CN114249680B - Indole derivatives, and synthesis method and application thereof - Google Patents
Indole derivatives, and synthesis method and application thereof Download PDFInfo
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Abstract
An indole derivative and a synthesis method and application thereof, wherein the compound contains a structure shown as a formula (I). The compound can effectively inhibit cancer cell proliferation, especially has significant inhibition effect on the proliferation of non-small cell lung cancer cells, and can be used for preparing medicines for treating and/or preventing cancers.
Description
Technical Field
The invention relates to the field of chemistry, in particular to indole derivatives, a synthesis method and application thereof.
Background
Lung cancer is one of the most common malignant tumors in the world, and the incidence rate of lung cancer is increasing with the increase of the population in the world and the aging of the population, so that the lung cancer becomes the tumor with the highest fatality rate. Non-small cell lung cancer (NSCLC) is a common malignant tumor of the lung, accounting for about 80-85% of the total lung cancer. It is a heterogeneous tumor that can be further classified as squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Most patients have been diagnosed at an advanced stage. The NSCLC patients with advanced local stage and good physical condition can achieve disease-free survival period of 8 months after a series of chemotherapy, radiotherapy and/or surgical treatment, and the 5-year survival rate is less than 15 percent.
It is therefore essential to find new effective therapeutic agents. There are some drugs currently on the market for the treatment of non-small cell lung cancer, such as the first generation epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) including gefitinib and erlotinib, the second generation EGFR-TKIs including afatinib and dacatinib, and the third generation EGFR-TKIs mainly being ocitinib. However, it is difficult to avoid acquired resistance in almost all patients who use these three classes of drugs. Acquired drug resistance refers to that the drug resistance of a patient to a drug is gradually increased, the therapeutic effect of the drug is reduced, and the tumor is developed. In order to avoid the unavailability of drugs after the patient develops acquired resistance, it is therefore necessary to develop new antitumor drugs continuously.
Disclosure of Invention
According to a first aspect, in one embodiment, there is provided a compound comprising an indole-containing core of the formula (I):
in the formula (I), R 1 Selected from substituted aryl, optionally substituted heterocyclic aryl, R 2 Selected from hydrogen, optionally substituted aryl, optionally substituted heterocycloaryl, R 3 Selected from hydrogen or amine substituents.
According to a second aspect, in one embodiment, there is provided a method of synthesis of a compound of the first aspect, synthesized according to the following reaction scheme:
x is halogen.
According to a third aspect, in one embodiment, there is provided a pharmaceutical composition comprising a compound of the first aspect together with a pharmaceutically acceptable carrier, diluent or excipient.
According to a fourth aspect, in an embodiment, there is provided the use of a compound of the first aspect, or a pharmaceutical composition of the third aspect, in the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
According to the indole derivative, the synthesis method and the application of the indole derivative, the compound can effectively inhibit cancer cell proliferation, particularly has a remarkable inhibition effect on inhibiting proliferation of non-small cell lung cancer cells, and can be used for preparing a medicament for treating and/or preventing cancer.
Detailed Description
The present invention will be described in further detail with reference to the following embodiments. Wherein like elements in different embodiments have been given like element numbers associated therewith. In the following description, numerous details are set forth in order to provide a better understanding of the present application. However, those skilled in the art will readily recognize that some of the features may be omitted or replaced with other elements, materials, methods in different instances. In some instances, certain operations related to the present application have not been shown or described in detail in order to avoid obscuring the core of the present application from excessive description, and it is not necessary for those skilled in the art to describe these operations in detail, so that they may be fully understood from the description in the specification and the general knowledge in the art.
Furthermore, the described features, operations, or characteristics may be combined in any suitable manner to form various embodiments. Also, the various steps or actions in the method descriptions may be transposed or transposed in order, as will be apparent to one of ordinary skill in the art. Thus, the various sequences in the specification are for the purpose of clearly describing one embodiment only and are not meant to be necessarily order unless otherwise indicated where a certain order must be followed.
The numbering of the components as such, e.g., "first", "second", etc., is used herein only to distinguish the objects as described, and does not have any sequential or technical meaning. The term "connected" and "coupled" when used in this application, unless otherwise indicated, includes both direct and indirect connections (couplings).
Indole derivatives are widely present in nature, are core structural units of a plurality of natural products and important drug active molecules, and the drug molecules containing indole structures can often show a plurality of important physiological and drug activities, and are widely used for disease treatment, such as treatment of nervous system diseases, alzheimer's disease, anti-tumor, sedation, antivirus and the like. Therefore, the preparation of the novel small molecular compound containing the indole structure has important theoretical significance and practical application value for treating the non-small cell lung cancer.
As used herein, "Et" refers to ethyl.
As used herein, "Me" refers to methyl.
As used herein, "MeOH" refers to methanol.
As used herein, "Ac" refers to acetyl.
As used herein, "OAc" refers to acetate.
As used herein, "Boc" refers to t-butyloxycarbonyl.
Based on the defects of the prior art, in one embodiment, the invention provides a compound containing an indole structure, which has high antitumor cell activity. In addition, the invention also provides a preparation method of the indole derivative.
According to a first aspect, in one embodiment, there is provided a compound comprising an indole-containing core of the formula (I):
in the formula (I), R 1 Selected from substituted aryl, optionally substituted heterocyclic aryl, R 2 Selected from hydrogen, optionally substituted aryl, optionally substituted heterocycloaryl, R 3 Selected from hydrogen or amine substituents. The compound shown in the formula (I) is an indole derivative, and the compound has a cancer inhibition effect.
In one embodiment, R 1 At least one selected from the group consisting of:
in one embodiment, R 2 At least one selected from the group consisting of:
in one embodiment, R 3 When selected from amine substituents, the amine substituents include, but are not limited to, at least one of the following structures:
in one embodiment, the structure of formula (I) includes, but is not limited to, at least one of the following structural formulas:
according to a second aspect, in one embodiment, there is provided a method of synthesis of a compound of the first aspect, synthesized according to the following reaction scheme:
x is halogen.
In one embodiment, when compound (a-2) is synthesized, the base includes, but is not limited to, at least one of potassium carbonate and sodium carbonate.
In one embodiment, when compound (a-4) is synthesized, the Pd-containing catalyst includes, but is not limited to Pd (PPh) 3 ) 2 Cl 2 。
In one embodiment, when compound (a-4) is synthesized, the Cu-containing catalyst includes, but is not limited to, at least one of CuI, cuBr.
In one embodiment, when compound (a-4) is synthesized, the base includes, but is not limited to, et 2 N (diethylamine), et 3 At least one of N (triethylamine).
In one embodiment, when compound (a-6) is synthesized, the Pd-containing catalyst includes, but is not limited to Pd (OAc) 2 、Pd 2 (dba) 3 At least one of (a).
