Five-membered and six-membered nitrogen heteroaromatic ring compound, preparation method thereof, medicinal composition and application thereof

文档序号：1409149 发布日期：2020-03-06 浏览：17次中文

阅读说明：本技术 五元并六元氮杂芳环类化合物、其制备方法、药用组合物及其应用 (Five-membered and six-membered nitrogen heteroaromatic ring compound, preparation method thereof, medicinal composition and application thereof ) 是由邓贤明王洪睿曾涛玲张婷姜婷婷于 2018-05-17 设计创作，主要内容包括：本发明涉及药物化学领域,五元并六元氮杂芳环类化合物、其制备方法、药用组合物及其应用。具体地,涉及一类具有通过特异性地增强Ras蛋白泛素化降解的化合物,其制备方法、包含该化合物的药物组合物,以及这些化合物在制备用于预防或治疗与生物体内与Ras活性相关的疾病的药物中的用途,尤其是在制备用于预防或治疗肿瘤生长与转移的药物中的用途。<Image he="546" wi="680" file="DDA0002278202600000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to the field of pharmaceutical chemistry, in particular to a five-membered and six-membered nitrogen-heterocyclic aromatic ring compound, a preparation method thereof, a medicinal composition and application thereof. In particular to a compound with the function of specifically enhancing the ubiquitination degradation of Ras protein, a preparation method thereof, a pharmaceutical composition containing the compound and the application of the compound in preparing medicaments for preventing or treating diseases related to Ras activity in organisms, in particular to the preparation of medicaments for preventing or treating the diseases in the organismsThe application of the compound in preparing medicines for preventing or treating tumor growth and metastasis.)

A compound of the general formula:

or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

wherein, X₁，X₂，X₃，X₄，X₅，X₆The following combinations can be included:

x is selected from O, S and NH;

preferably X is selected from O, S;

R¹selected from H, C1-C6 alkyl, C3-C6 cycloalkyl;

preferably R¹Selected from H, C1-C6 alkyl;

R²selected from:

preferably R²Selected from:

wherein Z is S, NH;

y is selected from C, S and P;

preferably Y is selected from C, S;

m is 1 or 2;

R³selected from:

1) amino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, N, N-dimethylamino, N, N-diethylamino, N, N-diisopropylamino, 2-N, N-dimethylaminoethylamino, 2-hydroxyethylamino, 2-morphinylethylamino, 2-thiomorpholinylethylamino, 2- (4-N-methylpiperazinyl) ethylamino, 3-N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-hydroxypropylamino, 3-morphinylpropylamino, 3-thiomorpholinylpropylamino, 3- (4-N-methylpiperazinyl) propylamino, n-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-isopropylpiperidin-4-amino, N-acetylpiperidin-4-amino;

2) arylamino or heteroarylamino optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C3 fluoroalkyl, C3-C6 cycloalkyl, halogen, nitro, cyano, amino, hydroxy, optionally substituted heterocyclyl, C1-C6 alkoxycarbonyl, C1-C6 acyl;

3) phenylmethylamino optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C3 fluoroalkyl, C3-C6 cycloalkyl, halogen, nitro, cyano, amino, hydroxy, optionally substituted heterocyclyl, C1-C6 alkoxycarbonyl, C1-C6 acyl;

4) phenylethylamino optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C3 fluoroalkyl, C3-C6 cycloalkyl, halogen, nitro, cyano, amino, hydroxy, optionally substituted heterocyclyl, C1-C6 alkoxycarbonyl, C1-C6 acyl;

