WO2007121662A1 - Diphenyl urea derivatives as kinase inhibitors, compositions and uses thereof - Google Patents

Abstract

The present application discloses the diphenyl urea derivatives of general formula (I), pharmaceutically acceptable salts, solvates or prodrugs thereof. The present compounds have the effective bioactivities in inhibiting the VEGFR2 and/or PDGRFβ.

Description

 Diphenylurea derivative for inhibiting protein kinase, composition and use thereof

 The invention relates to the field of medicine. In particular, the invention relates to diphenylurea derivatives for inhibiting protein kinases, as well as to compositions and uses thereof. Background technique

 Protein kinase is the largest family of human enzyme proteins, with more than 500 proteins. Peptidase plays an important role in the process of angiogenesis. Vascular growth is the process of forming new blood vessels based on existing blood vessels. This process plays a very important role in many pathological processes. These pathological processes include cancer, chronic immune diseases, diabetic retinopathy, psoriasis, rheumatoid arthritis, and macular degeneration. Anti-angiogenic therapy represents a potentially important means of treating solid tumors and other diseases associated with vascular growth disorders. The benefits of anti-angiogenic therapy in the clinical treatment of the disease are becoming more apparent from the approval of the use of a series of anti-angiogenic drugs (such as Avastin, Nexavar and Sutent). ,

 The process of blood vessel growth requires the participation of multiple vascular growth regulators and multiple cell types. Many important vascular growth regulators have been discovered, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), vascular protein 1 and 2 (angiopoietin 1). And 2 or Angl, Ang2), and platelet-derived growth factor (PDGF). Receptors corresponding to these vascular growth regulators, including vascular endothelial growth factor receptors (VEGF receptors or VEGFRs), fibroblast growth factor receptors (FGF receptors or FGFRs), and vascular protein 1 and 2 receptors Tiel And Tie2, and PDGF receptor PDGFR a and PDGFR have also been discovered. Among them, VEGFRs, FGFRs, Tiel and Tie2 were expressed on the surface of vascular endothelial cells, PDGFR a was expressed on the surface of vascular stromal cells secreting VEGF, and PDGFR 3 was expressed on the surface of perivascular cells and smooth muscle cells. The above various protein molecules including VEGF, FGF, PDGF, VEGFRs, FGFRs, PDGFRs, Tiel and Tie2 together constitute a complex molecular signaling network. This signaling network plays an important role in regulating and controlling blood vessel growth under physiological and pathological conditions (see review Caraieliet, R, 2005).

To block blood vessel growth, a variety of monoclonal antibodies designed for single vascular growth regulatory signaling molecules such as VEGF and FGF have been developed. These antibodies have been shown in preclinical and clinical trials. Delay the effect of tumor growth. However, vascular growth-blocking methods (such as monoclonal antibodies) designed for a single signaling pathway are often inefficient due to the redundancy of the signal pathways in the delivery network of vascular growth regulatory signals. In contrast, the vascular growth blocking method designed for multiple signal paths at the same time should produce good results. Therefore, the development of a multi-targeted multiplex small molecule kinase inhibitor is an effective way to achieve high efficiency of vascular growth blockade (see review Ferrara, N. and Kerbel, R., 2005). According to this logic, small molecule compounds that can be simultaneously screened to inhibit multiple protein kinases can effectively block angiogenesis in tumors, thereby delaying or interrupting tumor growth. To date, the US Food and Drug Administration (USFDA) has approved two clinical use of multiplexed small molecule protein kinase inhibitors (Bayer's Nexavar and Pfizer's Sutent) for angiogenesis (US FDA New Drug Database) : http:〃 www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfin; Sutent: FDA NDA #021938 and #021968; Nexavar: FDA NDA #021923 ). Nexavar is used for the treatment of advanced kidney cancer, while Sutent is used to treat advanced kidney cancer and gastrointestinal stromal cancer (GIST). Combining the above facts: 1) protein kinase plays an important role in the regulation of blood vessel growth; 2) vascular growth protein kinase inhibitor has a good clinical therapeutic effect, we can conclude that: for the treatment of cancer and diseases related to blood vessel growth In contrast, a multiplexed small molecule protein kinase inhibitor for blocking blood vessel growth is an ideal drug.

 Since both VEGFR2 (D) and PDGFR P are drug targets of Nexavar and Sutent, the clinical efficacy of Nexavar and Sutent undoubtedly demonstrates the value of inhibiting the activity of VEGRF2 (KDR) and PDGRFR beta in the treatment of diseases such as cancer ( Rini, BI, 2006; Motzer, RJ. et al., 2006). Therefore, from a pharmaceutical point of view, the development of multiplexed small molecule protein kinase inhibitors against VEGFR2 (KDR) and PDGFR P is very valuable for the treatment of cancer and other diseases associated with blood vessel growth.

 A variety of kinase inhibitors have now been disclosed in the art. For example, U.S. Patent Application US 2004/0209892 (published date: October 21, 2004) discloses VEGFR2/KDR with the following structure

国际专利出版物 WO 2004/085425(公布日： 2004年 10月 7日)公开了：具有以下 结构通式的稠合唑类化合物， 如 2，5-二取代的苯并咪唑、 苯并嗯唑和苯并噻唑作为 激酶抑制剂 <

International Patent Publication WO 2004/085425 (published: October 7, 2004) discloses: fused azole compounds having the following structural formula, such as 2,5-disubstituted benzimidazole, benzoxazole And benzothiazole as Kinase inhibitor

国际专利出版物 WO 00/09495(公布日： 2000年 2月 24日)公开了具有抑制血管 形成活性的具有下式结构的异喹啉衍生物 Vatalanib(VEGFR抑制剂)。

The international patent publication WO 00/09495 (published date: February 24, 2000) discloses an isoquinoline derivative Vatalanib (VEGFR inhibitor) having the structure of the following formula which inhibits angiogenic activity.

 The international patent publication WO 98/13354 discloses quinazoline derivatives having the following structure.

International Patent Publication WO-2004014426 discloses VEGF receptors and tyrosine kinases having the formula The composition of the formulation is for the treatment of cancer.

 However, there remains a need in the art to develop new protein kinase inhibitors. Summary of the invention

 In order to solve the above problems, an aspect of the present invention provides a compound having the following formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof,

 Formula (I)

 among them:

Χ Π Χ ₂ are each independently selected from CH and Ν;

 R7 is a substituted or unsubstituted aryl or heteroaryl group;

其中：

among them:

ZBZ ₃ is - CR ₉ R _1D -, wherein ₁₉ and R _1D are each independently selected from a hydrogen atom, a substituted or unsubstituted C _r C ₃ alkyl, and halo;

Z ₂ is absent or is selected from -O-, -S -, -NR -, wherein R is selected from H and -C3 fluorenyl;

 n and m are integers from 0 to 2;

R1 is absent or represents 1, 2 or 3 substituents, each substituent being independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halo, carboxy , substituted or unsubstituted acyl group, substituted or unsubstituted alkoxycarbonyl group, substituted or unsubstituted c ₃ fluorenyl group, substituted or unsubstituted c _r c ₃ decyloxy group, sulfonyl group, sulfinyl group, sulfonyl group;

R4 is absent or represents 1, 2, 3, 4 or 5 substituents, each substituent being independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl , halogenated, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted C ₆ alkyl, taken Substituted or unsubstituted <^ - ₍₆ alkoxy group, a substituted or unsubstituted aryloxy group, sulfonamide group, sulfinyl group, a sulfonyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted a heteroaromatic hydrocarbon group, a substituted or unsubstituted heterocyclic fluorenyl group; or an adjacent two R4 groups together with a carbon atom to be bonded to form an aromatic ring, a heteroaryl ring, an alkyl ring or a heterofluorenyl ring, The aromatic ring, heteroaryl ring, alkyl ring or heterofluorenyl ring is not substituted or substituted by 1, 2, 3 or 4 substituents each independently selected from the group consisting of: hydroxy, nitro, cyano, substituted Or unsubstituted amino, aminocarbonyl, 3⁄4, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted fluorenyloxy, substituted or unsubstituted fluorenyl, substituted or unsubstituted (^-( ₃垸oxy) Base, sulfonyl, sulfinyl, and sulfonyl groups.

 Another aspect of the invention provides a pharmaceutical composition comprising an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier. In a preferred embodiment, wherein the pharmaceutical composition is formulated in a form selected from the group consisting of an injection, an aerosol, a cream, a gel, a tablet, a pill, a capsule, a syrup, an eye drop, or Skin plaster.

 Still another aspect of the invention relates to the use of the above compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of a disease responsive to inhibition of a protein kinase. In a preferred embodiment, the disease is selected from the group consisting of: tumor, rheumatoid arthritis, arterial restenosis, autoimmune disease, acute inflammation, acute and chronic nephritis, diabetic retinopathy, psoriasis, or macular degeneration.

The present invention provides that certain compounds can significantly inhibit the biological activity of at least one of VEGFR2 and PDGFR P. Since the clinical efficacy of Nexavar and Sutent confirms the value of VEGFR2 and PDGFR P as drug targets (Rini, BI, 2006; Motzer, RJ et al, 2006), the inhibitory potency of these compounds for multiple targets or one of them It has a very high medical value for the treatment of diseases related to blood vessel growth. Diseases that can benefit from the therapeutic effects of these compounds include cancer (Gasparini, G. et al., 2005), rheumatoid arthritis (Taylor, PC & Sivakumar, B. ₅ 2005; Szekanecz, Z. ₅ Gaspar, L) & Koch, AE, 2005; Lainer, DT & Brahn, E., 2005; Arima, K. et al., 2005), Arterial Restenosis (Gennaro, G, 2003), Autoimmune Diseases (Ohno, A., etc.) People, 2004; Storkebaum, E. et al., 2004; Kirk, SL & Karlik, SJ, 2003), Acute and Chronic Inflammation, Acute and Chronic Nephritis (Konno, S. et al., 2004; Suthin, K. et al., 2003). Medina, J. et al., 2005), diabetic retinopathy (Campochiaro, PA, 2004), psoriasis (Voskas, D. et al., 2005; Leong, TT et al., 2005; Xia, YP et al., 2003), And macular degeneration (Rothen, M. et al., 2005; Campochiaro, R A., 2004) (see review Carmeliet, P., 2005 and Ferrara, N. and Kerbel, R., 2005).

detailed description The following are definitions of some words, words, abbreviations, and proper nouns. The definitions of these words, words, abbreviations and proper nouns are consistent with the meanings they represented when they appeared before. Unless the background used indicates a different meaning, the definitions of these words, words, abbreviations and proper nouns apply throughout.

 Chemical formula (I) contains all sub-chemical formulas. When a symbol appears multiple times in a chemical formula, the definition of each occurrence of the symbol is independent of the definition at any other time.

 When not appearing between two words, letters or symbols, "-" is used to represent the point of attachment of the substituent to the parent structure. For example, -( 0 (connected to the parent structure through a carbon atom).

The term "mercapto" includes both straight and branched chains having the specified number of carbon atoms. For example, cvc ₅ alkyl represents both straight and branched chains having from 1 to 5 carbon atoms. Examples of the alkyl group in the present invention include: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, Hexyl, 2-hexyl, 3-hexyl, 3-methylhexyl and the like. The fluorene group belongs to another subset of sulfhydryl groups, meaning that it has the same residue as the alkyl group but has two points of attachment. For example, C _Q fluorenylene means a covalent bond, and an anthranylene group is a methylene group. When a group with a specific number of carbon atoms is named, all geometric isomers with the same number of carbon atoms are included. For example, the term "butyl" includes n-butyl, sec-butyl, isobutyl, and tert-butyl; the term "propyl" includes n-propyl and isopropyl; and "lower thio" contains one. a sulfhydryl group to four carbon atoms.

 "Mercaptooxy" refers to a fluorenyl group having the specified number of carbon atoms attached to the parent structure through an oxygen atom bridge, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, Sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methyl Pentyloxy, and the like. "Lower decyloxy" means an alkoxy group having from one to four carbon atoms.

 "Alkylthio" refers to an alkyl group having the specified number of carbon atoms attached to the parent structure through a sulfur linkage. "Lower alkylthio" means a decyloxy group having from one to four carbon atoms.

"Acyl" includes a group (alkyl) -C(0)-, (cyclodecyl)-C(0)-, (aryl)-C(0)-, (heteroaryl)-C(O) - and (heterocyclic fluorenyl) -C(O)-. This group is attached to the parent structure by the function of a carbonyl group, meaning that an alkyl group as defined above is attached to the parent structure via a keto group (-(OO)-). When the number of carbon atoms of the acyl group is specified, the number of carbon atoms contains the carbon atoms carried by the ketone group. For example, the chemical formula of ( ₂ acyl group is CH ₃ (C=O)-.

"垸Oxycarbonyl" means an ester group of the formula (decyloxy) (C=0)- which is bonded to the parent structure through a carbon atom of a carbonyl group, wherein the number of carbon atoms of the specified number of carbon atoms is a decyloxy group. . Thus, C _r C ₆垸 oxycarbonyl represents a decyloxy group having 1 to 6 carbon atoms which is bonded to a carbonyl group through its oxygen atom.

"Amino" refers to a -NH ₂ group.

"Mono- and bis-alkylamino" embraces both secondary and tertiary mercaptoamino groups, wherein the alkyl group is as defined above and There are a specified number of carbon atoms. The point of attachment of the mercaptoamino group to the parent structure is at the nitrogen atom. Examples of the mono- and di-alkylamino groups include ethylamino, dimethylamino, and methylpropylamino.

 "Mono- and bis-alkylaminoalkyl" represents a group consisting of a mono- and bis-indenylamino group as defined above attached to an alkyl group.

 The term "aminoindolyl" refers to a group consisting of an amino group attached to an alkyl group of the specified number of carbon atoms. A similar "hydroxyindenyl" group is a group consisting of a hydroxyl group attached to a thiol group.

