CN112194652B - 4-hydroxymethyl-1H-indole compound, preparation method and application - Google Patents

4-hydroxymethyl-1H-indole compound, preparation method and application Download PDF

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CN112194652B
CN112194652B CN202011366782.2A CN202011366782A CN112194652B CN 112194652 B CN112194652 B CN 112194652B CN 202011366782 A CN202011366782 A CN 202011366782A CN 112194652 B CN112194652 B CN 112194652B
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王永广
万晓梦
张佳琪
苏小庭
戴信敏
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Beijing Fahrenheit Kaiyuan Pharmaceutical Technology Co ltd
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Abstract

The invention relates to a 4-hydroxymethyl-1H-indole compound, a preparation method and application thereof, wherein the 4-hydroxymethyl-1H-indole compound has a structure shown in a formula I:
Figure 785488DEST_PATH_IMAGE001
(ii) a Wherein R is1And R2Together construct 2-oxo-8-azaspiro [4.5]]Decan-8-yl, 1, 8-diazaspiro [4.5]]Decan-8-yl, 2, 8-diazaspiro [4.5]]One of decan-8-yl, 4-amino-4-methylpiperidin-1-yl, 3, 5-dimethylpiperazin-1-yl; r3Represents one of 2-chloro-6-fluorophenyl, 3-chloropyridin-4-yl, 2-chloro-6-methoxyphenyl, 2, 6-dichlorophenyl and 2, 3-dichlorophenyl. The 4-hydroxymethyl-1H-indole compound disclosed by the invention can achieve the purpose of treating tumors by inhibiting the activity of SHP 2.

Description

4-hydroxymethyl-1H-indole compound, preparation method and application
Technical Field
The invention relates to a 4-hydroxymethyl-1H-indole compound, a preparation method and application thereof, belonging to the technical field of chemical medicines.
Background
Cancer is one of the major diseases threatening human health, and the main treatment modalities of cancer are drug therapy, surgical therapy and radiation therapy, among which drug therapy is one of the most commonly used treatment modalities. The traditional antitumor drugs can not distinguish tumor cells from normal cells, so that serious side effects are often caused, and the targeted drugs take the tumor cells as specific targets, so that the targeted drugs can accurately act on tumors, the treatment level is greatly improved, and the adverse reaction rate is reduced.
Mutations of protein tyrosine kinase or protein tyrosine phosphokinase exist in various malignant tumors, inhibition of the activity of the protein tyrosine kinase becomes one of the most common strategies for tumor targeted therapy, and dozens of protein tyrosine kinase inhibitors have been approved for clinical use so far. However, the compound with the fastest progress in drug development as an anti-tumor target is also only in phase II clinics.
The protein tyrosine phosphatase (SHP2) is a non-receptor tyrosine phosphatase encoded by PTPN11 gene, and comprises a conserved tyrosine phosphatase domain, two N-terminal SH2 domains and a C-terminal tail, wherein the two SH2 domains determine the subcellular localization and function regulation of SHP 2. In the inactive state, the SH2 domain at the N-terminus binds to and inactivates the PTP domain, which is released when the SHP2 domain binds to a specific tyrosine residue on the receptor or adaptor protein, e.g., by stimulation with cytokines and growth factors resulting in exposure of a catalytic site leading to activation of SHP 2.
SHP2 is widely expressed and is involved in multiple cell signaling processes, such as RAS-ERk, JAK-STAT, FGFR, EGFR, etc., to dredge the channels, and plays an important role in cell proliferation, differentiation, cell cycle and migration.
The activation of SHP2 is related to various diseases, such as B cell acute lymphoblastic leukemia, acute myelogenous leukemia and the like, in addition, the activation mutation of PTPN1 is also found in solid tumors, such as lung cancer, liver cancer, colon cancer and the like, and therefore, the research and discovery of a novel SHP2 small-molecule inhibitor are of great significance.
Disclosure of Invention
The invention provides a 4-hydroxymethyl-1H-indole compound, a preparation method and application thereof as an SHP2 inhibitor, and the specific technical scheme is as follows:
the 4-hydroxymethyl-1H-indole compound or a pharmaceutically acceptable salt thereof, wherein the 4-hydroxymethyl-1H-indole compound has a structure shown in formula I:
Figure 195049DEST_PATH_IMAGE001
；
wherein R is1And R2Together construct 2-oxo-8-azaspiro [4.5]]Decan-8-yl, 1, 8-diazaspiro [4.5]]Decan-8-yl, 2, 8-diazaspiro [4.5]]One of decan-8-yl, 4-amino-4-methylpiperidin-1-yl, 3, 5-dimethylpiperazin-1-yl;
R3represents one of 2-chloro-6-fluorophenyl, 3-chloropyridin-4-yl, 2-chloro-6-methoxyphenyl, 2, 6-dichlorophenyl and 2, 3-dichlorophenyl.
