CN113527254B - 7-methoxy-1H-indole compound, preparation method, pharmaceutical composition and application - Google Patents

7-methoxy-1H-indole compound, preparation method, pharmaceutical composition and application Download PDF

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CN113527254B
CN113527254B CN202110767317.8A CN202110767317A CN113527254B CN 113527254 B CN113527254 B CN 113527254B CN 202110767317 A CN202110767317 A CN 202110767317A CN 113527254 B CN113527254 B CN 113527254B
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CN113527254A (en
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王永广
牛永涛
孙学涛
苏小庭
戴信敏
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Beijing Huashi Xinhuake Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Abstract

The invention relates to a 7-methoxy-1H-indole compound, a preparation method, a pharmaceutical composition and application, and belongs to the technical field of chemical drugs. The 7-methoxy-1H-indole compound has a structure shown in a formula I:
Figure DDA0003151255190000011
wherein R is1Represents a substituted or unsubstituted phenyl or an aromatic heterocyclic group, R2Represents a substituted or unsubstituted phenyl or an aromatic heterocyclic group, R1And R2May be the same or different. The 7-methoxy-1H-indole compounds, pharmaceutically acceptable salts and pharmaceutical compositions containing the compounds as active ingredients are used as GnRH antagonists for treating sex hormone related diseases, and have small side effects; the therapeutic objectives can be achieved by administering to a patient in need of such treatment or prevention a therapeutically effective amount of one or more of the 7-methoxy-1H-indoles of the present invention. The synthesis method of the 7-methoxy-1H-indole compound has few byproducts and high yield.

Description

7-methoxy-1H-indole compound, preparation method, pharmaceutical composition and application
Technical Field
The invention relates to a 7-methoxy-1H-indole compound, a preparation method, a pharmaceutical composition and application, and belongs to the technical field of chemical drugs.
Background
Gonadotropin-releasing hormone (GnRH), a decapeptide released from the hypothalamus, also known as luteinizing hormone-releasing hormone, is known as a hormone controlling sex hormone secretion at the uppermost position, and acts on the pituitary to stimulate biosynthesis and release of Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). Wherein LH is responsible for regulating the production of gonadal steroids in both sexes and regulating late ovarian follicular development and ovulation in female mammals. FSH regulates the formation of spermatozoa in males and follicular development in females. Since specific modulators of GnRH receptors can control the secretion of lower LH, FSH and sex hormones, they are expected to be used as gonadal-dependent diseases, for example: prevention and treatment of prostate cancer, breast cancer, endometriosis, uterine fibroids, and the like.
Leuprorelin is used as GnRH agonist for treating endometriosis, hysteromyoma, etc. and it induces the synthesis and release of gonadotropin through the GnRH receptor combination on pituitary gonadotropic cells. Chronic administration of GnRH agonists then reduces gonadotropin release from the pituitary and results in receptor downregulation, resulting in suppression of sex steroid hormone production after treatment. Moreover, the oral bioavailability of peptide compounds is low, limiting their clinical use.
Thus, the study and discovery of a novel and orally effective small molecule GnRH modulator, particularly compounds having antagonistic activity and pharmaceutical compositions containing such GnRH receptor antagonists, is of great interest for the treatment of sex hormone related disorders.
Disclosure of Invention
The present investigators have discovered that 7-methoxy-1H-indoles have activity as antagonists of GnRH receptors for treating sex hormone related disorders. The 7-methoxy-1H-indole compound and the pharmaceutically acceptable salt thereof have pharmacological activity of antagonizing GnRH receptors, and the specific technical scheme is as follows:
the 7-methoxy-1H-indole compound has a structure shown in a formula I:
Figure BDA0003151255180000021
wherein R is1Represents a substituted or unsubstituted phenyl or an aromatic heterocyclic group, R2Represents a substituted or unsubstituted phenyl or an aromatic heterocyclic group, R1And R2May be the same or different.
The 7-methoxy-1H-indole compound is selected from any one of the following compounds in a formula 1-formula 10, and the structural formula is as follows:
Figure BDA0003151255180000022
formula 1
Figure BDA0003151255180000023
Formula 2
Figure BDA0003151255180000024
Formula 3
Figure BDA0003151255180000031
Formula 4
Figure BDA0003151255180000032
Formula 5
Figure BDA0003151255180000033
Formula 6
Figure BDA0003151255180000034
Formula 7
Figure BDA0003151255180000041
Formula 8
Figure BDA0003151255180000042
Formula 9
Figure BDA0003151255180000043
Formula 10.