The term "aminocarbonyl" refers to a -CONR ^b R° group, wherein R ^{b is} selected from H, substituted or unsubstituted d-Ce alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl R ^{e is} selected from hydrogen and a substituted or unsubstituted CC ₄ alkyl group; or R ^b and R ^e and a nitrogen atom bonded thereto constitute a substituted or unsubstituted 5 to 7 membered nitrogen-containing heterocycloalkyl group, which is hetero The cycloalkyl group may also optionally contain 1 or 2 additional heteroatoms selected from O, N or S; each substituent is independently selected from the group consisting of: CC ₄ alkyl, aryl, heteroaryl, aromatic -Alkyl-, heteroaryl-C _r C ₄ fluorenyl-, -C ₄ halodecyl-, -O VC ₄ fluorenyl, -OCVC ₄ hydrocarbon phenyl, -C ₄ alkyl-OI^ -OCr haloalkyl, halo, -OH, -mercapto-NH2, -N(C _r C ₄ alkyl) (C,-C ₄ fluorenyl), -NH (CVC ₄ fluorenyl), -N (C _r C ₄ fluorenyl) (C _r C ₄ hydrocarbon phenyl), -NH(C _r C ₄ hydrocarbon phenyl), cyano, nitro, oxo (as a substituent of heteroaryl), -CO ₂ H, -CO alkyl, -CON(C _r C ₄ fluorenyl) (C _r C alkyl), -CONHC - alkyl), -CONH ₂ , -NHC(O)(C _r C ₄ alkyl) -NHC(O)(phenyl), -N O^- fluorenyl) C OXd-fluorenyl), -Ν(( ₄ alkyl)C(O)(phenyl), -C(O) VC ₄ fluorenyl, -C(0)CVC ₄ phenyl -C(0)CC ₄ haloalkyl, -OC(O)C _r C ₄ alkyl, -SO ₂ (C _r C ₄ alkyl), -SO ₂ (phenyl), -SO ₂ (CVC ₄ haloalkane) Base), -S0 ₂ NH ₂ , -80 ₂ ΝΗ (( ₄ alkyl), -SO ₂ NH (phenyl), - NHS0 ₂ (dC ₄ alkyl), -NHS0 ₂ (phenyl), and - NHSO ₂ (C,-C ₄ halodecyl).

"Aryl" includes: a 5- or 6-membered aromatic carbon atom ring (such as a phenyl group), at least one of which is an aromatic carbon ring ring bicyclic structure (such as naphthyl, indanyl, and tetrahydronaphthyl) And a tricyclic structure (such as a fluorenyl group) in which at least one of them is an aromatic carbon atom ring. For example, an aryl group comprises a structure in which a 5 and 6 membered aromatic carbon atom ring is fused to a 5 to 7 membered heteroalkyl ring, wherein the heterofluorenyl ring contains one or more (eg 1, 2 or 3). An atom selected from N, O and S. In a fused bicyclic structure in which only one ring is an aromatic carbon atom ring, its point of attachment to the parent structure may be either in the aromatic carbon atom ring or in the heteroalkyl ring. The divalent group formed by the free valence of the substituted benzene derivative and the atom on the ring is referred to as a substituted polyphenyl group. The name of the divalent group resulting from the removal of one hydrogen atom from a free-valent carbon atom in a monovalent polycyclic hydrocarbon group is preceded by the word "sub", for example, having two points of attachment. Naphthyl is referred to as a naphthylene group. However, the aryl group contains neither a heteroaryl group nor a definition of a heteroaryl group. Heteroaryl groups will be defined separately below. If one or more aromatic carbon atom rings are fused to an aromatic heterofluorenyl ring, the resulting ring structure belongs to heteroaryl The base is not within the aryl range defined herein.

 The term "aryloxy" refers to the group -O-aryl.

 The term "halo" includes fluoro, chloro, bromo, iodo. The term "halogen" includes fluorine, chlorine, bromine, and iodine.

 "Haloalkyl" means an alkyl group, as defined above, having the specified number of carbon atoms, substituted with one or more halogen atoms. The number of substituted halogen atoms can generally be as large as the maximum allowable number. Examples of halohydrazino groups include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

 "Heteroaryl" comprises: a 5 to 7 membered aromatic monocyclic structure containing one or more (eg 1 to 4, or in some embodiments 1 to 3) selected from N, O And a hetero atom of S and the remaining ring atom is a carbon atom; and a bicyclic heteroalkyl ring containing one or more (for example 1 to 4, or in some embodiments 1 to 3) selected from The hetero atoms of N, 0 and S and the remaining ring atoms are carbon atoms, and one aromatic ring contains at least one hetero atom. For example, the heteroaryl group has a structure in which a 5- to 7-membered aromatic heteroalkyl ring is fused to a 5- to 7-membered alkyl ring. For such a bicyclic heteroaryl structure in which only one ring contains one or more hetero atoms, the point of attachment to the parent structure can be either on the heteroaromatic ring or on the alkyl ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms cannot be adjacent. In some embodiments, the total number of S and 0 atoms in the heteroaryl group does not exceed two. In some implementations, the total number of S and O atoms in the aromatic heterocycle does not exceed one. Examples of heteroaryl groups include, but are not limited to, structural systems (where the point of attachment is designated as 1, and the rest of the positions are by sequence number) such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3 , 4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolyl, 2,4-imidazolinyl, isoxazolyl, oxazolinyl, thiazole Polinyl, thiadiazolyl, tetrazolinyl, dithienyl, benzothiophenyl, furyl, benzofuranyl, benzimidazolyl, porphyrin, pyridazine, Triazolyl, quinolyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinoline. The name of the divalent group resulting from the removal of a hydrogen atom from an atom having a free valence in a monovalent heteroaryl group is preceded by the word "sub", for example, a pyridyl group having two points of attachment. It is a pyridylene group. As defined previously, a heteroaryl group contains neither an aryl group nor an overlap with the definition of an aryl group.

 The heteroaromatic hydrocarbon and alkyl group in the term "heteroarylalkyl" are as defined above, and the point of attachment to the parent structure is on the alkyl group. The term includes, but is not limited to, pyridylmethyl, thiobenzyl, and (pyrrolyl) 1-ethyl.

"Heterocycloalkyl" means a single aliphatic ring structure containing at least 2 carbon atoms and 1 to 3 heteroatoms, wherein each heteroatom is independently selected from the group consisting of oxygen, sulfur and nitrogen, or a combination of heteroatoms At least one of these three atoms. Examples of suitable heterocycloalkyl groups include (the position of the point of attachment is specified as 1, and the remaining positions are arranged in order) 2-pyrroline, 2,4-imidazolidinyl, 2,3-pyrazolyl, 2-piperidinyl 3-piperidinyl, 4-piperidinyl and 2,5-piperazinyl. Morpholinyl also belongs to this class, which includes 2-morpholinyl and 3-morpholinyl (oxygen is designated as the 1-position). The term "alkylthio" embraces the following groups: -S-(substituted or unsubstituted alkyl), -S- (substituted or unsubstituted aryl), -S- (substituted or unsubstituted heteroaryl) And -S- (substituted or unsubstituted heterocyclic fluorenyl). Therefore, the sulfonyl group contains (^-( ₆垸thio group).

 The term "sulfinyl" embraces the following groups: - S(O)-H, -S(O)- (substituted or unsubstituted fluorenyl), -S(O)- (substituted or unsubstituted aryl) , -S(O)- (substituted or unsubstituted heteroaryl), -S(O)- (substituted or unsubstituted heterocyclic fluorenyl); and -S(O)- (substituted or unsubstituted) Amino).

The term "sulfonyl" embraces the following groups: -S(O ₂ )-H, -S(O ₂ )- (substituted or unsubstituted fluorenyl), -S(O ₂ )- (substituted or unsubstituted) Aryl), -S(O ₂ )- (substituted or unsubstituted heteroaryl), -S(O ₂ )- (substituted or unsubstituted heterocycloalkyl), -s(o ₂ )- (substituted Or unsubstituted alkoxy), -s(o ₂ M substituted or unsubstituted aryloxy), -S(O ₂ ) -(substituted or unsubstituted heteroaryloxy), -8(0 ₂ ) - (substituted or unsubstituted heterocyclic oxy); and -S(O ₂ )- (substituted or unsubstituted amino).

 The term "substituted" is used herein to mean: Replace a specified atom or group of any one or more hydrogen atoms with a selected group of atoms, but the number of substitutions must not exceed the price of the specified atom. number. For example, when the substituent is an oxo group (e.g., =0), two hydrogen atoms on the designated atom will be replaced. Combinations of such substituents and/or chemical formulas are permissible only if the combination of substituents and/or chemical formulas results in a stable compound or an intermediate of a useful synthetic reaction. A stable compound or structure means that a compound has sufficient stability so that the compound can be separated from the reaction mixture and used as a component for practical use in the subsequent formulation. Unless otherwise indicated, the nomenclature of the substituents is added to the nomenclature of the parent structure. For example, when [(cycloalkyl)alkyl] is listed as a possible substituent, the point of attachment of the substituent to the parent structure is on the fluorenyl group.

 Unless otherwise specifically defined, "substituted" alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl each represent alkyl, cyclodecyl, aryl, heterocycloalkyl, and heteroaryl, respectively. One or more of the latter (up to five, for example, up to three) hydrogen atoms are replaced by substituents selected from the following groups:

-R -OR ^b , -O(CVC ₂ fluorenyl) O- (for example, dioxymethane-), -SR ^b , fluorene, hydrazine, -NR ^{b in} which one or more hydrogen atoms are replaced by a lower alkyl group R. , halogenated, cyano, nitro, -COR ^b , -CO ₂ R ^b , -CONR ^b R ^e , -OCOR ^b , -OCO ₂ R ^a , -OCONR ^b R ^c , -NR ^c COR ^b , -NR °CO ₂ R\ -NR°CONR ^b R°> -CO ₂ R ^b , -CONR ^b R ^c , -NR°COR\ -SOR ^a , -SO ₂ R ^a , -SO ₂ NR ^b R° and -NR ^c S0 ₂ R ^a , where:

R ^{a is} selected from a substituted or unsubstituted CC ₆ alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

^ selected from 11, a substituted or unsubstituted CC ₆ alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; R ^{13 is} selected from hydrogen and a substituted or unsubstituted C _r C ₄ alkyl group;

Each substituted or unsubstituted group is either unsubstituted or each independently substituted with one or more (eg, 1 or 2 or 3) substituents, each substituent being independently selected from the group consisting of: C _r C ₄ fluorenyl, aryl, heteroaryl, aryl-C decyl-, heteroaryl-C _r C fluorenyl-, C _r C4 halogenated fluorenyl-, -O VC ₄ alkyl, -O VC ₄ hydrocarbon phenyl, -alkyl-OH, -OC!-Ct haloalkyl, halo, -OH, -NH ₂ , -dC ₄ alkyl-NH ₂ , -N(C _r C ₄ alkyl) (Cr fluorenyl), -ΝΗ((θ ₄ fluorenyl), -NCC alkyl) (CVC ₄ hydrocarbon phenyl), -NHCC C4 hydrocarbon phenyl), cyano, nitro, oxo (as heteroaryl) a substituent of a group), -CO ₂ H, -Q KX alkyl, -CON(CrC ₄ alkyl) (CC ₄ fluorenyl), -CONH (C _r C ₄ fluorenyl), -CONH ₂ , -NH OX Alkyl), -NHC(O)(phenyl), -N(C _r C ₄ alkyl) C OXC Cf alkyl), -N^-fluorenyl) C(O)(phenyl), -(: (ο) ο 4 alkyl, -QOK CA phenyl, -c (o) cvc ₄ haloalkyl, -oc (o) cvc ₄ alkyl, -

S0 ₂ (C _r C ₄ fluorenyl), -SO ₂ (phenyl), -SO C haloalkyl), -SO ₂丽₂ , -S0 ₂ NH((VC ₄ alkyl), -S0 ₂ NH (benzene Base), -NHSO C alkyl), -NHSO ₂ (phenyl), and -NHSO^C haloalkyl).

 "Substituted acyl" means a group: (substituted alkyl) -C(O)-, (substituted cyclodecyl) -C(0)-, (substituted aryl) -C( O)-, (substituted heteroaryl)-C(O)- and (substituted heterocyclic fluorenyl)-C(O)-. These groups are bonded to the parent structure through a carbonyl group, and the substituted alkyl group, cycloalkyl group, aryl group, heteroaryl group and heterocycloalkyl group each represent a fluorenyl group, a cycloalkyl group, an aryl group, a heteroaryl group and a hetero group, respectively. A cycloalkyl group in which one or more (up to five, for example, up to three) hydrogen atoms of the latter are replaced by a substituent selected from the group consisting of:

-R -OR ^b , -0 (CVC alkyl) 0- (for example, dioxymethane-), -SR ^b , fluorene, hydrazine, -NR ^b R in which one or more hydrogen atoms are replaced by a lower alkyl group ^e , halo, cyano, nitro, -COR ^b , -C0 ₂ R ^b , -CONR ^b R ^e , -OCOR ^b , -OC0 ₂ R ^a , -OCONR ^b R°> -NR ^c COR ^b , - NR ^c CO ₂ R ^a , -NR ^c CONR ^b R -CO ₂ R ^b , -CONR ^b R ^c , -NR ^c COR ^b , -SOR ^a , - SO ₂ R ^a , -SO ₂ NR ^b R ^c and - NR ^c SO ₂ R ^a , where:

R ^{A is} selected from a substituted or unsubstituted C _R C ₆ alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

Selected from 11, a substituted or unsubstituted cc ₆ alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

R ^{E is} selected from hydrogen and a substituted or unsubstituted C _R C ₄ alkyl group;

烃苯基)、 氰基、 硝基、 氧代基 (作为杂芳基的取代基)、 -CO₂H、 -C(O)OCVC₄垸基、 -CON( VC₄烷基) (C_rC₄烷基)、 -CONH ^- 烷基)、 -CONH₂、 -NHC(O)(CVC₄烷基)、 -NHC(0)(苯基）、 -N(C_rC₄烷基) QOXC 烷基）、 -N(C_rC₄烷基) C(O) (苯基）、 -C(O) VC₄垸基、 -C(O)C_rC₄苯基、 -C(O)C_rC₄卤代垸基、 -OQ X 垸基、 - SO₂(C_rC₄垸基)、 -SO₂(苯基)、 -SO₂(C_rC₄卤代垸基)、 -SO₂NH₂、 -SO₂NH(CVC₄烷基)、 -S0₂NH (苯基)、 -NHS0₂( VC₄烷基)、 -NHS0₂(苯基)以及 -NHSO C!- 卤代垸基)。 只要与母体结构的连接点仍然在羰基上，取代的酰基上的 1或多个碳原子就可为氮、 氧或硫所替代。 Each substituted or unsubstituted group is either unsubstituted or each independently substituted with one or more (eg, 1 or 2 or 3) substituents, each substituent being independently selected from the group consisting of: - Mercapto, aryl, heteroaryl, aryl-C alkyl-, heteroaryl--alkyl-, C C4 halogenated fluorenyl-, -OV alkyl, -OC _r C ₄ hydrocarbon phenyl, - Ci-C ₄ fluorenyl-OH, -OCVC ₄ haloalkyl, halo, -OH, -NH ₂ , -C alkyl-NH ₂ , -N(C _r C ₄ fluorenyl) (alkyl), - NH(C _r C ₄ alkyl),

Hydrocarbon phenyl), cyano, nitro, oxo (substituent as heteroaryl), -CO ₂ H, -C(O)OCVC ₄ fluorenyl, -CON(VC ₄ alkyl) (C _r C ₄ alkyl), -CONH ^-alkyl), -CONH ₂ , -NHC(O)(CVC ₄ alkyl), -NHC(0)(phenyl), -N(C _r C ₄ alkyl) QOXC alkyl), -N(C _r C ₄ alkyl) C(O) (phenyl), -C(O) VC ₄ fluorenyl, -C(O)C _r C ₄ phenyl, -C(O C _r C ₄ halo fluorenyl, -OQ X fluorenyl, -SO ₂ (C _r C ₄ fluorenyl), -SO ₂ (phenyl), -SO ₂ (C _r C ₄ halo fluorenyl), _{-SO 2 NH 2, -SO 2 NH} (CVC 4 alkyl), -S0 ₂ NH (phenyl), -NHS0 ₂ (VC ₄ alkyl), -NHS0 ₂ (phenyl), and -NHSO C -! halo代垸基). As long as the point of attachment to the parent structure remains on the carbonyl group, one or more carbon atoms on the substituted acyl group may be replaced by nitrogen, oxygen or sulfur.