In one embodiment, when compound (a-6) is synthesized, the ligand includes, but is not limited to, at least one of 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (x-phos, CAS registry number 564483-18-7), 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (xanthphos, CAS registry number 161265-03-8).
In one embodiment, when compound (a-6) is synthesized, the base includes, but is not limited to, at least one of potassium carbonate, cesium carbonate.
In one embodiment, compound (a-8) is synthesizedIncluding but not limited to Pd (OAc) 2 、Pd 2 (dba) 3 At least one of (1).
In one embodiment, when compound (a-8) is synthesized, the base includes, but is not limited to, at least one of potassium carbonate and sodium carbonate.
In one embodiment, when compound (a-8) is synthesized, the ligand includes, but is not limited to, at least one of 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (x-phos, CAS registry number 564483-18-7), 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (xanthphos, CAS registry number 161265-03-8).
In one embodiment, when compound (a-9) is synthesized, the acid includes, but is not limited to, at least one of trifluoroacetic acid, hydrochloric acid.
In one embodiment, the compound of the first aspect is synthesized by the following method: reacting the compound (a-1) with (1-diazo-2-oxo-propanol) -dimethyl phosphonate in an appropriate solvent (such as methanol, ethanol and the like) under the condition of alkalinity (such as potassium carbonate, sodium carbonate and the like) to obtain a compound (a-2); the compound (a-2) is reacted in the presence of a Pd-containing catalyst (e.g., pd (PPh) 3 ) 2 Cl 2 Etc.) and a Cu-containing catalyst (e.g., cuI, cuBr, etc.) and a suitable base (e.g., et 2 N、Et 3 N, etc.) and a suitable solvent (such as DMF, DMA, etc.) to obtain a compound (a-4); compound (a-4) in the presence of a Pd-containing catalyst (e.g., pd (OAc) 2 、Pd 2 (dba) 3 Etc.) and a suitable ligand (e.g., x-phos, xantphos, etc.), a suitable base (e.g., potassium carbonate, cesium carbonate, etc.), a suitable solvent (e.g., DMF, dioxane, etc.), to obtain a compound (a-6); compound (a-6) in the presence of a Pd-containing catalyst (e.g., pd (OAc) 2 、Pd 2 (dba) 3 Etc.), a ligand (e.g., x-phos, xanthphos, etc.), a suitable base (e.g., potassium carbonate, sodium carbonate, etc.), a suitable solvent (e.g., DMF, etc.), and an amine compound (a-7) protected by tert-butyloxycarbonyl (Boc), to obtain a compound (a-8), and removing the Boc protecting group from the compound (a-8) under a suitable acid (e.g., trifluoroacetic acid, hydrochloric acid, etc.) to obtain a final product (a-9), which is the compound of formula I.
According to a third aspect, in one embodiment, there is provided a pharmaceutical composition comprising a compound of the first aspect together with a pharmaceutically acceptable carrier, diluent or excipient.
In one embodiment, the compounds of formula I of the present invention may be formed into pharmaceutically acceptable acid addition salts with acids according to conventional methods in the art. The acid includes inorganic acids and organic acids, and particularly preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, in one embodiment, the present invention also includes prodrugs of the compounds of formula I of the present invention. Prodrugs described herein are derivatives of the compounds of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
In one embodiment, the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents, such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water soluble taste masking substances such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose, or time extending substances such as ethyl cellulose, cellulose acetate butyrate may be used.
In one embodiment, oral formulations may also be provided by hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules wherein the active ingredient is mixed with a water soluble carrier, for example polyethylene glycol, or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.
In one embodiment, the aqueous suspension contains the active substance and suitable excipients for the preparation of an aqueous suspension for mixing. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol (heptadecaethyleneoxy cetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyethylene oxide sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl paraben, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.
In one embodiment, an oil suspension may be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
In one embodiment, dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
In one embodiment, the pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soya bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening agents, flavouring agents, preservatives and antioxidants. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
In one embodiment, the pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding to a mixture of water and glycerol. The injection solution or microemulsion may be injected into the bloodstream of a patient by local bulk injection. Alternatively, it may be desirable to administer the solutions and microemulsions in such a way as to maintain a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.
In one embodiment, the pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular and subcutaneous administration. The suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
In one embodiment, the compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
In one embodiment, the dosage of the drug administered depends on a variety of factors, including but not limited to the following, as is well known to those skilled in the art: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the patient's integuments, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
In one embodiment, the compound of formula I, and pharmaceutically acceptable salts, hydrates, or solvates thereof can be used as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like. The compounds of the present invention may be used as the sole active ingredient, or in combination with other agents for the treatment of lung cancer (including, but not limited to, non-small cell lung cancer) or diseases associated with lung cancer. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately or sequentially.
In one embodiment, the compound of formula I of the present invention is found to have significant activity of inhibiting proliferation of non-small cell lung cancer cells through a non-small cell lung cancer cell inhibition test, so that the compound of the present invention can be used for treating and/or preventing lung cancer or a lung cancer-related disease, such as non-small cell lung cancer. In particular to the preparation of the medicine for treating and/or preventing the non-small cell lung cancer.
According to a fourth aspect, in an embodiment, there is provided the use of a compound of the first aspect, or a pharmaceutical composition of the third aspect, in the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
In one embodiment, the cancer includes, but is not limited to, lung cancer.
In one embodiment, the lung cancer includes, but is not limited to, non-small cell lung cancer.
In one embodiment, the non-small cell lung cancer includes, but is not limited to, at least one of squamous cell carcinoma, adenocarcinoma, large cell carcinoma.
Example 1:4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile
Step 1: synthesis of 4-ethynyl-2-fluoro-1-methoxybenzene
To a reaction flask was added 3-fluoro-4-methoxybenzaldehyde (1.0 eq), meOH, (1-diazo-2-oxo-propanol) -phosphonic acid dimethyl ester (2.2 eq), K 2 CO 3 (2.2 eq), after addition, the reaction was stirred at room temperature overnight. After the reaction was completed, the solvent was dried by spinning off, and purified by column chromatography (PE: EA =10, PE means petroleum ether, EA means ethyl acetate, and the same applies hereinafter) to obtain the title compound as a pale yellow oily liquid.
And 2, step: synthesis of 4-bromo-2- ((4-methoxy-3-methylphenyl) ethynyl) aniline
To a reaction flask were added 4-ethynyl-2-fluoro-1-methoxybenzene (1.2 eq), 4-bromo-2-iodoaniline (1.0 eq), DMA (dimethylacetamide, CAS registry No.: 127-19-5), pd (PPh) 3 ) 2 Cl 2 (0.2eq)、CuI(0.2eq)、Et 2 N (1.5eq, et means ethyl), nitrogen blanket, stirred the reaction at room temperature, TLC monitoring the progress of the reaction. After completion of the reaction, 100mL of ethyl acetate was added to the reaction flask to dilute, and then washed with water (100ml × 5 times, i.e., 5 times, each time with 100mL of water), and finally washed with saturated brine (100ml × 1), dried over anhydrous sodium sulfate, filtered, and then the solvent was spin-dried, and purified by column chromatography (PE: EA = 3:1) to obtain the title compound as a brown oil.