5) a five-or six-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, hydroxy, amino, C1-C6 alkoxycarbonyl, C1-C6 acyl, cyano, optionally substituted heterocyclyl,

including but not limited to: piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4- (N-methylpiperazinyl) piperidinyl, 4- (N-ethylpiperazinyl) piperidinyl, 4- (N-isopropylpiperazinyl) piperidinyl, 4- (N-acetylpiperazinyl) piperidinyl, 4- (N-t-butoxycarbonylpiperazinyl) piperidinyl, 4- (N-methanesulfonylpiperazinyl) piperidinyl, 4- (N- (2-hydroxyethyl) piperazinyl) piperidinyl, 4- (N- (2-cyanoethyl) piperazinyl) piperidinyl, 4- (N- (3-hydroxypropyl) piperazinyl) piperidinyl, 4- (N- (2-N, N-dimethylethyl) piperazinyl) piperidinyl, 4- (N- (2-N, N-diethylethyl) piperazinyl) piperidinyl, 4- (N- (3-N, N-dimethylpropyl) piperazinyl) piperidinyl, 4- (N- (3-N, N-diethylpropyl) piperazinyl) piperidinyl, 4- (tetrahydropyrrolyl) piperidinyl, 4- (3-N, N-dimethyltetrahydropyrrolyl) piperidinyl);

n-methylpiperazino, N-ethylpiperazino, N-isopropylpiperazinyl, N-acetylpiperazinyl, N-t-butoxycarbonylpiperazinyl, N-methylsulfonylpiperazino, N- (2-hydroxyethyl) piperazinyl, N- (2-cyanoethyl) piperazinyl, N- (3-hydroxypropyl) piperazinyl, N- (2-N, N-dimethylethyl) piperazinyl, N- (2-N, N-diethylethyl) piperazinyl, N- (3-N, N-dimethylpropyl) piperazinyl, N- (3-N, N-diethylpropyl) piperazinyl, 2-oxo-piperazin-4-yl, N- (N-methyl-4-piperidinyl) piperazinyl, n- (N-ethyl-4-piperidinyl) piperazinyl, N- (N-acetyl-4-piperidinyl) piperazinyl;

morphinyl, 3, 5-dimethylmorphinyl, thiomorpholinyl, tetrahydropyrrolyl, 3-N, N-dimethyltetrahydropyrrolyl, 3-N, N-diethyltetrahydropyrrolyl;

6) benzyl optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, C1-C3 fluoroalkyl, C3-C6 cycloalkyl, halogen, nitro, cyano, amino, hydroxy, optionally substituted heterocyclyl, C1-C6 alkoxycarbonyl, C1-C6 acyl;

7) hydroxy, 2-N, N-dimethylaminoethoxy, 2-N, N-diethylaminoethoxy, 2-N, N-diisopropylaminoethoxy, 2- (N-methylpiperazinyl) ethoxy, 2- (N-acetylpiperazinyl) ethoxy, 2-morphinylethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 3-N, N-dimethylaminopropoxy, 3-N, N-diethylaminopropoxy, 3-N, N-diisopropylaminopropoxy, 3- (N-methylpiperazinyl) propoxy, 3- (N-acetylpiperazinyl) propoxy, 3-morphinylpropoxy, 3-thiomorpholinylpropoxy, 3-piperidinylpropoxy, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, phenylmethoxy, mono-halogen substituted phenylmethoxy, gem-dihalo substituted phenylmethoxy, hetero-dihalo substituted phenylmethoxy;

preferably R³Selected from the following:

wherein n is 0 or 1,

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Any one of the compounds is selected from halogen, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, C1-C6 alkyl, C1-C6 alkoxy, di (C1-C6 alkyl) amino, C1-C6 alkoxycarbonyl, and the rest is hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅any two of which are each independently selected from halogen, C1-C3 fluoroalkyl, optionally substituted heterocyclyl selected from pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1, 3-dioxolane, piperidine, piperazine, morpholine, morphinyl, tetrahydropyrrolyl, thiomorpholinyl, and the remainder hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 fluoroalkyl, and the balance hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅any one of the fluorine-containing alkyl is selected from halogen, C1-C3 fluorine-containing alkyl, and the rest is hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅are all hydrogen;

2) C3-C6 cycloalkylamino;

3) HN-heteroaryl, wherein said heteroaryl is selected from pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, phenyl-pyrrolyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl;

