 to 8, wherein the B ₁ and B ₂ together form a 5-10 membered substituted or unsubstituted heterocyclic aryl group, or substituted or unsubstituted. Heterocycloalkyl. The compound of any one of claims 1 to 8, wherein the Q _{3 is} selected from a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic aryl group. The compound according to any one of claims 1 to 8, wherein the Q _{3 is} selected from a substituted or unsubstituted phenyl group. The compound according to any one of claims 1 to 8, wherein the Q _{3 is} selected from a phenyl group or a halogenated phenyl group. The compound according to any one of claims 1 to 8, wherein the Q _{3 is} selected from the group consisting of fluorophenyl groups. The compound according to any one of claims _{1 to 8} , wherein the X _{1 is} selected from the group consisting of NR ₈ . The compound according to any one of claims 1 to 8, wherein the X _{1 is} selected from the group consisting of NC _1-6 alkyl groups. The compound according to any one of claims 1 to 8, wherein the X ₁ is NCH ₃ . The compound according to any one of claims 1 to 8, wherein R ₇ , R ₈ and R _{11 are} independently selected from hydrogen, halogen or substituted or unsubstituted C _1-8 alkyl. . The compound according to any one of claims 1 to 8, wherein R ₇ , R ₈ and R _{11 are} independently selected from substituted or unsubstituted C _2-5 alkenyl, substituted or unsubstituted Substituted C _2-5 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycloalkyl, C _1-5 alkanoyl, C _1-5 alkane Oxycarbonyl, N-(C _1-5 alkyl)aminoindenyl, N,N-di(C _1-5 alkyl)aminoindenyl, C _1-5 alkanoate, arylsulfonyl, Cyano, nitro, hydroxy, amine, carboxyl, oxo, aminoguanidino, C _1-5 alkoxy, C _2-5 alkenyloxy, C _2-5 alkynyloxy, C _1-5 alkane Sulfuryl, C _1-5 alkanoguanamine, C _3-5 alkynylamino, N-(C _1-5 alkyl)aminosulfonyl, N,N-di(C _1-5 alkyl)amino Sulfhydryl, substituted or unsubstituted C _1-5 alkylaryl, substituted or unsubstituted C _1-5 alkylheteroaryl, or substituted or unsubstituted C _1-5 alkylheterocycloalkyl . The compound according to any one of claims 1 to 8, wherein the R ₇ , R ₈ and R ₁₁ are hydrogen. The compound according to any one of claims 1 to 8, wherein the R ₇ is a C _1-6 alkyl group. The compound according to any one of claims 1 to 8, wherein the R ₇ is -CH ₃ . The compound according to any one of claims 1 to 8, wherein the R _{7 is} selected from a phenyl group or a halogenated phenyl group. The compound according to any one of claims 1 to 8, wherein the R _{7 is} selected from the group consisting of fluorophenyl groups. The compound according to any one of claims 1 to 8, wherein the R ₈ is hydrogen. The compound according to any one of claims 1 to 8, wherein R ₅ and R _{6 are} independently selected from hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl or substituted or unsubstituted C _2-6 alkynyl. The compound according to any one of claims 1 to 8, wherein R ₅ and R ₆ are each hydrogen. The compound according to any one of claims 1 to 8, wherein R ₅ and R _{6 are} independently selected from C _1-5 alkanoyl, C _1-5 alkoxycarbonyl, C _1-5 alkyl sulfinylene or C _1-5 alkyl sulfonyl. The compound according to any one of claims 1 to 8, wherein R ₅ and R _{6 are} independently selected from the group consisting of a cyano group, a nitro group, a hydroxyl group, an amine group, a carboxyl group, an oxo group or an amino group.醯基. The compound according to any one of claims 1 to 8, wherein R ₅ and R _{6 are} independently selected from a cyano group, a nitro group, a hydroxyl group or an amine group. The compound according to any one of claims 1 to 8, wherein R ₉ and R _{10 are} independently selected from substituted or unsubstituted C _1-6 alkyl or substituted or unsubstituted C _6-12 aryl. The compound according to any one of claims 1 to 8, wherein R ₉ and R _{10 are} independently selected from halogenated C _6-12 aryl or unsubstituted C _1-6 alkyl. . The compound according to any one of claims 1 to 8, wherein R ₉ and R _{10 are} independently selected from methyl or halophenyl. The compound according to