The preparation method of the 7-methoxy-1H-indole compound or the pharmaceutically acceptable salt thereof comprises the following steps:
Figure BDA0003151255180000051
step 1), synthesis of compound IV (the structural formula of the compound IV is shown as IV, and the like below)
Reacting a compound II, a compound III, alkali and a catalyst in a reaction solvent to obtain a compound IV; wherein the reaction temperature is 40-120 ℃; the base is at least one selected from triethylamine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium phosphate and sodium acetate; the catalyst is selected from bis (triphenylphosphine) palladium (II) dichloride and tetrakis (triphenylphosphine) palladium (molecular formula is Pd (PPh)3)4) Bis (dibenzylideneacetone) palladium, palladium acetate (molecular formula is Pd (OAc))2) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (molecular formula is Pd (dppf)) Cl2) At least one of; the reaction solvent is at least one selected from toluene, acetonitrile, dioxane, dimethyl sulfoxide, N-Dimethylformamide (DMF) and dimethylacetamide.
Step 2) Synthesis of Compound VI
Carrying out coupling reaction on the compound IV, the compound V, alkali and a catalyst in a reaction solvent to obtain a compound VI; wherein the reaction temperature is 80-120 ℃, and the alkali is at least one selected from cesium carbonate, sodium tert-butoxide, potassium tert-butoxide and potassium carbonate; the catalyst is selected from tetrakis (triphenylphosphine) palladium (with the molecular formula of Pd (PPh)3)4) Palladium acetate (molecular formula is Pd (OAc))2) Tris (dibenzylideneacetone) dipalladium (A)Molecular formula is Pd2(dba)3) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (molecular formula is Pd (dppf)) Cl2) At least one of; the reaction solvent is at least one selected from Dioxane (English name), N-dimethylformamide and toluene.
Step 3), Synthesis of Compound VII
Reacting the compound VI with acid in a reaction solvent to obtain a compound VII; wherein the reaction temperature is 20-80 ℃; the acid is at least one of trifluoroacetic acid, ethyl acetate solution of hydrogen chloride and ethanol solution of hydrogen chloride; the reaction solvent is at least one of dichloromethane, ethanol and ethyl acetate.
Step 4), Synthesis of Compound VIII
The compound VII is firstly reacted under the action of hydrochloric acid and sodium nitrite, and the reaction temperature is-10 ℃ to 30 ℃; then reacting under the action of tin dichloride at the reaction temperature of 0-30 ℃ to obtain a compound VIII.
Step 5), Synthesis of Compound X
Reacting a compound VIII, a compound IX and an acid in a reaction solvent to obtain a compound X; wherein the reaction temperature is 0-100 ℃; the acid is at least one of acetic acid, formic acid, phosphoric acid, polyphosphoric acid, sulfuric acid, zinc chloride, ferric chloride, aluminum chloride and boron trifluoride; the reaction solvent is at least one of methanol, ethanol and acetic acid.
Step 6), Synthesis of Compound XI
Carrying out hydrogenation reaction on the compound X in a reaction solvent under the action of palladium carbon (Pd-C for short in English) to obtain a compound XI; wherein the reaction temperature is 20-40 ℃; the reaction solvent is at least one of methanol, ethanol, tetrahydrofuran and dioxane.
Step 7), Synthesis of Compound I
Reacting a compound XI, O-methylhydroxylamine hydrochloride, N' -carbonyldiimidazole (CDI for short), and alkali in a reaction solvent to obtain a compound I; wherein the reaction temperature is 20-100 ℃; the base is at least one of triethylamine, diisopropylethylamine (DIPEA for short), and N-methylmorpholine; the reaction solvent is at least one of N, N-Dimethylformamide (DMF), dichloromethane, acetonitrile, tetrahydrofuran and dioxane.
A pharmaceutical composition comprising: the 7-methoxy-1H-indole compound or the pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or diluents.
The 7-methoxy-1H-indole compound or the pharmaceutically acceptable salt thereof is applied to the preparation of medicines for treating or preventing sex hormone related diseases.
The sex hormone related disease is selected from any one of uterine leiomyoma, prostate cancer, breast cancer, ovarian cancer, endometriosis, assisted reproductive therapy and precocious puberty.