And step 3: synthesis of 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile
To a reaction flask was added 4-bromo-2- ((4-methoxy-3-methylphenyl) ethynyl) aniline (1.0 eq), 4-iodobenzonitrile (1.5 eq), pd (OAc) 2 (0.1 eq), xantphos (0.2eq, 4, 5-bis (diphenylphosphino) -9,9-dimethylxanthene, CAS registry No.: 161265-03-8), cs 2 CO 3 (2.0 eq), dioxane (1,4-dioxane), nitrogen protection, heating to 110 ℃, stirring for reaction, and monitoring the reaction progress by TLC. After the reaction was complete, DCM (CH) was added to the reaction flask 2 Cl 2 ) After stirring well, the insoluble matter was removed by filtration through celite, the filtrate was spin-dried, and the residue was purified by column chromatography (PE: EA: DCM =3:1: 1) The title compound was obtained as a yellow solid product.
1H NMR(400MHz,Chloroform-d)δ7.80(d,J＝1.9Hz,1H),7.75(d,J＝1.9Hz,1H),7.73(q,J＝1.7Hz,1H),7.35(d,J＝2.0Hz,1H),7.33(d,J＝1.9Hz,1H),7.30(dd,J＝8.7,1.9Hz,1H),7.15(dt,J＝8.8,0.7Hz,1H),6.97(ddd,J＝12.0,1.8,0.7Hz,1H),6.89–6.86(m,2H),6.71(d,J＝0.8Hz,1H),3.90(s,3H).
And 4, step 4: synthesis of tert-butyl 4- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperazine-1-carboxylate
To a reaction flask was added 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile (1.0 eq), N-Boc piperazine (1.0 eq), pd 2 (dba) 3 (0.11 eq), cesium carbonate, X-phos (0.22 eq), dioxane, protected by nitrogen, heated to 110 ℃ for reaction, and monitored by TLC for reaction progress. After completion of the reaction, the reaction solution was filtered through a filter, the filtrate was spin-dried, and the residue was purified by column chromatography (PE: EA =3:2 by volume) to give the title compound as a yellow solid. MS-ES (ESI, pos.ion) m/z 471.23[ 2 ], M + H]+。
And 5: synthesis of 4- (2- (3-fluoro-4-methoxyphenyl) -5- (piperazin-1-yl) -1H-indol-1-yl) benzonitrile
Tert-butyl 4- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperazine-1-carboxylate was added to the reaction flask, dissolved with DCM (3V), followed by addition of TFA (1v, TFA means trifluoroacetic acid) dropwise, after which the reaction was stirred at room temperature and the progress of the reaction was monitored by TLC. After the reaction was complete, the reaction was spun off, the residue was adjusted to pH =9 with methanol of ammonia, the solvent was spun off again, and the residue was purified by column chromatography (DCM: meOH = 10).
Example 2:4- (2- (3-fluoro-4-methoxyphenyl) -5- (4- (methylamino) piperidin-1-yl) -1H-indol-1-yl) benzonitrile (i.e., compound I-2)
Step 1: synthesis of tert-butyl (1- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperidin-4-yl) (methyl) carbamate
To a reaction flask was added 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile (1.0 eq), tert-butylmethyl (piperidin-4-yl) carbamate (1.0 eq), pd 2 (dba) 3 (0.11 eq), cesium carbonate (2.0 eq), X-phos (0.22 eq), dioxane, protected with nitrogen, heated to 110 ℃ for reaction, and monitored by TLC for the progress of the reaction. After completion of the reaction, the reaction solution was filtered through a filter, the filtrate was spin-dried, and the residue was purified by column chromatography (PE: EA = 3:2) to give the title compound as a yellow solid. MS-ES (ESI, pos.ion) m/z of 499.30[ m + H ]]+。
Step 2:4- (2- (3-fluoro-4-methoxyphenyl) -5- (4- (methylamino) piperidin-1-yl) -1H-indol-1-yl) benzonitrile
To a reaction flask was added tert-butyl (1- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperidin-4-yl) (methyl) carbamate (1.0 eq), dissolved with DCM (3V), followed by dropwise addition of TFA (1V), after which the reaction was stirred at room temperature and monitored by TLC for progress. After completion of the reaction, the reaction solution was dried by spinning, the residue was adjusted to pH =9 with a methanol solution of ammonia, the solvent was dried again by spinning, and the residue was purified by column chromatography (DCM: meOH = 10) to obtain the title compound as a light yellow solid.
Example 3:4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) -2-hydroxybenzonitrile
Step 1: synthesis of 5-bromo-2-cyanophenyl tert-butyl carbonate
4-bromo-2-hydroxybenzonitrile (1.0 eq), THF (10V), DMAP (0.2 eq), BOC anhydride (1.3 eq, di-tert-butyl dicarbonate), TEA (1.5 eq, triethanolamine) were added to the reaction flask, and after the addition, the reaction was stirred at room temperature and the progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate (10V) was added to the reaction flask, and then the system pH =3 was adjusted with 1N diluted hydrochloric acid, liquid separation was performed, the organic phase was washed with saturated brine again, dried over anhydrous sodium sulfate and the solvent was filtered off, and the residue was purified by column chromatography (PE: E A = 3:1) to obtain the title compound as a colorless oil.
And 2, step: synthesis of 5- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) -2-cyanophenyl tert-butyl carbonate
4-bromo-2- ((4-methoxy-3-methylphenyl) ethynyl) aniline (1.0 eq), 5-bromo-2-cyanophenyl tert-butyl carbonate (1.5 eq), cesium carbonate (2.0 eq), palladium acetate (0.1 eq), xantphos (0.2 eq), and DMF (10V) were added to a reaction flask, and after the addition was completed and nitrogen protection, the reaction was heated to 110 ℃ for reaction, and the progress of the reaction was monitored by TLC. After completion of the reaction, 100mL of water and 100mL of ethyl acetate were added to the reaction flask, and after stirring for a while, the mixture was allowed to stand for liquid separation, the organic phase was washed with water again (100ml × 5), then dried over anhydrous sodium sulfate, the solvent was dried by spin-drying, and the residue was purified by column chromatography (PE: EA = 3:1) to obtain the title compound as a pale yellow oil.
