CN115353506A

CN115353506A - 3-substituted phenanthridine compound, preparation method and application thereof, and pharmaceutical composition

Info

Publication number: CN115353506A
Application number: CN202210916603.0A
Authority: CN
Inventors: 田从魁; 王加维; 黄玉龙; 田从凡
Original assignee: Suzhou Shi'an Dingtai Biomedical Technology Co ltd
Current assignee: Suzhou Shi'an Dingtai Biomedical Technology Co ltd
Priority date: 2022-08-01
Filing date: 2022-08-01
Publication date: 2022-11-18

Abstract

The invention provides a 3-substituted phenanthridine compound, a preparation method and application thereof, and a pharmaceutical composition, and belongs to the technical field of medicines. The 3-substituted phenanthridine compound can be used as a main component of a pharmaceutical composition, KRASG12C is locked in an inactive GDP binding state, so that KRAS transitional activation caused by KRASG12C mutation is specifically and irreversibly inhibited to achieve the purpose of treating tumors, and one or more 3-substituted phenanthridine compounds can be administered to a patient in need of treatment or prevention in a therapeutically effective amount.

Description

3-substituted phenanthridine compound, preparation method and application thereof, and pharmaceutical composition

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a 3-substituted phenanthridine compound, and a preparation method, application and a pharmaceutical composition thereof.

Background

Tumor is a disease which seriously harms human health. The existing methods for treating tumors mainly comprise radiotherapy, surgical treatment and targeted therapy, and the targeted therapy has certain selectivity and becomes one of the current main treatment modes.

Scientists found that RAS protein mutation is related to about 30% of cancer patients, especially pancreatic cancer (90%), colorectal cancer (36-40%), lung cancer (17%) and the like, and the RAS protein mutation causes more than ten kinds of tumors in the tumor population, wherein the tumor population accounts for more than 2%, and theoretically, tumor drugs aiming at the indications can become heavy drugs, so the RAS is considered as the king of target. However, over the past decades, the search for anti-tumor drugs directed against the RAS target has failed and this target has also been considered as an unproofed target. Mainly because RAS has a very strong affinity for GTP and the concentration of GTP in cells is very high. This makes it difficult to effect inhibitors that target the GTP-binding site of the RAS directly. Furthermore, the RAS protein has a shallow pocket on its surface, which is not conducive to binding of the compound to the protein. With the recent rise of irreversible inhibitors, such as ibutinib, which is a B-cell lymphoma therapeutic drug, and oxitinib, which is a lung cancer therapeutic drug, the great success (mainly through the irreversible covalent bond formed between the thiol group of the cysteine residue and the α, β -unsaturated carbonyl compound), RAS targets have become hot spots for research again. However, studies have shown that AMG510 and MRTX849 inhibitors begin to develop resistance. Therefore, the research on the antitumor compound with a brand-new structure and high activity has important significance.

Disclosure of Invention

The invention aims to provide a 3-substituted phenanthridine compound, a preparation method and application thereof, and a pharmaceutical composition, wherein the 3-substituted phenanthridine compound has excellent antitumor activity.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a 3-substituted phenanthridine compound, which can be used as a main component of a pharmaceutical composition, specifically and irreversibly inhibits KRAS transitional activation caused by KRAS G12C mutation by locking KRAS G12C in an inactive GDP binding state so as to achieve the aim of treating tumors, and one or more 3-substituted phenanthridines compounds can be administered to a patient needing treatment or prevention in a therapeutically effective amount.

Compounds of the invention R ₁ Or R ₃ A group may have one or more asymmetric centers; thus can be prepared as individual (R) -stereoisomers or (S) -stereoisomers or as mixtures thereof.

Detailed Description

The invention provides a 3-substituted phenanthridine compound which has a structure shown in a formula I or a formula II:

in the formulae I and II, R ₁ Independently 2-fluoro-6-chlorophenyl, 2-fluoro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-cyanophenyl, 3-hydroxynaphthalen-1-yl, 3-acetoxynaphthalen-1-yl, naphthalen-1-yl, 5-methyl-1H-indazol-4-yl, or 8-chloronaphthalen-1-yl;

R ₃ independently is

(2-morpholinoethyl) -1-amino, 4-methoxybenzylamino, 3-methoxyazetidin-1-yl or 3-dimethylaminoazetidin-1-yl;

when said R is ₃ Is composed of

When R is ₂ Independently 4-methoxyphenylethyl, cyclopropanemethyl, cyclobutanemethyl, cyclopentanemethyl, or hydrogen; or, when said R is ₃ To remove

R when other substituent group is mentioned ₂ Is none;

R ₄ independently H or F.

In the present invention, the 3-substituted phenanthridines are preferably:

in the present invention, unless otherwise specified, all the required starting materials for the preparation are commercially available products well known to those skilled in the art.

The invention provides a preparation method of a 3-substituted phenanthridine compound in the technical scheme, which comprises the following steps:

when the 3-substituted phenanthridine compound is shown as a formula I and has no R ₂ When the method is used:

mixing a compound III, a compound IV, a first base and a first solvent, and carrying out a first substitution reaction to obtain a compound V;

mixing the compound V, a second alkali and a second solvent, and carrying out a first hydrolysis reaction to obtain a compound VI;

mixing the compound VI, the compound VII, a first condensing agent, a third base and a third solvent, and carrying out a first condensation reaction to obtain a compound VIII;

mixing the compound VIII, PMBCl, fourth alkali and a fourth solvent, and carrying out a second substitution reaction to obtain a compound IX;

mixing the compound IX, a first catalyst, a fifth base and a fifth solvent, and carrying out a ring closure reaction to obtain a compound X;

mixing the compound X, acid and a sixth solvent, and performing deprotection to obtain a compound XI;

mixing the compound XI, phosphorus oxychloride and a seventh solvent, and carrying out chlorination reaction to obtain a compound XII;

the compounds XII and R ₃ H. Mixing the sixth base and the eighth solvent, and carrying out a third substitution reaction to obtain a compound XIV;

mixing the compound XIV, the compound XV, the second catalyst, the seventh base and the ninth solvent, and performing a coupling reaction to obtain a compound XVI;

mixing the compound XVI, a third catalyst and a tenth solvent, and performing a second hydrolysis reaction to obtain a compound XVII; the third catalyst is acid or alkali;

mixing the compound XVII, the compound XVIII, an eighth base, a second condensing agent and an eleventh solvent, and carrying out a second condensation reaction to obtain a 3-substituted phenanthridine compound shown in the formula I;

when the 3-substituted phenanthridine compound is shown as a formula I and R ₂ When 4-methoxyphenethyl, cyclopropanemethyl, cyclobutanemethyl, cyclopentanemethyl or hydrogen,

subjecting the compound XI, R ₂ Mixing the X, the fourth alkali and the fourth solvent, and carrying out a second substitution reaction to obtain a compound XIV';

mixing the compound XIV ', the compound XV, the second catalyst, the seventh base and the ninth solvent, and performing a coupling reaction to obtain a compound XVI';

mixing the compound XVI ', a third catalyst and a tenth solvent, and performing a second hydrolysis reaction to obtain a compound XVII'; the third catalyst is acid or alkali;

mixing the compound XVII ', the compound XVIII', an eighth base, a second condensing agent and an eleventh solvent to carry out a second condensation reaction to obtain a 3-substituted phenanthridine compound shown in the formula I;

when saidThe 3-substituted phenanthridine compound is shown as a formula I and has no R ₂ The method comprises the following steps:

the compound V is obtained by mixing a compound III, a compound IV, a first base and a first solvent and carrying out a first substitution reaction.

In the present invention, the first base is preferably potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, triethylamine or diisopropylethylamine; the first solvent is preferably tetrahydrofuran, dioxane, toluene or acetonitrile; the molar ratio of the compound IV to the compound III is preferably (0.8-1.5) to 1, more preferably 1; the molar ratio of the first base to compound III is preferably (1.0 to 3.0): 1, more preferably 1.5; the temperature of the first substitution reaction is 20-120 ℃, and more preferably 80 ℃; the time is preferably 2 to 24 hours, and more preferably 6 hours; the amount of the first solvent is not particularly limited, and the smooth reaction can be ensured.

In the invention, TLC is preferably adopted to detect the first substitution reaction, water quenching reaction is carried out on the obtained product after the reaction is finished, ethyl acetate (1000 ml multiplied by 2) is used for extraction, and the obtained organic layer is dried, concentrated and separated by column chromatography to obtain the compound V. The quenching, extraction, drying, concentration and column chromatography separation processes are not particularly limited in the present invention, and can be performed according to the processes well known in the art.

After the compound V is obtained, the compound V, a second alkali and a second solvent are mixed for a first hydrolysis reaction to obtain a compound VI.

In the present invention, the second base is preferably lithium hydroxide, sodium hydroxide or potassium hydroxide; the second solvent is preferably methanol, ethanol, a tetrahydrofuran-water mixed solvent or a dioxane-water mixed solvent; the proportion of two solvents in the mixed solvent is not specially limited, and the mixed solvent can be adjusted according to actual requirements; the amount of the second solvent is not particularly limited, and can be adjusted according to actual requirements.

In the present invention, the molar ratio of the second base to the compound V is preferably (1.0 to 5.0): 1, more preferably 2.0; the temperature of the first hydrolysis reaction is 20-100 ℃, and more preferably 40 ℃; the time is preferably 2 to 24 hours, more preferably 6 hours.

The invention preferably adopts TLC to detect the reaction, after the reaction is finished, dilute hydrochloric acid (2N) is added into the obtained product to quench the reaction, ethyl acetate (1000 ml multiplied by 2) is extracted, organic layers are combined, concentrated, and the compound VI is obtained by column chromatography separation and purification. The quenching, extraction, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

After the compound VI is obtained, the compound VI, the compound VII, the first condensing agent, the third base, and the third solvent are mixed and subjected to a first condensation reaction to obtain a compound VIII.

In the invention, the first condensing agent is preferably 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole mixture with the molar ratio of 1; the third base is preferably triethylamine, diisopropylethylamine or 4-dimethylaminopyridine, and the third solvent is preferably dichloromethane, tetrahydrofuran, N-dimethylformamide or acetonitrile. The dosage of the third solvent is not specially limited, and the third solvent is adjusted according to actual requirements to ensure that the reaction is smoothly carried out.

In the present invention, the molar ratio of the compound VII to the compound VI is preferably (0.8 to 2.0): 1, more preferably 1.0; the molar ratio of the third base to compound VI is preferably (1.0-2.0): 1, more preferably 1.5; the molar ratio of the first condensing agent to compound VI is preferably (1.0-2.0): 1, more preferably 1.2; the temperature of the first condensation reaction is preferably 20 to 100 ℃, and more preferably 25 to 35 ℃; the time is preferably 2 to 24 hours, more preferably 4 hours.

After the first condensation reaction is completed, the invention preferably adds water to the obtained product for quenching reaction, after layering, extracts the obtained water phase with ethyl acetate (1000 ml × 2), combines the organic layers, dries, filters, and separates by column chromatography to obtain the compound VIII. The quenching, layering, extraction, drying, filtration and column chromatography separation processes are not particularly limited in the present invention and may be performed according to processes well known in the art.

After the compound VIII is obtained, the compound VIII, PMBCl, fourth alkali and a fourth solvent are mixed for a second substitution reaction to obtain a compound IX.

In the present invention, the fourth base is preferably sodium hydride, lithium hexamethylamide or sodium hexamethylamide; the fourth solvent is preferably DMF; the amount of the fourth solvent is not specially limited, and the smooth reaction is ensured.

In the invention, the PMBCl is 4-methoxy benzyl chloride.

In the present invention, the molar ratio of PMBCl to compound VIII is preferably (0.8 to 2.0): 1, more preferably 1.0; the molar ratio of the fourth base to compound VIII is preferably (1.0 to 4.0) to 1, more preferably 2.0; the temperature of the second substitution reaction is preferably 0 to 100 ℃, more preferably room temperature, and the time is preferably 0.5 to 24 hours, more preferably 10 hours.

After the second substitution reaction is finished, the invention preferably performs TLC detection reaction, after the reaction is finished, water is added into the obtained product for quenching reaction, ethyl acetate (1000 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered and separated by column chromatography, and the compound IX is obtained. The extraction, drying, filtration and column chromatography separation processes are not particularly limited in the present invention and may be performed according to processes well known in the art.

After the compound IX is obtained, the compound IX, a first catalyst, a fifth base and a fifth solvent are mixed for a ring closure reaction to obtain a compound X.

In the present invention, the first catalyst is preferably tetrakistriphenylphosphine palladium, palladium acetate, tris-dibenzylideneacetone dipalladium or 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium, and the fifth base is preferably cesium carbonate, potassium carbonate, sodium carbonate or potassium phosphate; the fifth solvent is preferably dioxane-water, tetrahydrofuran-water, N-dimethylformamide or toluene. The dosage of the fifth solvent and the mixture ratio of the fifth solvent are not specially limited, and the fifth solvent can be adjusted according to actual requirements.

In the present invention, the molar ratio of the fifth base to compound IX is preferably (1.0 to 5.0): 1, more preferably 2.0; the molar ratio of the first catalyst to compound IX is preferably (0.05 to 0.5): 1, more preferably 0.05; the temperature of the ring closing reaction is preferably 60-120 ℃, and the time is preferably 4-24 h, and more preferably 12h.

Preferably, TLC detection reaction is adopted, the obtained product is filtered after the reaction is finished, and the obtained filtrate is sequentially concentrated and separated by column chromatography to obtain the compound X. The process of filtration, concentration and column chromatography separation is not particularly limited in the present invention and may be performed according to a process well known in the art.