The invention has the beneficial effects that:
1) the 7-methoxy-1H-indole compound, the pharmaceutically acceptable salt and the pharmaceutical composition containing the compounds as active ingredients are used as GnRH antagonists for treating sex hormone related diseases, and have small side effects; therapeutic objectives can be achieved by administering to a patient in need of such treatment or prevention a therapeutically effective amount of one or more of the 7-methoxy-1H-indoles of the present invention.
2) The synthesis method of the 7-methoxy-1H-indole compound has the advantages of few byproducts and high yield in the synthesis reaction process, and has great application value.
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.
Definition of
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. The salt comprises: acid addition salts obtained by reaction of the free base of the parent compound with an inorganic acid or with an organic acid; such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, and the like; such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, malonic acid, or the like; preferably hydrochloric acid or (L) -malic acid; or when the acid proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or coordinated with an organic base, a salt is formed; such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
"substituted" means that 1, 2 or more hydrogen atoms in a molecule are replaced by a different atom or molecule, including 1, 2 or more substitutions on the same or different atoms in the molecule. The 'aromatic heterocycle' is a heterocycle with the characteristic of plain structure, atoms in the heterocycle form a closed-loop conjugated system, molecules are planar, annular delocalized electron clouds are arranged on the upper side and the lower side of the plane, and the number of P electrons in the conjugated system conforms to the Huckel rule. For example: pyridine, furan ring, thiazole ring, pyrimidine ring, etc.
The compounds of the invention may have one or more asymmetric centers; the compounds can thus be prepared as individual (R) -stereoisomers or (S) -stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or designation of a particular compound in the specification and claims is intended to include the individual enantiomers as well as racemic or other mixtures thereof. Methods for determining stereochemical configuration and separating stereoisomers are well known in the art (see the discussion in chapter 4 of "Advanced Organic Chemistry", 4 th edition, j. march, John Wiley and Sons, new york, 1992). Thus, the present invention also encompasses any stereoisomeric form having antagonistic GnRH receptor activity, its corresponding enantiomers (d-and l-or (+) and (-) isomers) and its diastereoisomers and mixtures thereof and is not limited to any one stereoisomeric form.
Example 1
A compound of formula 1: 1- (4- (4- (cyclopropyl (2, 6-difluorophenyl) amino) -6- (2-fluoro-4-methoxyphenyl) -7-methoxy-1H-indol-2-yl) -3-fluorophenyl) -3-methoxyurea; the synthesis reaction formula is as follows:
Figure BDA0003151255180000081
the first step is as follows: a mixture of compound 1a (113.7g, 300.0mmol), compound 1b (50.7g, 300.0mmol), Pd (dppf) Cl2Dissolving (11.0g, 15.0mmol) and potassium carbonate (92.9g, 720mmol) in DMF (800mL), heating to 100 ℃ and keeping the temperature for reaction for 10 hours, monitoring the reaction by TLC, adding water (500mL) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (500mL multiplied by 2), combining organic layers, drying and concentrating the organic layers, and performing column chromatography to obtain 106.4g of light yellow solid (compound 1c) with the yield of 75.8%. Wherein, the structural formula of the compound 1a is shown as the formula 1a, and the rest compounds are analogized in the same way.
The second step is that: a mixture of compound 1c (106.0g, 226.4mmol), compound 1d (38.5g, 226.4mmol), Pd (PPh)3)4(13.1g, 11.32mmol), cesium carbonate (110.0g, 339.6mmol) were dissolved in dioxane (500mL) and purified water (300mL), the temperature was raised to 80 ℃ and the reaction was stirred for 10 hours, the reaction was monitored by TLC, after completion of the reaction, extraction was performed with ethyl acetate (500 mL. times.2), the organic layer was concentrated and column chromatography was performed to obtain 78.3g (Compound 1e) as an off-white solid with a yield of 65.5%.
The third step: compound 1e (78.0g, 151.8mmol) was dissolved in dichloromethane (500mL), trifluoroacetic acid (200mL) 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 under reduced pressure, then pH was adjusted to 8-9 with saturated sodium carbonate solution, extraction was performed with ethyl acetate (400mL × 2), organic layers were combined, dried, filtered, and separated by column chromatography to give 48.4g of off-white solid (compound 1f) in 77.0% yield.