As an improvement of the technical scheme, the 4-hydroxymethyl-1H-indole compound is selected from any one of the following compounds in a formula 1-formula 23, and the structural formula is as follows:
Figure 908928DEST_PATH_IMAGE002
formula 1
Figure 219823DEST_PATH_IMAGE003
Formula 2
Figure 349453DEST_PATH_IMAGE004
Formula 3
Figure 694984DEST_PATH_IMAGE005
Formula 4
Figure 314184DEST_PATH_IMAGE006
Formula 5
Figure 315638DEST_PATH_IMAGE007
Formula 6
Figure 311276DEST_PATH_IMAGE008
Formula 7
Figure 511313DEST_PATH_IMAGE009
Formula 8
Figure 239098DEST_PATH_IMAGE010
Formula 9
Figure 790165DEST_PATH_IMAGE011
Formula 10
Figure 261597DEST_PATH_IMAGE012
Formula 11
Figure 83185DEST_PATH_IMAGE013
Formula 12
Figure 247450DEST_PATH_IMAGE014
Formula 13
Figure 20234DEST_PATH_IMAGE015
Formula 14
Figure 92095DEST_PATH_IMAGE016
Formula 15
Figure 469987DEST_PATH_IMAGE017
Formula 16
Figure 601891DEST_PATH_IMAGE018
Formula 17
Figure 861971DEST_PATH_IMAGE019
Formula 18
Figure 675206DEST_PATH_IMAGE020
Formula 19
Figure 969922DEST_PATH_IMAGE021
Formula 20
Figure 475989DEST_PATH_IMAGE022
Formula 21
Figure 223365DEST_PATH_IMAGE023
Formula 22
Figure 637029DEST_PATH_IMAGE024
And (3) formula 23.
The preparation method of the 4-hydroxymethyl-1H-indole compound or the pharmaceutically acceptable salt thereof comprises the following steps:
Figure 723934DEST_PATH_IMAGE025
1) reacting a compound shown as a formula II with a compound shown as a formula III under the action of a catalyst to obtain a compound shown as a formula IV, wherein the reaction temperature is 40-120 ℃;
and/or, the reaction is carried out in an alkaline environment, and the alkali is at least one of potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium phosphate and sodium acetate;
and/or the catalyst is selected from bis (triphenylphosphine) palladium (II) dichloride (formula abbreviated as PdCl)2(PPh3)2) Tetrakis (triphenylphosphine) palladium (formula abbreviated as Pd (PPh))3)4) Bis (dibenzylideneacetone) palladium (molecular formula is abbreviated as Pd (dba))2) Palladium acetate (molecular formula is abbreviated as Pd (OAc))2) 1,1' - [ bis (diphenylphosphino) ferrocene]Palladium dichloride (molecular formula abbreviated as Pd (dppf))2Cl2) At least one of;
and/or the ligand in the reaction is at least one selected from 1,1' -binaphthyl-2, 2' -bis-diphenylphosphine (BINAP), triphenylphosphine, tributylphosphine, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (SPhos), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (XantPhos);
and/or the reaction solvent is at least one of toluene, dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF) and N, N-Dimethylacetamide (DMA).
2) Reacting the compound shown in the formula IV under the action of a reducing agent to obtain a compound shown in the formula V, wherein the reaction temperature is 0-60 ℃;
and/or the reducing agent is at least one of lithium aluminum hydride, sodium borohydride, boron trifluoride and aluminum trichloride;
and/or the reaction solvent is at least one of methanol, ethanol, tetrahydrofuran and acetonitrile.
3) Reacting a compound shown as a formula V with a compound shown as a formula VI under the action of a catalyst to obtain a compound shown as a formula I, wherein the reaction temperature is 40-120 ℃;
and/or, the reaction is carried out in an alkaline environment, and the alkali is at least one of potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium phosphate and sodium acetate;
and/or, the catalyst is selected from at least one of cuprous iodide, cuprous chloride and cupric oxide;
and/or the ligand in the reaction is at least one selected from L-Proline (L-Proline), cyclohexyl diamine and N, N' -dimethylethylene diamine;
and/or the reaction solvent is at least one of toluene, dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF) and N, N-Dimethylacetamide (DMA).
When R is1And R2When the group constructed together contains a Boc-protected primary or secondary amine, the coupling product must be cleaved from the Boc-protecting group by the action of an acid (hydrochloric acid, trifluoroacetic acid, etc.) to give the desired product.
The 4-hydroxymethyl-1H-indole compound or the pharmaceutically acceptable salt thereof is used as an SHP2 inhibitor in the preparation of drugs for treating or preventing tumors.
In an improvement of the above technical means, the tumor is any one of 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, kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytoma, meningioma, hodgkin lymphoma, non-hodgkin 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, chondrosarcoma, myosarcoma, fibrosarcoma, and esophageal squamous carcinoma.
The invention has the beneficial effects that:
1) the 4-hydroxymethyl-1H-indole compound can achieve the purpose of treating tumors by inhibiting the activity of SHP 2; the 4-hydroxymethyl-1H-indole compound belongs to a small molecule SHP2 inhibitor, and has important significance and great research value in the research field of medicines for treating or preventing tumors. It is an object of the present invention to synthesize a novel small molecule SHP2 inhibitor comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of one or more compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof.
2) The synthesis method of the 4-hydroxymethyl-1H-indole compound has the advantages of few byproducts in the synthesis reaction process, high yield and great application value.
3) The compounds shown as formulas 2,3, 4, 11, 13, 14, 15 and 20 are used as SHP2 inhibitors, can obviously and effectively inhibit the proliferation of human esophageal squamous cell carcinoma cells, and have important significance and great research value in the field of tumor research.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the chemical compounds of the invention, when any variable (e.g. R)1、R2Etc.) occur more than one time in any constituent, then the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by those skilled in the art and by the methods set forth below from readily available starting materials. If a substituent is itself substituted with more than one group,it is to be understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.