And step 3: synthesis of tert-butyl (1- (1- (3- ((tert-butoxycarbonyl) oxy) -4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperidin-4-yl) carbamate
To a reaction flask was added 5- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) -2-cyanophenyl tert-butyl carbonate (1.0 eq), boc aminopiperidine (1.2 eq), pd 2 (dba) 3 (0.11 eq), cesium carbonate (2.0 eq), X-phos (0.23 eq), and DMF (10V), and then heated to 110 ℃ for reaction under nitrogen protection, and the progress of the reaction was monitored by TLC. After completion of the reaction, 100mL of ethyl acetate was added to the reaction flask, followed by washing with water several times (100ml × 5), drying with anhydrous sodium sulfate, spin-drying the solvent, and column chromatography of the residue (PE: EA = 3:1) to obtain the title compound as a yellow solid.
And 4, step 4: synthesis of 4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) -2-hydroxybenzonitrile
To the reaction flask was added tert-butyl (1- (1- (3- ((tert-butoxycarbonyl) oxy) -4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperidin-4-yl) carbamate (1.0 eq), dissolved with DCM (10V), added TFA (3V) dropwise, after addition, the reaction was stirred at room temperature and monitored by TLC for progress. After the reaction was complete, the solvent was spin-dried and the residue was adjusted to pH =9 with ammonia in methanol. The solvent was again spun dry and the residue was purified by p-TLC (DCM: meOH = 10) to give the title compound as a yellow solid.
Example 4:4- (2- (3-fluoro-4-methoxyphenyl) -5- (4-glycylpiperazin-1-yl) -1H-indol-1-yl) benzonitrile
Step 1: synthesis of tert-butyl (2- (4- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperazin-1-yl) -2-oxoethyl) carbamate
To the reaction flask was added 4- (2- (3-fluoro-4-methoxyphenyl) -5- (piperazin-1-yl) -1H-indol-1-yl) benzonitrile (1.0 eq), (tert-butoxycarbonyl) glycine (1.0 eq), DCM (10V), HATU (1.5 eq), DIPEA (1.5 e q), and after the addition, the reaction was stirred at room temperature and the progress of the reaction was monitored by TLC. After completion of the reaction, water (10V) was added to the reaction flask, and after stirring for 5min, liquid separation was performed, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was spin-dried, and the residue was purified by column chromatography (PE: EA = 2:3) to give the title compound as a pale yellow solid. MS-ES (ESI, pos.ion) m/z 528.30, [ M + H ] +;
step 2: synthesis of 4- (2- (3-fluoro-4-methoxyphenyl) -5- (4-glycylpiperazin-1-yl) -1H-indol-1-yl) benzonitrile
To a reaction flask was added tert-butyl (2- (4- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperazin-1-yl) -2-oxyethyl) carbamate (1.0 eq) dissolved with DCM (3V), followed by dropwise addition of TFA (1V), after which the reaction was stirred at room temperature and monitored by TLC for progress. After completion of the reaction, the reaction solution was dried by spinning, the residue was adjusted to pH =9 with a methanol solution of ammonia, the solvent was dried again by spinning, and the residue was purified by column chromatography (DCM: meOH = 10) to obtain the title compound as a light yellow solid.
Example 5:4- (5- (4- (aminomethyl) piperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile
Step 1: synthesis of tert-butyl ((1- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperidin-4-yl) methyl) carbamate
To a reaction flask was added 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile (1.0 eq), (piperidin-4-ylmethyl) carbamic acid tert-butyl ester (1.0 eq), pd 2 (dba) 3 (0.11 eq), cesium carbonate (2.0 eq), X-phos (0.22 eq), dioxane (10V), after nitrogen protection, heated to 110 ℃ for reaction, and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction solution was filtered through a filter, the filtrate was spin-dried, and the residue was purified by column chromatography (PE: EA = 3:2) to give the title compound as a yellow solid. MS-ES (ESI, pos.ion) m/z of 499.35[ m + H ])]+；
Step 2: synthesis of 4- (5- (4- (aminomethyl) piperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile
To the reaction flask was added tert-butyl ((1- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperidin-4-yl) methyl) carbamate (1.0 eq), dissolved with DCM (3V), followed by dropwise addition of TFA (1V), after which the reaction was stirred at room temperature and monitored by TLC for progress. After the reaction was complete, the reaction was spun off, the residue was adjusted to pH =9 with methanol of ammonia, the solvent was spun off again, and the residue was purified by column chromatography (DCM: meOH = 10) to give the title compound as a light yellow solid.
Example 6:4- (2- (3-fluoro-4-methoxyphenyl) -5- (2,7-diazaspiro [3.5] nonan-7-yl) -1H-indol-1-yl) benzonitrile
Step 1: synthesis of tert-butyl 7- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) -2,7-diazaspiro [3.5] nonane-2-carboxylate
Adding 4- (5-bromo-2- (3-fluoro-4-methoxybenzene) into a reaction bottle1H-indol-1-yl) benzonitrile (1.0 eq), 2,7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (1.0 eq), pd 2 (dba) 3 (0.11 eq), cesium carbonate (2.0 eq), X-phos (0.22 eq), dioxane (10V), after nitrogen protection, heated to 110 ℃ for reaction, and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction solution was filtered through a filter, the filtrate was spin-dried, and the residue was purified by column chromatography (PE: EA = 3:2) to give the title compound as a yellow solid. MS-ES (ESI, pos.ion) m/z 567.41M + H]+；
Step 2: synthesis of 4- (2- (3-fluoro-4-methoxyphenyl) -5- (2,7-diazaspiro [3.5]]Nonan-7-yl) -1H-indol-1-yl) benzonitrile
7- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) -2,7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (1.0 eq) was added to the reaction flask, dissolved with DCM (3V), followed by addition of TFA (1V) dropwise, the reaction stirred at room temperature after the addition was complete, and the progress of the reaction monitored by TLC. After completion of the reaction, the reaction solution was dried by spinning, the residue was adjusted to pH =9 with a methanol solution of ammonia, the solvent was again dried by spinning, and the residue was purified by column chromatography (DCM: meOH = 10) to give the title compound as a light yellow solid.
Example 7:4- (2- (3-fluoro-4-methoxyphenyl) -5- (2,8-diazaspiro [4.5] decan-8-yl) -1H-indol-1-yl) benzonitrile
Step 1: synthesis of tert-butyl 8- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) -2,8-diazaspiro [4.5] decane-2-carboxylate
To a reaction flask was added 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile (1.0 eq), 2,8-diazaspiro [4.5]Decane-2-carboxylic acid tert-butyl ester (1.0 eq), pd 2 (dba) 3 (0.11 eq), cesium carbonate (2.0 eq), X-phos (0.22 eq), and DMF (10V), and then heated to 110 ℃ for reaction under nitrogen protection, and the progress of the reaction was monitored by TLC. After completion of the reaction, 100mL of ethyl acetate and 100mL of water were added to the reaction mixture, and after stirring for 1min, the mixture was separated, the organic phase was washed with water (100mL. Multidot.5), washed with saturated brine (100mL. Multidot.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried, and the residue was purified by column chromatography (PE: EA = 3:2) to give the title compound as a yellow solid.