After the compound X is obtained, the compound X, acid and a sixth solvent are mixed and deprotected to obtain a compound XI.

In the present invention, the acid is preferably 4-methylbenzenesulfonic acid, methanesulfonic acid, trifluoroacetic acid or hydrochloric acid; the concentration of the hydrochloric acid is not particularly limited in the present invention, and commercially available products well known in the art may be used; the sixth solvent is preferably toluene or acetonitrile. The dosage of the sixth solvent is not particularly limited, and can be adjusted according to actual requirements.

In the present invention, the molar ratio of the acid to the compound X is preferably (1.0 to 5.0): 1, more preferably 2.0; the deprotection temperature is preferably 40-120 ℃, and the time is preferably 2-12 h, and more preferably 4h.

In the invention, TLC detection reaction is preferably adopted, after the reaction is finished, the obtained product is added into 2N sodium carbonate aqueous solution, after layering, the obtained organic layer is concentrated, and column chromatography separation is carried out to obtain the compound XI. The concentration and column chromatography separation process is not particularly limited in the present invention, and may be performed according to a process well known in the art.

After a compound XI is obtained, the compound XI, phosphorus oxychloride and a seventh solvent are mixed for chlorination reaction to obtain a compound XII.

In the present invention, the seventh solvent is preferably toluene or acetonitrile; the molar ratio of the phosphorus oxychloride to the compound XI is preferably (1.0-10): 1, more preferably 4.0; the dosage of the seventh solvent is not particularly limited, and can be adjusted according to actual requirements.

In the invention, the temperature of the chlorination reaction is preferably 40-120 ℃, and more preferably 100 ℃; the time is preferably 2 to 12 hours, more preferably 6 hours.

Preferably, TLC is adopted for detection reaction, after the reaction is finished, the obtained reaction solution is poured into saturated sodium carbonate aqueous solution at the temperature of-0-5 ℃, ethyl acetate (1000 ml multiplied by 2) is used for extraction, organic layers are combined, and the compound XII is obtained after drying, filtering, concentration and column chromatography separation. The extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

After the compound XII is obtained, the compounds XII and R are added ₃ H. And mixing the sixth base and the eighth solvent to perform a third substitution reaction to obtain a compound XIV.

In the present invention, the sixth base is preferably sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, triethylamine or diisopropylethylamine; the eighth solvent is preferably N, N-dimethylformamide, dichloromethane, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane or acetonitrile; the dosage of the eighth solvent is not particularly limited, and can be adjusted according to actual requirements.

In the present invention, said R ₃ R in H ₃ Preferably a

In the present invention, said R ₃ The molar ratio of H to compound XII is preferably (0.8 to 2.0): 1, more preferably 1.0; the molar ratio of the sixth base to compound XII is preferably (1.0 to 4.0): 1, more preferably 2.0; the temperature of the third substitution reaction is preferably 20 to 120 ℃, more preferably 80 ℃, and the time is preferably 2 to 12 hours, more preferably 6 hours.

The invention preferably adopts TLC detection reaction, after the reaction is finished, water is added into the obtained product for quenching reaction, ethyl acetate (100 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography, and the compound XIV is obtained. The extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

After the compound XIV is obtained, the compound XIV, the compound XV, the second catalyst, the seventh base and the ninth solvent are mixed for a coupling reaction to obtain the compound XVI.

In the present invention, the compound XV is preferably

In the present invention, the second catalyst is preferably tetrakistriphenylphosphine palladium, palladium acetate, tris-dibenzylideneacetone dipalladium or 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium; the ligand is preferably 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine, 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl or 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene, and the seventh base is preferably cesium carbonate, potassium carbonate, sodium carbonate or potassium phosphate; the ninth solvent is preferably dioxane-water, tetrahydrofuran-water-N, N-dimethylformamide or toluene; the dosage of the ninth solvent and the proportion of the mixed solvent are not specially limited, and the dosage can be adjusted according to actual requirements.

In the present invention, the molar ratio of the compound XV to the compound XIV is preferably (0.8 to 2.0): 1, more preferably 1.0; the molar ratio of the second catalyst to compound XIV is preferably (0.05-0.5): 1, more preferably 0.1; the molar ratio of the seventh base to compound XIV is preferably (1.0-3.0): 1, more preferably 2.0; the temperature of the coupling reaction is preferably 60-120 ℃, and more preferably 80 ℃; the time is preferably 4 to 24 hours, more preferably 5 hours.

Preferably, TLC detection reaction is adopted, after the reaction is finished, water is added into the obtained product for quenching reaction, ethyl acetate (100 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography, and the compound XVI is obtained; the extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention and may be performed according to the processes well known in the art.

After the compound XVI is obtained, the compound XVI, the third catalyst, and the tenth solvent are mixed to perform the second hydrolysis reaction, so as to obtain the compound XVII.

In the present invention, the third catalyst is an acid or a base; when the base is preferably sodium hydroxide or potassium hydroxide, the tenth solvent is preferably methanol, ethanol, isopropanol, n-butanol, isobutanol, or ethylene glycol; when the acid is preferably 36% hydrochloric acid, 33% hydrogen bromide in acetic acid or 33% hydrogen bromide in water by mass, the tenth solvent is preferably ethanol, acetic acid or water. The dosage of the tenth solvent is not particularly limited, and can be adjusted according to actual requirements.

In the present invention, the molar ratio of the third catalyst to the compound XVI is preferably (1.0 to 5.0): 1, more preferably 3.0; the temperature of the second hydrolysis reaction is preferably 20 to 100 ℃, more preferably 80 ℃, and the time is preferably 4 to 12 hours, more preferably 10 hours.

Preferably, TLC detection reaction is adopted, after the reaction is finished, water quenching reaction is added into the obtained product, ethyl acetate (100 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography, and the compound XVII is obtained; the extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

After the compound XVII is obtained, the compound XVII, the compound XVIII, the eighth base, the second condensing agent and the eleventh solvent are mixed for a second condensation reaction to obtain the 3-substituted phenanthridine compound shown in the formula I.

In the invention, the second condensing agent is preferably 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole in a molar ratio of 1; the eighth base is preferably triethylamine, diisopropylethylamine or 4-dimethylaminopyridine, and the eleventh solvent is preferably dichloromethane, tetrahydrofuran, N-dimethylformamide or acetonitrile. The dosage of the eleventh solvent is not particularly limited, and can be adjusted according to actual requirements.

In the present invention, the molar ratio of compound XVIII to compound XVII is preferably (0.8 to 2.0): 1, more preferably 1.0; the molar ratio of the second condensing agent to the compound XVII is preferably (1.0 to 3.0): 1, more preferably 1.4; the molar ratio of the eighth base to compound XVII is preferably (1-3.0): 1, more preferably 2.0; the temperature of the second condensation reaction is preferably 20-100 ℃, and more preferably room temperature; the time is preferably 4 to 12 hours, more preferably 6 hours.

Preferably, TLC detection reaction is adopted, after the reaction is completed, water quenching reaction is added into the obtained product, ethyl acetate (100 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography, and the 3-substituted phenanthridine compound shown in the formula I is obtained; the extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

In the present invention, the compound XVIII is R ₃ H derivatizing the fragment; r ₃ Preferably, the following components are used:

the compound XVIII' is R ₂ X (X is Br or Cl) derivatized fragment; r is ₂ Preferably, the following components are used:

in the invention, when the 3-substituted phenanthridine compound is shown as a formula I and R is ₂ When the reaction is absent, the reaction process is as follows:

in the invention, when the 3-substituted phenanthridine compound is shown as a formula I and R ₂ When 4-methoxyphenethyl, cyclopropanemethyl, cyclobutanemethyl, cyclopentanemethyl or hydrogen,

mixing the compound XVI ', a third catalyst and a tenth solvent, and carrying out a second hydrolysis reaction to obtain a compound XVII'; the third catalyst is acid or alkali;

and mixing the compound XVII ', the compound XVIII', the eighth base, the second condensing agent and the eleventh solvent, and carrying out a second condensation reaction to obtain the 3-substituted phenanthridine compound shown in the formula I.

The invention relates to the compounds XI and R ₂ And mixing the X, the fourth base and the fourth solvent, and carrying out a second substitution reaction to obtain a compound XIV'.

In the present invention, the fourth base is preferably the same as described above and will not be described in detail; r ₂ The molar ratio of X (X is Br or Cl) to compound XI is preferably (0.8-2.0) 1, more preferably 1.0; the molar ratio of the fourth base to compound XI is preferably (1.0-4.0): 1, more preferably 2.0;

the temperature of the second substitution reaction is preferably 0-100 ℃, and the time is preferably 4-24 h.

After the compound XIV ' is obtained, the compound XIV ', the compound XV, the second catalyst, the seventh base and the ninth solvent are mixed for coupling reaction to obtain the compound XVI '.

In the invention, the compound XIV 'and the compound XV are subjected to coupling reaction under the action of a catalyst and alkali, the temperature of the coupling reaction is preferably 60-120 ℃, the reaction time is preferably 4-24 h, and the second catalyst is preferably tetratriphenylphosphine palladium, palladium acetate, dibenzylidene acetone dipalladium, 1' -bis (diphenylphosphino) ferrocene palladium dichloride; the seventh base is preferably cesium carbonate, potassium carbonate, sodium carbonate or potassium phosphate; the fourth solvent is preferably the same as described above and will not be described in detail.

In the present invention, the molar ratio of the compound XV to the compound XIV' is preferably (0.8 to 2.0): 1, more preferably 1.0; the molar ratio of the second catalyst to compound XIV' is preferably (0.05 to 0.5): 1, more preferably 0.1; the molar ratio of the seventh base to compound XIV' is preferably (1.0 to 3.0): 1, more preferably 2.0.

After the compound XVI ' is obtained, the compound XVI ', the third catalyst, and the tenth solvent are mixed to perform a second hydrolysis reaction, so as to obtain a compound XVII '; the third catalyst is an acid or a base. In the invention, the compound XVII' is hydrolyzed under the action of acid or alkali, the temperature of the hydrolysis reaction is preferably 20-100 ℃, and the time is preferably 4-12 h; when the alkali is preferably sodium hydroxide or potassium hydroxide, the solvent is preferably methanol, ethanol, isopropanol, n-butanol, isobutanol or ethylene glycol; when the acid is preferably hydrochloric acid, hydrogen bromide in acetic acid or hydrogen bromide in water, the solvent is preferably ethanol, acetic acid or water. In the present invention, the molar ratio of the third catalyst to the compound XVII' is preferably (1.0 to 5.0): 1, more preferably 3.0.

After the compound XVII ' is obtained, the compound XVII ', the compound XVIII ', the eighth base, the second condensing agent and the eleventh solvent are mixed for a second condensation reaction to obtain the 3-substituted phenanthridine compound shown in the formula I.

In the invention, the compound XVII' and the compound XVIII undergo a condensation reaction under the action of a condensing agent, the temperature of the condensation reaction is preferably 20-100 ℃, and the time is preferably 4-12 h; the second condensing agent, the eighth base and the eleventh solvent are preferably the same as described above, and are not described in detail.

In the present invention, the molar ratio of compound XVIII to compound XVII' is preferably (0.8 to 2.0): 1, more preferably 1.0; the molar ratio of the second condensing agent to compound XVII' is preferably (1.0 to 3.0): 1, more preferably 1.4; the molar ratio of the eighth base to compound XVII' is preferably (1-3.0): 1, more preferably 2.0.

In the present invention, the compound XVIII' is R ₂ X (X is Br or Cl) derivatized fragment, R ₂ Preferably, the following components are used:

in the invention, when the 3-substituted phenanthridine compound is shown as a formula I and R is ₂ 4-methoxyphenethyl, cyclopropanemethyl, cyclobutanemethyl, cyclopentanemethyl, or hydrogen, the reaction formula is:

in the invention, when the 3-substituted phenanthridine compound is shown as the formula I, the total reaction process is as follows:

in the invention, when the 3-substituted phenanthridine compound is shown as a formula II and has no R ₂ When the temperature of the water is higher than the set temperature,

mixing a compound III-1, a compound VII, a first condensing agent, a third alkali and a third solvent, and carrying out a first condensation reaction to obtain a compound V-1;

mixing the compound V-1, PMBCl, fourth alkali and a fourth solvent, and carrying out a second substitution reaction to obtain a compound VI-1;

mixing the compound VI-1, a first catalyst, a fifth alkali and a fifth solvent, and carrying out a ring closure reaction to obtain a compound VII-1;

mixing the compound VII-1, acid and a sixth solvent, and carrying out deprotection to obtain a compound VIII-1;

mixing the compound VIII-1, phosphorus oxychloride and a seventh solvent, and carrying out chlorination reaction to obtain a compound IX-1;

the compound IX-1, R ₃ H. Mixing the sixth alkali and the eighth solvent, and carrying out a third substitution reaction to obtain a compound X-1;

mixing the compound X-1, the compound XV, a second catalyst, a seventh base and a ninth solvent, and carrying out a coupling reaction to obtain a compound XI-1;

mixing the compound XI-1, a second base and a second solvent, and carrying out a first hydrolysis reaction to obtain a compound XII-1;

and mixing the compound XII-1, the compound XIII-1, an eighth base, a second condensing agent and an eleventh solvent, and carrying out a second condensation reaction to obtain the 3-substituted phenanthridine compound shown in the formula II.