The invention comprises free forms of compounds shown as formulas 1-23, and also comprises pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine-based compounds. The term "free form" refers to the amine compound in a non-salt form. Pharmaceutically acceptable salts include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I. The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base, such as a dilute aqueous NaOH solution, a dilute aqueous potassium carbonate solution, dilute aqueous ammonia, and a dilute aqueous sodium bicarbonate solution. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-monobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.
If a compound of the invention is acidic, an appropriate "pharmaceutically acceptable salt" refers to a salt prepared by a pharmaceutically acceptable non-toxic base including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, piperdine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Berg et al, "Pharmaceutical Salts," J.pharm.Sci.1977:66:1-19. the preparation of the pharmaceutically acceptable Salts described above and other typical pharmaceutically acceptable Salts is described in more detail.
Since acidic moieties such as carboxyl groups deprotonated in a compound under physiological conditions may be anionic and such charge may then be balanced out by a protonated or alkylated basic moiety such as a quaternary nitrogen atom bearing a cation internally, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.
In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the invention can be prepared using reactions as shown in the following schemes. The following illustrative schemes are therefore for illustrative purposes and are not limited to the compounds listed or any particular substituents. The number of substituents shown in the schemes does not necessarily correspond to the number used in the claims and for the sake of clarity a single substituent is shown attached to the compound allowing for multiple substituents under the definition of formula I above.
Example 1
A compound of formula 1: a process for the preparation of (1- (2, 3-dichlorophenyl) -5- ((3S,5R) -3, 5-dimethylpiperidin-1-yl) -1H-indol-4-yl) methanol according to the following reaction scheme:
Figure 961755DEST_PATH_IMAGE026
the first step is as follows:
compound 1a (25.3 g, 100.0 mmol), compound 1b (25.7 g, 120.0 mmol), cesium carbonate (48.9 g, 150.0 mmol), palladium acetate (2.2 g, 10.0 mmol), BINAP (12.4 g, 20.0 mmol) were dissolved in DMF (200 mL), the reaction was incubated at 80 ℃ for 10 hours, the reaction was monitored by Thin Layer Chromatography (TLC), after completion of the reaction, water (200 mL) was added to quench the reaction, extraction was performed with ethyl acetate (200 mL. times.2), the organic Layer was dried, and column Chromatography gave 26.3g of compound 1c in 68.0% yield, which was a white-like solid.
The second step is that:
dissolving the obtained compound 1c (26.0 g and 61.2 mmol) in methanol (200 mL), adding sodium borohydride (10.2 g and 268.7 mmol) under ice bath, heating to 25 ℃ after the addition is finished, stirring for reaction for 4 hours, monitoring the reaction by TLC, adding water after the reaction is finished to quench the reaction, extracting with ethyl acetate (200 mL multiplied by 2), drying an organic layer, filtering, concentrating, and carrying out column chromatography separation to obtain 18.5g of a compound 1d, wherein the yield is 84.2%, and the compound 1d is a white-like solid.
The third step:
compound 1d (3.6 g, 10.0 mmol), compound 1e (2.2 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 ℃ and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and separated by column chromatography to give 2.5g of compound 1f, yield 49.7%, and compound 1f was an off-white solid.
The fourth step:
compound 1f (503 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 198mg of compound 1 with a yield of 49.1%, ESI (+) m/z =404.1, and compound 1 was a white solid.
Example 2
A compound of formula 2: a process for the preparation of (1- (2, 6-dichlorophenyl) -5- ((3S,5R) -3, 5-dimethylpiperidin-1-yl) -1H-indol-4-yl) methanol, of the formula:
Figure 134110DEST_PATH_IMAGE027
compound 1d (3.6 g, 10.0 mmol), compound 2a (2.2 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 deg.C and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 3.1g of compound 2b, yield 61.6%, compound 2b was a white-like solid.
Compound 2b (503 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 225mg of compound 2, yield 55.7%, ESI (+) m/z =404.1, compound 2 was a white solid.
Example 3
A compound of formula 3: a process for the preparation of (1- (2-chloro-6-methoxyphenyl) -5- ((3S,5R) -3, 5-dimethylpiperidin-1-yl) -1H-indol-4-yl) methanol, of the formula:
Figure 351465DEST_PATH_IMAGE028
compound 1d (3.6 g, 10.0 mmol), compound 3a (2.2 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 deg.C and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 2.3g of compound 3b, with a yield of 46.1%, compound 3b was a white-like solid.
Compound 3b (499 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 231mg of compound 3 in 57.9% yield, ESI (+) m/z =400.2, and compound 3 was a white solid.
Example 4
A compound of formula 4: a process for the preparation of (1- (2-chloro-6-fluorophenyl) -5- ((3S,5R) -3, 5-dimethylpiperidin-1-yl) -1H-indol-4-yl) methanol having the following reaction formula:
Figure 355193DEST_PATH_IMAGE029
compound 1d (3.6 g, 10.0 mmol), compound 4a (2.1 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 deg.C and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 3.3g of compound 4b, which was 67.8% yield and compound 4b was a white-like solid.