 "Substituted alkoxy" refers to an alkoxy group whose alkyl moiety is substituted (eg, -O-(substituted fluorenyl), wherein "substituted fluorenyl" refers to one or more (may be more Up to 5, for example, up to 3) sulfhydryl groups in which a hydrogen atom is replaced by a substituent selected from the following groups:

-R ^a , -OR ^b , - 0 (CC ₂ alkyl) O- (for example, dioxymethane-), -SR ^b , - fluorene, hydrazine in which one or more hydrogen atoms are replaced by a lower sulfhydryl group, -NR ^b R halo, cyano, nitro, -COR ^b , -CO ₂ R ^b , -CONR ^b R -OCOR ^b , -OC0 ₂ R\ -OCONR ^c , -NR ^c COR ^b , -N ^c CO _{^{2 R \ -NR c CONR b R}} c, -CO 2 R b, -CONR b R c, -NR ° COR \ -SOR a, -S0 2 R a, -SO 2 NR b R. And -NR ^c SO ₂ R ^a , where:

R ^{a is} selected from a substituted or unsubstituted C _r C ₆ fluorenyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

R^AH, a substituted or unsubstituted -C ₆ alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

R ^{e is} selected from hydrogen and a substituted or unsubstituted CH alkyl group;

Each substituted or unsubstituted group is either unsubstituted or each independently substituted with one or more (eg, 1 or 2 or 3) substituents, each substituent being independently selected from the group consisting of: CC _4- alkyl, aryl, heteroaryl, aryl-fluorenyl-, heteroaryl-C _r C ₄ alkyl-, CVC4 haloalkyl-, -OC _r C ₄ fluorenyl, -O-hydrocarbylphenyl, -CVC ₄ alkyl-OH, -OC _r C ₄ halodecyl, halo, -OH, -NH ₂ , -C _r C ₄ alkyl-NH ₂ , -NC alkyl) (CVC ₄ fluorenyl) ), -NH alkyl), -N(C _r C ₄ alkyl) (VC ₄ hydrocarbon phenyl), -NH(dC ₄ hydrocarbon phenyl), cyano, nitro, oxo (as heteroaryl) Substituents), -C0 ₂ H, -C(0)OC _r C ₄ alkyl, -CON(CVC ₄ fluorenyl) (C decyl), -CONH(VC ₄ alkyl), -CONH ₂ , - NHQ XC alkyl), -NHC(O)(phenyl), -N(dC ₄ alkyl) C(O)(CVC ₄ alkyl), -N(CVC ₄ alkyl) C(O) (phenyl ), -C(O)CVC ₄ fluorenyl, -( ^^广^phenyl, - o^!-halogen fluorenyl, -OC(O)C]-C ₄ fluorenyl, - SO ₂ ((VC ₄ alkyl), -SO ₂ (phenyl), -SO ₂ (C _r C ₄ haloalkyl), -SO ₂ NH ₂ , -SO ₂ NH(C _r C ₄ fluorenyl), -SO ₂ NH (phenyl), -NHS0 ₂ (CrC ₄ fluorenyl), -NHSO ₂ (phenyl), and -NHSO^C halogenated fluorenyl). In certain embodiments, a class of substituted alkoxy is "polymethoxy" or is expressed as -O-(substituted or unsubstituted alkylene)-(substituted or unsubstituted alkoxy), And includes some groups such as -OCH ₂ CH ₂ OCH ₃ , some ethylene glycol esters such as polyethylene glycol, and -O(CH ₂ CH ₂ O) _x CH ₃ (where X is an integer of 2-20, for example, 2-10 and 2-5). Another type of substituted indolyloxy group is hydroxymethoxy or is expressed as -OCH ₂ (CH ₂ ) _y OH, where y is an integer from 1 to 10 (eg, 1-4).

 "Substituted oxime oxycarbonyl" refers to a group of the structure (substituted alkyl)-O-C(0)-. The group is bonded to the parent structure through its carbonyl moiety, and the "substituted alkyl group" in the group means that one or more (up to 5, for example, up to 3) hydrogen atoms are from the following groups. The alkyl group replaced by the selected substituent:

其中： -R ^a , -OR ^b , -O Cr alkyl) O- (for example, dioxymethane-), -SR ^b , fluorene, hydrazine, -NR ^{b in} which one or more hydrogen atoms are replaced by a lower alkyl group R ^e , halo, cyano, nitro, -COR ^b , -CO ₂ R ^b , -CONR ^b R ^e , -OCOR ^b , -OCO ₂ R ^a , -OCONR ^b R ^c , -NR ^c COR ^b , -NR ^c CO ₂ R ^a , -NR°CONR ^b R -CO ₂ R ^b , -CONR ^b R%

among them:

R ^{a is} selected from a substituted or unsubstituted C ₆ fluorenyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

 R A HU substituted or unsubstituted c alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

R is selected from hydrogen and a substituted or unsubstituted C ₄ alkyl group;

Each substituted or unsubstituted group is either unsubstituted or each independently substituted with one or more (eg, 1 or 2 or 3) substituents, each substituent being independently selected from the group consisting of: C _r C ₄ alkyl, aryl, heteroaryl, aryl-CV alkyl-, heteroaryl-C _r C ₄ alkyl-, C _r C4 halogenated fluorenyl-, -OC fluorenyl, -OC _r C ₄ hydrocarbon phenyl, -CC alkyl-OH, -OCi-haloalkyl, halo, -OH, -NH ₂ , alkyl-NH ₂ ,

-N(C _r C ₄ fluorenyl) (C _r C ₄ alkyl), -NH(C _r C ₄ alkyl), -N(CrC ₄ alkyl) (VC ₄ hydrocarbon phenyl), -NH -Cj Hydrocarbon phenyl), cyano, nitro, oxo (substituent as heteroaryl), -CO ₂ H, -C(O)O -C ₄ alkyl, -CON(CVC ₄ fluorenyl) Alkyl), -CONH(C _r C ₄ fluorenyl), -CONH ₂ , -NHC(O)( -C ₄ alkyl), -NHC(0)(phenyl), -N( VC ₄ alkyl) C(0)(C _r C ₄ alkyl), -N(C _r decyl) C(0)(phenyl), -C(0)CVC ₄ fluorenyl, -C(0) -C ₄ phenyl -C(0)CVC ₄ halodecyl, -OC(O)-C ₄ alkyl, -SO^C alkyl), -SO ₂ (phenyl), -SO ₂ (C _r C ₄ haloalkyl ), -S0 ₂ NH ₂ , -SOsNH C Oj alkyl), -S0 ₂ NH (phenyl), -NHS0 ₂ (VC ₄ alkyl), -NHSO ₂ (phenyl), and -NHSO^ - halogenated hydrazine base).

"Substituted amino" refers to a group of the structure -NHR ^d or -NR ^d R ^d . Each R ^{d is} each independently selected from the group consisting of a substituted or unsubstituted alkyl group, a substituted or unsubstituted cyclodecyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted group. Heteroaryl, substituted or unsubstituted heterocycloalkyl, alkoxycarbonyl, a sulfinyl group and a sulfonyl group, wherein the substituted indenyl, cyclodecyl, aryl, heterocycloalkyl and heteroaryl are referred to as fluorenyl, cyclodecyl, aryl, heterocycloalkyl and hetero 1 or more of aryl groups (up to 5, for example, up to

The three) hydrogen atoms are each independently replaced by a group selected from the following substituents:

-R ^a , -OR ^b , -0 (CVC ₂ fluorenyl) O- (for example, dioxin), -SR ^b , hydrazine, hydrazine in which one or more hydrogen atoms are replaced by a lower alkyl group, -NR ^b R. , halogenated, cyano, nitro, -COR ^b , -CO ₂ R ^b , -CONR ^b R. -OCOR ^b , -OCO ₂ R ^a , -OCONR ^b R ^c , -NR ^c COR\ -NR°CO ₂ R ^a -NR ^c CONR ^b R. -CO ₂ R ^b , -CONR ^b R% -NR ^c COR\ -SOR ^a , -SO ₂ R ^a , -SO ₂ NR ^b R ^c and -NR ^e SO ₂ R ^a , wherein:

R ^{a is} selected from a substituted or unsubstituted C ₆ fluorenyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

^ selected from 11, a substituted or unsubstituted c ₆ fluorenyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

R ^{e is} selected from hydrogen and a substituted or unsubstituted C ₄ fluorenyl group;

Each substituted or unsubstituted group is either unsubstituted or each independently substituted with one or more (eg, 1 or 2 or 3) substituents, each substituent being independently selected from the group consisting of: C _r C ₄ alkyl, aryl, heteroaryl, aryl-dC ₄ fluorenyl-, heteroaryl-Cr alkyl-, C _r C4 haloalkyl-, -OC _r C ₄ fluorenyl, -OCVC ₄ hydrocarbon Phenyl, -C decyl-OH, -OCVC ₄ haloalkyl, halo, -OH, -NH ₂ , -CC ₄ fluorenyl-NH ₂ , -N(CVC ₄ fluorenyl) (fluorenyl), - NH C alkyl), -N(C _r C ₄ fluorenyl) (C hydrocarbon phenyl), -NH^-hydrocarbylphenyl), cyano, nitro, oxo (substituent as heteroaryl) -CO ₂ H, - O d- fluorenyl, -CON((VC ₄ fluorenyl) (C _r C ₄ fluorenyl), -CONH(C _r C ₄ alkyl), -CONH ₂ , -NHC(O )(CrC ₄ alkyl), -NHC(O)(phenyl), -N(C _r C ₄ alkyl)C OXd-decyl), -N(CVC ₄ alkyl) C(O)(phenyl ), -QC alkyl, -C(O)CVC ₄ phenyl, -QK halogenated fluorenyl, -OC O^!-C^alkyl, -SO ₂ ((VC ₄ fluorenyl), -SO ₂ ( Phenyl), -SO ₂ (VC ₄ haloalkyl), -SO ₂ NH ₂ , -S0 ₂ NH(CVC ₄ alkyl), -SO ₂ NH (phenyl), - NHSO ₂ (C _r C ₄ alkyl), -NHS0 ₂ (phenyl) and -NHSO^C haloalkyl); wherein the substituted or unsubstituted acyl group, alkoxycarbonyl group, sulfinyl group and decanoyl group are as defined above.

 "Effective amount" means the amount of a chemical substance capable of producing a therapeutic effect on a disease when the chemical substance of the present invention is used in a patient. For example, an effective dose can be an amount sufficient to treat a chemical that inhibits a protein kinase. The effective dose can be measured by testing, for example, by analyzing the concentration of chemicals in the blood. The effective dose can also be theoretically calculated, for example, by calculating bioavailability.

"Significant" means that any detectable change is statistically significant. This statistical significance can be derived from a parametric or non-parametric hypothesis test, for example, Student's t-test gives a result of p < 0.05. "Patient" means an animal (such as a human) that has or will be a subject of treatment, observation, or testing. The methods provided by the present invention can be beneficial for both human therapeutic and veterinary applications. In certain embodiments, the patient is a mammal. In yet other specific embodiments, the patient is a human.

 "Angiogenic protein kinase" refers to a protein kinase involved in the process of angiogenesis, including but not limited to VEGFR2 and PDGFRp.

 "Inhibition" refers to a decrease in the activity of a protein kinase which is directly or indirectly caused by the presence of a compound represented by the formula (I), and the decrease in the activity of the kinase is relative to the activity of the kinase in the absence of the compound. This decrease in activity may be due to a direct interaction of the compound with the protein kinase, or due to the interaction of the compound with one or more other factors that affects the activity of the kinase. For example, the presence of a compound can reduce its activity by binding directly to a protein kinase, or by (directly or indirectly) causing another factor to reduce the activity of a protein kinase, or by (directly or indirectly) reducing a protein kinase in a cell or organism. The content in the medium.

 "Treatment" refers to any treatment of a patient's condition, including: prevention of the disease, ie, the clinical symptoms of the disease cease to develop; inhibition of the disease; slowing or blocking the development of clinical symptoms; and alleviating the disease, which causes the deterioration of clinical symptoms.