4) a heterocyclyl group, wherein the heterocyclyl group is selected from the group consisting of pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1, 3-dioxolane, piperidine, piperazine, morpholine, morphinyl, tetrahydropyrrolyl, thiomorpholinyl;

5)-NH-C₂H₄-R₆wherein R is₆Is selected fromHydroxy, phenyl, halo-substituted phenyl;

R⁴selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, halogen, nitro, cyano, amino and hydroxyl;

preferably R⁴Selected from H, halogen, amino, hydroxy;

preferably, the pharmaceutically acceptable salt is inorganic acid salt selected from hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate and carbonate, sulfate or phosphate, or organic acid salt selected from formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, α -ketoglutarate, α -glycerophosphate, alkyl sulfonate or aryl sulfonate, preferably, the alkyl sulfonate is methyl sulfonate or ethyl sulfonate, and the aryl sulfonate is benzene sulfonate or p-toluene sulfonate;

however, the compounds of the general formula exclude the following compounds:

a compound according to claim 1 which is the following:

wherein R is¹Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl;

preferably R¹Selected from H, C1-C6 alkyl;

most preferred is R¹Selected from H, methyl;

R²selected from:

preferably R²Selected from:

y is selected from C, S and P;

preferably Y is C;

m is 1 or 2;

preferably m is 1;

R³selected from:

morphinyl, 3, 5-dimethylmorphinyl, thiomorpholinyl, tetrahydropyrrolyl, 3-N, N-dimethyltetrahydropyrrolyl, 3-N, N-diethyltetrahydropyrrolyl;

preferably R³Selected from the following:

wherein n is 0 or 1,

when n is 0，Z₁，Z₂，Z₃，Z₄，Z₅Any one of the group consisting of halogen, C1-C3 fluoroalkyl, C1-C6 alkyl, C1-C6 alkoxy, di (C1-C6 alkyl) amino, and the balance hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are independently selected from halogen, C1-C3 fluoroalkyl, C1-C6 alkyl, C1-C6 alkoxy, and the balance hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅are all hydrogen;

2) C3-C6 cycloalkylamino;

3) HN-heteroaryl, wherein said heteroaryl is selected from pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, phenyl-pyrrolyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl;

5)-NH-C₂H₄-R₆wherein R is₆Selected from phenyl, halogen substituted phenyl;

more preferably R³Selected from the following:

wherein n is 0 or 1,

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₂Selected from halogen, C1-C3 fluorine-containing alkyl, and the rest is hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₃Selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, di (C1-C6 alkyl) amino, and the balance hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from halogen, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂，Z₃Each independently selected from halogen, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₃Each independently selected from C1-C6 alkoxy, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₄Each independently selected from halogen, C1-C3 fluoroalkyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₅Each independently selected from halogen, C1-C3 fluoroalkyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₃Selected from halogens, the balance being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂Selected from C1-C3 fluoroalkyl groups, the balance being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅are all hydrogen;

2) C3-C6 cycloalkylamino;

3) HN-heteroaryl, wherein said heteroaryl is selected from pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, phenyl-pyrrolyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl;

5)-NH-C₂H₄-R₆wherein R is₆Selected from phenyl, halogen substituted phenyl;

most preferred is R³Selected from the following:

wherein n is 0 or 1,

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₂Selected from fluorine, chlorine, trifluoromethyl and the rest is hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₃Selected from methyl, methoxy, isopropoxy, fluoro, dimethylamino, the rest is hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from fluorine, chlorine, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂，Z₃Each independently selected from chlorine, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₃Each independently selected from methoxy and the remainder hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₄Each independently selected from fluoro, trifluoromethyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₅Each independently selected from fluoro, trifluoromethyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₃Selected from chlorine and fluorine, and the rest is hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂Selected from trifluoromethyl and the balance hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅are all hydrogen;

3) HN-heteroaryl, wherein said heteroaryl is selected from 2-methyl-pyridin-5-yl, pyridin-3-yl;

4) heterocyclyl, wherein the heterocyclyl is selected from 4-methylpiperazin-1-yl, morpholin-4-yl;

5)-NH-C₂H₄-R₆wherein R is₆Selected from phenyl, 4-fluorophenyl;

R⁴selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, halogen, nitro, cyano, amino and hydroxyl;

preferably R⁴Selected from H, C1-C3 alkyl, halogen, amino, hydroxyl;

more preferably R⁴Selected from H, fluoro, chloro, bromo, amino;

most preferred is R⁴Selected from H, 4-chloro, 6-amino.