Compound 4b (487 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, TLC monitored, after the reaction was completed, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and column chromatography was performed to obtain 255mg of compound 4, yield 65.9%, ESI (+) m/z =388.2, and compound 4 was a white solid.
Example 5
A compound of formula 5: a process for the preparation of (1- (3-chloropyridin-4-yl) -5- ((3S,5R) -3, 5-dimethylpiperidin-1-yl) -1H-indol-4-yl) methanol having the following reaction formula:
Figure 203063DEST_PATH_IMAGE030
compound 1d (3.6 g, 10.0 mmol), compound 5a (1.9 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), warmed to 100 ℃ and stirred for 6 hours, after the reaction was completed, quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 1.8g of compound 5b in 38.3% yield, which was a white-like solid.
Compound 5b (470 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was detected by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and column chromatography was performed to give 279mg of compound 5, yield 75.4%, ESI (+) m/z =371.2, and compound 5 was a white solid.
Example 6
A compound of formula 6: a process for the preparation of (5- (4-amino-4-methylpiperidin-1-yl) -1- (2, 3-dichlorophenyl) -1H-indol-4-yl) methanol having the following reaction formula:
Figure 925032DEST_PATH_IMAGE031
the first step is as follows:
compound 1a (25.3 g, 100.0 mmol), compound 6a (25.7 g, 120.0 mmol), cesium carbonate (48.9 g, 150.0 mmol), palladium acetate (2.2 g, 10.0 mmol), BINAP (12.4 g, 20.0 mmol) were dissolved in DMF (200 mL), warmed to 80 ℃ and reacted for 10 hours, monitored by TLC, quenched with water (200 mL), extracted with ethyl acetate (200 mL. times.2), the organic layer was dried, and column chromatography gave 23.3g of compound 6b in 60.2% yield, compound 6b was an off-white solid.
The second step is that:
dissolving the obtained compound 6b (23.0 g and 59.4 mmol) in methanol (200 mL), adding sodium borohydride (9.0 g and 237.7 mmol) under ice bath, heating to 30 ℃ after the addition, stirring for reaction for 4 hours, monitoring the reaction by TLC, adding water after the reaction is finished, quenching the reaction, extracting with ethyl acetate (200 mL multiplied by 2), drying an organic layer, filtering, concentrating, and carrying out column chromatography separation to obtain 16.1g of a compound 6c, wherein the yield is 75.5%, and the compound 6c is a white-like solid.
The third step:
compound 6c (3.6 g, 10.0 mmol), compound 1e (2.2 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), warmed to 100 ℃ and stirred for reaction for 6 hours, after the reaction was completed, quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 2.9g of compound 6d, with a yield of 57.7%, compound 6d was a white-like solid.
The fourth step:
compound 6d (503 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 255mg of compound 6, yield 63.3%, ESI (+) m/z =404.1, compound 6 was a white solid.
Example 7
A compound of formula 7: a process for the preparation of (5- (4-amino-4-methylpiperidin-1-yl) -1- (2, 6-dichlorophenyl) -1H-indol-4-yl) methanol having the following reaction formula:
Figure 883760DEST_PATH_IMAGE032
compound 6c (3.6 g, 10.0 mmol), compound 2a (2.2 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 deg.C and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 3.0g of compound 7a, yield was 59.6%, and compound 7a was a white-like solid.
Compound 7a (503 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 288mg of compound 7 with a yield of 71.5%, ESI (+) m/z =404.1, and compound 7 was a white solid.
Example 8
A compound represented by formula 8: a process for the preparation of (5- (4-amino-4-methylpiperidin-1-yl) -1- (2-chloro-6-methoxyphenyl) -1H-indol-4-yl) methanol having the following reaction formula:
Figure 741995DEST_PATH_IMAGE033
compound 6c (3.6 g, 10.0 mmol), compound 3a (2.2 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), warmed to 100 ℃ and stirred for 6 hours, after the reaction was completed, quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 2.5g of compound 8a, yield 50.2%, compound 8a was a white-like solid.
Compound 8a (499 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 268mg of compound 8, yield 67.2%, ESI (+) m/z =400.2, and compound 8 was a white solid.
Example 9
A compound of formula 9: a process for the preparation of (5- (4-amino-4-methylpiperidin-1-yl) -1- (2-chloro-6-fluorophenyl) -1H-indol-4-yl) methanol having the following reaction formula:
Figure 760767DEST_PATH_IMAGE034
compound 6c (3.6 g, 10.0 mmol), compound 4a (2.1 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), warmed to 100 ℃ and stirred for 6 hours, after the reaction was completed, quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 2.9g of compound 9a, yield was 59.5%, and compound 9a was a white-like solid.
Compound 9a (487 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 302mg of compound 9 in 78.0% yield, ESI (+) m/z =388.1, and compound 9 was a white solid.
Example 10
A compound according to formula 10: a process for the preparation of (5- (4-amino-4-methylpiperidin-1-yl) -1- (3-chloropyridin-4-yl) -1H-indol-4-yl) methanol of the formula:
Figure 970031DEST_PATH_IMAGE035
compound 6c (3.6 g, 10.0 mmol), compound 5a (1.9 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 ℃ and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 3.5g of compound 10a, yield 74.5%, compound 10a was a white-like solid.
Compound 10a (470 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and column chromatography was performed to give 278mg of compound 10, yield 75.1%, ESI (+) m/z =371.1, compound 10 was a white solid.