Step 2: synthesis of 4- (2- (3-fluoro-4-methoxyphenyl) -5- (2,8-diazaspiro [4.5] decan-8-yl) -1H-indol-1-yl) benzonitrile
To the reaction flask was added tert-butyl 8- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) -2,8-diazaspiro [4.5] decane-2-carboxylate (1.0 eq), dissolved with DCM (3V), followed by dropwise addition of TFA (1V), after which the reaction was stirred at room temperature and monitored by TLC for progress. After completion of the reaction, the reaction solution was dried by spinning, the residue was adjusted to pH =9 with a methanol solution of ammonia, the solvent was dried again by spinning, and the residue was purified by column chromatography (DCM: meOH = 10) to obtain the title compound as a light yellow solid.
Example 8:4- (5- (4-amino-4-methylpiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile
Step 1: synthesis of (1- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester
To a reaction flask was added 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile (1.0 eq), tert-butyl(4-methylpiperidin-4-yl)carbamate(1.0eq)、Pd 2 (dba) 3 (0.11 eq), cesium carbonate (2.0 eq), X-phos (0.22 eq), dioxane (10V), after nitrogen protection, heated to 110 ℃ for reaction, and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction solution was filtered through a filter, the filtrate was spin-dried, and the residue was purified by column chromatography (PE: EA = 3:2) to give the title compound as a yellow solid. MS-ES (ESI, pos.ion) m/z of 499.35[ m + H ])]+；
Step 2: synthesis of 4- (5- (4-amino-4-methylpiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile
To a reaction flask was added tert-butyl (1- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) -4-methylpiperidin-4-yl) carbamate (1.0 eq), dissolved with DCM (3V), followed by dropwise addition of TFA (1V), after completion of addition, the reaction was stirred at room temperature and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction solution was dried by spinning, the residue was adjusted to pH =9 with a methanol solution of ammonia, the solvent was dried again by spinning, and the residue was purified by column chromatography (DCM: meOH = 10) to obtain the title compound as a light yellow solid.
Example 9: (S) -4- (2- (3-fluoro-4-methoxyphenyl) -5- (pyrrolidin-3-ylamino) -1H-indol-1-yl) benzonitrile
Step 1: synthesis of tert-butyl (S) -3- ((1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) amino) pyrrolidine-1-carboxylate
To a reaction flask was added 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile (1.0 eq), (S) -3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (1.0 eq), pd 2 (dba) 3 (0.11 eq), cesium carbonate (2.0 eq), X-phos (0.22 eq), dioxane (10V), after protection with nitrogen, heated to 110 ℃ for reaction, and the progress of the reaction was monitored by TLC. After completion of the reaction, the insoluble matter was removed by filtration through a filter, the filtrate was dried by rotary drying, and the residue was purified by column chromatography (PE: EA = 3:2) to give the title compound as a yellow solid.
Step 2: synthesis of (S) -4- (2- (3-fluoro-4-methoxyphenyl) -5- (pyrrolidin-3-ylamino) -1H-indol-1-yl) benzonitrile
To the reaction flask was added tert-butyl (S) -3- ((1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) amino) pyrrolidine-1-carboxylate (1.0 eq), dissolved with DCM (3V), followed by dropwise addition of TFA (1V), after which the reaction was stirred at room temperature and monitored by TLC for progress. After completion of the reaction, the reaction solution was dried by spinning, the residue was adjusted to pH =9 with a methanol solution of ammonia, the solvent was again dried by spinning, and the residue was purified by column chromatography (DCM: meOH = 10) to give the title compound as a light yellow solid.
Example 10: (R) -4- (2- (3-fluoro-4-methoxyphenyl) -5- (pyrrolidin-3-ylamino) -1H-indol-1-yl) benzonitrile
Step 1: synthesis of tert-butyl (R) -3- ((1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) amino) pyrrolidine-1-carboxylate
To a reaction flask was added 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile (1.0 eq), (R) -3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (1.0 eq), pd 2 (dba) 3 (0.11 eq), cesium carbonate (2.0 eq), X-phos (0.22 eq), dioxane (10V) under nitrogen protection, then addThe reaction was heated to 110 ℃ and the progress of the reaction was monitored by TLC. After completion of the reaction, insoluble matter was removed by filtration through a filter, the filtrate was dried by spinning, and the residue was purified by column chromatography (PE: EA = 3:2) to give the title compound as a yellow solid.
Step 2: synthesis of (S) -4- (2- (3-fluoro-4-methoxyphenyl) -5- (pyrrolidin-3-ylamino) -1H-indol-1-yl) benzonitrile
To the reaction flask was added tert-butyl (R) -3- ((1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) amino) pyrrolidine-1-carboxylate (1.0 eq), dissolved with DCM (3V), followed by dropwise addition of TFA (1V), after which the reaction was stirred at room temperature and monitored by TLC for progress. After completion of the reaction, the reaction solution was dried by spinning, the residue was adjusted to pH =9 with a methanol solution of ammonia, the solvent was again dried by spinning, and the residue was purified by column chromatography (DCM: meOH = 10) to give the title compound as a light yellow solid.
Example 11: (S) -4- (2- (3-fluoro-4-methoxyphenyl) -5- (piperidin-3-ylamino) -1H-indol-1-yl) benzonitrile
Step 1: synthesis of (S) -3- ((1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
To a reaction flask was added 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile (1.0 eq), (S) -3-aminopiperidine-1-carboxylic acid tert-butyl ester (1.0 eq), pd 2 (dba) 3 (0.11 eq), cesium carbonate (2.0 eq), X-phos (0.22 eq), dioxane (10V), after protection with nitrogen, heated to 110 ℃ for reaction, and the progress of the reaction was monitored by TLC. After the reaction is completed, filtering with a filter membrane to remove insoluble substances, and spin-drying the filtrate to obtain residueThe material was purified by column chromatography (PE: EA = 3:2) to afford the title compound as a yellow solid.
Step 2: synthesis of (S) -4- (2- (3-fluoro-4-methoxyphenyl) -5- (piperidin-3-ylamino) -1H-indol-1-yl) benzonitrile
To the reaction flask was added tert-butyl (S) -3- ((1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) amino) piperidine-1-carboxylate (1.0 eq), dissolved with DCM (3V), followed by dropwise addition of TFA (1V), after which the reaction was stirred at room temperature and monitored by TLC for progress. After completion of the reaction, the reaction solution was dried by spinning, the residue was adjusted to pH with a methanol solution of ammonia, the solvent was dried again by spinning, and the residue was purified by column chromatography (DCM: meOH = 10.