A compound according to claim 1 which is the following:

wherein the content of the first and second substances,

R¹selected from H, C1-C6 alkyl, C3-C6 cycloalkyl;

preferably R¹Selected from H, C1-C3 alkyl;

most preferred is R¹Is selected from H;

R²selected from:

1)wherein Z is selected from S, O, NH;

preferably R²Selected from:

1)wherein Z is selected from S, O;

y is selected from C, S and P;

preferably Y is selected from C;

m is 1 or 2;

preferably m is 1;

R³selected from:

morphinyl, 3, 5-dimethylmorphinyl, thiomorpholinyl, tetrahydropyrrolyl, 3-N, N-dimethyltetrahydropyrrolyl, 3-N, N-diethyltetrahydropyrrolyl;

preferably R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and the remainder are hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Any one of which is selected from C1-C3 fluoroalkyl groups, the remainder being hydrogen;

more preferably R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from halogen, the remainder being hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₂Selected from C1-C3 fluoroalkyl groups, the balance being hydrogen;

optimization ofR is selected³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from fluorine, chlorine, the remainder being hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₂Selected from trifluoromethyl and the balance hydrogen;

R⁴selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, halogen, nitro, cyano, amino and hydroxyl;

preferably R⁴Selected from H, C1-C3 alkyl, amino, hydroxy;

most preferred is R⁴Is H.

A compound according to claim 1 which is the following:

wherein R is¹Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl;

preferably R¹Selected from H, C1-C3 alkyl;

most preferred is R¹Is selected from H;

R²selected from:

preferably R²Selected from:

1)wherein Z is selected from S, O, NH;wherein Z is S, NH;

y is selected from C, S and P;

preferably Y is selected from C, S;

m is 1 or 2;

wherein, when Y is C, m is 1;

when Y is S, m is 2;

R³selected from:

morphinyl, 3, 5-dimethylmorphinyl, thiomorpholinyl, tetrahydropyrrolyl, 3-N, N-dimethyltetrahydropyrrolyl, 3-N, N-diethyltetrahydropyrrolyl;

preferably R³Selected from the following:

1)wherein n is 0 or 1

When n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are independently selected from halogen, C1-C3 fluoroalkyl, optionally substituted heterocyclyl selected from pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, pyrazoline, and a pharmaceutically acceptable salt thereof,Thiazolidine, dihydrofuran, tetrahydrofuran, 1, 3-dioxolane, piperidine, piperazine, morpholine, morphinyl, tetrahydropyrrole, thiomorpholinyl, and the balance hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅any one of the halogen, C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, C1-C6 alkyl, C1-C6 alkoxy, and the rest is hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are independently selected from halogen, C1-C6 alkoxy, C1-C3 fluoroalkyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅any one of which is independently selected from halogen, C1-C6 alkyl, C1-C3 fluoroalkyl, C1-C6 alkoxy, C1-C3 fluoroalkoxy, hydroxyl, cyano, amino, nitro, the balance being hydrogen; alternatively, the first and second electrodes may be,

Z₁－Z₅are all hydrogen;

2) C3-C6 cycloalkylamino;

3) HN-heteroaryl, wherein said heteroaryl is selected from pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, phenyl-pyrrolyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl;

5)-NH-C₂H₄-R₆wherein R is₆Selected from hydroxy, halogen substituted phenyl;

more preferably R³Selected from the following:

When n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from halogen, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂Selected from halogen, C1-C3 fluorine-containing alkyl, and the rest is hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂，Z₃Each independently selected from C1-C3 fluoroalkyl, an optionally substituted heterocyclyl selected from pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1, 3-dioxolane, piperidine, piperazine, morpholine, morphinyl, tetrahydropyrrolyl, thiomorpholinyl, and the remainder hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₃Selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C3 fluorine-containing alkoxy, and the rest is hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from halogen, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₃Each independently selected from C1-C6 alkoxy, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂，Z₃Each independently selected from halogen, C1-C3 fluoroalkyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₃，Z₄Each independently selected from halogen, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₄Each independently selected from halogen, C1-C3 fluoroalkyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂，Z₄Each independently selected from halogen, C1-C3 fluoroalkyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₂Each independently selected from halogen, C1-C3 fluoroalkyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁Selected from halogen, C1-C6 alkyl, C1-C3 fluorine-containing alkyl, C1-C6 alkoxy, C1-C3 fluorine-containing alkoxy, hydroxyl and the balance of hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₂Selected from C1-C3 fluorine-containing alkyl, C1-C3 fluorine-containing alkoxy, cyano, halogen, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, and the rest is hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₃Selected from cyano, C1-C6 alkyl, C1-C3 fluorine-containing alkyl, C1-C6 alkoxy, C1-C3 fluorine-containing alkoxy, hydroxyl, halogen and the balance of hydrogen; or

Z₁－Z₅Are all hydrogen;

2) C3-C6 cycloalkylamino;

3) HN-heteroaryl, wherein said heteroaryl is selected from pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, phenyl-pyrrolyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl;

5)-NH-C₂H₄-R₆wherein R is₆Selected from hydroxy, halogen substituted phenyl;

most preferred is R³Selected from the following:

When n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from fluorine, chlorine, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂Selected from fluorine, chlorine, trifluoromethyl and the rest is hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂，Z₃Each independently selected from trifluoromethyl, 4-methylpiperazin-1-yl-methyl, and the remainder hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₃Selected from methyl, methoxy, isopropoxy, fluorine, trifluoromethoxy and the rest is hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅are all hydrogen;

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₃Each independently selected from methoxy and the rest is hydrogen(ii) a Alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂，Z₃Each independently selected from chlorine, fluorine, trifluoromethyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₃，Z₄Each independently selected from fluorine and the remainder hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₄Each independently selected from fluoro, trifluoromethyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂，Z₄Each independently selected from fluoro, trifluoromethyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₂Each independently selected from fluoro, trifluoromethyl, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁Selected from fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy and hydroxyl, the rest is hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂Selected from trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro, bromo, amino, nitro, methyl, methoxy, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₃Selected from cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, bromo, the remainder being hydrogen; alternatively, the first and second electrodes may be,

Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₂Selected from trifluoromethyl and the balance hydrogen; alternatively, the first and second electrodes may be,

Z₁－Z₅are all hydrogen；

3) HN-heteroaryl, wherein said heteroaryl is selected from the group consisting of 2-methyl-pyridin-5-yl, pyridin-3-yl, pyridin-2-yl;

4) heterocyclyl, wherein the heterocyclyl is selected from 4-methylpiperazin-1-yl, morpholin-4-yl;

5)-NH-C₂H₄-R₆wherein R is₆Selected from 4-chlorophenyl, 4-fluorophenyl;

R⁴selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, halogen, nitro, cyano, amino and hydroxyl;

preferably R⁴Selected from H, fluoro, chloro, bromo, amino;

most preferred is R⁴Selected from H, 6-chloro.

A compound according to claim 1 which is the following:

wherein the content of the first and second substances,

R¹is H;

R²selected from:

preferably R²Selected from:

y is selected from C, S and P;

preferably Y is C;

m is 1 or 2;

preferably m is 1;

R³selected from:

morphinyl, 3, 5-dimethylmorphinyl, thiomorpholinyl, tetrahydropyrrolyl, 3-N, N-dimethyltetrahydropyrrolyl, 3-N, N-diethyltetrahydropyrrolyl;

preferably R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and the remainder are hydrogen;

2) C3-C6 cycloalkylamino;

more preferably R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from halogen, the remainder being hydrogen;

2) C3-C6 cycloalkylamino;

most preferred is R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from fluorine, chlorine, the remainder being hydrogen;

R⁴selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, halogen, nitro, cyano, amino and hydroxyl;

preferably R⁴Selected from H, C1-C3 alkyl, amino, hydroxy;

most preferred is R⁴Is H.