Example 11
A compound of formula 11: a process for the preparation of (1- (2, 3-dichlorophenyl) -5- (2, 8-diazaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol having the formula:
Figure 529188DEST_PATH_IMAGE036
the first step is as follows:
compound 1a (25.3 g, 100.0 mmol), compound 11a (28.8 g, 120.0 mmol), cesium carbonate (48.9 g, 150.0 mmol), palladium acetate (2.2 g, 10.0 mmol), BINAP (12.4 g, 20.0 mmol) were dissolved in DMF (200 mL), warmed to 80 ℃ for 10 hours, subjected to TLC detection, quenched with water (200 mL), extracted with ethyl acetate (200 mL. times.2), the organic layer was dried, and column chromatography gave 24.9g of compound 11b in 60.3% yield, which was an off-white solid.
The second step is that:
dissolving the obtained compound 11b (24.0 g and 58.1 mmol) in methanol (200 mL), adding sodium borohydride (8.8 g and 232.4 mmol) under ice bath, heating to 25 ℃ after the addition is finished, stirring for reaction for 5 hours, detecting the reaction by TLC, adding water after the reaction is finished, quenching the reaction, extracting by ethyl acetate (200 mL multiplied by 2), drying an organic layer, filtering, concentrating, and separating by column chromatography to obtain 16.5g of a compound 11c, wherein the yield is 73.8 percent and the compound 11c is a white-like solid.
The third step:
compound 1c (3.9 g, 10.0 mmol), compound 1e (2.2 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 deg.C and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 3.6g of compound 11d, yield 69.1%, compound 11d was a white-like solid.
The fourth step:
compound 11d (529 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was detected by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 301mg of compound 11 with a yield of 70.2%, ESI (+) m/z =430.1, and compound 11 was a white solid.
Example 12
A compound of formula 12: a process for the preparation of (1- (2, 6-dichlorophenyl) -5- (2, 8-diazaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol having the formula:
Figure 445192DEST_PATH_IMAGE037
compound 11c (3.9 g, 10.0 mmol), compound 2a (2.2 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 ℃ and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 3.2g of compound 12a, with a yield of 60.5%, compound 12a was a white-like solid.
Compound 12a (529 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 255mg of compound 12, yield 59.4%, ESI (+) m/z =430.1, and compound 12 was a white solid.
Example 13
A compound of formula 13: a process for the preparation of (1- (2-chloro-6-methoxyphenyl) -5- (2, 8-diazaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol, of the formula:
Figure 166023DEST_PATH_IMAGE038
compound 11c (3.9 g, 10.0 mmol), compound 3a (2.2 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 ℃ and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 2.7g of compound 13a, the yield was 51.4%, and compound 13a was a white-like solid.
Compound 13a (525 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 312mg of compound 13 in 73.4% yield, ESI (+) m/z =426.2, and compound 13 was a white solid.
Example 14
A compound of formula 14: a process for the preparation of (1- (2-chloro-6-fluorophenyl) -5- (2, 8-diazaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol having the formula:
Figure 364049DEST_PATH_IMAGE039
compound 11c (3.9 g, 10.0 mmol), compound 4a (2.1 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 deg.C and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 3.2g of compound 14a, with a yield of 62.4%, compound 14a was an off-white solid.
Compound 14a (513 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and column chromatography was performed to give 334mg of compound 14, yield 80.9%, ESI (+) m/z =414.2, and compound 14 was a white solid.
Example 15
A compound according to formula 15: a process for the preparation of (1- (3-chloropyridin-4-yl) -5- (2, 8-diazaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol of the formula:
Figure 664580DEST_PATH_IMAGE040
compound 11c (3.9 g, 10.0 mmol), compound 5a (1.9 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 deg.C and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 2.6g of compound 15a, yield 52.4%, compound 15a was a white-like solid.
Compound 15a (496 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 298mg of compound 15 in 75.3% yield, ESI (+) m/z =397.2, and compound 15 was a white solid.
Example 16
A compound according to formula 16: a process for the preparation of (1- (2, 3-dichlorophenyl) -5- (1, 8-diazaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol having the formula:
Figure 762986DEST_PATH_IMAGE041
the first step is as follows:
compound 1a (25.3 g, 100.0 mmol), compound 16a (24.0 g, 120.0 mmol), cesium carbonate (48.9 g, 150.0 mmol), palladium acetate (2.2 g, 10.0 mmol), BINAP (12.4 g, 20.0 mmol) were dissolved in DMF (200 mL), warmed to 80 ℃ for 10 hours, subjected to TLC detection, quenched with water (200 mL), extracted with ethyl acetate (200 mL. times.2), the organic layer was dried, and column chromatography gave 25.5g of compound 16b in 61.7% yield as an off-white solid.
The second step is that:
dissolving the compound 16b (25.0 g and 60.5 mmol) obtained above in methanol (200 mL), adding sodium borohydride (9.2 g and 242.1 mmol) under ice bath, heating to 25 ℃ after the addition is finished, stirring for reaction for 3 hours, detecting the reaction by TLC, adding water after the reaction is finished to quench the reaction, extracting with ethyl acetate (200 mL multiplied by 2), drying an organic layer, filtering, concentrating, and separating by column chromatography to obtain 13.8g of a compound 16c, wherein the yield is 59.3 percent and the compound 16c is a white-like solid.