Example 12: (R) -4- (2- (3-fluoro-4-methoxyphenyl) -5- (piperidin-3-ylamino) -1H-indol-1-yl) benzonitrile
Synthetic procedure with reference to step 1 and step 2 in example 11, only the starting material tert-butyl (S) -3-aminopiperidine-1-carboxylate in step 1 was replaced with tert-butyl (R) -3-aminopiperidine-1-carboxylate.
Example 13:4- (5- (4-Aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoic acid methyl ester
Step 1: synthesis of methyl 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoate
4-bromo-2- ((4-methoxy-3-methylphenyl) ethynyl) aniline (1.0 eq), methyl 4-iodobenzoate (1.5 eq), cesium carbonate (2.0 eq), palladium acetate (0.1 eq), xanthphos (0.2 eq), dioxane (10V) were added to a reaction flask, and after the addition was completed, the reaction was protected with nitrogen, and then the temperature was raised to 110 ℃ for reaction, and the progress of the reaction was monitored by TLC. After completion of the reaction, the insoluble matter was removed by filtration with celite, the filtrate was dried by spinning, and the residue was purified by column chromatography (PE: DCM: EA = 5. MS-ES (ESI, pos. Ion) m/z 454.18, [ M + H ] +.
Step 2: synthesis of methyl 4- (5- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoate
To a reaction flask was added methyl 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoate (1.0 eq), tert-butylpiperidin-4-ylcarbamate (1.0 eq), pd 2 (dba) 3 (0.11 eq), cesium carbonate (2.0 eq), X-phos (0.22 eq), and DMF (10V), and then heated to 110 ℃ for reaction under nitrogen protection, and the progress of the reaction was monitored by TLC. After completion of the reaction, 20V water and 20V ethyl acetate were added to the reaction solution, and after stirring for 1min, the reaction solution was separated, and the organic phase was washed with water (20V × 5), then dried over anhydrous sodium sulfate, the filtrate was spin-dried, and the residue was purified by column chromatography (PE: EA = 3:1) to give the title compound as a yellow solid.
And step 3: synthesis of methyl 4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoate
To the reaction flask was added methyl 4- (5- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoate (1.0 eq), dissolved with DCM (3V), followed by dropwise addition of TFA (1V), after which the reaction was stirred at room temperature and monitored by TLC for progress. After the reaction was complete, the reaction was spun off, the residue was adjusted to pH =9 with methanol of ammonia, the solvent was spun off again, and the residue was purified by column chromatography (DCM: meOH = 10).
Example 14:4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoic acid
Step 1: synthesis of 4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoic acid
Methyl 4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoate (1.0 eq) was charged into a reaction flask, dissolved in a mixed solvent (methanol: dichloromethane = 5:1), and 10eq of lithium hydroxide monohydrate was added thereto, and after the addition was completed, the reaction was stirred at room temperature, and the progress of the reaction was monitored by TLC. After the reaction is completed, the solvent is dried by spinning, the pH of the residue is adjusted to be neutral by using 1N diluted hydrochloric acid, a large amount of white solid is separated out, the white solid is filtered, and the filter cake is washed twice by using water. The filter cake was dried to give the title compound as a white solid.
Example 15:1- (2- (3-fluoro-4-methoxyphenyl) -1- (4- (methylsulfonyl) phenyl) -1H-indol-5-yl) piperidin-4-amine
Step 1: synthesis of 5-bromo-2- (3-fluoro-4-methoxyphenyl) -1- (4- (methylsulfonyl) phenyl) -1H-indole
4-bromo-2- ((4-methoxy-3-methylphenyl) ethynyl) aniline (1.0 eq), 4-bromobenzenesulfone (1.5 eq), cesium carbonate (2.0 eq), palladium acetate (0.1 eq), xantphos (0.2 eq), and DMF (10V) were added to a reaction flask, and after the addition was completed and nitrogen was protected, the temperature was raised to 110 ℃ for reaction, and the progress of the reaction was monitored by TLC. After the reaction was complete, 100mL of water and 100mL of ethyl acetate were added to the reaction flask, stirred for a while, and allowed to stand for liquid separation, the organic phase was washed with water again multiple times (100ml × 5), then dried over anhydrous sodium sulfate, the solvent was dried, and the residue was purified by column chromatography (PE: EA: DCM =3 1) to obtain the title compound as a light brown solid.
Step 2: synthesis of tert-butyl (1- (2- (3-fluoro-4-methoxyphenyl) -1- (4- (methylsulfonyl) phenyl) -1H-indol-5-yl) piperidin-4-yl) carbamate
To a reaction flask was added 5-bromo-2- (3-fluoro-4-methoxyphenyl) -1- (4- (methylsulfonyl) phenyl) -1H-indole (1.0 eq), boc aminopiperidine (1.2 eq), pd 2 (dba) 3 (0.11 eq), cesium carbonate (2.0 eq), X-phos (0.23 eq), D MF (10V), after nitrogen protection, heating to 110 ℃ for reaction, and monitoring the reaction progress by TLC. After completion of the reaction, 100mL of dichloromethane was added to the reaction flask, followed by washing with water several times (100ml × 5), drying with anhydrous sodium sulfate, spin-drying the solvent, and column chromatography of the residue (PE: EA = 1:1) to obtain the title compound as a yellow solid.
And step 3: synthesis of 1- (2- (3-fluoro-4-methoxyphenyl) -1- (4- (methylsulfonyl) phenyl) -1H-indol-5-yl) piperidin-4-amine
To a reaction flask was added tert-butyl (1- (2- (3-fluoro-4-methoxyphenyl) -1- (4- (methylsulfonyl) phenyl) -1H-indol-5-yl) piperidin-4-yl) carbamate (1.0 eq), dissolved with DCM (10V), added TFA (3V) dropwise, after completion of addition, the reaction was stirred at room temperature and monitored by TLC for progress of the reaction. After the reaction was complete, the solvent was spin dried and the residue was adjusted to pH =9 with ammonia in methanol. The solvent was again spun dry and the residue was purified by p-TLC (DCM: meOH = 10) to give the title compound as a yellow solid.
Example 16:4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzamide
Step 1: synthesis of tert-butyl (1- (1- (4-carbamoylphenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperidin-4-yl) carbamate
To the sealed tube was added methyl 4- (5- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoate (1.0 eq) and 20V ammonia in methanol (7 mol/L), and after sealing, the mixture was heated to 70 ℃ for reaction and the progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was dried and the residue was purified by P-TLC (DCM: meOH = 10.