 "Diseases that are responsive to inhibition of protein kinases" refers to pathological conditions that are at least partially dependent on the activity of one or more protein kinases (e.g., angiogenic protein kinases). Protein kinases are involved directly or indirectly in signaling pathways for various cellular activities, such as cell division, differentiation, and migration. Diseases that are responsive to inhibition of protein kinases include, but are not limited to, tumor growth, growth of solid tumors supported by angiogenesis, and diseases characterized by excessive local vascular growth (e.g., diabetic retinopathy, macular degeneration, and inflammation). The present invention provides a diphenylurea derivative represented by the formula (I), and pharmaceutically acceptable salts, solvates, crystals, chelating agents, non-covalent complexes, prodrugs, and mixtures thereof,

 Formula (I)

 among them-

X, and X ₂ are each independently selected from CH and N;

R7 is a substituted or unsubstituted aryl or heteroaryl group; Z is -, where:

Ζ^Π Ζ ₃ is - CR ₉ R _1Q -, where R ₉ and. Each independently selected from a hydrogen atom, a substituted or unsubstituted dC ₃ alkyl group, and a halogen;

Z ₂ is absent or is selected from -O-, -S -, -NR -, wherein R is selected from H and C 3 alkyl;

 n and m are integers from 0 to 2; '

R1 is absent or represents 1, 2 or 3 substituents, each substituent being independently selected from the group consisting of hydroxyl, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halo, carboxy , substituted or unsubstituted acyl group, substituted or unsubstituted alkoxycarbonyl group, substituted or unsubstituted fluorenyl group, substituted or unsubstituted C _r C3 alkoxy group, sulfonyl group, sulfinyl group, sulfonyl group;

R4 is absent or represents 1, 2, 3, 4 or 5 substituents, each substituent being independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl , halo, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cvc ₆ fluorenyl, substituted or unsubstituted <^-0 ₆ decyloxy, a substituted or unsubstituted aryloxy group, a sulfonyl group, a sulfinyl group, a sulfonyl group, a substituted or unsubstituted arene group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocycloalkyl group; Or an adjacent two R 4 groups together with the attached carbon atom form an aromatic ring, a heteroaryl ring, an alkyl ring or a heterofluorenyl ring, said aromatic ring, heteroaryl ring, alkyl ring or heteroalkyl ring Not substituted or substituted by 1, 2, 3 or 4 substituents each independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halo, carboxy, substituted Or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted C _r C ₃ fluorenyl, substituted or unsubstituted (C ₃ alkoxy, sulfonyl, sulfinyl, and sulfonyl.

In certain embodiments, R1 represents 0 or 1 or 2 or 3 substituents, wherein the substituents are independently selected from halo, CC ₃ alkyl, and a group selected among CrC ₃ embankment. In certain embodiments, R1 represents 1 or 2 or 3 substituents, wherein each substituent is independently selected from the group consisting of dentate, methyl, and methoxy. In certain embodiments, R1 represents a substituent selected from the group consisting of halo, methyl, and methoxy. In certain embodiments, R1 does not occur.

In certain specific embodiments, R.sup.4 represents 0 to 5 substituents, wherein each substituent is independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, halo, Carboxyl, substituted or unsubstituted -C ₆ fluorenyl, substituted or unsubstituted (^-^ methoxy, substituted or unsubstituted phenoxy, C _r C ₆ alkoxysulfonyl, C _r C ₆ Acyl, C _r C ₆垸oxycarbonyl, substituted or unsubstituted heteroaryl, and heterocycloalkyl.

In certain embodiments, R.sup.4 represents 1 to 5 substituents, wherein each substituent is independently Among the following groups are selected: hydroxy, cyano, halo, substituted or unsubstituted dC ₂ fluorenyl, phenoxy, substituted or unsubstituted -( ₂ fluorenyloxy.

 In certain embodiments, R.sup.4 represents 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of halo, methyl, methoxy, ethoxy, and trifluoromethyl. .

 In certain embodiments, R.sup.4 represents 3 substituents, wherein each substituent is independently selected from the group consisting of: hydrogen atom, halo, methyl, methoxy, ethoxy, and trifluoromethyl. And at least one of the three substituents is not a hydrogen atom.

 In certain embodiments, R.sup.4 represents 2 substituents, wherein each substituent is independently selected from the group consisting of: hydrogen atom, halo, methyl, methoxy, ethoxy, and trifluoromethyl. And at least one of the two substituents is not a hydrogen atom.

 In certain embodiments, R4 does not occur.

In certain embodiments, R7 is selected from the group consisting of pyrimidinyl and substituted pyrimidinyl, wherein the substituted pyrimidinyl is selected from the group consisting of mono-, di-, and tri-substituted pyrimidinyl groups, wherein each substituent is independently Selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halo, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted fluorenyloxy, substituted Or unsubstituted (^-^alkyl, substituted or unsubstituted-( ₆ alkoxy, sulfonyl, sulfinyl, sulfonyl, substituted or unsubstituted arene, substituted or unsubstituted) An aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic hydrocarbon group.

In certain specific embodiments, R7 is selected from the group consisting of pyrimidinyl and substituted pyrimidinyl, wherein substituted pyrimidinyl is selected from the group consisting of mono-, di-, and tri-substituted pyrimidinyl groups, wherein substituents on substituted pyrimidinyl groups Separately selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, halo, carboxy, substituted or unsubstituted cc ₆ alkyl, substituted or unsubstituted c _r c ₆ methoxy, c _r c ₆ sulfonylamino, cc ₆ acyl, c _r c ₆ alkoxycarbonyl, substituted or unsubstituted heteroaryl, and heterocycloalkyl.

In certain specific embodiments, R7 is selected from the group consisting of pyrimidinyl and substituted pyrimidinyl, wherein substituted pyrimidinyl is selected from the group consisting of mono-, di-, and tri-substituted pyrimidinyl groups, wherein substituents on substituted pyrimidinyl groups independently selected from the group consisting of: hydroxy, cyano, halo, a substituted or unsubstituted alkyl with C _r C _2, and a substituted or unsubstituted (^ - (^ embankment group.

In certain particular embodiments, R7 is selected from pyrimidin-4-yl and substituted pyrimidin-4-yl, wherein substituted pyrimidin-4-yl is derived from mono-, di-, and tri-substituted pyrimidin-4-yl Selected as follows, wherein each substituent is independently selected from the group consisting of: hydroxy, nitro, aryl, substituted or unsubstituted amino, aminocarbonyl, halo, carboxy, substituted or unsubstituted acyl, substituted Or unsubstituted alkoxycarbonyl, substituted or unsubstituted C^ group, substituted or unsubstituted (^-( ₆ alkoxy, sulfonyl, sulfinyl, sulfonyl, substituted or unsubstituted a substituted aromatic hydrocarbon group, a substituted or unsubstituted heteroaryl hydrocarbon group, a substituted or unsubstituted heterocyclic hydrocarbon group.

In certain specific embodiments, R7 is selected from pyrimidin-4-yl and substituted pyrimidin-4-yl, wherein substituted pyrimidin-4-yl is derived from mono-, di-, and tri-substituted pyrimidin-4-yl Selected from the substituents on the substituted pyrimidin-4-yl group, each independently selected from the group consisting of hydroxy, nitro, cyano, substituted or unsubstituted amino, halo, carboxy, substituted or unsubstituted Substituted C alkyl, substituted or unsubstituted -( ₀ methoxy, -C ₆ alkoxysulfonyl, C _r C ₆ acyl, C _r C ₆ alkoxycarbonyl, substituted or unsubstituted heteroaryl, And a heterocyclic hydrocarbon group.

In certain specific embodiments, R7 is selected from pyrimidin-4-yl and substituted pyrimidin-4-yl, wherein substituted pyrimidin-4-yl is derived from mono-, di-, and tri-substituted pyrimidin-4-yl Selected from the substituents on the substituted pyrimidin-4-yl group, each independently selected from the group consisting of hydroxy, cyano, halo, substituted or unsubstituted dC ₂ alkyl, and substituted or unsubstituted -( ₂ alkoxy.

 In certain specific embodiments, R7' is pyrimidin-4-yl.

 In certain embodiments, R7 is selected from the group consisting of pyridyl and substituted pyridyl, wherein the substituted pyridyl is selected from the group consisting of mono-, di-, and tri-substituted pyridyl groups, wherein each substituent is independently selected from The following groups: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted fluorenyloxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, sulfonyl, sulfinyl, sulfonyl, substituted or unsubstituted arene, substituted or unsubstituted heteroaryl, substituted Or unsubstituted heterocycloalkyl.

In certain embodiments, R7 is selected from the group consisting of pyridinyl and substituted pyridyl, wherein the substituted pyridyl group is selected from the group consisting of mono-, di-, and tri-substituted pyridyl groups, wherein the substituent on the substituted pyridyl group Individually selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, halo, carboxy, substituted or unsubstituted C ₆ alkyl, substituted or unsubstituted C alkane An oxy group, a _Cr C ₆ hydrocarbon sulfonamide group, a C Ce acyl group, a C alkoxycarbonyl group, a substituted or unsubstituted heteroaryl hydrocarbon group, and a heterocyclic hydrocarbon group.

In certain embodiments, R7 is selected from the group consisting of pyridinyl and substituted pyridyl, wherein the substituted pyridyl group is selected from the group consisting of mono-, di-, and tri-substituted pyridyl groups, wherein the substituent on the substituted pyridyl group Each of them is independently selected from the group consisting of a hydroxyl group, a cyano group, a halogenated group, a substituted or unsubstituted _Cr C ₂ alkyl group, and a substituted or unsubstituted -( ₂ methoxy group.

In certain embodiments, R7 is selected from the group consisting of pyridin-4-yl and substituted pyridin-4-yl, wherein substituted pyridin-4-yl is derived from mono-, di-, and tri-substituted pyridin-4-yl Selected, wherein each substituent is independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halo, carboxy, substituted or unsubstituted acyl, substituted Or unsubstituted alkoxycarbonyl, substituted or unsubstituted c _r c ₆垸 A substituted, unsubstituted or unsubstituted aryloxy group, a sulfonyl group, a sulfinyl group, a sulfonyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heteroaryl hydrocarbon group, a substituted or unsubstituted group. Heterocyclic hydrocarbon group.

In certain embodiments, R7 is selected from the group consisting of pyridin-4-yl and substituted pyridin-4-yl, wherein substituted pyridin-4-yl is derived from mono-, di-, and tri-substituted pyridin-4-yl The substituents on the substituted pyridin-4-yl group are each independently selected from the group consisting of: a hydroxyl group, a nitro group, a cyano group, a substituted or unsubstituted amino group, a halogenated group, a carboxyl group, a substituted or an unsubstituted group. Substituted CC ₆ alkyl, substituted or unsubstituted (^-^ alkoxy, C _r C ₆ alkoxysulfonyl, -C ₆ acyl, CC ₆ fluorenyloxycarbonyl, substituted or unsubstituted heteroaryl); And a heterocyclic hydrocarbon group.

In certain embodiments, R7 is selected from the group consisting of pyridin-4-yl and substituted pyridin-4-yl, wherein substituted pyridin-4-yl is derived from mono-, di-, and tri-substituted pyridin-4-yl Selected from the substituents wherein the substituted pyridin-4-yl group is independently selected from the group consisting of hydroxy, cyano, halo, substituted or unsubstituted _cr c ₂ alkyl, and substituted or Unsubstituted (^-( ₂ alkoxy).

 In certain embodiments, R7 is pyridin-4-yl.

 In some embodiments, ^ and :^ are both ^^.

 In some embodiments, 1^ and: 3⁄4 are (:11.

 In certain embodiments, an aromatic ring, a heteroaryl ring, an indenyl ring or a heterofluorenyl ring formed by two adjacent R4 groups together with a carbon atom to which they are attached is a 5- or 6-membered ring having 1 or 2 heteroatoms selected from 0, S or N. In a more preferred embodiment, the aromatic ring, heteroaryl ring, indenyl ring or heteroalkyl ring is ring-bonded to the attached benzene to form a bicyclic system selected from the group consisting of benzofuran, benzothiophene, Anthracene, carbazole, quinoline, pyridazine, quinoxaline.

In certain embodiments, N and X ₂ are CH, the R1 group is substituted at the 7 position of the indole ring, and the -NH-CO-NH- is substituted at the 4 position of the indole ring.

In certain embodiments, ₁ is >^ and X ₂ is N, the R1 group is substituted at the 7 position of the benzimidazole ring, and the -NH-CO-NH- is substituted at the 4 position of the indole ring. .

In certain embodiments, Z is selected from -O-, -S -, CC ₅ alkylene group, -NR -, wherein R is selected from H and C _r C ₃ alkyl.

In certain embodiments, the substituent -ZR7 has a structure represented by the formula (II),

Chemical formula (II) among them:

R8 is absent or represents 1, 2, 3, 4 or 5 substituents, each substituent being independently selected from the group consisting of hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halogenated , a carboxy group, a substituted or unsubstituted acyl group, a substituted or unsubstituted fluorenyloxycarbonyl group, a substituted or unsubstituted C _r C ₆ alkyl group, a substituted or unsubstituted C _r C ₆ decyloxy group, a substituted or unsubstituted aryl group Oxyl, sulfonyl, sulfinyl, sulfonyl, substituted or unsubstituted arene, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl;

 Y1 and Y2 are each independently selected from CH and N. '

In certain embodiments, at least one of YBY ₂ is N. In certain embodiments, R8 represents 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl , halo, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted c _r c ₅ alkyl, substituted or unsubstituted cc alkoxy, substituted Or unsubstituted aryloxy, sulfonyl, sulfinyl, sulfonyl, substituted or unsubstituted arene, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl.

In certain specific embodiments, R8 represents 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of: hydroxy, cyano, substituted or unsubstituted amino, halo, substituted Or unsubstituted cvc ₂ alkyl, phenoxy, (^-(^ alkoxy).

 In certain embodiments, R.sup.8 represents 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of substituted or unsubstituted amino, halo, methyl, methoxy, B. Oxyl, and trifluoromethyl.

 In certain embodiments, R8 does not occur.