In the invention, the reaction process of the method is as follows:

the compound III-1, the compound VII, the first condensing agent, the third base and the third solvent are mixed to carry out a first condensation reaction, so as to obtain a compound V-1.

In the invention, the first condensing agent is preferably 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/and 1-hydroxybenzotriazole mixture with the molar ratio of 1; the third base is preferably triethylamine, diisopropylethylamine or 4-dimethylaminopyridine, and the third solvent is preferably dichloromethane, tetrahydrofuran, N-dimethylformamide or acetonitrile. The dosage of the third solvent is not specially limited, and the third solvent is adjusted according to actual requirements to ensure that the reaction is smoothly carried out.

In the present invention, the molar ratio of the compound VII to the compound III-1 is preferably (0.8 to 2.0): 1, more preferably 1.0; the molar ratio of the third base to compound III-1 is preferably (1.0-2.0): 1, more preferably 1.5; the molar ratio of the first condensing agent to the compound III-1 is preferably (1.0 to 2.0): 1, more preferably 1.2; the temperature of the first condensation reaction is preferably 20-100 ℃, and more preferably 25-35 ℃; the time is preferably 2 to 24 hours, more preferably 4 hours.

After the first condensation reaction is completed, the invention preferably adds water to the obtained product for quenching reaction, after layering, extracts the obtained water phase with ethyl acetate (1000 ml × 2), combines the organic layers, dries, filters, and separates by column chromatography to obtain the compound V-1. The quenching, layering, extraction, drying, filtration and column chromatography separation processes are not particularly limited in the present invention and may be performed according to processes well known in the art.

After the compound V-1 is obtained, the compound V-1, PMBCl, fourth alkali and a fourth solvent are mixed for a second substitution reaction to obtain a compound VI-1.

In the invention, the PMBCl is 4-methoxy benzyl chloride.

In the present invention, the molar ratio of PMBCl to compound V-1 is preferably (0.8-2.0): 1, more preferably 1.0; the molar ratio of the fourth base to the compound V-1 is preferably (1.0 to 4.0): 1, more preferably 2.0; the temperature of the second substitution reaction is preferably 0 to 100 ℃, more preferably room temperature, and the time is preferably 4 to 24 hours, more preferably 10 hours.

After the second substitution reaction is finished, the invention preferably adopts TLC detection reaction, after the reaction is finished, water is added into the obtained product for quenching reaction, ethyl acetate (1000 ml multiplied by 2) is used for extraction, organic layers are combined, and the compound VI-1 is obtained after drying, filtration and column chromatography separation. The extraction, drying, filtration and column chromatography separation processes are not particularly limited in the present invention and may be performed according to processes well known in the art. After the compound VI-1 is obtained, the compound VI-1, a first catalyst, a fifth alkali and a fifth solvent are mixed for a ring closing reaction to obtain a compound VII-1.

In the present invention, the molar ratio of the fifth base to compound VI-1 is preferably (1.0 to 5.0): 1, more preferably 2.0; the molar ratio of the first catalyst to compound VI-1 is preferably (0.05-0.5): 1, more preferably 0.05; the temperature of the ring closing reaction is preferably 60-120 ℃, and the time is preferably 4-24 h, and more preferably 12h.

Preferably, TLC detection reaction is adopted, the obtained product is filtered after the reaction is finished, and the obtained filtrate is sequentially concentrated and separated by column chromatography to obtain the compound VII-1. The process of filtration, concentration and column chromatography separation is not particularly limited in the present invention and may be performed according to a process well known in the art.

After the compound VII-1 is obtained, the compound VII-1, acid and a sixth solvent are mixed and deprotected to obtain the compound VIII-1.

In the present invention, the molar ratio of the acid to the compound VII-1 is preferably (1.0 to 5.0): 1, more preferably 2.0; the deprotection temperature is preferably 40-120 ℃, and the time is preferably 2-12 h, and more preferably 4h.

Preferably, TLC is adopted for detection reaction, after the reaction is finished, the obtained product is added into 2N sodium carbonate aqueous solution, after layering, the obtained organic layer is concentrated, and column chromatography separation is carried out, so that the compound VIII-1 is obtained. The concentration and column chromatography separation process is not particularly limited in the present invention, and may be performed according to a process well known in the art.

After the compound VIII-1 is obtained, the compound VIII-1, phosphorus oxychloride and a seventh solvent are mixed for chlorination reaction to obtain a compound IX-1.

In the present invention, the seventh solvent is preferably toluene or acetonitrile; the molar ratio of the phosphorus oxychloride to the compound VIII-1 is preferably (1.0-10) to 1, more preferably 4.0; the dosage of the seventh solvent is not particularly limited, and can be adjusted according to actual requirements.

In the present invention, the temperature of the chlorination reaction is preferably 40 to 120 ℃, and more preferably 100 ℃; the time is preferably 2 to 12 hours, more preferably 6 hours.

Preferably, TLC is adopted for detection reaction, after the reaction is finished, the obtained reaction solution is poured into a cold saturated sodium carbonate aqueous solution with the concentration of-0-5 ℃, ethyl acetate (1000 ml multiplied by 2) is used for extraction, organic layers are combined, and the compound IX-1 is obtained after drying, filtering, concentration and column chromatography separation. The extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

After the compound IX-1 is obtained, the invention uses the compound IX-1 and R ₃ H. And mixing the sixth base and the eighth solvent to carry out a third substitution reaction to obtain the compound X-1.

In the present invention, said R ₃ R in H ₃ Preference is given to

Comprises the following steps:

in the present invention, said R ₃ The molar ratio of H to compound IX-1 is preferably (0.8 to 2.0): 1, more preferably 1.0; the molar ratio of the sixth base to compound IX-1 is preferably (1.0 to 4.0) 1, more preferably 2.0; said third substitutionThe reaction temperature is preferably 20 to 120 ℃, more preferably 80 ℃ and the reaction time is preferably 2 to 12 hours, more preferably 6 hours.

Preferably, TLC is adopted for detection reaction, after the reaction is finished, water is added into the obtained product for quenching reaction, ethyl acetate (100 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography, and the compound X-1 is obtained. The extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

After the compound X-1 is obtained, the compound X-1, the compound XV, the second catalyst, the ligand, the seventh base and the ninth solvent are mixed for coupling reaction to obtain the compound XI-1. In the present invention, the second catalyst is preferably tetrakistriphenylphosphine palladium, palladium acetate, tris-dibenzylideneacetone dipalladium or 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium; the ligand is preferably 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine, 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl, or 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene, and the seventh base is preferably cesium carbonate, potassium carbonate, sodium carbonate, or potassium phosphate; the ninth solvent is preferably dioxane-water, tetrahydrofuran-water-N, N-dimethylformamide or toluene; the dosage of the ninth solvent and the proportion of the mixed solvent are not specially limited, and the dosage can be adjusted according to actual requirements.

In the present invention, the molar ratio of the compound XV to the compound X-1 is preferably (0.8 to 2.0): 1, more preferably 1.0; the molar ratio of the second catalyst to the compound X-1 is preferably (0.05 to 0.5): 1, more preferably 0.1; the molar ratio of the seventh base to compound X-1 is preferably (1.0 to 3.0): 1, more preferably 2.0; the temperature of the coupling reaction is preferably 60-120 ℃, and more preferably 80 ℃; the time is preferably 4 to 24 hours, more preferably 5 hours.

The invention preferably adopts TLC detection reaction, after the reaction is finished, water quenching reaction is added into the obtained product, ethyl acetate (100 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography, and the compound XI-1 is obtained; the extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

After the compound XI-1 is obtained, the compound XI-1, a third catalyst and a tenth solvent are mixed for a second hydrolysis reaction to obtain a compound XII-1.

In the present invention, the molar ratio of the third catalyst to the compound XI-1 is preferably (1.0 to 5.0): 1, more preferably 3.0; the temperature of the second hydrolysis reaction is preferably 20 to 100 ℃, more preferably 80 ℃, and the time is preferably 4 to 12 hours, more preferably 10 hours.

Preferably, TLC detection reaction is adopted, after the reaction is finished, water quenching reaction is added into the obtained product, ethyl acetate (100 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography, and the compound XII-1 is obtained; the extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention and may be performed according to the processes well known in the art.

After the compound XII-1 is obtained, the compound XII-1, the compound XIII-1, the eighth base, the second condensing agent and the eleventh solvent are mixed for a second condensation reaction to obtain the 3-substituted phenanthridine compound shown in the formula II.

In the invention, the second condensing agent is preferably 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and/or 1-hydroxybenzotriazole composition with a molar ratio of 1; the eighth base is preferably triethylamine, diisopropylethylamine or 4-dimethylaminopyridine, and the eleventh solvent is preferably dichloromethane, tetrahydrofuran, N-dimethylformamide or acetonitrile. The dosage of the eleventh solvent is not particularly limited, and can be adjusted according to actual requirements.

In the present invention, the molar ratio of the compound XIII-1 to the compound XII-1 is preferably

(0.8-2.0) 1, more preferably 1.0; the molar ratio of the second condensing agent to the compound XII-1 is preferably (1.0 to 3.0): 1, more preferably 1.4; the molar ratio of the eighth base to the compound XII-1 is preferably (1 to 3.0): 1, more preferably 2.0; the temperature of the second condensation reaction is preferably 20-100 ℃, and more preferably room temperature; the time is preferably 4 to 12 hours, more preferably 6 hours.

Preferably, TLC detection reaction is adopted, after the reaction is completed, water quenching reaction is added into the obtained product, ethyl acetate (100 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography, and the 3-substituted phenanthridine compound shown in the formula II is obtained; the extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

In the invention, when the 3-substituted phenanthridine compound is shown as a formula II and R ₂ When 4-methoxyphenethyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl or hydrogen,

the compound VIII' -1, R ₂ Mixing the X, the sixth alkali and the eighth solvent, and carrying out a third substitution reaction to obtain a compound X' -1;

mixing the compound X '-1, the compound XV, a second catalyst, a seventh base and a ninth solvent for a coupling reaction to obtain a compound XI' -1;

mixing the compound XI '-1, a third catalyst and a tenth solvent, and performing a second hydrolysis reaction to obtain a compound XII' -1;

and mixing the compound XII' -1, the compound XIII-1, an eighth base, a second condensing agent and an eleventh solvent, and carrying out a second condensation reaction to obtain the 3-substituted phenanthridine compound shown in the formula II.

In the invention, when the 3-substituted phenanthridines areThe compound is of formula II and R ₂ When 4-methoxy phenethyl, cyclopropane methyl, cyclobutane methyl or cyclopentane methyl or hydrogen, the reaction process is as follows:

after the compound VIII' -1 is obtained, the invention uses the compound VIII-1 and the compound R ₂ And mixing the X, the sixth base and the eighth solvent, and carrying out a third substitution reaction to obtain a compound X' -1.

In the present invention, said R ₂ X (X is Br or Cl); r ₂ Preferably:

In the present invention, said R ₂ The molar ratio of X to the compound VIII' -1 is preferably (0.8 to 2.0): 1, more preferably 1.0; the molar ratio of the sixth base to compound VIII' -1 is preferably (1.0 to 4.0): 1, more preferably 2.0; the temperature of the third substitution reaction is preferably 20 to 120 ℃, more preferably 80 ℃, and the time is preferably 2 to 12 hours, more preferably 6 hours.

The invention preferably adopts TLC detection reaction, after the reaction is finished, water is added into the obtained product for quenching reaction, ethyl acetate (100 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography, and the compound X' -1 is obtained. The extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

After the compound X ' -1 is obtained, the compound X ' -1, the compound XV, the second catalyst, the seventh base and the ninth solvent are mixed for coupling reaction, and the compound XI ' -1 is obtained.

In the present invention, the second catalyst is preferably tetrakis triphenylphosphine palladium, palladium acetate, tris dibenzylideneacetone dipalladium or 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium; the seventh base is preferably cesium carbonate, potassium carbonate, sodium carbonate or potassium phosphate; the ninth solvent is preferably dioxane-water, tetrahydrofuran-water-N, N-dimethylformamide or toluene; the dosage of the ninth solvent and the proportion of the mixed solvent are not specially limited, and the dosage can be adjusted according to actual requirements.

In the present invention, the molar ratio of the compound XV to the compound X' -1 is preferably (0.8 to 2.0): 1, more preferably 1.0; the molar ratio of the second catalyst to compound X' -1 is preferably (0.05 to 0.5) 1, more preferably 0.1; the molar ratio of the seventh base to compound X' -1 is preferably (1.0 to 3.0): 1, more preferably 2.0; the temperature of the coupling reaction is preferably 60-120 ℃, and more preferably 80 ℃; the time is preferably 4 to 24 hours, more preferably 5 hours.

The invention preferably adopts TLC detection reaction, after the reaction is finished, water quenching reaction is added into the obtained product, ethyl acetate (100 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography, and the compound XI' -1 is obtained; the extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

After the compound XI ' -1 is obtained, the compound XI ' -1, a third catalyst and a tenth solvent are mixed for a second hydrolysis reaction to obtain the compound XII ' -1.

In the present invention, the third catalyst is preferably an acid or a base; when the base is preferably sodium hydroxide or potassium hydroxide, the tenth solvent is preferably methanol, ethanol, isopropanol, n-butanol, isobutanol, or ethylene glycol; when the acid is preferably 36% hydrochloric acid, 33% hydrogen bromide in acetic acid or 33% hydrogen bromide in water by mass, the tenth solvent is preferably ethanol, acetic acid or water. The dosage of the tenth solvent is not particularly limited, and can be adjusted according to actual requirements.