Step 2: synthesis of 4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzamide
To a reaction flask was added tert-butyl (1- (1- (4-carbamoylphenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperidin-4-yl) carbamate (1.0 eq), dissolved with DCM (10V), added TFA (3V) dropwise, after completion of addition, the reaction was stirred at room temperature and monitored by TLC for progress of the reaction. After the reaction was complete, the solvent was spin dried and the residue was adjusted to pH =9 with ammonia in methanol. The solvent was again spun dry and the residue was purified by p-TLC (DCM: meOH = 10).
Example 17:4- (5- (4-Aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoic acid ethyl ester
Synthesis procedure with reference to example 13, only the starting material methyl 4-iodobenzoate in step 1 was replaced with ethyl 4-iodobenzoate.
Example 18:4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) -N-methylbenzamide
Step 1: synthesis of 4- (5- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoic acid
To the reaction flask was added methyl 4- (5- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoate (1.0 eq), dissolved in methanol (10V), and added NaOH (5.0 eq), and after the addition, the reaction was stirred at room temperature and monitored for progress by TLC. After completion of the reaction, 1N diluted hydrochloric acid was added to the reaction flask to adjust pH =3, liquid separation was performed, the organic phase was dried over anhydrous sodium sulfate, and the solvent was dried by rotation after filtration to obtain the title compound as a yellow solid.
Step 2: synthesis of tert-butyl (1- (2- (3-fluoro-4-methoxyphenyl) -1- (4- (methylcarbamoyl) phenyl) -1H-indol-5-yl) piperidin-4-yl) carbamate
To a reaction flask was added 4- (5- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoic acid (1.0 eq), methylamine hydrochloride (1.5 eq), HATU (1.5eq, 2- (7-azobenzotriazol) -N, N' -tetramethylurea hexafluorophosphate, CAS accession No. 148893-10-1), DCM (10V), DIPEA (2.5eq, N-diisopropylethylamine, CAS accession No. 7087-68-5) was added under ice bath, the reaction was stirred at room temperature, and the progress of the reaction was monitored by TLC. After the reaction was completed, water (10V) was added to the reaction flask, and after stirring for a while, the mixture was allowed to stand for liquid separation, and the organic phase was dried over anhydrous sodium sulfate, and after filtration and spin-drying, the title compound was obtained as a yellow solid and was used in the next reaction without purification.
And step 3: synthesis of 4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) -N-methylbenzamide
To a reaction flask was added tert-butyl (1- (2- (3-fluoro-4-methoxyphenyl) -1- (4- (methylcarbamoyl) phenyl) -1H-indol-5-yl) piperidin-4-yl) carbamate (1.0 eq), dissolved with DCM (3V), followed by dropwise addition of TFA (1V), after which the reaction was stirred at room temperature and monitored by TLC for progress. After completion of the reaction, the reaction solution was dried by spinning, the residue was adjusted to pH =9 with a methanol solution of ammonia, the solvent was dried again by spinning, and the residue was purified by column chromatography (DCM: meOH = 10) to obtain the title compound as a light yellow solid.
Example 19:4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) -N, N-dimethylbenzamide
Synthetic procedure with reference to example 18, only the starting methylamine hydrochloride in step 2 of the example was replaced with dimethylamine hydrochloride.
Example 20: methyl-d 3- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoate
D is deuterium.
Step 1: synthesis of methyl d 3-4-iodobenzoate
4-iodobenzoic acid (1.0 eq), deuterated methanol (5.0 eq), DMAP (0.2 eq), THF (10V) and DCC (2 eq) were added to a reaction flask, and after the addition, the reaction was stirred at room temperature and the progress of the reaction was monitored by TLC. After the reaction was complete, the solvent was spin dried over the column (P E: EA = 10).
Step 2: synthesis of methyl-d 3- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzoate
The synthesis is as described in example 13, except that methyl 4-iodobenzoate in step 1 of example 13 is replaced by methyl d 3-4-iodobenzoate.
Example 21:4- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile
Synthesis method referring to step 4 and step 5 of example 1, the raw material, piperazine-1-carboxylic acid tert-butyl ester in step 4 was replaced with 4-tert-butoxycarbonylaminopiperidine.
Example 22: (S) -4- (5- (3-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile
Synthetic method referring to step 4 and step 5 of example 1, the raw material, i.e., tert-butyl piperazine-1-carboxylate in step 4 was replaced with (S) -3-tert-butyloxycarbonylaminopiperidine.
Example 23: (R) -4- (5- (3-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) benzonitrile
Synthetic method referring to step 4 and step 5 of example 1, the raw material, i.e., tert-butyl piperazine-1-carboxylate in step 4 was replaced with (R) -3-tert-butyloxycarbonylaminopiperidine.
Example 24- (2- (3-fluoro-4-methoxyphenyl) -5- (4-glycylpiperidin-1-yl) -1H-indol-1-yl) benzonitrile
Synthetic method referring to step 4 and step 5 of example 1, the raw material tert-butyl piperazine-1-carboxylate in step 4 was replaced with tert-butyl (2-oxo-2- (piperidin-1-yl) ethyl) carbamate.
Example 25:1- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperidine-4-carboxamide
Synthetic method referring to step 4 and step 5 of example 1, the raw material tert-butyl piperazine-1-carboxylate in step 4 was replaced with tert-butyl (piperidine-4-carbonyl) carbamate.
Example 26:4- (2- (3-fluoro-4-methoxyphenyl) -5- (piperidin-4-ylamino) -1H-indol-1-yl) benzonitrile
Synthetic method referring to step 4 and step 5 of example 1, the raw material of tert-butyl piperazine-1-carboxylate in step 4 was replaced with tert-butyl 4-aminopiperidine-1-carboxylate.
Example 27: n- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-5-yl) piperidine-4-carboxamide
Synthetic method referring to step 4 and step 5 of example 1, the raw material, piperazine-1-carboxylic acid tert-butyl ester in step 4 was replaced with 4-carbamoylpiperidine-1-carboxylic acid tert-butyl ester.
Example 28:6- (5- (4-aminopiperidin-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indol-1-yl) nicotinonitrile
Synthetic method referring to step 3 to step 5 of example 1, the raw material 4-iodobenzonitrile in step 3 was replaced with 6-iodonicotinonitrile. And 4, replacing the raw material of the piperazine-1-carboxylic acid tert-butyl ester in the step 4 with 4-tert-butyloxycarbonylaminopiperidine.
Table 1 characterization data of the compounds
Activity test method:
a549 cells, namely human non-small cell lung cancer cells, and the biological activity is tested to play a role in proliferation inhibition in the A549 cells, wherein the detection method is a CCK8 detection method.
The experimental steps are as follows:
methods of dilution of the compounds of the examples: an appropriate amount of each of the compounds prepared in examples was weighed, dissolved in DMSO (dimethyl sulfoxide) so that the concentration of the sample in the solution was 20mmol/L, and diluted 20-fold with the complete medium so that the concentration was 1mmol/L. The assay was repeated with two-fold dilution, eight concentration gradients, and three replicates per well. The dilution method of the standard control gefitinib and ocitinib was identical to that of the example compounds.