 In certain embodiments, the compound has the structure shown by formula (III)

化学式 （III) 其中：

Chemical formula (III) among them:

 R8 is absent or represents 1, 2, 3, 4 or 5 substituents, each substituent being independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halogenated , a carboxy group, a substituted or unsubstituted acyl group, a substituted or unsubstituted fluorenyloxycarbonyl group, a substituted or unsubstituted group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a sulfonyl group, a sulfinyl group a sulfonyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heteroaryl hydrocarbon group, a substituted or unsubstituted heterocyclic hydrocarbon group;

Y, and Y ₂ are each independently selected from CH and Ν;

R5 and R6 are each independently selected from the group consisting of hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halo, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted c ₃ alkyl group, a substituted or unsubstituted (^-yloxy group, a sulfonyl group, a sulfinyl group, a sulfonyl group, a substituted or unsubstituted arene group, a substituted or unsubstituted heteroaryl group, And a substituted or unsubstituted heterocyclic hydrocarbon group.

 The description about R1 is the same as in the description of the compound represented by the chemical formula (I).

In some embodiments, at least one of Χ^Β Χ ₂ is N.

In some embodiments, at least one of Υ^Β Υ ₂ is N.

 In certain embodiments, R5 and R6 are each independently selected from the group consisting of: a hydrogen atom, a halo, a methyl group, a trifluoromethyl group, a methoxy group, and an ethoxy group.

 In certain embodiments, at least one of R5 and R6 is not a hydrogen atom.

 In certain embodiments, R5 and R6 are each independently selected from the group consisting of halo, methyl, trifluoromethyl, methoxy, and ethoxy.

In certain embodiments, R.sup.8 represents 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halo, carboxy, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted C _r C ₅ embankment group, a substituted or unsubstituted (^ - ₅ alkoxy group, A substituted or unsubstituted aryloxy group, a sulfonyl group, a sulfinyl group, a sulfonyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heteroaryl hydrocarbon group, a substituted or unsubstituted heterocyclic hydrocarbon group.

In certain embodiments, R8 represents from 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of: hydroxy, cyano, amino, halo, substituted or unsubstituted _{CrC 2} alkyl, phenoxy, (^-decyloxy).

 In certain embodiments, R8 represents from 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of amino, halo, methyl, methoxy, ethoxy, and trifluoro. methyl.

In certain embodiments, R8 does not occur. In certain specific embodiments, the compound has the structure shown in formula (IV)

 Chemical formula (IV)

 among them:

R8 is absent or represents 1, 2, 3, 4 or 5 substituents, each substituent being independently selected from the group consisting of hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halogenated , carboxy, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cvc ₆ alkyl, substituted or unsubstituted (^-0 ₆ methoxy, substituted or unsubstituted aryl Oxyl, sulfonyl, sulfinyl, sulfonyl, substituted or unsubstituted arene, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl;

And Y ₂ are each independently selected from CH and Ν;

R6 and R11 are each independently selected from the group consisting of hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halo, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted alkane oxycarbonyl group, a substituted or unsubstituted C, -C ₃ alkyl with, a substituted or unsubstituted - € ₃ alkoxy group, a sulfonamide group, a sulfinyl group, a sulfonyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted Or unsubstituted heteroaryl hydrocarbon group, and substituted or unsubstituted heterocyclic hydrocarbon group.

 Here, the description about R1 is the same as in the description of the compound represented by the chemical formula (I).

In some embodiments, at least one of Χ Χ ₂ is N.

 In certain embodiments, at least one of Y1 and Y2 is N.

 In certain embodiments, R6 and R11 are each independently selected from the group consisting of hydrogen atom, halo, methyl, trifluoromethyl, methoxy, and ethoxy.

 In certain embodiments, at least one of R6 and R11 is not a hydrogen atom.

In certain embodiments, R6 and R11 are each independently selected from the group consisting of halo, methyl, trifluoromethyl, methoxy, and ethoxy. In certain embodiments, R.sup.8 represents 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, Halogenated, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted (V

C ₅ alkyl, substituted or unsubstituted (^-( ₅ alkoxy, substituted or unsubstituted aryloxy, sulfonyl, sulfinyl, sulfonyl, substituted or unsubstituted arene, substituted Or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl.

In certain embodiments, R.sup.8 represents 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of: hydroxy, cyano, amino, 3⁄4, substituted or unsubstituted fluorenyl, Phenoxy group, C wide C ₂ decyloxy group.

 In certain embodiments, R8 represents from 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of amino, halo, methyl, methoxy, ethoxy, and trifluoro. methyl.

 In certain embodiments, R8 does not occur.

 In certain embodiments, preferred chemistries of the invention comprise the following compounds:

 1-(4-methyl-3-trifluoromethyl-phenyl)-3-(1-pyridine-4-methylene-1H-indol-4-yl)-urea;

 1-(4-chloro-3-trifluoromethyl-phenyl)-3-(1-pyridin-4-methylene-1H-indol-4-yl)-urea;

 1-(4-fluoro-3-trifluoromethyl-phenyl)-3-(1-pyridin-4-methylene-1H-indol-4-yl)-urea;

1-[1-(2-Amino-P-pyridyl-4-methylene)-1H-indol-4-yl]-3-(5-bromo-2-methoxy-phenyl)-urea 1-[1-(2-Amino-pyridin-4-methylene)-1Η-indol-4-yl]-3-(5-chloro-2-methoxy-phenyl)-urea; ( ₄ _{4-[3-(5-Bromo-2-methoxy-phenyl)-ureido]-inden-1-methylene}-pyridin-2-yl)-carbamic acid methyl ester;

 1-[1-(2-Amino-pyridin-4-methylene)-1Η-indol-4-yl]-3-(5-bromo-2,3-dihydro-benzofuran-7- Base) - urea

 And pharmaceutically acceptable salts, solvates, crystals, chelating agents, non-covalent complexes, prodrugs, and mixtures thereof.

The compounds represented by the various chemical formulas of the present invention include, but are not limited to, optical isomers, racemic isomers, and other mixtures of the compounds represented by the chemical formula. Moreover, the compounds also include Z- and E-form (or cis- and trans-) structures of compounds having a double bond therein. Individual enantiomers or diastereomers (e.g., optically active configurations) can be obtained by asymmetric synthesis or separation of racemic isomers. Separation of racemic isomers can be achieved by conventional means such as crystallization by addition of a separating agent, or by liquid chromatography using chiral symmetry high pressure liquid chromatography (chiral HPLC). )column. When a compound is present in a tautomeric form, the chemistry of the invention comprises all tautomeric forms of the compound. Compounds of the invention also include, but are not limited to, all pharmaceutically acceptable forms of the compounds and compounds represented by the formulas shown. Pharmaceutically acceptable forms of the compounds include: pharmaceutically acceptable salts, solvates, crystalline forms (including polymorphs and clathrates), chelating agents, non-covalent complexes, precursors Medicine, and mixture. In certain embodiments, the compounds described herein occur in the form of a pharmaceutically acceptable salt. Thus, the term "chemical substance" also includes pharmaceutically acceptable salts, solvates, crystalline forms, chelating agents, non-covalent complexes, prodrugs, and mixtures.

"Pharmaceutically acceptable salts" include, but are not limited to, mineral acid salts (eg, hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfites, nitrates, etc.) and organic acids. Salts (eg malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethyl) Sulfonic acid salts, benzoates, salicylates, stearates, and stearates (such as acetate and HOOC-(CH ₂ ) _n -COOH, where _n is 0-4), etc.) . Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonia.

 Further, if the obtained compound represented by the formula (I) is an acidic salt, the free base can be obtained by alkalizing an acidic salt solution. In contrast, if the reaction product obtained is a free base, the free base can be dissolved in a suitable organic solvent and the solution is acid treated to obtain an addition salt, especially a pharmaceutically acceptable addition. salt. This process is consistent with conventional methods for producing acidic addition salts from basic compounds. Professionals in this field should be able to propose a variety of synthetic methods suitable for the formation of non-toxic pharmaceutically acceptable addition salts.

 As described above, the prodrug also falls within the scope of the chemical substance, for example, an ester or an amide derivative of the compound represented by the formula (I). "Prodrug" - the term includes any compound which, when administered to a patient, can be converted to a compound represented by formula (I). For example, a metabolic process in a patient converts a prodrug into a compound represented by formula (I). Examples of prodrugs include, but are not limited to, functional groups in compounds represented by formula (I)

A similar derivative of acetate, formate, benzoate or the like (e.g., hydroxy or amide group).

 The term "solvate" refers to a chemical produced by the interaction of a compound and a solvent. Suitable solvates can be pharmaceutically acceptable solvates, for example, hydrates (including monohydrate and hemihydrate).

 The term "chelating agent" refers to a chemical substance obtained by integrating a compound and a metal ion at two (or more) points.

The term "non-covalent complex" refers to a chemical produced by the interaction of one compound with another molecule in which no covalent bond is formed between the compound and the molecule. For example, this compositing can be achieved by van der Waals forces, hydrogen bonds, and electrostatic forces (also known as ionic bonds). The term "active substance" is used to refer to a biologically active chemical. In certain embodiments, an "active substance" is a compound having pharmaceutical use. For example, an active substance can be an anti-tumor drug.

 The compound represented by the formula (I) or a salt of the compound and other compounds in the present invention can be synthesized by an appropriate chemical reaction process. The present invention will utilize the following reaction schemes and synthetic products as an example to illustrate this chemical reaction process. The description of this chemical reaction process will be apparent to those of ordinary skill in the art of organic synthesis.

 The following description of this chemical reaction process (Scheme 1) forms part of the invention:

 102 103 104

Reaction route 1

 In Reaction Route 1, the first step (step:

In compound 102, XI is N or CH, and X2 is H, F, CI or Br; and compound 102 is first dissolved in an inert solvent such as THF (tetrahydrofuran) or cyclohexane hydrocarbon in an amount of 5 to 50 times that of compound 102 ( V/W); further adding a base such as NaH (sodium hydride), Na ₂ CO ₃ (sodium carbonate) or NaHCO ₃ (sodium hydrogencarbonate) in an amount of 1 to 3 times (molar ratio) of the compound 102; After the reaction mixture is completely dissolved, 1 to 1.5 times the molar ratio of the compound 103 is added thereto, and then the reaction is stirred at 0 ° C to 70 ° C for 2 hr to 24 hr _{; after} completion of the reaction, water is added and mixed, using AcOEt (ethyl acetate). The organic phase was extracted and further purified to give compound 104. Note: If the base used is NaH, the reaction temperature should be low (0 ° C ~ 3 (TC) _; if other bases are used, the reaction temperature can be increased.

In Reaction Route 1, the second step (step ₂ ):

 The compound 104 is dissolved in a solvent of methanol, ethanol, ethyl acetate or a mixed solvent containing the same, and a catalyst M or Pd/C is added thereto, and hydrogenation is carried out at normal temperature and normal pressure (hydrogen pressure) for about 2 to 5 hr. After reduction, filtration and further purification afforded compound 105.

In Reaction Route 1, the third step (step ₃ ):

After compound 105 is dissolved in an inert solvent such as THF, cyclohexyl hydrocarbon, chloroform, dichloromethane or petroleum ether, the same molar ratio of compound 106 is added thereto, and then the reaction is stirred at 0 ° C to 40 ° C. 2hr~24hr _{; after} completion of the reaction, water is added, filtered, and the organic phase is combined and further purified to obtain compound 107.

In Reaction Route 1, the fourth step (step ₄ ):

 Compound 107 is added to 5~10 times (V/W), 5mol/L HCl/AcOEt or 2~5 times (VAV) TFA (trifluoroacetic acid), and the reaction is stirred at 0°C~10°C for 0.5hr~3hr. . After completion of the reaction, the solvent was evaporated under reduced pressure or water was added, and the mixture was neutralized to pH about 7.0, and separated and extracted with AcOEt. The organic phase was combined and further purified to afford compound 101.

For a description of Reaction Scheme 1: V: volume, in milliliters (ml); W: weight, in units (g) _; Boc: tert-butoxycarbonyl, a protecting group for an amino group.

 In order to screen for the corresponding inhibitors, the intracellular portion of the receptor kinase containing the intact kinase active center in the VEGFR2 (KDR) and PDGFR P proteins was first cloned and expressed, and the cloned and expressed partial receptor kinase protein was preserved intact. Kinase activity. Analytical detection of receptor kinase activity can be performed by testing the activity of the purified partial receptor kinase protein using LanthaScreenT TR-FRET (Invitrogen). By adding a compound represented by formula (I) to the kinase test reaction, the LanthaScreenTM TR-FRET assay can screen for certain compounds that are effective in inhibiting VEGFR2 (KDR) or/and PDGFR P kinase activity.

 The compounds of the present invention, and pharmaceutically acceptable salts, solvates, crystals, chelating agents, non-covalent complexes, prodrugs, and mixtures thereof, may be formulated alone or in combination with one or more pharmaceutically acceptable carriers For example, a solvent, a diluent, or the like is administered for administration, and can be orally administered in the following dosage forms: tablets, capsules, dispersible powders, granules, for example, suspensions containing about 0.05-5% of a suspending agent, for example, 10-50% sugar. The syrup and, for example, an elixir containing 20-50% ethanol, or the like, are administered parenterally in the form of a suspension in a sterile injectable solution or an isotonic medium containing about 0.05-5% of a suspending agent. These pharmaceutical preparations may contain, for example, from about 0.05% to about 90% of the active ingredient in combination with the carrier, more usually from 5% to 60% by weight.

 Accordingly, another aspect of the invention also provides a pharmaceutical composition. The composition comprises at least one of the chemicals described herein and pharmaceutically acceptable salts thereof (particularly hydrochloride, methanesulfonate, tosylate, lactate, and glucuronate) And solvates, crystallization, chelating agents, non-covalent complexes, prodrugs, and mixtures, and at least one pharmaceutically acceptable excipient, or adjuvant, or carrier.

 The pharmaceutical composition of the present invention can be administered orally, such as a tablet or a capsule; in a non-oral infusion form (including intravenous, subcutaneous, intramuscular, intravenous drip, eye drop, inhalation or spray) For example, a sterile solution, a suspension or an emulsion; it is applied in the form of a body surface, such as an ointment or an emulsion cream; or in the form of an anal plug, such as a suppository.