In the present invention, the molar ratio of the third catalyst to the compound XI' -1 is preferably (1.0 to 5.0): 1, more preferably 3.0; the temperature of the second hydrolysis reaction is preferably 20 to 100 ℃, more preferably 80 ℃, and the time is preferably 4 to 12 hours, more preferably 10 hours.

Preferably, TLC is adopted for detection reaction, after the reaction is finished, water is added into the obtained product for quenching reaction, ethyl acetate (100 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography, and the compound XII' -1 is obtained; the extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

After the compound XII '-1 is obtained, the compound XII' -1, the compound XIII-1, the eighth base, the second condensing agent and the eleventh solvent are mixed for a second condensation reaction to obtain the 3-substituted phenanthridine compound shown in the formula II.

In the present invention, the molar ratio of the compound XIII-1 to the compound XII' -1 is preferably

(0.8-2.0) 1, more preferably 1.0; the molar ratio of the second condensing agent to the compound XII' -1 is preferably (1.0 to 3.0): 1, more preferably 1.4; the molar ratio of the eighth base to the compound XII' -1 is preferably (1 to 3.0): 1, more preferably 2.0; the temperature of the second condensation reaction is preferably 20-100 ℃, and more preferably room temperature; the time is preferably 4 to 12 hours, more preferably 6 hours.

The invention preferably adopts TLC detection reaction, after the reaction is completed, water quenching reaction is added into the obtained product, ethyl acetate (100 ml multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography, and the 3-substituted phenanthridine compound shown in the formula II is obtained; the extraction, drying, filtration, concentration and column chromatography separation processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.

In the invention, when the 3-substituted phenanthridine compound is represented by the formula II, the reaction process is as follows:

the invention provides application of the 3-substituted phenanthridine compound in the technical scheme or the 3-substituted phenanthridine compound prepared by the preparation method in the technical scheme in preparation of a KRAS-G12C inhibitor. The invention achieves the aim of treating tumors by inhibiting the activity of KRAS-G12C through the 3-substituted phenanthridine compound.

The invention provides a tumor-inhibiting pharmaceutical composition, which comprises the 3-substituted phenanthridine compound in the technical scheme, or comprises a stereoisomer, a non-toxic pharmaceutically acceptable salt, a hydrate, a solvate or an isotope compound of the 3-substituted phenanthridine compound.

In the present invention, the pharmaceutical composition for inhibiting tumor preferably further comprises a pharmaceutically acceptable carrier and/or diluent. The invention is not limited to the types of the pharmaceutically acceptable carriers and diluents, and the pharmaceutically acceptable carriers and diluents can be any corresponding agents known in the art.

In the present invention, the tumor preferably includes skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, stomach cancer, kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytoma, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphatic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, myosarcoma, or fibrosarcoma.

In the present invention, "pharmaceutically acceptable salts" refer to salts that retain the biological effectiveness and properties of the parent compound, including: acid addition salts obtained by reaction of the free base of the parent compound with an inorganic acid or with an organic acid; such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, or perchloric acid; such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, or malonic acid; preferably hydrochloric acid or (L) -malic acid; or when an acid proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinated with an organic base, a salt is formed; such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

"pharmaceutical composition" refers to a mixture of one or more of the compounds described herein or a physiologically acceptable salt thereof with other chemical ingredients such as physiologically acceptable carriers and excipients.

"carrier" when used herein refers to a carrier or diluent that does not produce a significant stimulus to an organism and does not abrogate the biological activity and properties of the administered compound.

"phenyl" refers to a group having a benzene ring as a functional group.

"aryl" refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Preferably, the aryl group has 6 to 12 carbon atoms in the ring.

Unless otherwise indicated, the description or designation of a particular compound in the specification and claims is intended to include the individual enantiomers as well as racemic or other mixtures thereof. Methods for determining stereochemical configuration and separating stereoisomers are well known in the art. Thus, the present invention also encompasses any stereoisomeric form, its corresponding enantiomers (d-and l-or (+) and (-) isomers), and diastereomers thereof, and mixtures thereof, and is not limited to any one stereoisomeric form, having activity for inhibiting KRAS-G12C.

The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.

Example 1

Compound 1: synthesis of 1- (4- (3- (2-chloro-6-fluorophenyl) -10-fluoro-6- (3-methoxyazetidin-1-yl) phenanthridin-9-yl) piperazin-1-yl) prop-2-en-1-one:

the first step is as follows:

compound 1a (172.0g, 1.0mol), compound 1b (206.1g, 1.0mol), and cesium carbonate (486.0g, 1.5mol) were dissolved in acetonitrile (1000 mL), the temperature was raised to 80 ℃, the reaction was stirred for 6 hours, the TLC detection reaction was performed, after the reaction was completed, water (1000 mL) was added to quench the reaction, extraction was performed with ethyl acetate (1000 mL. Times.2), the organic layer was dried, concentrated, and column chromatography was performed to obtain 241.3g of an off-white solid, with a yield of 67.3%.

The second step is that:

compound 1c (241.0 g, 673.2mmol) and lithium hydroxide (32.3 g, 1.34mol) were dissolved in methanol (1000 mL) and water (500 mL), the reaction was stirred at 40 ℃ for 6h, TLC detected, after completion of the reaction, diluted hydrochloric acid (2N) was added to quench the reaction, extraction was performed with ethyl acetate (1000 mL. Times.2), the organic layers were combined, concentrated, and column chromatography was performed to obtain 197.3g of an off-white solid in 85.2% yield. The third step:

compound 1d (197.0g, 572.7mmol), compound 1e (170.0g, 572.7mmol) and triethylamine (86.8g, 859.1mmol) were dissolved in DMF (1000 mL), HATU (261.1g, 687.2mmol) was added at room temperature, reaction was stirred for 4 hours, after completion of the reaction, 500mL of water was added to quench the reaction, the layers were separated, the aqueous phase was extracted with ethyl acetate (1000 mL. Times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 278.4g of an off-white solid with a yield of 78.0%.

The fourth step:

compound 1f (278g, 446.9mmol) was dissolved in DMF (1000 mL), sodium hydride (35.8g, 893.9mmol) was added thereto at room temperature and the mixture was stirred for 1 hour, 4-methoxybenzyl chloride (67.7g, 446.9mmol) was added thereto and the reaction was stirred for 1 hour at room temperature and detected by TLC, after completion of the reaction, water was added thereto and the reaction mixture was quenched with 500mL of water, extracted with ethyl acetate (1000 mL. Times.2), the organic layers were combined, dried, filtered and separated by column chromatography to give 268.5g of an off-white solid with a yield of 80.8%.

The fifth step:

1g (270.0g, 363.4mmol) of the compound, potassium carbonate (100.3g, 726.8mmol) and tetrakistriphenylphosphine palladium (21.0g, 18.2mol) were placed in toluene (1000 mL), the temperature was raised to reflux, the reaction was stirred for 12h, the TLC detection reaction was performed, after the reaction was completed, filtration was performed, the filtrate was concentrated, and column chromatography was performed to obtain 189.5g of a gray solid, with the yield being 89.2%.

And a sixth step:

compound 1h (189.0g, 307.3mmol) and p-toluenesulfonic acid (105.7g, 614.6mmol) are placed in toluene (1000 mL) and heated to reflux, the reaction is stirred for 4h, TLC detection reaction is carried out, after the reaction is finished, the obtained product is poured into 1000mL of 2N sodium carbonate solution, layering is carried out, an organic layer is concentrated, column chromatography separation is carried out, and 130.4g of white-like solid is obtained, wherein the yield is 85.7%.

The seventh step:

putting the compound 1i (49.5g, 100mmol) and the phosphorus oxychloride (60.7g, 400mmol) in acetonitrile (500 mL), heating to 100 ℃, stirring for 6h, detecting by TLC, pouring the reaction liquid into a saturated sodium carbonate solution (500 mL) at 0-5 ℃ after the reaction is finished, extracting by using ethyl acetate (1000 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, and separating by column chromatography to obtain 32.1g of white-like solid with the yield of 62.6%.

Eighth step:

compound 1j (5.1g, 10mmol), 1k (1.22g, 10mmol) and potassium carbonate (2.8g, 20mmol) were dissolved in 1, 4-dioxane (100 mL), the temperature was raised to 80 ℃, the reaction was stirred for 6h, the TLC detection reaction was performed, after completion of the reaction, 50mL of water was added to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to give 3.1g of an off-white solid, with a yield of 55.0%.

The ninth step:

1l (2.82g, 5.0 mmol), 1m (870 mg,5.0 mmol), pd (dppf) Cl ₂ (366mg, 0.5mmol), sodium carbonate (1.0g, 10mmol) are placed in tetrahydrofuran (50 mL) and water (10 mL), the temperature is increased to 80 ℃, the reaction is stirred for 5h, TLC detection reaction is carried out, 50mL of water is added after the reaction is finished, the reaction is quenched, ethyl acetate (100 mL multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography to obtain 1.7g of off-white solid, the yield is 55.4 percent

The tenth step:

compound 1n (1.7g, 2.8mmol), sodium hydroxide (331mg, 8.4mmol) were placed in ethanol (30 mL), the temperature was raised to 80 ℃ and the reaction was stirred for 10h, the TLC detection reaction was carried out, 50mL of water was added after the completion of the reaction to quench the reaction, extraction was carried out with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and subjected to column chromatography to give 1.0g of an off-white solid in a yield of 72.3%.

The eleventh step:

placing compound 1o (297mg, 0.5mmol), acrylic acid (43mg, 0.6mmol) and diisopropylethylamine (129mg, 1.0mmol) in DMF (30 mL), adding HATU (266mg, 0.7mmol) at room temperature, stirring for 6h, detecting by TLC, adding water 50mL after reaction, quenching, extracting with ethyl acetate (100 mL. Times.2), combining organic layers, drying, filtering, concentrating, and separating by column chromatography to obtain off-white solid 156mg with a yield of 56.9%. ESI (+) m/z =549.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ8.75(d,J＝8.4Hz,1H),7.90(d,J＝8.5Hz,1H),7.82(d,J＝1.8Hz,1H),7.57-7.42(m,3H),7.38-7.30(m,1H),7.21(dd,J＝8.5,5.0Hz,1H),6.89(dd,J＝16.6,10.5Hz,1H),6.18(dd,J＝16.6,2.4Hz,1H),5.74(dd,J＝10.5,2.4Hz,1H),4.63-4.60(m,2H),4.35(tq,J＝7.3,3.9Hz,1H),4.26-4.20(m,2H),3.83-3.80(m,4H),3.303.24(m,7H).

example 2

Compound 2: synthesis of 1- (4- (3- (2-chloro-6-fluorophenyl) -10-fluoro-6- ((2-morpholinoethyl) amino) phenanthridin-9-yl) piperazin-1-yl) prop-2-en-1-one

The first step is as follows:

compound 1j (5.1g, 10mmol), 1k (1.3g, 10mmol) and potassium carbonate (2.8g, 20mmol) were dissolved in 1, 4-dioxane (100 mL), the temperature was raised to 80 ℃, the reaction was stirred for 6 hours, the reaction was detected by TLC, after the reaction was completed, 50mL of water was added to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to give 3.6g of an off-white solid in a yield of 59.3%.

The second step is that:

compound 2b (3.0g, 5.0mmol), 1m (870mg, 5.0mmol), pd (dppf) Cl ₂ (366mg, 0.5mmol), sodium carbonate (1.0g, 10mmol) are placed in tetrahydrofuran (50 mL) and water (10 mL), the temperature is increased to 80 ℃, the reaction is stirred for 5h, TLC detection reaction is carried out, 50mL of water is added after the reaction is finished, the reaction is quenched, ethyl acetate (100 mL multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography to obtain 2.0g of off-white solid, the yield is 60.9 percent

The third step:

compound 2c (2.0g, 3.0mmol), potassium hydroxide (504mg, 9.0mmol) were placed in ethanol (30 mL), the temperature was raised to 80 ℃, the reaction was stirred for 10h, TLC detection reaction was performed, 50mL of water was added after the reaction was completed to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.2), organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to give 1.3g of an off-white solid, with a yield of 80.7%.

The fourth step:

compound 2d (269mg, 0.5mmol), acrylic acid (43mg, 0.6mmol), diisopropylethylamine (129mg, 1.0mmol) were placed in DMF (30 mL), HATU (266mg, 0.7mmol) was added at room temperature, the reaction was stirred for 6h, TLC detection was performed, water was added to 50mL after the reaction was completed to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and column chromatography gave 171mg of off-white solid in a yield of 57.9%. ESI (+) m/z =592.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ8.71(d,J＝8.7Hz,1H),8.14(d,J＝8.7Hz,1H),7.79(s,1H),7.69-7.65(m,1H),7.59-7.43(m,3H),7.39-7.36(m,2H),6.89(dd,J＝16.7,10.5Hz,1H),6.18(dd,J＝16.7,2.4Hz,1H),5.75(dd,J＝10.5,2.4Hz,1H),3.98-3.64(m,12H),3.27(s,8H).

example 3

Compound 3: synthesis of 1- (4- (3- (2-chloro-6-fluorophenyl) -8-fluoro-6- ((4-methoxybenzyl) amino) phenanthridin-9-yl) piperazin-1-yl) prop-2-en-1-one

The first step is as follows:

compound 1j (5.1g, 10mmol), 1k (1.4g, 10mmol) and potassium carbonate (2.8g, 20mmol) were dissolved in 1, 4-dioxane (100 mL), the temperature was raised to 80 ℃, the reaction was stirred for 6h, the reaction was detected by TLC, after completion of the reaction, 50mL of water was added to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to give 3.8g of an off-white solid in a yield of 61.9%. The second step is that:

compound 3b (3.0g, 5.0mmol), 1m (870mg, 5.0mmol), pd (dppf) Cl ₂ (366mg, 0.5mmol), sodium carbonate (1.0g, 10mmol) are placed in tetrahydrofuran (50 mL) and water (10 mL), the temperature is increased to 80 ℃, the reaction is stirred for 5h, TLC detection reaction is carried out, 50mL of water is added after the reaction is finished, the reaction is quenched, ethyl acetate (100 mL multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography to obtain 2.2g of off-white solid, the yield is 66.3 percent

The third step:

compound 3c (2.2 g,3.3 mmol), potassium hydroxide (554mg, 9.9 mmol) were placed in ethanol (30 mL), the temperature was raised to 80 ℃, the reaction was stirred for 10h, TLC detection was performed, 50mL of water was added after the reaction was completed to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and isolated by column chromatography to give 1.1g of an off-white solid with a yield of 61.3%.