The third step:
compound 16c (3.9 g, 10.0 mmol), compound 1e (2.2 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 deg.C and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 3.4g of compound 16d, which was 64.3% yield and compound 16d was a white-like solid.
The fourth step:
compound 16d (529 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and column chromatography was performed to give 318mg of compound 16, yield 74.1%, ESI (+) m/z =430.1, and compound 16 was a white solid.
Example 17
A compound according to formula 17: a process for the preparation of (1- (2, 6-dichlorophenyl) -5- (1, 8-diazaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol having the formula:
Figure 857981DEST_PATH_IMAGE042
compound 16c (3.9 g, 10.0 mmol), compound 2a (2.2 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 ℃ and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 2.7g of compound 17a, the yield was 51.0%, and compound 17a was a white-like solid.
Compound 17a (529 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 296mg of compound 17 with a yield of 69.0%, ESI (+) m/z =430.1, and compound 17 was a white solid.
Example 18
A compound according to formula 18: a process for the preparation of (1- (2-chloro-6-methoxyphenyl) -5- (1, 8-diazaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol, of the formula:
Figure 776258DEST_PATH_IMAGE043
compound 16c (3.9 g, 10.0 mmol), compound 3a (2.2 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 ℃ and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 3.1g of compound 18a, yield was 59.0%, and compound 18a was a white-like solid.
Compound 18a (525 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 311mg of compound 18, yield 73.2%, ESI (+) m/z =426.1, compound 18 was a white solid.
Example 19
A compound according to formula 19: a process for the preparation of (1- (2-chloro-6-fluorophenyl) -5- (1, 8-diazaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol having the formula:
Figure 942797DEST_PATH_IMAGE044
compound 16c (3.9 g, 10.0 mmol), compound 4a (2.1 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 deg.C and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 3.5g of compound 19a, yield 68.2%, compound 19a was a white-like solid.
Compound 19a (513 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and column chromatography was performed to give 325mg of compound 19 with a yield of 78.7%, ESI (+) m/z =414.2, and compound 19 was a white solid.
Example 20
A compound represented by formula 20: a process for the preparation of (1- (3-chloropyridin-4-yl) -5- (1, 8-diazaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol of the formula:
Figure 567814DEST_PATH_IMAGE045
compound 16c (3.9 g, 10.0 mmol), compound 5a (1.9 g, 10.0 mmol), potassium carbonate (2.8 g, 20.0 mmol), cuprous iodide (380 mg, 2.0 mmol), L-Proline (460 mg, 4.0 mmol) were dissolved in DMSO (300 mL), heated to 100 ℃ and stirred for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 3.6g of compound 20a, yield 72.6%, compound 20a was a white-like solid.
Compound 20a (496 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the solvent was removed by rotary evaporation, a saturated sodium bicarbonate solution (10 mL) was added, extraction was performed with ethyl acetate (50 mL × 2), the organic layer was dried, filtered, concentrated, and isolated by column chromatography to give 308mg of compound 20 in 77.8% yield, ESI (+) m/z =397.2, and compound 20 was a white solid.
Example 21
A compound of formula 21: a process for the preparation of (1- (2, 3-dichlorophenyl) -5- (2-oxazole-8-azaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol having the formula:
Figure 161606DEST_PATH_IMAGE046
the first step is as follows:
compound 1a (25.3 g, 100.0 mmol), compound 21a (14.1 g, 100.0 mmol), cesium carbonate (48.9 g, 150.0 mmol), palladium acetate (2.2 g, 10.0 mmol), BINAP (12.4 g, 20.0 mmol) were dissolved in DMF (200 mL), the reaction was incubated at 80 ℃ for 10 hours, TLC was used to monitor the reaction, after the reaction was completed, water (200 mL) was added to quench the reaction, extraction was performed with ethyl acetate (200 mL. times.2), the organic layer was dried, and column chromatography was performed to give 20.3g of compound 21b in 64.6% yield, which was a white-like solid.
The second step is that:
dissolving the compound 21b (20.0 g, 63.7 mmol) obtained above in methanol (200 mL), adding sodium borohydride (9.7 g, 254.8 mmol) under ice bath, heating to 25 ℃ after the addition, stirring for reaction for 5 hours, monitoring the reaction by TLC, adding water after the reaction to quench the reaction, extracting with ethyl acetate (200 mL. times.2), drying the organic layer, filtering, concentrating, and separating by column chromatography to obtain 15.1g of a compound 21c with yield of 83.0% and the compound 21c as a white-like solid.
The third step:
compound 21c (286 mg, 1.0 mmol), compound 1e (224 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), cuprous iodide (38 mg, 0.2 mmol), L-Proline (46 mg, 0.4 mmol) were dissolved in DMSO (20 mL), heated to 100 ℃ and stirred for reaction for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL × 2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 198mg of compound 21, yield 46.0%, ESI (+) m/z =431.1, compound 21 was an off-white solid.
Example 22
A compound represented by formula 22: a process for the preparation of (1- (2, 6-dichlorophenyl) -5- (2-oxazole-8-azaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol having the formula:
Figure 504863DEST_PATH_IMAGE047
compound 21c (286 mg, 1.0 mmol), compound 2a (224 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), cuprous iodide (38 mg, 0.2 mmol), L-Proline (46 mg, 0.4 mmol) were dissolved in DMSO (20 mL), heated to 100 ℃ and stirred for reaction for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL × 2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 211mg of compound 22 with a yield of 49.1%, ESI (+) m/z =431.1, compound 22 was an off-white solid.