In general, solid carriers for use in pharmaceutical compositions include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, and kaolin, while liquid carriers include sterile water, polyethylene glycol, nonionic surfactants, and edibles. Oils such as corn oil, peanut oil and sesame oil, which are suitable for the characteristics of the active ingredient and the particular form of administration desired. Adjuvants such as flavoring agents, coloring agents, preservatives, and antioxidants such as vitamins £, ascorbic acid, BHT, and BHA, which are commonly used in the preparation of pharmaceutical compositions, may also be included in the compositions. From the standpoint of ease of preparation and administration, preferred pharmaceutical compositions are solid compositions, especially tablets and capsules filled with solid or liquid. Oral administration of the compound is preferred. In some cases, it may be desirable to administer the compound directly to the trachea in the form of an aerosol. In summary, the above pharmaceutical compositions can be prepared in a conventional manner using conventional excipients. The solution or suspension of these active compounds as a free base or a pharmaceutically acceptable salt can be prepared in water to be mixed with a surfactant such as hydroxypropylcellulose, as administered parenterally or intraperitoneally. Dispersions can also be prepared in glycerol, polyethylene glycol liquids, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

 The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions, and sterile powders for the preparation of sterile injectable solutions or dispersions. In all cases, the dosage form must be sterile and liquid for injection. It must be stable under the conditions of manufacture and storage and must be resistant to microbial contamination such as bacteria and fungi. The carrier may be, for example, a solvent or dispersion medium containing water, ethanol, a polyol (e.g., glycerol, propylene glycol, and polyethylene glycol liquid), a suitable mixture thereof, and a vegetable oil.

 The pharmaceutical compositions of the invention can be described in dosage units. In some embodiments, usually

A dose of 5 to 5000 mg/m ^{2 of} body surface area is administered to a warm-blooded animal, for example, about 0.1 to 100 mg/kg. A unit dosage within a certain range, such as 1-100 mg/kg (preferably 1-60 mg/kg), is a conceivable dosage form of the drug which usually produces a therapeutic effect. A unit dosage form such as a tablet or a capsule usually contains from 1 to 500 mg of the active ingredient.

 The frequency of use of the drug varies depending on the compound used and the disease. In some embodiments, the drug is usually administered 4 times or less. In some embodiments, the number of doses may also be one to two times per day.

 The present invention also proposes the use of a compound represented by the formula (I) or a pharmaceutically acceptable salt, solvate, crystallization, chelating agent, non-covalent complex, prodrug, or mixture thereof for the treatment of a disease. The disease to be treated should be responsive to inhibition of protein kinase activity in human or animal body due to treatment.

 In certain embodiments, the compounds described herein have an inhibitory effect on at least one of VEGFR2 and PDGFRβ. Therefore they are very valuable for anti-vascular growth. In certain embodiments, certain compounds have an inhibitory effect on both VEGFR2 and PDGFR P kinases. Therefore, these compounds are also valuable for anti-angiogenesis.

 The present invention further provides a compound represented by the formula (I) or a pharmaceutically acceptable salt, solvate, crystal, chelating agent, non-covalent complex, prodrug or mixture thereof as a medicament. Anti-angiogenic effects are produced in warm-blooded animals (including humans).

 The present invention further proposes that the compound represented by the formula (I) or a pharmaceutically acceptable salt, solvate, crystal, chelating agent, non-covalent complex, prodrug or mixture thereof can be used for the manufacture of warm blood. An animal (such as a human) that produces an anti-angiogenic effect in the body.

The invention further proposes a method for producing an anti-angiogenic effect in a warm-blooded animal such as a human. The method, wherein: the animal is in need of anti-angiogenic therapy, and the therapy comprises: administering an effective amount of the compound represented by the formula (I) or a pharmaceutically acceptable salt, solvate, crystal, chelating agent, non- A covalent complex, prodrug, or mixture is used on the animal.

 As indicated above, the size of the dose required for the treatment or prophylaxis of a particular disease needs to be adjusted accordingly, depending on the subject being treated, the route of administration, and the severity of the condition being treated. Typically, the daily dose is controlled in the range of 1 to 60 mg/kg. However, the daily dose must be adjusted depending on the subject being treated, the route of administration, and the severity of the condition. Therefore, the optimal dose should be determined by the doctor or nurse treating the patient.

 The anti-angiogenic therapy as defined above may be used alone as a treatment or in combination with one or more other substances or therapies as a treatment. This combination therapy can be achieved by performing a single therapy in combination therapy simultaneously, sequentially or completely separately. In the field of oncology treatment, it is common to use a variety of different treatments to treat cancer patients. In the composition of this combination therapy, in addition to the aforementioned anti-angiogenic therapy, other common constitutional therapies include surgery, radiation therapy, and chemotherapy.

 In certain embodiments, the chemistry of at least one of the compounds represented by Formula 00, or a pharmaceutically acceptable salt, solvate, crystallization, chelate, non-covalent complex, prodrug, and mixtures thereof The substance is combined with the other at least one reactive monomer in a single dose. Antitumor drugs for radiation therapy can be used alone or in combination with chemotherapy drugs. Suitable anti-tumor therapies that can be used in combination with at least one of the above-described chemicals are as follows. In general, examples of such anti-tumor therapies include: microtubule stabilizers such as paclitaxel (trade name Taxol), polyene melamine (trade name Taxotere), epothilone A, epothilone Epothilone B, desoxyepothilone A. deoxyepothilone B or derivatives thereof; microtubule disrupting agent; alkylating agent; antimetabolite; An anti-neoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum complex; biological effect modifier; growth inhibitory factor; hormone/antihormone therapeutic and hematopoietic growth factor.

Examples of typical anti-tumor therapies include: anthracyclines, vinca, mitomycins, spectinomycins, cytotoxic nucleosides, taxanes, epothilones, discoderm ₀ lide, The pteridine drugs, diyn _enes , podophyllotoxins; preferred in these examples are doxorubicin, _noredamycin , daunorubicin, alanine, methotrexate, Methyl folate, ampicillin, mitomycin (, methyl mitomycin, her _Ce ptin, 5-fluorouracil, 6-mercaptopurine, 2,2-difluorodeoxygenation Cytosine, cytarabine, podophyllotoxin or podophyllotoxin (such as scorpion scorpion, ghost white sulphur phosphate, ghost thiophene) 甙), melphalan, vinblastine, vincristine, isovinblastine, vindesine, vinorelbine, paclitaxel and the like. Other anti-tumor agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, isophosphoramide, hexamethyl melamine, triethylene thiophosphoramide, idatr _exa te, Trimetrexate, carbazole, L-asparaginase, camptothecin, CPT-11, topotecan, cytarabine, bicalutamide, flutamide, leuprolide acetate, pyridinium And pyrrole derivatives, interferons and interleukins.

 In certain embodiments, at least one of the compounds represented by formula (I) or a pharmaceutically acceptable salt, solvate, crystal, chelate, non-covalent complex, prodrug thereof, and mixtures thereof The chemical substance can be administered in combination with an anti-inflammatory agent (anti-inflammatory drug). Anti-inflammatory drugs include NSAIDs (non-steroidal anti-inflammatory drugs), non-specific and COX-2 (epoxidase 2)-specific cyclooxygenase inhibitors, gold-containing compounds, corticosteroids, methotrexate, Tumor necrosis factor (TNF) receptor antagonists, immunosuppressive agents and methotrexate. NSAIDs (non-anti-inflammatory drugs) include ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, sodium diclofenac complex, misoprostol, sulindac, oxaprozin, Diflunisal, piroxicam, indomethacin, etodolac, fenoprofen, ketoprofen, nabumetone, sulfamethazine, tolbutine sodium and hydroxychloroquine. Examples of NSAIDs (non-steroidal anti-inflammatory drugs) also include COX-2 (epoxidase 2)-specific inhibitors (such as a compound that inhibits COX-2, which has an IC50 value at least lower than COX-2) It is 50 times the IC50 value for COX-1, such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib. In certain embodiments, the anti-inflammatory agent can also be a salicylate; the salicylate comprises acetylsalicylic acid (aspirin), sodium salicylate, magnesium salicylate, and choline. The anti-inflammatory agent may also be a corticosteroid such as cortisone, dexamethasone, methylprednisolone, dehydrocortisone, dehydrocortisone sodium phosphate and prednisone. In certain embodiments, the anti-inflammatory agent can be a gold-containing compound such as gold, thiomalic acid or auranofin sodium. In certain embodiments, the anti-inflammatory agent can also be a metabolic inhibitor such as a dihydrofolate reductase inhibitor, aminomethylfolate or a dihydroorotate dehydrogenase inhibitor, leflunomide. Certain embodiments of the invention also include certain co-administrations wherein the anti-inflammatory agent used may be an anti-C5 monoclonal antibody (e.g., eculizumab or pexelizumab), and TNF (tumor necrosis factor) may be anti-qi (e.g., entanercept or infliximab) (Infliximab)), an anti-TNF a monoclonal antibody, or at least one of immunosuppressive agents such as methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine Or an active compound of mycophenolate mofetil.

As described above, the compounds defined in the present invention and pharmaceutically acceptable salts, solvates, crystals, chelates, non-covalent complexes, prodrugs thereof, and mixtures thereof have Extremely high value. Vascular growth is a process of forming new blood vessels based on existing blood vessels. Since blood vessels grow in many pathological states (including but not limited to tumors (Gasparini, G. et al., 2005), chronic inflammation (Konno, S. et al., 2004; Suthin, K. et al., 2003; Medina, J. et al. People, 2005), diabetic retinopathy (Campochiaro ₅ P. A, 2004), and macular degeneration (Rothen, M. et al, 2005; Campochiaro, PA, 2004) have a key role, it is foreseeable that the chemicals described in the present invention will be against many diseases. The treatment is effective. It is especially foreseeable that the chemicals described herein will be effective in slowing the growth of solid tumors (e.g., rectal cancer, breast cancer, prostate cancer, kidney cancer, lung cancer, and skin cancer). More particularly, the chemicals described herein will be effective in inhibiting the growth of solid tumors associated with VEGFR2 and/or PDGFR P. This inhibition of solid tumor growth will be particularly effective when tumor growth and proliferation are dependent on VEGFR2 and/or PDGFR 0 (see review Gasparini, G. et al., 2005).

 In certain embodiments, the physiological conditions and diseases in which the compound represented by the formula (I) and the pharmaceutical composition containing the compound are capable of producing effects include, but are not limited to, psoriasis, blood vessel growth, tumor (for example, chronic granulocyte Leukemia, gastrointestinal stromal cancer, non-small cell lung cancer, breast cancer, ovarian cancer, recurrent ovarian cancer, prostate cancer, especially hormone-refractory prostate cancer, kidney cancer, head and neck cancer, or rectal cancer), immune regulation ( Graft rejection), atherosclerosis, rheumatoid arthritis, Parkinson's disease, Alzheimer's disease, diabetes (such as type 2 diabetes and diabetic retinopathy), septic shock, and so on.

 In addition to medical applications, the compound represented by the formula (I) or a pharmaceutically acceptable salt, solvate, crystal, chelate, non-covalent complex, prodrug thereof and mixtures thereof may also be used. Development and standardization of ex vivo test systems for VEGFR2 and/or PDGFR P kinase activity inhibitors as a tool for pharmaceutical research. Such ex vivo testing systems can be used to assess the effects of inhibitors of VEGFR2 and/or PDGFR kinase activity in test animals such as cats, dogs, rabbits, monkeys, rats, and mice. The following are examples of the invention. The examples are for illustrative purposes only and are not limiting as to the possible embodiments of the invention. '

 The following table lists the English abbreviations that will appear in the examples and the full names in both Chinese and English. If an abbreviation not included in the table below appears in the examples, it represents a generally accepted meaning.

 DMSO = dimethyl sulfoxide

 g = g

 Hr = hour

IC ₅₀ = concentration required to produce a 50% inhibitory effect

 Mg = mg

 Min = minute

 Ml = ml

Mol = mole Mmmol = mmol

 m = millim

 μΜ = micro-mo

 Mpa = MPa

 MS = mass spectrometry

 Ng = ng

 Nm = nanometer

 nM = Namo

 TFA = trifluoroacetic acid Implementation 1. Synthesis of the compound N-(2-Fluoro-5-bromo-phenyl)-N'-[l-(3-amino-methylenebenzene)imidazole-4]-urea

4-nitro-1-(3-tert-butoxycarbonylamino-methylenebenzene)-benzimidazole: 5.0 g (0.031 mol) 4-nitro-benzimidazole, dissolved in 200 ml of cyclohexane, ice bath Cool to 0 ° C, add 1.2 g (0.045 mol) of NaH (90%) with stirring, and keep for 0.5 hr; slowly add 10.5 g (0.037 mol) of 3-tert-butoxycarbonylamino-bromobenzyl, and then react at room temperature. _12hr; completion of the reaction, 50ml of water was added, the organic phase separated, then AcOEt (50mlX 3) extraction of the aqueous phase; the organic phases were combined, dried anhydrous MgSO _4, filtered, solvent was drained under reduced pressure, the resulting solid was purified by silica gel column chromatography Purification (MeOH/CH3⁄4 elution) gave y.

4-amino-1-(3-tert-butoxycarbonylamino-methylenebenzene)-benzimidazole: 8.1 g (0.022 mol) 4-nitro-1-(3-tert-butoxycarbonylamino-methylene Benzene)-benzimidazole, stirred and dissolved in 80 ml of methanol, 0.4 g of Pd/C was added, and the reaction was stirred under a hydrogen pressure of 0.1 MPa at room temperature for 2 hr. After completion of the reaction, the mixture was filtered, and the solvent was evaporated to dryness. Chromatography (1^6013⁄4/01 (1 ₃ elution) gave 5.9 g of white solid.

N-(2-Fluoro-5-bromo-phenyl)-N'-[l-(3-tert-butoxycarbonylamino-methylenebenzene)-benzimidazole-4]-urea: 5.9 g (0.017 mol) 4-Amino-1-(3-tert-butoxycarbonylamino-methylenebenzene)-benzimidazole, dissolved in 60 ml of dichloromethane, cooled to 0 ° C in an ice bath, and slowly added 3.7 g (0.017 mol) 2-Fluoro-5-bromo-isocyanate benzene, and reacted at room temperature for 24 hr _{; after} completion of the reaction, 50 ml of water was added, filtered, and washed with a small amount of cold dichloromethane to give a white solid; Filtration to -10 ° C, and washed with a little cold dichloromethane to give a white solid.