The fourth step:

after compound 3d (272mg, 0.5 mmol), acrylic acid (43mg, 0.6 mmol) and diisopropylethylamine (129mg, 1.0 mmol) were placed in DMF (30 mL), HATU (266mg, 0.7 mmol) was added at room temperature, the reaction was stirred for 6h, TLC detection was performed, 50mL of water was added to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to give 184mg of off-white solid in a yield of 61.3%. ESI (+) m/z =599.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ8.71(d,J＝8.7Hz,1H),8.14(d,J＝8.7Hz,1H),7.79(s,1H),7.69-7.65(m,1H),7.59-7.43(m,3H),7.39-7.36(m,2H),6.89(dd,J＝16.7,10.5Hz,1H),6.18(dd,J＝16.7,2.4Hz,1H),3.87-3.78(s,6H),3.68(s,3H),3.28(s,4H).

example 4

Compound 4: synthesis of 9- (4-acryloylpiperazin-1-yl) -3- (2-chloro-6-fluorophenyl) -10-fluoro-5- (4-methoxybenzyl) phenanthridin-6 (5H) -one

First step of

Compound 1i (2.0 g,4.0 mmol) was dissolved in DMF (10 mL), and sodium hydride (320mg, 8.0 mmol) was added at room temperature. Stirring reaction for 30 molecules, adding 4-methoxybenzyl chloride (626mg, 4mmol), stirring reaction for 10h, detecting reaction by TLC, adding 50mL of water to quench reaction after the reaction is finished, extracting by ethyl acetate (100 mL multiplied by 2), combining organic layers, concentrating, and performing column chromatography to obtain 1.8g of off-white solid with the yield of 74.1%.

The second step is that:

compound 4a (1.7g, 2.8mmol), 1m (488mg, 2.8mmol), pd (dppf) Cl ₂ (219mg, 0.3mmol), sodium carbonate (592mg, 5.6mmol) in tetrahydrofuran(40 mL) and water (20 mL), heating to 80 ℃, stirring for reaction for 8h, detecting by TLC, adding 50mL water to quench the reaction, extracting with ethyl acetate (100 mL. Times.2), combining the organic layers, drying, filtering, concentrating, and separating by column chromatography to obtain an off-white solid 1.3g with a yield of 71.6%.

The third step:

placing compound 4b (986 mg,1.5 mmol) and sodium hydroxide (252mg, 4.5 mmol) in ethanol (30 mL), heating to 80 ℃, stirring for reaction for 10h, detecting by TLC, adding 50mL of water after the reaction is finished, quenching the reaction, extracting with ethyl acetate (100 mL. Times.2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain an off-white solid 568mg, wherein the yield is 69.5%.

The fourth step:

placing compound 4c (273mg, 0.5mmol), acrylic acid (43mg, 0.6mmol) and diisopropylethylamine (129mg, 1.0mmol) in DMF (30 mL), adding HATU (266mg, 0.7mmol) at room temperature, stirring for 6h, detecting by TLC, adding 50mL of water after reaction, extracting with ethyl acetate (100 mL. Times.2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain quasi-white solid 181mg with yield of 60.4% and ESI (+) m/z =600.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ8.74(d,J＝8.6,1H),8.28(d,J＝8.8Hz,1H),7.53-7.42(m,4H),7.39-7.31(m,2H),7.14(d,J＝6.5Hz,2H),6.89(dd,J＝16.7,10.5Hz,1H),6.84(d,J＝8.8Hz,2H),6.18(dd,J＝16.7,2.4Hz,1H),5.74(dd,J＝10.5,2.4Hz,1H),3.87-3.78(s,6H),3.68(s,3H),3.28(s,4H).

example 5

Compound 5:3- (2-chloro-6-fluorophenyl) -10-fluoro-9- (4- (2-fluoropropoyl) piperazin-1-yl) -5- (4-methoxybenzyl) phenanthridin-6 (5H) -one

Placing compound 4c (273mg, 0.5mmol), 2-fluoroacrylic acid (543mg, 0.6mmol), diisopropylethylamine (129mg, 1.0mmol) in DMF (30 mL), adding HATU (266mg, 0.7mmol) at room temperature, stirring for reaction for 3h, detecting by TLC, adding 50mL of water after the reaction, quenchingQuenching reaction, extracting with ethyl acetate (100 mL × 2), mixing organic layers, drying, filtering, concentrating, and separating by column chromatography to obtain off-white solid 155mg with yield of 50.2% and ESI (+) m/z =618.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ8.73(d,J＝8.6,1H),8.28(d,J＝8.7Hz,1H),7.66-7.61(m,4H),7.52-7.42(m,4H),7.39-7.30(m,2H),7.19-7.11(m,2H),6.89-6.80(m,2H),5.56(s,2H),5.36(dd,J＝18.2,4.0Hz,1H),5.27(dd,J＝50.1,4.0Hz,1H),3.83-3.74(m,4H),3.68(s,3H),3.32-3.30(m,4H).

example 6

Compound 6: synthesis of 9- (4-acryloylpiperazin-1-yl) -3- (2-chloro-6-fluorophenyl) -5- (cyclopentylmethyl) -10-fluorophenanthridin-6 (5H) -one.

The first step is as follows:

1i (2.5g, 5.0 mmol) was dissolved in DMF (25 mL), and sodium hydride (400mg, 10.0 mmol) was added at room temperature. Stirring to react for 30 molecules, adding bromomethylcyclopentane (815mg, 5mmol), stirring to react for 10h, detecting by TLC, adding 50mL water to quench the reaction after the reaction is finished, extracting with ethyl acetate (100 mL x 2), combining organic layers, concentrating, and separating by column chromatography to obtain the compound 6a as off-white solid 2.2g with 73.8% yield.

The second step:

compound 6a (1.7g, 3.0mmol), 1m (523mg, 3.0mmol), pd (dppf) Cl2 (219mg, 0.3mmol) and sodium carbonate (636mg, 6.0mmol) were placed in tetrahydrofuran (10 mL) and water (2 mL), the temperature was raised to 80 ℃, the reaction was stirred for 8h, TLC detection was performed, after completion of the reaction, 10mL of water was added to quench the reaction, extraction was performed with ethyl acetate (20 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and isolated by column chromatography to give compound 6b as a white-like solid, 1.3g, with a yield of 69.1%.

The third step:

compound 6b (1022mg, 1.6mmol), potassium hydroxide (269mg, 4.8mmol) were placed in ethanol (30 mL), the temperature was raised to 80 ℃, the reaction was stirred for 10h, the TLC detection reaction was carried out, 50mL of water was added after the reaction was completed to quench the reaction, extraction was carried out with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and column chromatography was carried out to give 611mg of an off-white solid with a yield of 75.3%.

The fourth step:

placing compound 6c (254mg, 0.5mmol), acrylic acid (43mg, 0.6mmol), diisopropylethylamine (129mg, 1.0mmol) in DMF (30 mL), adding HATU (266mg, 0.7mmol) at room temperature, stirring for 6h, detecting by TLC, adding 50mL of water after reaction, quenching, extracting with ethyl acetate (100 mL. Times.2), combining organic layers, drying, filtering, concentrating, and separating by column chromatography to obtain 133mg of off-white solid with the yield of 47.4% and ESI (+) m/z =562.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ8.75(d,J＝8.4Hz,1H),8.20(d,J＝8.5Hz,1H),7.82(d,J＝1.8Hz,1H),7.57-7.42(m,3H),7.38-7.35(m,2H),6.89(dd,J＝16.7,10.5Hz,1H),6.17(dt,J＝16.7,2.6Hz,1H),5.74(dt,J＝10.5,2.6Hz,1H),4.40-4.36(m,2H),3.84-3.72(m,4H),3.25(s,4H),2.46-2.32(m,1H),1.72-1.53(m,4H),1.47(td,J＝10.8,9.0,3.9Hz,2H),1.35(tt,J＝15.2,5.6Hz,2H).

example 7

Compound 7: summation of 9- (4-acryloylpiperazin-1-yl) -3- (2-chloro-6-fluorophenyl) -5- (cyclopropylmethyl) -10-fluorophenanthridin-6 (5H) -one

First step of

1i (2.5g, 5.0 mmol) was dissolved in DMF (25 mL), and sodium hydride (400mg, 10.0 mmol) was added at room temperature. Stirring to react for 30 molecules, adding bromomethylcyclopropane (675mg, 5mmol), stirring to react for 10h, detecting by TLC, adding 50mL water to quench the reaction after the reaction is finished, extracting with ethyl acetate (100 mL. Times.2), combining organic layers, concentrating, and separating by column chromatography to obtain compound 7a as off-white solid 2.0g with yield of 72.7%.

The second step is that:

compound 7a (1.7g, 3.0mmol), 1m (523mg, 3.0mmol), pd (dppf) Cl2 (219mg, 0.3mmol) and sodium carbonate (636mg, 6.0mmol) are placed in tetrahydrofuran (10 mL) and water (2 mL), the temperature is increased to 80 ℃, the reaction is stirred for 8h, the TLC detection reaction is carried out, 10mL of water is added for quenching reaction after the reaction is finished, ethyl acetate (20 mL multiplied by 2) is used for extraction, organic layers are combined, drying, filtering, concentrating and column chromatography separation is carried out to obtain 1.2g of compound 6b which is an off-white solid, and the yield is 64.8%.

The third step:

compound 7b (895mg, 1.9mmol) and potassium hydroxide (313mg, 5.6mmol) were placed in ethanol (30 mL), the temperature was raised to 80 ℃, the reaction was stirred for 10h, TLC detection was performed, 50mL of water was added after the reaction to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and column chromatography gave 508mg of off-white solid in 55.8% yield.

The fourth step:

placing compound 7c (240mg, 0.5 mmol), acrylic acid (43mg, 0.6 mmol), diisopropylethylamine (129mg, 1.0 mmol) in DMF (30 mL), adding HATU (266mg, 0.7 mmol) at room temperature, stirring for 6h, detecting by TLC, adding 50mL of water after reaction to quench reaction, extracting with ethyl acetate (100 mL. Times.2), combining organic layers, drying, filtering, concentrating, and separating by column chromatography to obtain off-white solid 160mg with yield of 60.0%, ESI (+) m/z =534.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ8.75(d,J＝8.9,Hz,1H),8.21(d,J＝8.7,1H),7.68-7.59(m,H),7.59-7.50(m,2H),7.46-7.34(m,3H),6.89(dd,J＝16.7,10.5Hz,1H),6.17(dt,J＝16.7,2.6Hz,1H),5.74(dt,J＝10.5,2.6Hz,1H),4.43-4.31(m,1H),3.80-3.78(m,4H),3.26(s,4H),2.45(q,J＝6.9Hz,1H),1.33-1.22(m,2H),1.18(t,J＝7.1Hz,1H),0.46(tt,J＝7.6,1.8Hz,1H).

example 8

Compound 8: synthesis of 9- (4-acryloylpiperazin-1-yl) -3- (2-chloro-6-fluorophenyl) -10-fluorophenanthridin-6 (5H) -one.

The first step is as follows:

compound 1i (1.5g, 3.0mmol), 1m (523mg, 3.0mmol), pd (dppf) Cl2 (219mg, 0.3mmol) and sodium carbonate (636mg, 6.0mmol) are placed in tetrahydrofuran (10 mL) and water (2 mL), the temperature is increased to 80 ℃, the reaction is stirred for 8h, the TLC detection reaction is carried out, 10mL of water is added for quenching reaction after the reaction is finished, ethyl acetate (20 mL multiplied by 2) is used for extraction, organic layers are combined, drying, filtering, concentrating and column chromatography separation is carried out to obtain 1.4g of compound 6b which is an off-white solid, and the yield is 85.4%.

The second step is that:

compound 8a (1.1g, 2.0mmol), potassium hydroxide (336mg, 6.0mmol) were placed in ethanol (30 mL), the temperature was raised to 80 ℃, the reaction was stirred for 10h, the TLC detection reaction was performed, 50mL of water was added after the reaction was completed to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to give 621mg of an off-white solid with a yield of 73.1%.