The fourth step: dissolving the compound 1f (48.0g, 115.9mmol) in hydrochloric acid solution (4mol/L, 300mL), adding sodium nitrite (16.0g, 231.9mmol) under ice bath, keeping the temperature and stirring for reaction for 3 hours, then adding tin dichloride (66.1g, 347.9mmol), heating to 30 ℃ for reaction for 5 hours, monitoring the reaction by TLC, after the reaction is finished, adding saturated sodium carbonate solution to adjust the pH to 8-9, extracting with ethyl acetate (600 mL. times.2), combining organic layers, drying, filtering, and separating by column chromatography to obtain 36.8g of off-white solid (compound 1g) with the yield of 74.0%.
The fifth step: dissolving compound 1g (4.3g, 10.0mmol) and compound 1h (2.4g, 10.0mmol) in acetic acid (50mL), heating to 50 deg.C, stirring for 4 hr, monitoring reaction by TLC, removing acetic acid under reduced pressure after reaction, adding water (50mL), quenching reaction, extracting with ethyl acetate (2X 50mL), combining organic layers, drying, concentrating, and separating by column chromatography to obtain off-white solid 3.5g (compound 1i) with yield of 54.9%.
And a sixth step: compound 1i (3.5g, 5.4mmol) was dissolved in methanol (30mL), palladium on carbon (500mg) was added at room temperature, hydrogen was replaced 3 times, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, filtration was carried out, and the filtrate was concentrated to give 2.2g of an off-white solid (Compound 1j), yield 74.5%.
The seventh step: compound 1j (2.0g, 3.7mmol), CDI (599mg, 3.7mmol), DIPEA (954mg, 7.4mmol) were dissolved in DMF (30mL), stirred for reaction at room temperature for 2 hours, then O-methylhydroxylamine hydrochloride (307mg, 3.7mmol) was added, stirred for reaction for 6 hours, TLC monitored for reaction, quenched with 50mL water after completion of reaction, extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried, filtered, and isolated by column chromatography to give 1.2g of an off-white solid (compound 1) with a yield of 52.3% and ESI (+) m/z ═ 621.2.
Example 2
A compound of formula 2: 1- (4- (4- ((2-chloro-6-fluorophenyl) (cyclopropyl) amino) -6- (2-fluoro-4-methoxyphenyl) -7-methoxy-1H-indol-2-yl) -3-fluorophenyl) -3-methoxyurea; the synthesis reaction formula is as follows:
Figure BDA0003151255180000091
the first step is as follows: a mixture of compound 1a (37.9g, 100.0mmol), compound 2a (18.5g, 100.0mmol), Pd (dppf) Cl2Dissolving (3.7g, 5.0mmol) and potassium carbonate (20.7g, 150.0mmol) in DMF (200mL), heating to 100 ℃ for reaction under constant temperature for 10 hours, monitoring the reaction by TLC, adding water (200mL) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (200mL multiplied by 2), combining organic layers, drying, concentrating and separating by column chromatography to obtain light yellow solid 36.4g (compound 2b) with yield of 75.2%.
The second step is that: compound 2b (35.0g, 72.3mmol), compound 1d (12.3g, 72.3mmol), Pd (PPh)3)4(4.2g, 3.6mmol), cesium carbonate (35.1g, 108.5mmol) were dissolved in dioxane (300mL) and purified water (200mL), the temperature was raised to 80 ℃ and the reaction was stirred for 10 hours, the reaction was monitored by TLC, after completion of the reaction, extraction was performed with ethyl acetate (500 mL. times.2), the organic layer was concentrated and column chromatography was performed to obtain 26.5g of an off-white solid (Compound 2c) with a yield of 69.2%.
The third step: compound 2c (26.0g, 49.1mmol) was dissolved in dichloromethane (300mL), trifluoroacetic acid (100mL) 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 under reduced pressure, then pH was adjusted to 8-9 with saturated sodium carbonate solution, extraction was performed with ethyl acetate (400mL × 2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 15.1g of off-white solid (compound 2d) with a yield of 71.6%.
The fourth step: dissolving the compound 2d (15.0g, 34.9mmol) in hydrochloric acid solution (4mol/L, 300mL), adding sodium nitrite (4.8g, 69.8mmol) under ice bath, stirring for reaction at constant temperature for 3 hours, then adding tin dichloride (19.9g, 104.7mmol), heating to 30 ℃ for 5 hours, monitoring the reaction by TLC, after the reaction is finished, adding saturated sodium carbonate solution to adjust the pH to 8-9, extracting with ethyl acetate (300 mL. times.2), combining organic layers, drying, filtering, and separating by column chromatography to obtain 11.3g of off-white solid (compound 2e) with the yield of 72.8%.