And (3) culturing the cells:
1) The preparation method of the complete culture medium comprises the following steps: 1640 culture medium with 1% double antibody and 10% inactivated fetal calf serum.
2) And (3) culturing the cells: inoculating A549 cells in culture medium, standing at 37 deg.C, 5% 2 Culturing in the incubator, and carrying out passage for 2-3 d.
3) The inhibition of the growth of a549 cells by the sample is determined.
Table 2 materials used for activity testing
| For short | Full scale | Brand | Goods number |
| CCK8 | Cell Counting Kit-8 (CCK-8) Kit | YEASEN | 40203ES80 |
| DMSO | Dimethyl Sulfoxide | SIGMA | D2650-100ML |
| 1640 medium | RPMI+GLutaMAXTM-I(1X)RPMI Medium 1640 | gibco | 61870-036 |
| Double antibody | Pen Strep Penicillin Streptomycin | gibco | 15140-122 100mL |
| Inactivated fetal bovine serum | FBS Fetal Bovine Serum,Qualified | gibco | 10099-141C |
| EDTA-pancreatin | 0.25％Trypsin-EDTA(1X)Trypsin-EDTA | gibco | 25200-072 |
| PBS | PBS pH7.2(1X)Phosphate Buffered Saline | gibco | 20012-027 |
| T25 culture bottle | 25 cm2 Cell Culture Flask | NEST | 707003 |
| T75 culture bottle | 75 cm2 Cell Culture Flask | NEST | 708003 |
| 96-well transparent culture plate | 96Well Cell Culture Plate | NEST | 701001 |
| 96-well white culture plate | 96Well White Plate | SPL | 30196 |
| Culture box | FORMA STERT-CYCLE CO2 Incubator | Thermo | 371 |
| Hand-held cell counter | Handheld Automated Cell Counter | Scepter | A506RDTM |
| Gefitinib | Gefitinib | An Naiji | E1200780010 |
| Oscetitinib | Ocitinib | An Naiji | B011037 |
Digesting cells by EDTA-pancreatin digestive juice, centrifuging for 5min at 1000r, discarding the supernatant, resuspending by a culture medium, taking 100 mu L of the resuspended cell solution to dilute by 10 times and mixing uniformly, counting by a handheld cell counter, diluting to 2x104 cells/mL by the culture medium, taking 100 mu L/Kong Jiadao-hole culture plates, and placing in a 37 ℃ CO2 incubator containing 5%. After 24h of incubation, 25. Mu.L of the diluted sample was added to each well at an initial concentration of 200. Mu. Mol/L and placed in an incubator, after 48h, 10. Mu.L of CCK8 detection reagent was added to each well, placed in the incubator and incubated for 1h, and absorbance (OD value) was measured with a microplate reader at a wavelength of 450 nm. The IC50 of the sample compounds in a549 cells was calculated under the same conditions using cells without sample, with the same concentration of DMSO as a positive control and complete medium as a negative control, and the results are shown in table 3.
TABLE 3 inhibitory Activity of Compounds on human non-Small cell Lung cancer cells (A549) (IC 50, μ M)
As shown in Table 3, the synthesized indole derivatives show different degrees of inhibition effects on non-small cell lung cancer cell A549, the compounds I-6, I-7, I-13, I-17, I-21 and I-22 have stronger cytotoxic activity on the A549, the IC50 values are respectively 4.45 mu M, 4.52 mu M, 3.82 mu M, 3.18 mu M, 2.82 mu M and 3.25 mu M, and the activity is equivalent to the positive control ocitinib. The activity of I-21 is even better than that of ocitinib. While compounds I-8, I-10, I-15, I-20, I-23 also exhibited moderate cytotoxic activity against A549 cells with IC 50's of 5.97. Mu.M, 5.43. Mu.M, 5.5. Mu.M, 5.92. Mu.M and 5.79. Mu.M, respectively. The results show that the compounds have the potential of developing anti-cancer drugs.
In one embodiment, the present invention develops indole derivatives of novel structure and methods for their preparation. The indole derivative provided by the invention shows good anti-tumor activity, lays a foundation for screening and developing new drugs, and has good practical value.
The present invention has been described in terms of specific examples, which are provided to aid understanding of the invention and are not intended to be limiting. Numerous simple deductions, modifications or substitutions may also be made by those skilled in the art in light of the present teachings.
Claims (7)
1. A compound comprising at least one of the following structural formulas:
2. a method of synthesizing a compound according to claim 1, according to the following reaction scheme:
x is halogen;
the compound (a-9) is the compound according to claim 1, R 1 、R 2 、R 3 Is a substituent at a corresponding position in the compound of claim 1; in the compound (a-8), R 3 One hydrogen of (a) is removed.
3. The method according to claim 2, wherein the base is at least one of potassium carbonate and sodium carbonate when the compound (a-2) is synthesized;
when the compound (a-4) is synthesized, theThe Pd-containing catalyst is Pd (PPh) 3 ) 2 Cl 2 ；
When the compound (a-4) is synthesized, the Cu-containing catalyst is at least one of CuI and CuBr;
when Compound (a-4) is synthesized, the base is Et 2 N、Et 3 At least one of N;
when the compound (a-6) is synthesized, the Pd-containing catalyst is Pd (OAc) 2 、Pd 2 (dba) 3 At least one of;
when the compound (a-6) is synthesized, the ligand is at least one of 2-dicyclohexyl phosphorus-2 ',4',6' -triisopropyl biphenyl, 4,5-bis (diphenylphosphine) -9,9-dimethyl xanthene;
when the compound (a-6) is synthesized, the base is at least one of potassium carbonate and cesium carbonate;
when the compound (a-8) is synthesized, the Pd-containing catalyst is Pd (OAc) 2 、Pd 2 (dba) 3 At least one of (a);
when the compound (a-8) is synthesized, the alkali is at least one of potassium carbonate and sodium carbonate;
when the compound (a-8) is synthesized, the ligand is at least one of 2-dicyclohexyl phosphorus-2 ',4',6' -triisopropyl biphenyl, 4,5-bis (diphenylphosphine) -9,9-dimethyl xanthene;
when the compound (a-9) is synthesized, the acid is at least one of trifluoroacetic acid and hydrochloric acid.
4. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
5. Use of a compound according to claim 1, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the treatment of cancer, which is lung cancer.
6. The use of claim 5, wherein the lung cancer is non-small cell lung cancer.
7. The use of claim 6, wherein the non-small cell lung cancer is at least one of squamous cell carcinoma, adenocarcinoma, large cell carcinoma.
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