 N-(2-Fluoro-5-bromo-phenyl)-N'-[l-(3-amino-methylenebenzene)-benzimidazole-41-urea: In 12 ml TFA, add 4.5 g (0.0081 Mol) N-(2-fluoro-5-bromo-phenyl)-N'-[l-(3-tert-butoxycarbonylamino-methylenebenzene)-benzimidazole-4]-urea, at room temperature The reaction was carried out for 0.75 hr. After the reaction mixture was evaporated to dryness elution elution elution elution elution elution elution elution elution

 Implementation 2. Synthesis of more compounds

 The compound of the following Table 1 was synthesized in a similar manner to Example 1.

 The MS data reported in the table is obtained under the following experimental conditions:

The Finnigan LCQ DECA XP Ion Well Mass Spectrometer connected to the Agilent 1100 HPLC uses an electronic spray ion source. The instrument carries a LockSpray source for accurate quality measurements. The resolution of the mass spectrometer was adjusted to 5000 (FWHM) for acquisition of a positive ion mode mass spectrum between 100-100 ODA. In mass spectrometry, Leucine enkephalin (556.2771 [M+H]+) was used to provide a mass reference. Table 1

 Chemical Structural Formula Name / Molecular Formula / Molecular Weight M+

 N-(2-fluoro-5-bromo-phenyl)-N41- 454.02 (3-amino-methylenebenzene)-benzimidazole

 Azole-4'-urea

Molecular formula: C ₂₁ H ₁₇ BrFN ₅ O

 Molecular weight: 454.29

 1-[1-(3-Amino-benzyl)-7-fluoro- 456.05 1H-benzimidazol-4-yl]-3-(5-chloro

 -2-methoxy-phenyl)-urea

Molecular formula: C ₂₃ H ₂₃ ClFN ₅ O ₂

 Molecular weight: 455.92

 1_(5-bromo-2-methoxy-phenyl)-3- 465.29 [1-(3-methyl-benzyl)-1H-benzoim

 Azyl-4-yl]-urea

Molecular formula: C ₂₃ H ₂₁ BrN ₄ O ₂

 Molecular weight: 465.35

 1-[1-(3-Amino-nodal)-1E 哚 - 434.28

4-yl]-3-(5-fluoro-2,4-dimethoxy

 Base-phenyl)-urea

Molecular formula: C ₂₄ H ₂₃ FN ₄ O ₃

 Molecular weight: 434.47

 1-(5-bromo-2-methoxy-phenyl)-3- 480.05 [1-(3-methoxy-benzyl)-1Η-吲哚-4-yl]-urea

Molecular formula: C ₂₄ H ₂₂ BrN ₃ O ₃

分子量： 480.37 l-[l-(2-氨基 -吡啶 -4-亚甲 421.65 基) -1H-吲哚 -4-基] -3-(5-氯代

Molecular weight: 480.37 L-[l-(2-Amino-pyridin-4-methylene 421.75yl)-1H-indol-4-yl]-3-(5-chloro

 -2-methoxy-phenyl)-urea

Molecular formula: C ₂₂ H _2Q ClN ₅ O ₂

 ° I Molecular weight: 421.99

 1-[1-(2-Amino-pyridine-4-methylene 466.65 base)-1H-吲哚-4-yl]-3-(5-bromo

 -2-methoxy-phenyl)-urea

 Molecular formula: C22H20BrN5O2

分子量： 466.34

Molecular weight: 466.34

1-[1-(2-Amino-pyrimidin-4-methylene 444.99-yl)-1H-indol-4-yl]- 3-(2-fluoro

 -5-trifluoromethyl-phenyl)-urea

Molecular formula: C ₂₁ H ₁₆ F ₄ N ₆ O

分子量： 444.39

Molecular weight: 444.39

1-[1-(2-Amino-pyrimidine-4-methylene 440.49 base)-7-fluoro-1H-indol-4-yl]-3-(5-chloro-2-methoxy-benzene -urea

Molecular formula: C ₂₁ H ₁₈ ClFN ₆ O ₂

 Molecular weight: 440.87

 1-(5-bromo-2-methoxy-phenyl)-3- 466.84 [1-(2-methyl-pyrimidine-4-methylene)-1H-indol-4-yl]-urea

Molecular formula: C ₂₂ H ₂₀ BrN ₅ O ₂

Molecular weight: 466.34 1-[1-(2-Amino-pyrimidine-4-methylene 497.98-yl)-7-methoxy-1H-indol-4-yl]-3-(5-bromo-2-methoxy- Phenyl)-urea

 Molecular formula: C22H21BrN603

 Molecular weight: 497.36

 1-(4-methyl-3-trifluoromethyl-phenyl)-424.75 3-(1-pyridyl-4-methylene-1H-indole

 -4-yl)-urea

Molecular formula: C ₂₃ H ₁₉ F ₃ N ₄ O

 Molecular weight: 424.43

 1-(4-Chloro-3-trifluoromethyl-phenyl) - 445.51 3-(1-P ratio P-1,4-methylene-1H-FI 哚

分子式： C₂₂H₁₆ClF₃N₄O -4-yl)-urea

Molecular formula: C ₂₂ H ₁₆ ClF ₃ N ₄ O

 Molecular weight: 444.85

 1-(3-bromo-4-methyl-phenyl)-3-(1- 435.90 pyridine-4-methylene-1H-indol-4-yl)-urea

分子式： C₂₂H₁₉BrN₄O

Molecular formula: C ₂₂ H ₁₉ BrN ₄ O

 Molecular weight: 435.33

 1-(4-Fluoro-3-trifluoromethyl-phenyl) - 428.94 3-(1-pyridine-4-methylene-1H-indole

 -4-yl)-urea

分子式： C₂₂H₁₆F₄N₄0

Molecular formula: C ₂₂ H ₁₆ F ₄ N ₄ 0

l-(3-溴代 -4-甲基-苯基： I-3- 1- 436.97 嘧啶 -4-亚甲基 -m-吲哚 -4- 基) -脲 Molecular weight: 428.39

L-(3-Bromo-4-methyl-phenyl: I-3- 1- 436.97 pyrimidine-4-methylene-m-indol-4-yl)-urea

0 Molecular formula: C ₂₁ H ₁₈ BrN ₅ O

 Molecular weight: 436.31

 1-(4-Fluoro-3-trifluoromethyl-phenyl)- 429.15 3-(1-pyrimidine-4-methylene-1H-indole

 -4-yl)-urea

分子式： C₂₁H₁₅F₄N₅O

Molecular formula: C ₂₁ H ₁₅ F ₄ N ₅ O

 Molecular weight: 429.38

 (4-{4-[3-(5-Bromo-2-methoxy-524.87)

— 0 person N _Br phenyl) -ureido] -吲哚-1-methylene

 Pyridyl-2-yl)-carbamate

Molecular formula: C ₂₄ H ₂₂ BrN ₅ O ₄

 Molecular weight: 524.38

 N-(4-{4-[3-(5-Bromo-2-methoxy 562.77-phenyl)-ureido]-吲哚-1-lanthanide

 -pyridine-2-yl)-2,2,2-trifluoro

⁰ L -acetamide

Molecular formula: C ₂₄ H _I9 BrF ₃ N ₅ O ₃

 Molecular weight: 562.35

 1-(5-chloro-2-methoxy-phenyl)-3- 499.81 {1-[2-(pyrazin-2-imino)-pyridine-4-methylidene]-1Η-吲哚-4-urea

Molecular formula: C ₂₆ H ₂₂ ClN ₇ O ₂

Molecular weight: 499.96 (4-{4-[3-(5-Bromo-2-methoxy-525.82-0 ^N ΒΓ phenyl)-ureido]-benzimidazole-1-Asia

 Λ Methyl } -pyridin-2-yl) -carbamic acid

 o methyl ester

Molecular formula: C ₂₃ H ₂₁ BrN ₆ O ₄

 Molecular weight: 525.37

分子式： C₂₅H₂₁ClN₈O₂ 1-(5-Chloro-2-methoxy-phenyl)-3- 501.21 {1-[2-(Pyrazin-2-imino)-pyridine-4-imino]-1H-indole- 4-base urea

Molecular formula: C ₂₅ H ₂₁ ClN ₈ O ₂

 Molecular weight: 500.95

 1-[1-(2-Amino-pyridine-4-methylene 494.31 yl)-1H-indol-4-yl]-3-(5-bromo

 -2,3-dihydro-benzo[b]thiophene-7-yl)-indoleurea

Molecular formula: C ₂₃ H _2Q BrN ₅ OS

 Molecular weight: 494.42

 1-[1-(2-Amino-P-pyridyl-4-methylene 478.88-yl)-1H-indole-4-yl]-3-(5-bromo

 -2,3-dihydro-benzofuran-7-yl)-urea

, ,丫^ ) Molecular formula: C ₂₃ H _2Q BrN ₅ O ₂

 Molecular weight: 478.35

 1-[1-(2-Amino-pyridine-4-methylene 475.90 base)-1H-吲哚-4-yl]-3-(5-bromo

 -3H-吲哚-7-yl)-urea

丫 Formula: C ₂₃ H ₁₉ BrN ₆ O

Molecular weight: 475.35 L-[l-(2-amino-pyridine-4-methylene)

 Base) -1Η-吲哚-4-yl]-3-(7-bromo

 - quinoxaline -5-yl)-urea

Molecular formula: C ₂₃ H ₁₈ BrN ₇ O

 Molecular weight: 488.35

Example 3. High Throughput Screening Test of Effective Compounds

 The biochemical experimental methods and procedures for measuring VEGFR2 and PDGFR P protein kinase activities will be described below. This experimental method can be used to test the compounds described in the present invention and can be used to identify and discover various small molecule inhibitors of VEGFR2 and PDGFRβ.

 The VEGFR2 (KDR) protein used in the inhibitor screening assay contains only the portion of the receptor protein that is exposed to the cytoplasm, i.e., the portion of the amino acid sequence since the methionine at position 806. The PDGFR P protein used in the experiment contained the tyrosine kinase domain part of the receptor protein. Since these two partial proteins are functionally equivalent to their overall structure, they are used instead of their overall structure for testing compounds for inhibition of protein kinase activity (Oncogene, 1990, 5: 519-524). To construct two receptor protein molecules for testing, the cDNA molecules were first cloned and isolated (Molecular Cloning: A Laboratory Manual, Sambrook et al., 1989), and the desired cDNA fragment was cloned into the insect baculovirus. The vector (baculoviurs vector) was used for subsequent protein expression and purification (The Baculovirus Expression System: A Laboratory Guide, LA King and RD Possee, Chapman and Hall, 1992).

 Expression and purification of VEGFR2 and PDGFR P protein kinases were performed according to published standard operating procedures. After passing the enzyme activity test, each batch of newly acquired protein kinase was divided into small portions and then refrigerated in a -70 C environment. In the enzyme activity test, the protein kinase was diluted to a different concentration using an enzyme dilution buffer to use 'the active concentration of the titration enzyme solution. In general, first prepare the IX enzyme buffer, that is, add 4 ml of 5X enzyme buffer and other reactants required by the kinase, such as MnCl, DTT, and calmodulin, to a certain container, and finally dilute with water to the end. The volume is 20 ml. The protein kinase used in the test was diluted with the above IX enzyme buffer at a ratio of 1 to 2000, and 50 μl of the diluted kinase solution was added to each well of a 96-well reaction plate for testing.

Invitrogen's Ζ'-LYTE Protein Kinase Test Kit (Part# PV3192) is used for high-throughput screening of compounds. Before performing screening experiments, various experimental parameters such as reaction time, incubation must be determined and optimized. Temperature, and the concentration of protein kinase and ATP required, thus The greatest degree of substrate phosphorylation should be obtained. First, the compound to be tested was carefully dissolved in DMSO to a concentration of 10 mM, and the solution was stored in an environment of - 20 C. At the same time, the substrate solution was prepared by diluting Poly-Glu, Ala, and Tyr (Sigma P3899) to a concentration of 1 mg/ml in a ratio of 1:500 with PBS. One day before the screening, the diluted substrate solution of ΙΟΟμΙ was added to each well of a 96-well reaction plate, and the reaction plate was sealed and placed in 4C overnight. On the next day, the substrate solution was discarded and the wells were washed once with PBST (PBS containing 0.05% (v/v) TWEEN20), and the following substances were added to each well in order: 2.5 μl of 4X compound solution ( In 4% DMSO), 5 μl of kinase/polypeptide substrate mixture solution, and 4 ΑΤΡ ΑΤΡ solution. When preparing a control reaction with 100% inhibition (no sputum), 2.5 μl of 4% DMSO was mixed with 5 μl of the kinase/polypeptide substrate mixture solution and 1.33X kinase buffer. When a control reaction with a 0% inhibitory effect was prepared, 2.5 μl of 4% DMSO was mixed with a 5 μl of the kinase/polypeptide substrate mixture solution and 2.5 μl of the 4 ΑΤΡ 。 solution. When preparing a control reaction for 100% substrate phosphorylation, 2.5 μl of 4% DMSO was mixed with 5 μl of the phosphorylated polypeptide substrate solution and 2.5 μl of the 4 ΑΤΡ ΑΤΡ solution. The final total reaction volume reached 10 μl. The porous reaction plate was shaken to mix the kinase reaction in each well, and then reacted at room temperature for one hour. Next, 5 μl of development solution was added to each reaction and the reaction was continued for one hour. Finally, 5 μl of stop reagent was added to each reaction to stop the reaction. The fluorescent signal generated in each reaction can be measured by a suitable fluorometer. Relevant experimental data such as fluorescence emission ratio, percent phosphorylation of the polypeptide substrate, Z, factor value, etc. can be calculated according to the method provided by the test kit.

The inhibitory effect of the compound of Example 2 on VEGFR2 and PDGFR protein kinase activity was tested by the above method (results are shown in Table 2 below), and some of the compounds exhibited an inhibitory effect on VEGFR2 protein kinase activity with a ΙμΜ or lower IC50. value. In addition, inhibition of PDGFR P protein kinase activity by certain compounds showed an IC50 value of ΙμΜ or lower. There are also compounds that inhibit both VEGFR2 and PDGFR P protein kinase activity with an IC50 value of ΙμΜ or lower.