A compound according to claim 1 which is,

wherein the content of the first and second substances,

wherein R is¹Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl;

preferably R¹Selected from H, tert-butyl;

R²selected from:

preferably R²Selected from:

y is selected from C, S and P;

preferably Y is C;

m is 1 or 2;

preferably m is 1;

R³selected from:

morphinyl, 3, 5-dimethylmorphinyl, thiomorpholinyl, tetrahydropyrrolyl, 3-N, N-dimethyltetrahydropyrrolyl, 3-N, N-diethyltetrahydropyrrolyl;

preferably R³Selected from: 1)

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and the remainder are hydrogen;

2) C3-C6 cycloalkylamino;

more preferably R³Selected from: 1)

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from halogen, the remainder being hydrogen;

2) C3-C6 cycloalkylamino;

most preferred is R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from fluorine, chlorine, the remainder being hydrogen;

R⁴selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, halogen, nitro, cyano, amino and hydroxyl;

preferably R⁴Selected from H, C1-C3 alkyl, amino, hydroxy;

most preferred is R⁴Selected from H, 4-amino.

A compound according to claim 1 which is,

wherein the content of the first and second substances,

R²selected from:

preferably R²Selected from:

y is selected from C, S and P;

preferably Y is C;

m is 1 or 2;

preferably m is 1;

R³selected from:

morphinyl, 3, 5-dimethylmorphinyl, thiomorpholinyl, tetrahydropyrrolyl, 3-N, N-dimethyltetrahydropyrrolyl, 3-N, N-diethyltetrahydropyrrolyl;

preferably R³Is selected from

Wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and the remainder are hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Any one of which is selected from C1-C3 fluoroalkyl groups, the remainder being hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are selected from halogen, C1-C3 fluorine-containing alkyl, and the rest is hydrogen;

2) C3-C6 cycloalkylamino;

more preferably R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is equal to 1, the compound is,Z₁，Z₂，Z₃，Z₄，Z₅z in (1)₁，Z₅Each independently selected from halogen, the remainder being hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₂Selected from C1-C3 fluoroalkyl groups, the balance being hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₃，Z₄Selected from halogen, C1-C3 fluorine-containing alkyl, and the rest is hydrogen;

2) C3-C6 cycloalkylamino;

most preferred is R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from fluorine, chlorine, the remainder being hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₂Selected from trifluoromethyl and the balance hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₃，Z₄Selected from fluorine and trifluoromethyl, and the rest is hydrogen;

R⁴selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, halogen, nitro, cyano, amino and hydroxyl;

preferably R⁴Selected from H, C1-C3 alkyl, amino, hydroxy;

most preferred is R⁴Is H.

A compound according to claim 1 which is,

wherein the content of the first and second substances,

R²selected from:

preferably R²Selected from:

y is selected from C, S and P;

preferably Y is C;

m is 1 or 2;

preferably m is 1;

R³selected from:

morphinyl, 3, 5-dimethylmorphinyl, thiomorpholinyl, tetrahydropyrrolyl, 3-N, N-dimethyltetrahydropyrrolyl, 3-N, N-diethyltetrahydropyrrolyl;

preferably R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and the remainder are hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Any one of which is selected from C1-C3 fluoroalkyl groups, the remainder being hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are selected from halogen, C1-C3 fluorine-containing alkyl, and the rest is hydrogen;

2) C3-C6 cycloalkylamino;

more preferably R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from halogen, the remainder being hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₂Selected from C1-C3 fluoroalkyl groups, the balance being hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₃，Z₄Selected from halogen, C1-C3 fluorine-containing alkyl, and the rest is hydrogen;

2) C3-C6 cycloalkylamino;

most preferred is R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from fluorine, chlorine, the remainder being hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₂Selected from trifluoromethyl and the balance hydrogen; or

Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₃，Z₄Selected from fluorine and trifluoromethyl, and the rest is hydrogen;

R⁴selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, halogen, nitro, cyano, amino and hydroxyl;

preferably R⁴Selected from H, C1-C3 alkyl, amino, hydroxy;

most preferred is R⁴Is H.