any one of claims 1 to 8, wherein R ₉ and R _{10 are} independently selected from methyl or fluorophenyl. A compound selected from the group consisting of: 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8) ,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododecane[b]naphthalene-4-oxy)-phenyl]- Indoleamine; ● 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13 ,14-hexahydro-6,9,12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine; [2-(4-Fluoro-phenyl)-ethinyl]cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15 -tetraoxo-1,3-diaza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine; ● 3-(4-fluoro-phenyl)-2-oxo -Imidazoline-1-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxo-1,3-diaza- Cyclododecane[b]naphthalen-4-yloxy)-phenyl]-guanamine; ● 2-(4-fluoro-phenyl)-1.5-dimethyl-3-oxo-2,3-di Hydrogen-1H-pyrazole-4-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxy-1,3-di) Aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-guanamine; ● 2-(4-fluoro-phenylamino)-5-[5-(7,8,10, 11,13,14-hexahydro-6,9,12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalen-4-yloxy)-pyridin-2-yl] 3-methyl-3H-pyrimidin-4-one; ● 5-[5-([1,3]dioxo[4,5-g]quinazolin-8-oxy)-pyridin-2-yl ]-2-(4-fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one; ● 5-[5-(2,2-difluoro-[1,3]dioxo[4 , 5-g]quinazoline-8-oxy)-pyridin-2-yl]-2-(4-fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one; ● 5- (4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [4-([1,3]dioxo[4,5-g]quinazoline-8 -oxy)-3-fluoro-phenyl]-nonylamine; ● 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro -4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-oxy)- Phenyl]-nonylamine; ● 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10) ,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine; ● 2 -(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid [3-fluoro-4-(7,8) ,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalen-4-yloxy)-phenyl]-decylamine; ● 1-[2-(4-Fluoro-phenyl)-ethenyl]cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9, 12,15-tetraoxa-1-aza-cyclode Alkane [b]naphthalen-4-yloxy)-phenyl]-decylamine; ● 3-(4-fluoro-phenyl)-2-oxo-imidazoline-1-carboxylic acid [3-fluoro-4- (7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-oxy)-phenyl] -decylamine 5-[5-(2,2-difluoro-[1,3]dioxo[4,5-g]quinazolin-8-oxy)-pyridin-2-yl]-2- (2-fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one; ● 5-[5-(2,2-difluoro-[1,3]dioxy[4,5-g Uquinazoline-8-oxy)-pyridin-2-yl]-2-(phenylamino)-3-methyl-3H-pyrimidin-4-one; ● 5-(4-fluoro-phenyl) 4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15- Tetraoxa-1-aza-cyclododecane[b]naphthalene-4-amino)-phenyl]-decylamine; ● 5-(4-fluoro-phenyl)-4-oxo-1,4- Dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclo-decene) Dialkyl [b]naphthalen-4-indolyl)-phenyl]-nonylamine; ● 3-methyl-2-phenylamino-5-[5-(2,5,7,10-tetraoxane-14, 16-diaza-tricyclo[9.8.0.013,18]nonadecane-1(11),12,14,16,18-pentenyl-17-oxy)-pyridin-2-yl]-3H -pyrimidin-4-one; ● 5-[5-([8,9]dihydro-7H-6,10-dioxo-1,3-diaza-cycloheptane[b]naphthalene-4-oxo Base)-pyridine 2-yl]-2-(4-fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one; ● 2-(4-fluoro-phenylamino)-3-methyl-5 -[5-(9-methyl-8,9,10,11-tetrahydro-7H-6,12-dioxo-1,3,9-triaza-cyclodecane[b]naphthalene-4- Oxy)-pyridin-2-yl]-3H-pyrimidin-4-one; ● 2-(4-fluoro-phenylamino)-3-methyl-5-[5-(7,8,10,11 -tetrahydro-6,9,12-trioxa-1,3-diaza-cyclodecane[b]naphthalene-4-oxy)-pyridin-2-yl]-3H-pyrimidin-4-one; 5-[5-(8,9-Dihydro-7H-6,10-dioxo-1-aza-cycloheptane[b]naphthalen-4-yloxy)-pyridin-2-yl]-2 -(4-fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one; ● 2-(4-fluoro-phenylamino)-3-methyl-5-[5-(9- Methyl-8,9,10,11-tetrahydro-7H-6,12-dioxo-1,9-diaza-cyclodecane[b]naphthalen-4-yloxy)-pyridin-2-yl -3H-pyrimidin-4-one; ● 2-(4-fluoro-phenylamino)-3-methyl-5-[5-(7,8,10,11-tetrahydro-6,9,12 -trioxo-1-aza-cyclodecane [b]naphthalene-4-oxy)-pyridin-2-yl]-3H-pyrimidin-4-one; ● 3-methyl-2-phenylamino- 5-[5-(2,5,7,10-tetraoxa-14-aza-tricyclo[9.8.0.013,18]nonane-1(11),12,14,16,18-pentene -17-17-oxy)-pyridin-2-yl]-3H-pyrimidin-4-one; ● 