Table 2

 VEGFR2 PDGFRp compound name

IC ₅₀ (μΜ) IC ₅₀ (μΜ)

N-(2-Fluoro-5-bromo-phenyl)-N'-[l-(3-amino-methylenebenzene) 1.5-2.5 2.0-2.5-benzimidazole-4]-urea

 1-[1-(3-Amino-benzyl)-7-fluoro-1H-benzimidazol-4-yl]-3-1.0-1.5 1.5-2.0 (5-chloro-2-methoxy- Phenyl)-urea

 1-(5-Bromo-2-methoxy-phenyl)-3-[1-(3-methyl-benzyl)-1H-1.0-2.0 1.0-2.0 benzimidazol-4-yl] Urea

 1-[1-(3-Amino-benzyl)-1H-indol-4-yl]-3-(5-fluoro-2,4-1.5-2.0 1.5-2.0 dimethoxy-phenyl) -urea

 1-(5-Bromo-2-methoxy-phenyl)-3-[1-(3-methoxy-benzyl)-0.3-1.0 0.3-1.0 1H-indol-4-yl] Urea

 1-[1-(2-Amino-pyridin-4-methylene)-1Η-indol-4-yl]-3-(5- <0.5 <0.5 chloro-2-methoxy-phenyl) -urea

 1-[1-(2-Amino-pyridin-4-methylene)-1H-indol-4-yl]-3-(5- <0.5 <0.5 bromo-2-methoxy-phenyl) -urea

 1-[1-(2-Amino-pyrimidine-4-methylene)-1Η-indol-4-yl]-3-(2-0.3-1.0 0.3-1.0 fluoro-5-trifluoromethyl- Phenyl)-urea

 1-[1-(2-Amino-pyrimidine-4-methylene)-7-fluoro-1H-indole-4- 1.0-1.5 1.5-2.0 base] -3-(5-chloro-2- Methoxy-phenyl)-urea

 1-(5-Bromo-2-methoxy-phenyl)-3-[1-(2-methyl-pyrimidin-4-yin 0.3-1.0 0.3-1.0 methyl)-1H-indole-4 -urea-urea

 1-[1-(2-Amino-pyrimidine-4-methylene)-7-methoxy-1H-indole- 1.0-2.0 1.0-2.0 4-yl]-3-(5-bromo-2 -methoxy-phenyl)-urea

1-(4-methyl-3-trifluoromethyl-phenyl)-3-(1-pyridyl-4-methylene- <0.5 <0.5 1H-indol-4-yl)-urea L-(4-Chloro-3-trifluoromethyl-phenyl)-3-(l-pyridine-4-methylene- <0.5 <0.5 1H-indol-4-yl)-urea

 1-(3-Bromo-4-methyl-phenyl)-3-(1-pyridine-4-methylene-1H- <0.5 <0.5 吲哚-4-yl)-urea

 1-(4-Fluoro-3-trifluoromethyl-phenyl)-3-(1-pyridine-4-methylene- <0.5 <0.5 1H-indol-4-yl)-urea

 1-(4-methyl-3-trifluoromethyl-phenyl)-3-[1-(pyridin-4-imin 0.3-1.0 0.3-1.0 base)-1H-indol-4-yl] Urea

 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[1-(pyridin-4-oxo 0.3-1.0 0.3-1.0 base)-1H-indol-4-yl] - Urea

 1-(4-Fluoro-3-trifluoromethyl-phenyl)-3-[1-(pyridine-4-oxo-1.5-2.0 1.5-2.0 base)-1H-indol-4-yl] Urea

 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(1-pyridyl-4-methylene-1.0-1.5 1.0-2.0 1H-benzimidazol-4-yl)-urea

 1-(3-bromo-4-methyl-phenyl)-3-(1-pyrimidin-4-methylene-1H-1.0-1.5 1.0-1.5 吲哚-4-yl)-urea

 1-(4-fluoro-3-trifluoromethyl-phenyl)-3-(1-pyrimidine-4-methylene-1.5-2.0 1.5-2.0 1Η-η引哚-4-yl)-urea

 (4-{4-[3-(5-Bromo-2-methoxy-phenyl)-ureido]-inden-1-ylidene 1.5-2.0 1.5-2.0 methyl}-pyridin-2-yl )-carbamic acid methyl ester

_N _(4-{4-[3-(5-Bromo-2-methoxy-phenyl)-ureido] -吲哚-1- 0.3-1.0 0.3-1.0 methylene: H-pyridine- 2-yl)-2,2,2-trifluoro-acetamide

 1-(5-Chloro-2-methoxy-phenyl)-3-{1-[2-(pyrazine-2-imin 0.3-1.0 0.3-1.0 base)-pyridine-4-methylene ] -m-吲哚-4-yl}-urea

₍₄ _{ ₄ _[3-(5-Bromo-2-methoxy-phenyl)-ureido]-benzimidazole-0.3-1.0 0.3-1.0

1-methylenepyridine-2-yl)-carbamic acid methyl ester

1-(5-chloro-2-methoxy-phenyl)-3-{1-[2-(pyrazine-2-imine 0.3-1.0 0.3-1.0 -pyridine-4-imino]-1Η-indole-4-ylurea

 1-[1-(2-Amino-indoleridin-4-methylene H-indol-4-yl)-3-(5-0.3-1.0 0.3-1.0 bromo-2,3-dihydro- Benzo[b]thiophen-7-yl)-urea

 1-[1-(2-Amino-pyridin-4-methylene)-1Η-indol-4-yl]-3-(5-0.3-1.0 0.3-1.0 bromo-2,3-dihydro- Benzofuran-7-yl)-urea

1-[1-(2-Amino-indenyl-methylene)-1Η-indol-4-yl]-3-(5-0.3-1.0 0.3-1.0 bromo- ³ H-indole-7 -base)-urea

 1-[1-(2-Amino-pyridin-4-methylene)-1H-indol-4-yl]-3-(7-1.0-2.0 1.0-2..0 bromo-quinoxaline- 5-base)-urea

Although an embodiment of the invention has been described herein, it is still within the spirit and scope of the invention that various modifications and alternatives may be made to these specific embodiments. Therefore, the description of the present invention is intended to be illustrative only and not restrictive.

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Claims

Rights request A compound having the following formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof,

 Formula (I)  among them- Χ^Π Χ ₂ are each independently selected from CH and N;  R7 is a substituted or unsubstituted aryl or heteroaryl group; Z 3⁄4-(Z ₁ ) _n Z ₂ (Z ₃ ) _m -, where: ZBZ ₃ -CR ₉ R _1Q -, wherein R _{1Q and} each of R _1Q are independently selected from a hydrogen atom, a substituted or unsubstituted (C ₃ alkyl group, and a halogen; Z ₂ is absent or is selected from -0-, -S-, -NR-, wherein R is selected from H and dC ₃ alkyl;  n and m are integers from 0 to 2;  R1 is absent or represents 1, 2 or 3 substituents, each substituent being independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halo, carboxy , substituted or unsubstituted acyl group, substituted or unsubstituted fluorenyloxycarbonyl, substituted or unsubstituted ee; alkyl, substituted or unsubstituted C3 alkoxy, sulfonyl, sulfinyl, sulfonyl; R4 is absent or represents 1, 2, 3, 4 or 5 substituents, each substituent being independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl , halo, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted fluorenyloxycarbonyl, substituted or unsubstituted cc ₆ fluorenyl, substituted or unsubstituted (^-(: ₆ alkoxy) , substituted or unsubstituted aryloxy, sulfonyl, sulfinyl, sulfonyl, substituted or unsubstituted arene, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic fluorenyl Or two adjacent R4 groups together with the carbon atom to which they are attached form an aromatic ring, a heteroaryl ring, an indenyl ring or a heteroalkyl ring, said aromatic ring, heteroaryl ring, indenyl ring or heteroalkyl group The ring is not substituted or substituted by 1, 2, 3 or 4 substituents each independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halo, carboxy, Substituted or unsubstituted acyl, substituted or unsubstituted anthraceneoxycarbonyl, substituted or unsubstituted The embankment group C _r C _3, C a substituted or unsubstituted alkoxy group, sulfonamide group, sulfinyl group, and a sulfo 2. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein Χ^Ρ Χ ₂ is N.  3. The compound of claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein ^ is! ^ and is 03⁄4. 4. acceptable salt, solvate, or prodrug, or a pharmaceutically acceptable compound according to claim 1, wherein Z is selected from _{-O-, -S -, C r C} 5 alkylene group, -NR - Wherein R is selected from the group consisting of H and CC ₃ fluorenyl.  The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the substituent -ZR7 has a structure represented by a chemical formula (Π),

 Chemical formula (II) R8 is absent or represents 1, 2, 3, 4 or 5 substituents, each substituent being independently selected from the group consisting of hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halogenated , a carboxy group, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted C _r C ₆ fluorenyl group, a substituted or unsubstituted (^-^ methoxy group, a substituted or unsubstituted aryl group) Oxyl, sulfonyl, sulfinyl, sulfonyl, substituted or unsubstituted arene, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl;  Y1 and Y2 are each independently selected from CH and N. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R7 is selected from phenyl, pyridyl or pyrimidinyl, wherein the phenyl, pyridyl or pyrimidine The base is not substituted or substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of: hydroxy, nitro, cyano, carboxy, C _r C ₆ alkyl, halogenated CC ₆ fluorenyl, ₆ alkane Oxyl, amino, (C6 alkanoylamino, dC ₆ alkoxyamido, halogenated C ₆ oxalylamino, pyrazinylamino.  The compound according to claim 6 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R7 is pyrimidin-4-yl or pyridin-4-yl, the pyrimidin-4-yl or Pyridin-4-yl is not substituted or 1, 2, 3, 4 or 5 substituents selected from the group consisting of: hydroxy, nitro, cyano, carboxy, (C ₆ alkyl, halogenated CC ₆ fluorenyl, C _r C ₆ alkoxy, amino, C _r C ₆ Alkanoylamino, C _r C ₆ oxime acylamino, halogenated C _r C ₆ oximelylamino, pyrazinylamino. The compound of claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, Wherein Rl represents 1, 2 or 3 substituents, each of said substituents are each independently selected from the group of radicals: halogen, C] _{- C 3 ^ ¾, C r} C 3 ^ ft¾. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 4 represents 1, 2, 3, 4 or 5 substituents, each of which is selected From hydroxy, cyano, halo, C _r C ₆ alkyl, halogenated C alkyl, decyloxy.  The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the compound has the structure represented by the formula (III)

Chemical formula (III) R8 is absent or represents 1, 1, 3, 4 or 5 substituents, each substituent being independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, generation, a carboxy group, a substituted or unsubstituted acyl group, a substituted or unsubstituted fluorenyloxycarbonyl group, a substituted or unsubstituted C _r C ₆ alkyl group, a substituted or unsubstituted (^-^ methoxy group, a substituted or unsubstituted aryloxy group) a sulfonyl group, a sulfinyl group, a sulfonyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heteroaryl hydrocarbon group, a substituted or unsubstituted heterocyclic hydrocarbon group; Yj and Y ₂ are each independently selected from CH and Ν; R5 and R6 are each independently selected from the group consisting of hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted Or unsubstituted C ₃ alkyl, substituted or unsubstituted -C ₃ alkoxy, sulfonyl, sulfinyl, sulfonyl, substituted or unsubstituted arene, substituted or unsubstituted heteroaryl, and substituted Or an unsubstituted heterocycloalkyl group. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the compound has a structure represented by the formula (IV)

Chemical formula (IV)  among them: R8 is absent or represents 1, 2, 3, 4 or 5 substituents, each substituent being independently selected from the group consisting of: hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halogenated , a carboxy group, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted c ₆ alkyl group, a substituted or unsubstituted (^-^ alkoxy group, a substituted or unsubstituted aryloxy group) Sulfonyl, sulfinyl, sulfonyl, substituted or unsubstituted arene, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl; Y, and Y ₂ are each independently selected from CH and Ν; R6 and R11 are each independently selected from the group consisting of hydroxy, nitro, cyano, substituted or unsubstituted amino, aminocarbonyl, halo, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted alkane Oxycarbonyl, substituted or unsubstituted c ₃ fluorenyl, substituted or unsubstituted cc methoxy, sulfonyl, sulfinyl, sulfonyl, substituted or unsubstituted arene, substituted or unsubstituted a heteroaromatic hydrocarbon group, and a substituted or unsubstituted heterocyclic hydrocarbon group.  The compound of claim 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein an adjacent two R4 groups are bonded together with a carbon atom to which they are attached, an aromatic ring, a heteroaryl group The ring, alkyl ring or heteroalkyl ring is a 5- or 6-membered ring having 1 or 2 heteroatoms selected from O, S or N. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein X, is N and X ₂ is CH, and the R1 group is substituted at the 7 position of the indole ring. The -NH-CO-NH- is substituted at the 4-position of the anthracene ring. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein ₂ and ₂ are substituted, and the R1 group is substituted at the 7 position of the benzimidazole ring. Above, the -NH-CO-NH- is substituted at the 4-position of the anthracene ring. The compound of claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, Wherein the compound is selected from the group consisting of: 1-( ⁴ -methyl-3-trifluoromethyl-phenyl)-3-(1:pyridin-4-methylene-1H-indol-4-yl)-urea;  1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(1-pyridin-4-methylene-1H-indole)-urea;  1-(4-Fluoro-3-trifluoromethyl-phenyl)-3-(1-pyridin-4-methylene-1H-indol-4-yl)-urea;  1-[1-(2-Amino-B-pyridyl-4-methylene)-1Η-indol-4-yl]-3-(5-bromo-2-methoxy-phenyl)-urea ; 1-[1-(2-Amino-pyridin-4-methylene)-1Η-indol-4-yl]-3-(5-chloro-2-methoxy-phenyl)-urea; 4-{4-[3-(5-Bromo-2-methoxy-phenyl)-ureido]-indole-1-methylenepyridin-2-yl)-carbamic acid methyl ester;  1-[1-(2-Amino-pyridine-4-methylene)-1Η-indol-4-yl]-3-(5-bromo-2,3-dihydro-benzofuran-7- Base) - Urea.  A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.  17. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition is formulated in a form selected from the group consisting of an injection, an aerosol, a cream, a gel, a tablet, a pill, a capsule, a syrup, Eye drops, or skin patches.  Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of a disease responsive to inhibition of a protein kinase. '  19. The use according to claim 18, wherein the disease is selected from the group consisting of: tumor, rheumatoid arthritis, arterial restenosis, autoimmune disease, acute inflammation, acute and chronic nephritis, diabetic retinopathy, psoriasis, or macula Departmental degeneration.