Example 23
A compound according to formula 23: a process for the preparation of (1- (2-chloro-6-methoxyphenyl) -5- (2-oxazole-8-azaspiro [4.5] decan-8-yl) -1H-indol-4-yl) methanol, of the formula:
Figure 209514DEST_PATH_IMAGE048
compound 21c (286 mg, 1.0 mmol), compound 3a (220 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), cuprous iodide (38 mg, 0.2 mmol), L-Proline (46 mg, 0.4 mmol) were dissolved in DMSO (20 mL), heated to 100 ℃ and stirred for reaction for 6 hours, after the reaction was completed, the reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate (50 mL × 2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 238mg of compound 23, yield 55.9%, ESI (+) m/z =427.2, compound 23 was an off-white solid.
Example 24
Biological evaluation experiment
24.1 phosphatase Activity assay (IC)50）
Using 6, 8-difluoro-4-methyl umbelliferyl phosphate (DiFMUP) as a reaction substrate, incubating SHP2 enzyme solution (reaction diluted to 0.5 nM) with dPEG8 peptide in a reaction solution (60 mM 4-hydroxyethyl-piperazineethanesulfonic acid (HEPES), pH =7.2, 75mM NaCl, 75mM KCl, 1mM EDTA, 0.05% Tween 20, 2mM Dithiothreitol (DTT)) for 30 minutes to activate PTP, DMSO (0.5% (V/V)) or a compound (concentration 0.3 nM-1. mu.M) is added to the mixture, incubating is continued at room temperature for 30 minutes, DiFMUP (12. mu.M, reaction solution 100. mu.L) is added to start the reaction, incubating is kept away from light for 30 minutes at room temperature, and SHP2 inhibitory activity, IC, corresponding to the compound shown in formula 1-23 is obtained by detecting the fluorescence intensity of the reaction solution (excitation light 340nM, emission 450 nM)50See table 1 below: (Note: IC corresponding to the compound represented by the formula 1 in Table 150And the rest is grade B, and so on. )
TABLE 1
Structural formula of compound IC50 Structural formula of compound IC50
Formula 1 B Formula 13 A
Formula 2 A Formula 14 A
Formula 3 A Formula 15 A
Formula 4 A Formula 16 B
Formula 5 C Formula 17 C
Formula 6 B Formula 18 B
Formula 7 B Formula 19 B
Formula 8 C Formula 20 A
Formula 9 C Formula 21 C
Formula 10 C Formula 22 B
Formula 11 A Formula 23 A
Formula 12 B
Wherein A is less than 100nM, B is more than or equal to 100nM and less than or equal to 1000 nM, and C is more than or equal to 1000 nM.
In this example, compounds of formula 1-23 were included as SHP2 inhibitors for the treatment of tumors. Among them, the compounds corresponding to the A and B grades, which are used as SHP2 inhibitor, have good activity; especially the compound corresponding to the A gear has the best activity.
The compounds shown in the formulas 1-23 are used as SHP2 inhibitors, and have great guiding value in clinical trial research of tumor drugs.
The tumor is any one of 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, kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytic cancer, meningioma, Hodgkin lymphoma, non-Hodgkin 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, chondrosarcoma, myosarcoma, fibrosarcoma and esophageal squamous carcinoma.
24.2 human esophageal squamous carcinoma cell proliferation assay
KYSE-520 cells are inoculated into a 96-well plate by adjusting the concentration of the cell with RPMI-1640 culture solution of 3% fetal calf serum, after 24 hours of culture, compounds with different concentrations prepared by the culture solution of 3% fetal calf serum are added for incubation, on day 6, 50 mu of LMTS/PMS mixed solution is added into each well, the light absorption value is detected according to the instruction (Promega), and IC corresponding to the compounds shown as formulas 1-2350The values are shown in table 2:
TABLE 2
Structural formula of compound IC50(μM) Compound (I) IC50(μM)
Formula 2 11.5 Formula 13 25.6
Formula 3 20.6 Formula 14 15.5
Formula 4 16.4 Formula 15 16.7
Formula 11 12.8 Formula 20 9.0
As can be seen from table 2: the IC of the compounds of formula 2,3, 4, 11, 13, 14, 15, 20 in assays for the inhibition of proliferation of human esophageal squamous carcinoma cells as SHP2 inhibitors50The value is far less than 100 mu M, which indicates that the SHP2 inhibitor containing the compounds shown in the formulas 2,3, 4, 11, 13, 14, 15 and 20 can obviously inhibit the proliferation of human esophageal squamous cell carcinoma cells.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (8)

  1. The 4-hydroxymethyl-1H-indole compound or pharmaceutically acceptable salt thereof is characterized in that the 4-hydroxymethyl-1H-indole compound has a structure shown in a formula I:
    Figure DEST_PATH_IMAGE001
    ；
    wherein R is1And R2Together construct 2-oxo-8-azaspiro [4.5]]Decan-8-yl, 1, 8-diazaspiro [4.5]]Decan-8-yl, 2, 8-diazaspiro [4.5]]One of decan-8-yl, 4-amino-4-methylpiperidin-1-yl, 3, 5-dimethylpiperazin-1-yl;
    R3represents one of 2-chloro-6-fluorophenyl, 3-chloropyridin-4-yl, 2-chloro-6-methoxyphenyl, 2, 6-dichlorophenyl and 2, 3-dichlorophenyl.