The fifth step: dissolving compound 2e (4.5g, 10.0mmol) and compound 1h (2.4g, 10.0mmol) in acetic acid (50mL), heating to 50 deg.C, stirring for 4 hours, monitoring the reaction by TLC, removing acetic acid under reduced pressure after the reaction is finished, adding water (50mL) to quench the reaction, extracting with ethyl acetate (2X 50mL), combining organic layers, drying, concentrating, and separating by column chromatography to obtain off-white solid 4.4g (compound 2f) with yield of 67.4%.
And a sixth step: compound 2f (4.0g, 6.1mmol) was dissolved in methanol (30mL), palladium on carbon (500mg) was added at room temperature, hydrogen was substituted for 3 times, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, filtration was carried out, and the filtrate was concentrated to give 3.1g (compound 2g) of an off-white solid in a yield of 90.4%.
The seventh step: compound 2g (563mg, 1.0mmol), CDI (194mg, 1.2mmol), DIPEA (387mg, 3.0mmol) were dissolved in DMF (30mL), stirred at room temperature for reaction for 2 hours, then O-methylhydroxylamine hydrochloride (88mg, 1.0mmol) was added, stirred for reaction for 8 hours, monitored by TLC, after the reaction was completed, 50mL of water was added to quench the reaction, extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 356mg of off-white solid (compound 2) in 56.0% yield, ESI (+) m/z was 637.2.
Example 3
A compound of formula 3: 1- (4- (4- (cyclopropyl (2-fluoro-6-methoxyphenyl) amino) -6- (2-fluoro-4-methoxyphenyl) -7-methoxy-1H-indol-2-yl) -3-fluorophenyl) -3-methoxyurea; the synthesis reaction formula is as follows:
Figure BDA0003151255180000111
the first step is as follows: a mixture of compound 1a (37.9g, 100.0mmol), compound 3a (18.1g, 100.0mmol), Pd (dppf) Cl2(3.7g, 5.0mmol) and potassium carbonate (20.7g, 150.0mmol) are dissolved in DMF (200mL), the temperature is raised to 100 ℃ and the reaction is kept for 10 hours, TLC monitors the reaction, after the reaction is finished, water (200mL) is added to quench the reaction, ethyl acetate (200mL multiplied by 2) is used for extraction, organic layers are combined, dried, concentrated and separated by column chromatography to obtain 34.5g of light yellow solid (compound 3b), and the yield is 71.9%.
The second step is that: compound 3b (24.0g, 50.0mmol), compound 1d (8.5g, 50.0mmol), Pd (PPh)3)4(2.9g, 2.5mmol), cesium carbonate (32.4g, 100.0mmol) in dioxane (300mL)And purified water (200mL), heated to 80 ℃ and stirred for reaction for 10 hours, the reaction was monitored by TLC, after completion of the reaction, extraction was performed with ethyl acetate (500 mL. times.2), the organic layer was concentrated, and column chromatography was performed to obtain 18.4g of an off-white solid (Compound 3c) in a yield of 70.0%.
The third step: compound 3c (15.0g, 28.5mmol) was dissolved in dichloromethane (200mL), trifluoroacetic acid (50mL) was added at room temperature, the reaction was stirred at room temperature for 4 hours, TLC monitored, after the reaction was completed, the solvent was removed under reduced pressure, then pH was adjusted to 8-9 with saturated sodium carbonate solution, extraction was performed with ethyl acetate (200mL × 2), organic layers were combined, dried, filtered, and separated by column chromatography to give 11.3g of off-white solid (compound 3d) with a yield of 93.1%.
The fourth step: dissolving the compound 3d (11.0g, 25.8mmol) in hydrochloric acid solution (4mol/L, 200mL), adding sodium nitrite (3.6g, 51.6mmol) under ice bath, keeping the temperature and stirring for reaction for 3 hours, then adding tin dichloride (19.6g, 103.2mmol), heating to 30 ℃ for reaction for 5 hours, monitoring the reaction by TLC, after the reaction is finished, adding saturated sodium carbonate solution to adjust the pH to 8-9, extracting with ethyl acetate (300mL multiplied by 2), combining organic layers, drying, filtering, and separating by column chromatography to obtain 7.8g of off-white solid (compound 3e), wherein the yield is 54.1%.