The third step:

placing compound 8b (212mg, 0.5mmol), acrylic acid (43mg, 0.6 mmol), diisopropylethylamine (129mg, 1.0mmol) in DMF (30 mL), adding HATU (266mg, 0.7 mmol) at room temperature, stirring for 6h, detecting by TLC, adding 50mL of water after reaction, extracting with ethyl acetate (100 mL. Times.2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain 182mg of off-white solid with the yield of 76.0% and ESI (+) m/z =480.1; ¹ H NMR(500MHz,DMSO-d ₆ )δ11.75(s,1H),8.65-8.60(m,1H),8.17(d,J＝8.7,1H),7.44-7.39(m,3H),7.36(d,J＝1.8Hz,1H),7.27(dd,J＝8.6,1.8Hz,2H),6.89(dd,J＝16.7,10.5Hz,1H),6.17(dt,J＝16.7,2.5Hz,1H),5.74(dt,J＝10.5,2.5Hz,1H),3.86-3.76(m,4H),3.28-3.26(m,4H).

example 9

Compound 9: synthesis of 3- (2-chloro-6-fluorophenyl) -10-fluoro-9- (4- (2-fluoropropy l) piperazin-1-yl) phenanthridin-6 (5H) -one.

Placing compound 8b (212mg, 0.5mmol), 2-fluoroacrylic acid (54mg, 0.6 mmol), diisopropylethylamine (129mg, 1.0 mmol) in DMF (30 mL), adding HATU (266mg, 0.7 mmol) at room temperature, stirring for 6h, detecting by TLC, quenching with 50mL of water, extracting with ethyl acetate (100 mL. Times.2), and combining organic layersDrying, filtering, concentrating, and separating by column chromatography to obtain white solid 168mg with yield of 67.6% and ESI (+) m/z =498.1; ¹ H NMR(500MHz,DMSO-d ₆ )δ11.77(s,1H),8.61(dd,J＝8.4,2.0Hz,1H),8.16(d,J＝8.6Hz,1H),7.62(d,J＝8.5Hz,1H),7.55-7.49(m,2H),7.45-7.38(m,2H),7.36(d,J＝1.8Hz,1H),7.26(dd,J＝8.5,1.8Hz,1H),5.35(dd,J＝18.1,4.0Hz,1H),5.27(dd,J＝50.2,4.0Hz,1H),3.80-3.76(m,4H),3.30-3.28(m,4H).

example 10

Compound 10: synthesis of 1- (4- (3- (8-chloronaphthalen-1-yl) -10-fluoro-6- (3-methoxyazetidin-1-yl) phenanthridin-9-yl) piperazin-1-yl) prop-2-en-1-one.

The first step is as follows:

putting the compound 1i (15.0g, 30mmol) and phosphorus oxychloride (18.6g, 120mmol) in an acetonitrile solution (300 mL), heating to 100 ℃, stirring for 6h for reaction, detecting by TLC, pouring the reaction solution after the reaction is finished into 150mL of a sodium carbonate solution (2N) at 0-5 ℃, extracting by using ethyl acetate (300 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, and carrying out column chromatography separation to obtain the compound 10a as a white-like solid with the yield of 12.9g and 83.4%.

The second step is that:

dissolving compound 10a (4.1g, 8.0mmol), 1k (989 mg, 8.0mmol) and potassium carbonate (2.2g, 169mmol) in dioxane (50 mL), heating to 80 ℃, stirring for 6h, detecting by TLC, adding 50mL of water to quench the reaction after the reaction is finished, extracting with ethyl acetate (100 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, and carrying out column chromatography to obtain 3.9g of off-white solid with the yield of 86.7%. The third step:

compound 1b (1.2g, 2.0mmol), 10c (588mg, 2.0mmol), pd (dppf) Cl2 (146mg, 0.2mmol) and sodium carbonate (423mg, 4.0mmol) were placed in tetrahydrofuran (10 mL) and water (2 mL), the temperature was raised to 80 ℃, the reaction was stirred for 8h, the reaction was detected by TLC, 10mL of water was added after the reaction was completed to quench the reaction, extraction was performed with ethyl acetate (20 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to give 896mg of an off-white solid, a yield of 69.3%.

The fourth step

Placing compound 10d (646mg, 1.0 mmol) and potassium hydroxide (170mg, 3.0 mmol) in ethanol (10 mL), heating to 80 ℃, stirring for reaction for 6h, detecting by TLC, adding 10mL of water after the reaction is finished, quenching the reaction, extracting with ethyl acetate (20 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain a similar-color solid 443mg with the yield of 84.0%.

The fifth step:

placing compound 10e (263mg, 0.5mmol), acrylic acid (43mg, 0.6mmol), diisopropylethylamine (129mg, 1.0mmol) in DMF (30 mL), adding HATU (266mg, 0.7mmol) at room temperature, stirring for 6h, detecting by TLC, adding 50mL of water after reaction, extracting with ethyl acetate (100 mL. Times.2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain off-white solid 166mg, wherein the yield is 57.2%, and ESI (+) m/z =581.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ8.79(d,J＝7.2,1H),8.33(d,J＝8.6,Hz,1H),8.18(d,J＝8.4,1.8Hz,1H),8.12(dd,J＝8.4,1.7Hz,1H),7.98(d,J＝1.8Hz,1H),7.71-7.58(m,6H),6.89(dd,J＝16.6,10.5Hz,1H),6.19(dd,J＝16.7,2.4Hz,1H),5.76(dd,J＝10.5,2.4Hz,1H),4.77-4.58(m,1H),4.43-4.35(m,1H),4.24(p,J＝2.9Hz,1H),3.85-3.75(m,6H),3.46-3.41(m,4H),3.36(s,3H).

example 11

Compound 11: synthesis of 9- (4-acryloylpiperazin-1-yl) -3- (8-chloronaphthalen-1-yl) -10-fluorophenanthridin-6 (5H) -one

First step of

Compound 1b (2.5g, 5.0mmol), 10c (1.5g, 5.0mmol), pd (dppf) Cl2 (366mg, 0.5mmol) and sodium carbonate (1.1g, 10.0mmol) were placed in tetrahydrofuran (25 mL) and water (5 mL), the temperature was raised to 80 ℃, reaction was stirred for 8h, reaction was detected by tlc, reaction was quenched by addition of 20mL of water after completion of the reaction, extracted with ethyl acetate (100 mL × 2), the organic layers were combined, dried, filtered, concentrated, and isolated by column chromatography to give 1.9mg of an off-white solid with a yield of 67.2%.

Second step of

Compound 11a (1.2g, 2.0mmol), sodium hydroxide (336mg, 6.0mmol) were placed in ethanol (30 mL), the temperature was raised to 80 ℃, the reaction was stirred for 10h, the TLC detection reaction was performed, 50mL of water was added after the reaction was completed to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and subjected to column chromatography to give 0.7g of an off-white solid, with a yield of 76.6%.

The third step:

placing compound 11b (229mg, 0.5mmol), acrylic acid (42mg, 0.6mmol) and diisopropylethylamine (129mg, 1.0mmol) in DMF (30 mL), adding HATU (266mg, 0.7mmol) at room temperature, stirring for 6h, detecting by TLC, adding 50mL of water after reaction, extracting with ethyl acetate (100 mL. Times.2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain off-white solid 175mg, wherein the yield is 68.5%, and ESI (+) m/z =512.1; ¹ H NMR(500MHz,DMSO-d ₆ )δ11.63(s,1H),8.52(d,J＝8.2Hz,1H),8.17-8.10(m,2H),7.53-7.49(m,2H),7.44-7.34(m,4H),7.31-7.24(m,2H),6.88(dd,J＝16.7,10.5Hz,1H),6.19(dd,J＝16.7,2.4Hz,1H),5.76(dd,J＝10.5,2.4Hz,1H),3.78-3.74(m,4H),3.29-3.26(m,4H).

example 12

Compound 12: synthesis of 3- (8-chloronaphthalen-1-yl) -10-fluoro-9- (4- (2-fluoropropoyl) piperazin-1-yl) phenanthridin-6 (5H) -one.

Placing compound 11b (229mg, 0.5mmol), 2-fluoroacrylic acid (54mg, 0.6mmol) and diisopropylethylamine (129mg, 1.0mmol) in DMF (30 mL), adding HATU (266mg, 0.7mmol) at room temperature, stirring for 6h, detecting by TLC, adding 50mL of water for quenching reaction after the reaction is finished, extracting with ethyl acetate (100 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain 149mg of quasi-white solid, wherein the yield is 56.3%, ESI (+) m/z =530.1; ¹ HNMR(500MHz,DMSO-d ₆ )δ11.63(s,1H),8.52(d,J＝8.2Hz,1H),8.17-8.10(m,2H),7.53-7.49(m,2H),7.44-7.34(m,4H),7.31-7.24(m,2H),5.35(dd,J＝18.1,4.0Hz,1H),5.26(dd,J＝50.2,4.0Hz,1H),3.78–3.73(m,4H),3.28(t,J＝5.0Hz,4H).

example 13

Compound 13: synthesis of 1- (4- (6- (3- (dimethylamino)) azetidin-1-yl) -10-fluoro-3- (naphthalen-1-yl) phenanthridin-9-yl) piperazin-1-yl) prop-2-en-1-one.

The first step is as follows:

dissolving compound 10a (4.2g, 8.0mmol), 13a (802mg, 8.0mmol) and potassium carbonate (2.2g, 16.0mmol) in dioxane (50 mL), heating to 80 ℃, stirring for reaction for 6h, detecting by TLC, adding 50mL of water to quench the reaction after the reaction is finished, extracting by using ethyl acetate (50 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain 3.8g of off-white solid with the yield of 81.2%. The second step is that:

compound 13b (1.7g, 3.0mmol), 13c (762mg, 3.0mmol), pd (dppf) Cl ₂ (219mg, 0.3mmol) and sodium carbonate (636mg, 6.0mmol) are placed in tetrahydrofuran (20 mL) and water (4 mL), the temperature is increased to 80 ℃, the reaction is stirred for 6h, TLC detection reaction is carried out, 20mL of water is added after the reaction is finished, the reaction is quenched, ethyl acetate (20 mL multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography to obtain 1.4g of off-white solid, and the yield is 73.7%.

The third step:

placing compound 13d (1.3 g,2.0 mmol) and potassium hydroxide (336mg, 6.0 mmol) in ethanol (30 mL), heating to 80 ℃, stirring for reaction for 6h, detecting by TLC, adding 50mL of water after the reaction is finished, quenching the reaction, extracting with ethyl acetate (100 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, and separating by column chromatography to obtain a similar color solid of 0.8g with the yield of 79.2%.

The fourth step:

the reaction mixture 13e (253mg, 0.5mmol), acrylic acid (43mg, 0.6mmol), diisopropylethylamine (129mg, 1.0mmol) was placed in DMF (30 mL) and the chamberAdding HATU (266mg, 0.7mmol) at room temperature, stirring for 6h, detecting by TLC, adding water 50mL after reaction, quenching, extracting with ethyl acetate (100 mL. Times.2), mixing organic layers, drying, filtering, concentrating, separating by column chromatography to obtain off-white solid 133mg, yield 47.6%, ESI (+) m/z =560.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ8.82-8.76(m,1H),8.66(d,J＝8.6Hz,1H),8.13(d,J＝1.8Hz,1H),8.12-7.98(m,2H),7.97-7.89(m,2H),7.73(d,J＝1.8Hz,1H),7.69-7.37(m,4H),4.44(ddd,J＝12.8,8.8,6.8Hz,2H),4.18(ddd,J＝13.4,8.8,5.7Hz,2H),3.63(dq,J＝10.1,4.9Hz,4H),3.31-3.12(m,5H),2.13(s,6H).

example 14

Compound 14: synthesis of 1- (4- (10-fluoro-6- (3-methoxyazetidin-1-yl) -3- (naphthalen-1-yl) phenanthridin-9-yl) piperazin-1-yl) prop-2-en-1-one.

The first step is as follows:

compounds 10b (850g, 1.5mmol), 13c (381mg, 1.5mmol), pd (dppf) Cl ₂ (146mg, 0.2mmol), sodium carbonate (318mg, 3.0mmol) in tetrahydrofuran (10 mL) and water (2 mL), heating to 80 ℃, stirring for reaction for 6h, detecting by TLC, adding 10mL water after the reaction is finished, quenching the reaction, extracting with ethyl acetate (10 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain a white-like solid of 722mg, wherein the yield is 78.6%.

The second step:

compound 14a (500mg, 0.8mmol) and potassium hydroxide (135mg, 2.4mmol) were placed in ethanol (10 mL), the temperature was raised to 80 ℃, the reaction was stirred for 6h, the reaction was detected by TLC, 10mL of water was added after the reaction was completed to quench the reaction, extraction was performed with ethyl acetate (10 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to give 308mg of a color-like solid with a yield of 78.2%.

The third step:

the reaction product 14b (246mg, 0.5mmol), acrylic acid (43mg, 0.6mmol), diisopropylethylamine (129mg, 1.0mmol) was placed in DMF (30 mL) and added at room temperatureHATU (266mg, 0.7mmol), stirring for 6h, detecting by tlc, quenching with 50mL water after reaction, extracting with ethyl acetate (100 mL × 2), combining organic layers, drying, filtering, concentrating, separating by column chromatography to obtain 138mg off-white solid with 50.5% yield and ESI (+) m/z =547.2; ¹ HNMR(500MHz,DMSO-d ₆ )δ8.79(d,J＝8.7Hz,1H),8.06-8.03(m,1H),8.00(d,J＝8.2Hz,1H),7.96-7.94(m,1H),7.93(s,1H),7.74(d,J＝2.0Hz,1H),7.65-7.62(m,1H),7.59-7.47(m,5H),6.88(dd,J＝16.7,10.5Hz,1H),6.19(dd,J＝16.7,2.4Hz,1H),5.76(dd,J＝10.5,2.4Hz,1H),4.62-4.59(m,2H),4.35(td,J＝3.9,2.0Hz,1H),4.26-4.23(m,2H),3.83-3.79(m,4H),3.29-3.27(m,7H).

example 15

Compound 15: synthesis of 1- (4- (10-fluoro-6- ((2-morpholinoethyl) amino) -3- (naphthalen-1-yl) phenanthridin-9-yl) piperazin-1-yl) prop-2-en-1-one.