A compound according to claim 1 which is,

wherein the content of the first and second substances,

R²selected from:

preferably R²Selected from:

y is selected from C, S and P;

preferably Y is C;

m is 1 or 2;

preferably m is 1;

R³selected from:

morphinyl, 3, 5-dimethylmorphinyl, thiomorpholinyl, tetrahydropyrrolyl, 3-N, N-dimethyltetrahydropyrrolyl, 3-N, N-diethyltetrahydropyrrolyl;

preferably R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and the remainder are hydrogen;

more preferably R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from halogen, the remainder being hydrogen;

most preferred is R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from fluorine, chlorine, the remainder being hydrogen;

R⁴selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, halogen, nitro, cyano, amino and hydroxyl;

preferably R⁴Is selected fromH, C1-C3 alkyl, amino, hydroxyl;

most preferred is R⁴Is H.

A compound according to claim 1 which is,

wherein the content of the first and second substances,

R²selected from:

1)wherein Z is selected from S, O, NH;

preferably R²Selected from:

y is selected from C, S and P;

preferably Y is C;

m is 1 or 2;

preferably m is 1;

R³selected from:

morphinyl, 3, 5-dimethylmorphinyl, thiomorpholinyl, tetrahydropyrrolyl, 3-N, N-dimethyltetrahydropyrrolyl, 3-N, N-diethyltetrahydropyrrolyl;

preferably R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Any two of which are each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and the remainder are hydrogen;

more preferably R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from halogen, the remainder being hydrogen;

most preferred is R³Selected from:

wherein n is 0 or 1;

when n is 0, Z₁，Z₂，Z₃，Z₄，Z₅Are all hydrogen;

when n is 1, Z₁，Z₂，Z₃，Z₄，Z₅Z in (1)₁，Z₅Each independently selected from fluorine, chlorine, the rest is hydrogen；

R⁴Selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, halogen, nitro, cyano, amino and hydroxyl;

preferably R⁴Selected from H, C1-C3 alkyl, amino, hydroxy;

most preferred is R⁴Is H.

A compound according to any one of claims 1 to 10, selected from the following:

or a stereoisomer of the above compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

A process for the preparation of a compound according to any one of claims 1 to 11, comprising the steps of:

wherein the content of the first and second substances,

reaction conditions are as follows: (a) a coupling reaction of carbon-carbon bond formation catalyzed by metallic palladium; (b) ester hydrolysis under alkaline conditions (LiOH, or NaOH, etc.); (c) performing amide condensation reaction under alkaline conditions (HOBT or HATU; triethylamine or diisopropylethylamine, etc.);

a process for producing the compound (III-g), comprising the steps of:

a process for producing the compound (III-h), comprising the steps of:

the above-mentioned formulae III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h correspond to R in formula III²Are respectively as

A pharmaceutical composition comprising a compound of any one of claims 1-11, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and optionally a pharmaceutically acceptable excipient.

Use of a compound according to any one of claims 1 to 11 and additionally of the following specific compounds or stereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof or pharmaceutically acceptable solvates thereof, or a pharmaceutical composition according to claim 13, for the preparation of a medicament for the prophylaxis or treatment of diseases associated with Ras activity in an organism, in particular for the prophylaxis or treatment of tumor growth and metastasis:

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Five-membered and six-membered nitrogen heteroaromatic ring compound, preparation method thereof, medicinal composition and application thereof

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