5-[5-(2,2-difluoro-[1,3]dioxy[4,5-g Quinazoline- 8-oxy)-pyridin-2-yl]-2-(2-fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one; ● 5-[5-(2,2-di Fluoro-[1,3]dioxo[4,5-g]quinazolin-8-oxy)-pyridin-2-yl]-2-(phenylamino)-3-methyl-3H-pyrimidine- 4-ketone; ● 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11, 13,14-hexahydro-6,9,12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalene-4-amino)-phenyl]-decylamine; ● 5- (4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro- 6,9,12,15-tetraoxy-1,3-diaza-cyclododecane[b]naphthalen-4-indolyl)-phenyl]-decylamine; ● 5-[5-(2,5 ,8,11,14,17-hexaoxy-21-aza-tricyclo[16.8.0.020,25]dihexadecan-1(18),19,21,23,25-pentenyl-24- Oxy)-pyridin-2-yl]-3-methyl-2-phenylamino-3H-pyrimidin-4-one. A pharmaceutical composition comprising at least one compound of any one of claims 1-64 and at least one pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 65, wherein the weight ratio of the compound to the excipient is 0.0001 to 10. Use of a pharmaceutical composition according to claim 65 or 66 for the preparation of a medicament. The use of the preparation of a medicament as described in claim 67 for the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, immune disorder or visual disturbance. The use of the preparation of a medicament as described in claim 67, for delaying or preventing progression of cancer, cancer metastasis, cardiovascular disease, immune disorder or visual disorder. The use of the preparation of a medicament as described in claim 67 for the treatment or delay of progression or onset of cancer, cancer metastasis, cardiovascular disease, immune disorder or visual disturbance. Use of at least one compound according to any one of claims 1-64 to prepare a medicament. The use of the preparation of a medicament as described in claim 71 for the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, immune disorder or visual disturbance. The use of the preparation of a medicament as described in claim 71 of the patent application is for delaying or preventing progression of cancer, cancer metastasis, cardiovascular disease, immune disorder or visual disturbance. The use of a preparation for the preparation of a medicament according to claim 71 for treating or delaying the progression or onset of cancer, cancer metastasis, cardiovascular disease, immune disorder or visual disturbance. At least one compound of any one of claims 1-64 for use in the treatment of cancer, prevention of cancer metastasis or treatment of cardiovascular disease, immune disorder or visual disorder. A medicament prepared using at least one compound according to any one of claims 1-64, for use as a c-Met inhibitor. A method of treating a patient suffering from a disorder of a protein kinase activity, comprising administering to a patient a therapeutically effective amount of at least one compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof. The method of claim 77, wherein the protein kinase is KDR, Tie-2, Flt3, FGFR3, AbI, Aurora A, c-Src, IGF-IR, ALK, c-MET, RON, PAK1, PAK2 or TAK1. The method of claim 77, wherein the disorder in which the protein kinase activity is disordered is cancer. The method of claim 79, wherein the cancer is solid tumor, sarcoma, fibrosarcoma, osteoma, malignant melanoma, retinoblastoma, rhabdomyosarcoma, glioblastoma, neuromuscular Cell tumor, teratoma, hematopoietic malignancy or malignant ascites. Use of at least one compound according to any one of claims 1-64, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament. Use of at least one compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, for the treatment of cancer. A method of treating at least one compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, in a mammal in need of such treatment, in a mammal in need of such treatment, for treating cancer in the mammal The cancer is selected from the group consisting of lung cancer, breast cancer, colon cancer, kidney cancer, pancreatic cancer, head cancer, neck cancer, hereditary papillary renal cell carcinoma, childhood liver cancer, and gastric cancer.