The first step is as follows:

compound 10a (2.6g, 5.0mmol), 15a (650mg, 5.0mmol), potassium carbonate (1.4g, 10.0mmol) were dissolved in dioxane (100 mL), the temperature was raised to 80 ℃, the reaction was stirred for 8h, the reaction was detected by TLC, after the reaction was completed, 50mL of water was added to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to give 2.1g of an off-white solid with a yield of 66.2%.

The second step is that:

compound 15a (1.8g, 3.0mmol), 13c (762mg, 3.0mmol), pd (dppf) Cl ₂ (219mg, 0.3mmol) and sodium carbonate (636mg, 6.0mmol) are placed in tetrahydrofuran (20 mL) and water (4 mL), the temperature is increased to 80 ℃, the reaction is stirred for 6h, TLC detection reaction is carried out, 20mL of water is added after the reaction is finished, the reaction is quenched, ethyl acetate (20 mL multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography to obtain 1.5g of off-white solid, and the yield is 76.3%.

The third step:

placing compound 15c (1.3 g, 2.0mmol) and potassium hydroxide (336mg, 6.0mmol) in ethanol (30 mL), heating to 80 ℃, stirring for 6h, detecting by TLC, adding 50mL of water after the reaction is finished, quenching the reaction, extracting with ethyl acetate (100 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain a color-like solid of 0.9g, wherein the yield is 84.1%.

The third step:

placing the compound 15d (268mg, 0.5mmol), acrylic acid (43mg, 0.6mmol) and diisopropylethylamine (129mg, 1.0mmol) in DMF (30 mL), adding HATU (266mg, 0.7mmol) at room temperature, stirring for 6h, detecting by TLC, adding 50mL of water after the reaction is finished, quenching with ethyl acetate (100 mL. Times.2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain 172mg of off-white solid, wherein the yield is 58.4%, and ESI (+) m/z =590.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ8.78(d,J＝8.7Hz,1H),8.05-8.03(m,1H),8.01(d,J＝8.2Hz,1H),7.97-7.94(m,1H),7.94(s,1H),7.79(s,1H),7.73(d,J＝2.0Hz,1H),7.65-7.62(m,1H),7.59-7.47(m,5H),6.88(dd,J＝16.7,10.5Hz,1H),6.19(dd,J＝16.7,2.4Hz,1H),5.76(dd,J＝10.5,2.4Hz,1H),3.98-3.64(m,12H),3.27(s,8H).

example 16

Compound 16: synthesis of 1- (4- (6- (3- (dimethylamino)) azetidin-1-yl) -10-fluoro-3- (5-methyl-1H-indazol-4-yl) phenanthridin-9-yl) piperazin-1-yl) prop-2-en-1-one.

First step of

Compound 13b (1.7g, 3.0 mmol), 16a (774mg, 3.0 mmol), pd (dppf) Cl ₂ (219mg, 0.3mmol) and sodium carbonate (636mg, 6.0mmol) are placed in tetrahydrofuran (20 mL) and water (4 mL), the temperature is increased to 80 ℃, the reaction is stirred for 6h, TLC detection reaction is carried out, 20mL of water is added after the reaction is finished, the reaction is quenched, ethyl acetate (20 mL multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography to obtain 1.4g of off-white solid, and the yield is 73.7%.

The second step is that:

placing compound 16b (1.3 g,2.0 mmol) and potassium hydroxide (336mg, 6.0 mmol) in ethanol (30 mL), heating to 80 ℃, stirring for 6h, detecting by TLC, adding 50mL of water after the reaction is finished, quenching the reaction, extracting with ethyl acetate (100 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain a color-like solid of 0.7g, wherein the yield is 68.8%.

The fifth step:

the compound 16c (255mg, 0.5mmol), acrylic acid (43mg, 0.6mmol), diisopropylethylamine (129mg, 1.0mmol) were placed in DMF (30 mL), HATU (266mg, 0.7 mmol) was added at room temperature, the reaction was stirred for 6h, tlc detection was performed, 50mL of water was added to quench the reaction, extraction was performed with ethyl acetate (100 mL × 2), the organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to give off-white solid 134mg with a yield of 47.6%. ESI (+) m/z =564.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ13.08(s,1H),8.89(d,J＝8.5Hz,1H),7.93(d,J＝8.5Hz,1H),7.65(s,2H),7.52-7.38(m,4H),7.33(d,J＝8.5Hz,1H),6.88(dd,J＝16.7,10.5Hz,1H),6.17(dd,J＝16.7,2.4Hz,1H),5.77(dd,J＝10.5,2.4Hz,1H),4.44(ddd,J＝12.8,8.8,6.8Hz,2H),4.18(ddd,J＝13.4,8.8,5.7Hz,2H),3.63(dq,J＝10.1,4.9Hz,4H),3.31-3.12(m,5H),2.35(s,3H),2.13(s,6H).

example 17

Compound 17: synthesis of 1- (4- (10-fluoro-6- (3-methoxyazetidin-1-yl) -3- (5-methyl-1H-indazol-4-yl) phenanthridin-9-yl) piperazin-1-yl) prop-2-en-1-one

The first step is as follows:

compound 1b (1.7g, 3.0mmol), 16a (774mg, 3.0mmol), pd (dppf) Cl ₂ (219mg, 0.3mmol) and sodium carbonate (636mg, 6.0mmol) are placed in tetrahydrofuran (20 mL) and water (4 mL), the temperature is increased to 80 ℃, the reaction is stirred for 6h, TLC detection reaction is carried out, 20mL of water is added after the reaction is finished, the reaction is quenched, ethyl acetate (20 mL multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography to obtain 1.3g of off-white solid, and the yield is 69.7%.

The second step:

placing compound 17b (1.2g, 2.0mmol) and potassium hydroxide (336mg, 6.0mmol) in ethanol (30 mL), heating to 80 ℃, stirring for 6h, detecting by TLC, adding 50mL of water after the reaction is finished, quenching the reaction, extracting with ethyl acetate (100 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain a color-like solid of 0.7g, wherein the yield is 70.6%.

The third step:

compound 17c (248mg, 0.5mmol), acrylic acid (43mg, 0.6mmol), diisopropylethylamine (129mg, 1.0mmol) were placed in DMF (30 mL), HATU (266mg, 0.7mmol) was added at room temperature, reaction was stirred for 6h, detection reaction by TLC was carried out, after completion of the reaction, 50mL of water was added to quench the reaction, extraction was carried out with ethyl acetate (100 mL. Times.2), organic layers were combined, dried, filtered, concentrated, and column chromatography was carried out to give 167mg of off-white solid in a yield of 60.7%. ESI (+) m/z =551.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ13.09(s,1H),8.89(d,J＝8.5Hz,1H),7.92(d,J＝8.5Hz,1H),7.66(s,2H),7.52-7.39(m,4H),7.34(d,J＝8.5Hz,1H),6.89(dd,J＝16.6,10.5Hz,1H),6.18(dd,J＝16.7,2.4Hz,1H),5.76(dd,J＝10.5,2.4Hz,1H),4.64-4.57(m,2H),4.34(tt,J＝6.3,4.0Hz,1H),4.27-4.20(m,2H),3.84-3.80(m,4H),3.31-3.28(m,7H),2.35(s,3H).

example 18

Compound 18: synthesis of N' -acryloyl-3- (8-chloronaphthalene-1-yl) -6- (3-methoxy azetidin-1-yl) phenanthridine-9-carbohydrazide.

The first step is as follows:

compound 18a (19.4 g,100.0 mol), compound 1e (29.7 g,100.0 mol), and cesium carbonate (48.6 g,150.0 mol) were dissolved in acetonitrile (400 mL), the temperature was raised to 80 ℃, the reaction was stirred for 6h, the reaction was detected by TLC, after the reaction was complete, water (500 mL) was added to quench the reaction, which was extracted with ethyl acetate (500 mL. Times.2), the organic layer was dried, concentrated, and column chromatography was performed to give 33.1g of an off-white solid at a yield of 70.0%.

The second step is that:

compound 18b (33.0g, 69.9mmol) is dissolved in DMF (500 mL), sodium hydride (5.6g, 139.8mmol) is added at room temperature and stirred for reaction for 1h, then 4-methoxy benzyl chloride (10.6g, 69.9mmol) is added, stirring for reaction for 8h at room temperature, TLC detection is carried out, after the reaction is finished, the reaction is quenched by adding 500mL of water and extracted by ethyl acetate (500 mL x 2), organic layers are combined, dried, filtered and separated by column chromatography to obtain 32.5g of off-white solid, and the yield is 78.5%.

The third step:

placing compound 18c (29.6g, 50.0 mmol), potassium carbonate (13.8g, 100.0 mmol) and tetrakistriphenylphosphine palladium (5.8g, 5 mol) in toluene (500 mL), heating to reflux, stirring for reaction for 10h, detecting the reaction by TLC, filtering after the reaction is finished, concentrating the filtrate, and performing column chromatography to obtain 17.4g of gray solid, wherein the yield is 72.0%.

The fourth step:

compound 18d (17.0g, 35.2mmol) and p-toluenesulfonic acid (12.1g, 70.4mmol) are placed in toluene (400 mL) and heated to reflux, the stirring reaction is carried out for 4h, the TLC detection reaction is carried out, after the reaction is finished, the obtained product is poured into 500mL of sodium carbonate (2N) solution with the temperature of 0-5 ℃, an organic layer is concentrated, and column chromatography separation is carried out to obtain 9.3g of off-white solid, wherein the yield is 76.6%.

The fifth step:

placing compound 18e (3.5g, 10mmol) and phosphorus oxychloride (4.4g, 40.0mmol) in acetonitrile (100 mL) to be heated to reflux, stirring for reaction for 4h, detecting by TLC, pouring the mixture into 100mL of 2N sodium carbonate solution after the reaction is finished, precipitating a solid, filtering, and drying the solid to obtain 2.9g of an off-white solid, wherein the yield is 79.2%.

And a sixth step:

compound 18f (1.0g, 2.5mmol), 1k (308mg, 2.5mmol), potassium carbonate (691mg, 5.0mmol) were placed in 1, 4-dioxane (10 mL), the temperature was raised to 100 ℃, the reaction was stirred for 4h, the reaction was detected by TLC, after the reaction was completed, 10mL of water was added to quench the reaction, extraction was performed with ethyl acetate (10 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and isolated by column chromatography to give 812mg of an off-white solid in a yield of 78.5%.

The seventh step:

18g (800mg, 1.9mmol), 10c (548mg, 1.9mmol), pd (dppf) Cl ₂ (146mg，0.2mmol) Placing sodium carbonate (424mg, 4mmol) in tetrahydrofuran (10 mL) and water (2 mL), heating to 80 ℃, stirring for reaction for 5h, detecting by TLC, adding water 10mL after the reaction is finished, quenching the reaction, extracting by ethyl acetate (10 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, separating by column chromatography to obtain 686mg of white-like solid with the yield of 72.6 percent

Eighth step:

dissolving compound 18h (600mg, 1.2mmol) and sodium hydroxide (144mg, 3.6 mmol) in methanol (15 mL), heating to 40 ℃, stirring for reaction for 5h, detecting by TLC, adding 20mL (2N) of diluted hydrochloric acid after the reaction is finished, quenching the reaction, extracting with ethyl acetate (20 mL. Times.2), combining organic layers, drying, filtering, concentrating, and separating by column chromatography to obtain an off-white solid 376mg, wherein the yield is 66.8%.

The ninth step:

placing compound 18i (234mg, 0.5mmol), 18j (52mg, 0.6mmol) and diisopropylethylamine (129mg, 1.0mmol) in DMF (10 mL), adding HATU (266mg, 0.7mmol) at room temperature, stirring for 6h, detecting by TLC, adding 20mL of water after reaction, extracting with ethyl acetate (50 mL. Times.2), combining organic layers, drying, filtering, concentrating, and performing column chromatography to obtain an off-white solid of 155mg with a yield of 55.8%. ESI (+) m/z =537.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ10.95(s,1H),10.41(s,1H),9.28(d,J＝1.7Hz,1H),8.59(d,J＝8.4Hz,1H),8.25(d,J＝8.6Hz,1H),8.16-8.05(m,3H),7.70-7.60(m,3H),7.59-7.51(m,2H),7.38(dd,J＝8.3,1.9Hz,1H),6.42(dd,J＝17.2,10.3Hz,1H),6.28(dd,J＝17.2,2.1Hz,1H),5.80(dd,J＝10.3,2.1Hz,1H),4.72-4.65(m,2H),4.42-4.35(m,1H),4.34-4.27(m,2H),3.30(s,3H).

example 19

Compound 19: synthesis of N' -acryloyl-3- (8-chloronaphthalene-1-yl) -6- (3- (dimethylamino) azetidin-1-yl) phenanthridine-9-carbohydrazide.

The first step is as follows:

compound 18f (1.8g, 5.0mmol), 13a (680mg, 5.0mmol), potassium carbonate (1.4g, 10.0mmol) were placed in 1, 4-dioxane (50 mL), the temperature was raised to 100 ℃, the reaction was stirred for 4 hours, the reaction was detected by TLC, after the reaction was completed, 50mL of water was added to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to give 1.5g of an off-white solid in a yield of 70.7%.