  2. 2. The 4-hydroxymethyl-1H-indole compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the 4-hydroxymethyl-1H-indole compound is selected from any one of the following formulas 1 to 23, and has the following structural formula:
    Figure 885754DEST_PATH_IMAGE002
    formula 1
    Figure DEST_PATH_IMAGE003
    Formula 2
    Figure 537315DEST_PATH_IMAGE004
    Formula 3
    Figure DEST_PATH_IMAGE005
    Formula 4
    Figure 35161DEST_PATH_IMAGE006
    Formula 5
    Figure DEST_PATH_IMAGE007
    Formula 6
    Figure 102474DEST_PATH_IMAGE008
    Formula 7
    Figure DEST_PATH_IMAGE009
    Formula 8
    Figure 385688DEST_PATH_IMAGE010
    Formula 9
    Figure DEST_PATH_IMAGE011
    Formula 10
    Figure 395101DEST_PATH_IMAGE012
    Formula 11
    Figure DEST_PATH_IMAGE013
    Formula 12
    Figure 396555DEST_PATH_IMAGE014
    Formula 13
    Figure DEST_PATH_IMAGE015
    Formula 14
    Figure 64297DEST_PATH_IMAGE016
    Formula 15
    Figure DEST_PATH_IMAGE017
    Formula 16
    Figure 657477DEST_PATH_IMAGE018
    Formula 17
    Figure DEST_PATH_IMAGE019
    Formula 18
    Figure 119682DEST_PATH_IMAGE020
    Formula 19
    Figure DEST_PATH_IMAGE021
    Formula 20
    Figure 608433DEST_PATH_IMAGE022
    Formula 21
    Figure DEST_PATH_IMAGE023
    Formula 22
    Figure 63554DEST_PATH_IMAGE024
    And (3) formula 23.
  3. 3. The process for preparing 4-hydroxymethyl-1H-indoles or pharmaceutically acceptable salts thereof as claimed in claim 1, comprising the steps of:
    Figure DEST_PATH_IMAGE025
    1) reacting the compound shown in the formula II with the compound shown in the formula III under the action of a catalyst to obtain a compound shown in the formula IV;
    2) reacting the compound shown in the formula IV under the action of a reducing agent to obtain a compound shown in a formula V;
    3) and reacting the compound shown in the formula V with the compound shown in the formula VI under the action of a catalyst to obtain the compound shown in the formula I.
  4. 4. The method for preparing 4-hydroxymethyl-1H-indoles or their pharmaceutically acceptable salts as claimed in claim 3, wherein in the step of synthesizing the compound of formula IV, the reaction temperature is 40-120 ℃;
    and/or, the reaction is carried out in an alkaline environment, and the alkali is at least one of potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium phosphate and sodium acetate;
    and/or the catalyst is selected from at least one of bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) palladium, palladium acetate, 1' - [ bis (diphenylphosphino) ferrocene ] palladium dichloride;
    and/or the ligand in the reaction is at least one selected from 1,1' -binaphthyl-2, 2' -bis-diphenylphosphine, triphenylphosphine, tributylphosphine, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene;
    and/or the reaction solvent is at least one of toluene, dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide.
  5. 5. The method for preparing 4-hydroxymethyl-1H-indoles or their pharmaceutically acceptable salts as claimed in claim 3, wherein in the step of synthesizing the compound of formula V, the reaction temperature is 0-60 ℃;
    and/or the reducing agent is at least one of lithium aluminum hydride, sodium borohydride, boron trifluoride and aluminum trichloride;
    and/or the reaction solvent is at least one of methanol, ethanol, tetrahydrofuran and acetonitrile.
  6. 6. The method for preparing 4-hydroxymethyl-1H-indoles or their pharmaceutically acceptable salts as claimed in claim 3, wherein in the step of synthesizing the compound of formula I, the reaction temperature is 40-120 ℃;
    and/or, the reaction is carried out in an alkaline environment, and the alkali is at least one of potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium phosphate and sodium acetate;
    and/or, the catalyst is selected from at least one of cuprous iodide, cuprous chloride and cupric oxide;
    and/or the ligand in the reaction is at least one selected from L-proline, cyclohexyl diamine and N, N' -dimethylethylene diamine;
    and/or the reaction solvent is at least one of toluene, dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide.
  7. 7. The use of the 4-hydroxymethyl-1H-indoles of claim 1 or 2 or their pharmaceutically acceptable salts as SHP2 inhibitors in the manufacture of a medicament for the treatment or prevention of tumors.
  8. 8. The use of 4-hydroxymethyl-1H-indoles or pharmaceutically acceptable salts thereof as an SHP2 inhibitor for the manufacture of a medicament for the treatment or prevention of a tumor as claimed in claim 7, wherein the tumor is 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, kidney cancer, cervical 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 myelogenous leukemia, chronic granulocytic leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, multiple myeloma, basal cell tumor, seminoma, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, renal cancer, cervical cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytoma, meningio, Chondrosarcoma, myosarcoma, fibrosarcoma, and esophageal squamous carcinoma.
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