The second step:

compound 19a (1.3g, 3mmol), 10c (866mg, 3mmol), pd (dppf) Cl ₂ (219mg, 0.3mmol) and sodium carbonate (636mg, 6mmol) are placed in tetrahydrofuran (100 mL) and water (20 mL), the temperature is raised to 80 ℃, the stirring reaction is carried out for 5h, the TLC detection reaction is carried out, after the reaction is finished, 100mL of water is added for quenching reaction, ethyl acetate (100 mL multiplied by 2) is used for extraction, organic layers are combined, dried, filtered, concentrated and separated by column chromatography to obtain 1.2g of off-white solid, and the yield is 78.4 percent

The third step:

dissolving compound 19b (1.1.1 g,2.0 mmol) and sodium hydroxide (240mg, 6.0 mmol) in methanol (50 mL), heating to 40 ℃, stirring for reaction for 5h, detecting by TLC, adding diluted hydrochloric acid 50mL (2N) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (100 mL. Times.2), combining organic layers, drying, filtering, concentrating, and separating by column chromatography to obtain 596mg of off-white solid with the yield of 61.8%.

The third step:

compound 19c (240mg, 0.5 mmol), 18j (52mg, 0.6 mmol), diisopropylethylamine (129mg, 1.0 mmol) were placed in DMF (10 mL), HATU (266mg, 0.7 mmol) was added at room temperature, the reaction was stirred for 6h, tlc detection was performed, 20mL of water was added after the reaction was completed to quench the reaction, extraction was performed with ethyl acetate (50 mL × 2), the organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to obtain 190mg of off-white solid in a yield of 69.1%. ESI (+) m/z =550.2; ¹ H NMR(500MHz,DMSO-d ₆ )δ10.97(s,1H),10.43(s,1H),9.27(d,J＝1.7Hz,1H),8.58(d,J＝8.4Hz,1H),8.26(d,J＝8.6Hz,1H),8.16-8.06(m,3H),7.72-7.60(m,3H),7.59-7.52(m,2H),7.38(dd,J＝8.3,1.9Hz,1H),6.42(dd,J＝17.2,10.3Hz,1H),6.28(dd,J＝17.2,2.1Hz,1H),5.80(dd,J＝10.3,2.1Hz,1H),4.45-4,47(m,2H),4.18-4.15(m,2H),3.29-3.27(m,1H),2.13(s,6H).

example 20

Compound 20: synthesis of N' -acryloyl-3- (2-chloro-6-fluorophenyl) -6-oxo-5, 6-dihydrophenanthridine-9-carbohydrazide.

The first step is as follows:

compound 18e (3.5g, 10.0mmol), 1m (1.7g, 10.0mmol), pd (dppf) Cl ₂ (366mg, 0.5mmol), sodium carbonate (2.8g, 20.0mmol) in tetrahydrofuran (50 mL) and water (10 mL), heating to 80 ℃, stirring for reaction for 5h, detecting by TLC, adding 50mL of water to quench the reaction after the reaction is finished, extracting with ethyl acetate (100 mL multiplied by 2), combining organic layers, drying, filtering, concentrating, and carrying out column chromatography to obtain 2.7g of off-white solid with the yield of 68.4%.

The second step is that:

dissolving compound 20a (2.7g, 6.8mmol) and sodium hydroxide (820mg, 20.5mmol) in methanol (50 mL), heating to 40 ℃, stirring for reaction for 5h, detecting by TLC, adding diluted hydrochloric acid 50mL (2N) to quench the reaction, extracting with ethyl acetate (100 mL. Times.2), combining organic layers, drying, filtering, concentrating, and separating by column chromatography to obtain 1.9g of off-white solid with the yield of 76.1%.

The third step:

compound 20b (183mg, 0.5mmol), 18j (52mg, 0.6mmol), diisopropylethylamine (129mg, 1.0mmol) was placed in DMF (10 mL), HATU (266mg, 0.7mmol) was added at room temperature, reaction was stirred for 6h, tlc detection reaction was performed, reaction was quenched with 20mL of water, extraction was performed with ethyl acetate (50 mL × 2), organic layers were combined, dried, filtered, concentrated, and column chromatography was performed to obtain 121mg of off-white solid in 55.6% yield. ESI (+) m/z =436.1; ¹ H NMR(500MHz,DMSO-d ₆ )δ11.78(s,1H),10.96(s,1H),10.43(s,1H),8.65-8.60(m,1H),8.17(d,J＝8.7,1H),7.44-7.39(m,3H),7.36(d,J＝1.8Hz,1H),7.27(dd,J＝8.6,1.8Hz,2H),7.36(d,J＝1.8Hz,1H),6.43(dd,J＝17.2,10.3Hz,1H),6.29(dd,J＝17.2,2.1Hz,1H),5.80(dd,J＝10.3,2.1Hz,1H).

example 21

Determination of cell proliferation

Preparing a compound into a solution by DMSO, and diluting the solution by 3 times to 9 solubility gradients for later use;

the lung cancer cell line NCI-H358 containing KRAS G12C mutation was cultured in RPMI 1640 medium containing 10% fetal bovine serum, penicillin/streptomycin. Inoculating 150. Mu.L of medium containing 2000 cells per well into 96-well plates, and 5% CO at 37% ₂ The incubator was left overnight and then 0.75. Mu.L of the diluted compound was added. Cells were treated in incubator for 5 days, referenced to Cell Titer Glo (CTG) kit method, 120 μ L of CTG reagent was added to each well and incubated at room temperature for 10 minutes, and finally optical signals were collected on Envision 2104 plate reader to calculate IC of compound on NCI-H358 cell proliferation ₅₀ As in table 1 below.

TABLE 1 IC of Compounds prepared in examples 1 to 10 ₅₀

As shown in Table 1, the 3-substituted phenanthridine compound prepared by the invention has excellent anti-KRASG 12C mutant cancer cell proliferation activity, wherein the representative compound 19 has cell proliferation inhibition activity IC50 of 22nM, and has extremely strong physiological activity.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims

1. A3-substituted phenanthridine compound is characterized by having a structure shown in a formula I or a formula II:

R ₃ independently is

when said R is ₃ Is composed of

R when other substituent group is mentioned ₂ Is absent;

R ₄ independently H or F.

2. The 3-substituted phenanthridine compound of claim 1, wherein the 3-substituted phenanthridine compound is:

3. a method for producing a 3-substituted phenanthridine compound according to claim 1 or 2, characterized by comprising the steps of:

when the 3-substituted phenanthridine compound is shown as a formula I and has no R ₂ The method comprises the following steps:

mixing the compound VIII, PMBCl, a fourth base and a fourth solvent, and carrying out a second substitution reaction to obtain a compound IX;

mixing the compound IX, a first catalyst, a fifth alkali and a fifth solvent, and carrying out a ring closure reaction to obtain a compound X;

mixing the compound X, acid and a sixth solvent, and carrying out deprotection to obtain a compound XI;

mixing the compound XVI, a third catalyst and a tenth solvent, and performing a second hydrolysis reaction to obtain a compound XVII; the third catalyst is an acid or a base;

mixing the compound XIV ', the compound XV, a second catalyst, a seventh base and a ninth solvent for a coupling reaction to obtain a compound XVI';

mixing the compound XVI ', a third catalyst and a tenth solvent, and carrying out a second hydrolysis reaction to obtain a compound XVII'; the third catalyst is an acid or a base;

XV is

4. The method according to claim 3, wherein the molar ratio of compound IV to compound III is (0.8-1.5): 1; the molar ratio of the first base to the compound III is (1.0-3.0): 1; the temperature of the first substitution reaction is 20-120 ℃, and the time is 2-24 h;

the molar ratio of the second alkali to the compound V is (1.0-5.0): 1; the temperature of the first hydrolysis reaction is 20-100 ℃, and the time is 2-24 h;

the molar ratio of the compound VII to the compound VI is (0.8-2.0): 1; the molar ratio of the third base to the compound VI is (1.0-2.0): 1; the molar ratio of the first condensing agent to the compound VI is (1.0-2.0): 1; the temperature of the first condensation reaction is 20-100 ℃, and the time is 2-24 h;

the molar ratio of the PMBCl to the compound VIII is (0.8-2.0): 1; the molar ratio of the fourth base to the compound VIII is (1.0-4.0) to 1; the temperature of the second substitution reaction is 0-100 ℃, and the time is 0.5-24 h;

the molar ratio of the fifth base to the compound IX is (1.0-5.0) to 1; the molar ratio of the first catalyst to the compound IX is (0.05-0.5): 1; the temperature of the ring closing reaction is 60-120 ℃, and the time is 4-24 h.

5. The method according to claim 3, wherein when the 3-substituted phenanthridine compound is of formula I and R is absent ₂ When the method is used: the molar ratio of the acid to the compound X is (1.0-5.0): 1; the deprotection temperature is 40-120 ℃, and the time is 2-12 h;

the molar ratio of the phosphorus oxychloride to the compound XI is (1.0-10) to 1; the temperature of the chlorination reaction is 40-120 ℃, and the time is 2-12 h;

the R is ₃ The molar ratio of H to the compound XII is (0.8-2.0): 1; the molar ratio of the sixth alkali to the compound XII is (1.0-4.0): 1; the temperature of the third substitution reaction is 20-120 ℃, and the time is 2-12 h;

the molar ratio of the compound XV to the compound XIV is (0.8-2.0): 1; the molar ratio of the second catalyst to the compound XIV is (0.05-0.5): 1; the molar ratio of the seventh base to the compound XIV is (1.0-3.0): 1; the temperature of the coupling reaction is 60-120 ℃, and the time is 4-24 h;

the molar ratio of the third catalyst to the compound XVI is (1.0-5.0): 1; the temperature of the second hydrolysis reaction is 20-100 ℃, and the time is 4-12 h;

the molar ratio of the compound XVIII to the compound XVII is (0.8-2.0): 1; the molar ratio of the second condensing agent to the compound XVII is (1.0-3.0): 1; the molar ratio of the eighth base to the compound XVII is (1-3.0): 1; the temperature of the second condensation reaction is 20-100 ℃, and the time is 4-12 h;

when the 3-substituted phenanthridine compound is shown as a formula I and R ₂ When 4-methoxyphenethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or hydrogen ₂ The molar ratio of X to the compound XI is (0.8-2.0): 1; the molar ratio of the fourth base to the compound XI is (1.0-4.0) to 1; the temperature of the substitution reaction is 0-100 ℃, and the time is 0.5-24 h;

the molar ratio of the compound XV to the compound XIV' is (0.8-2.0): 1; the molar ratio of the second catalyst to the compound XIV' is (0.05-0.5) to 1; the molar ratio of the seventh base to the compound XIV' is (1.0-3.0): 1; the temperature of the coupling reaction is 60-120 ℃, and the time is 4-24 h;

the molar ratio of the third catalyst to the compound XVI' is (1.0-5.0): 1; the temperature of the second hydrolysis reaction is 20-100 ℃, and the time is 4-12 h;

the molar ratio of the compound XVIII 'to the compound XVII' is (0.8-2.0): 1; the molar ratio of the second condensing agent to the compound XVII' is (1.0-3.0): 1; the molar ratio of the eighth base to the compound XVII' is (1-3.0): 1; the temperature of the second condensation reaction is 20-100 ℃, and the time is 4-12 h.

6. A method for producing a 3-substituted phenanthridine compound according to claim 1 or 2, characterized by comprising the steps of:

when the 3-substituted phenanthridine compound is shown as a formula II and has no R ₂ When the temperature of the water is higher than the set temperature,

mixing the compound IX-1, R ₃ H. Mixing the sixth alkali and the eighth solvent to carry out a third substitution reaction to obtain a compound X-1;

mixing the compound XII-1, the compound XIII-1, an eighth base, a second condensing agent and an eleventh solvent, and carrying out a second condensation reaction to obtain a 3-substituted phenanthridine compound shown in a formula II;

when the 3-substituted phenanthridine compound is shown as a formula II and R ₂ When 4-methoxyphenethyl, cyclopropanemethyl, cyclobutanemethyl or cyclopentanemethyl or hydrogen,

mixing the compound X '-1, the compound XV, a second catalyst, a seventh base and a ninth solvent, and carrying out a coupling reaction to obtain a compound XI' -1;

mixing the compound XII' -1, the compound XIII-1, an eighth base, a second condensing agent and an eleventh solvent, and carrying out a second condensation reaction to obtain a 3-substituted phenanthridine compound shown in a formula II;

7. use of a 3-substituted phenanthridine compound according to claim 1 or 2 or a 3-substituted phenanthridine compound prepared by a preparation method according to any one of claims 3 to 6 in the preparation of a KRAS-G12C inhibitor.

8. A pharmaceutical composition for inhibiting tumor, comprising the 3-substituted phenanthridine compound of claim 1 or 2, or a stereoisomer, non-toxic pharmaceutically acceptable salt, hydrate, solvate or isotopic compound of the 3-substituted phenanthridine compound,

9. the pharmaceutical composition of claim 8, further comprising a pharmaceutically acceptable carrier and/or diluent.

10. The pharmaceutical composition for suppressing tumor according to claim 8 or 9, wherein the tumor comprises skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, stomach cancer, kidney cancer, renal parenchymal cancer, cervical cancer, uterine body cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytic cancer, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphatic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic granulocytic leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, myosarcoma, or fibrosarcoma.