The fifth step: dissolving compound 3e (5.6g, 10.0mmol) and compound 1h (2.4g, 10.0mmol) in acetic acid (50mL), heating to 50 deg.C, stirring for 4 hr, monitoring reaction by TLC, removing acetic acid under reduced pressure after reaction, adding water (50mL), quenching reaction, extracting with ethyl acetate (2X 50mL), combining organic layers, drying, concentrating, and separating by column chromatography to obtain off-white solid 4.1g (compound 3f) with yield of 64.9%.
And a sixth step: compound 3f (4.0g, 6.3mmol) was dissolved in methanol (30mL), palladium on carbon (500mg) was added at room temperature, hydrogen gas was substituted for 3 times, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, filtration was carried out, and the filtrate was concentrated to give 2.7g (compound 3g) of an off-white solid in a yield of 76.7%.
The seventh step: compound 3g (559mg, 1.0mmol), CDI (194mg, 1.2mmol) and DIPEA (387mg, 3.0mmol) were dissolved in DMF (30mL), stirred at room temperature for reaction for 2 hours, then O-methylhydroxylamine hydrochloride (88mg, 1.0mmol) was added, stirred for reaction for 8 hours, monitored by TLC, after the reaction was completed, 50mL of water was added to quench the reaction, extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried, filtered, and isolated by column chromatography to give 405mg of off-white solid (compound 3) in 64.1% yield and ESI (+) m/z 633.2.
Example 4
A compound of formula 4: 1- (4- (4- (cyclopropyl (2, 6-dimethoxyphenyl) amino) -6- (2-fluoro-4-methoxyphenyl) -7-methoxy-1H-indol-2-yl) -3-fluorophenyl) -3-methoxyurea; the synthesis reaction formula is as follows:
Figure BDA0003151255180000121
the first step is as follows: a mixture of compound 1a (37.9g, 100.0mmol), compound 4a (19.3g, 100.0mmol), Pd (dppf) Cl2(3.7g, 5.0mmol) and potassium carbonate (20.7g, 150.0mmol) are dissolved in DMF (200mL), the temperature is raised to 100 ℃ and the reaction is kept for 8 hours, TLC monitors the reaction, after the reaction is finished, water (200mL) is added to quench the reaction, ethyl acetate (200mL multiplied by 2) is used for extraction, organic layers are combined, dried, concentrated and separated by column chromatography to obtain 30.5g (compound 4b) of light yellow solid with the yield of 62.0%.
The second step is that: compound 4b (30.0g, 61.0mmol), compound 1d (10.4g, 61.0mmol), Pd (PPh)3)4(3.5g, 3.0mmol) and cesium carbonate (39.5g, 122.0mmol) were dissolved in dioxane (300mL) and purified water (200mL), the temperature was raised to 80 ℃ and the reaction was stirred for 8 hours, the reaction was monitored by TLC, after completion of the reaction, extraction was performed with ethyl acetate (500 mL. times.2), the organic layer was concentrated and column chromatography was performed to obtain 26.4g of an off-white solid (Compound 4c) with a yield of 80.4%.
The third step: compound 4c (26.0g, 48.3mmol) was dissolved in dichloromethane (200mL), trifluoroacetic acid (50mL) was added at room temperature, the reaction was stirred at room temperature for 4 hours, TLC monitored, after the reaction was completed, the solvent was removed under reduced pressure, then pH was adjusted to 8-9 with saturated sodium carbonate solution, extraction was performed with ethyl acetate (200mL × 2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 15.2g of off-white solid (compound 4d) with a yield of 71.8%.
The fourth step: dissolving compound 4d (15.0g, 34.2mmol) in hydrochloric acid solution (4mol/L, 200mL), adding sodium nitrite (4.7g, 68.4mmol) under ice bath, stirring for reaction at constant temperature for 3 hours, then adding tin dichloride (26.0g, 136.8mmol), heating to 30 ℃ for reaction for 5 hours, monitoring the reaction by TLC, after the reaction is finished, adding saturated sodium carbonate solution to adjust pH to 8-9, extracting with ethyl acetate (300 mL. times.2), combining organic layers, drying, filtering, and separating by column chromatography to obtain 8.7g of off-white solid (compound 4e), wherein the yield is 51.6%.
The fifth step: dissolving compound 4e (4.5g, 10.0mmol) and compound 1h (2.4g, 10.0mmol) in acetic acid (50mL), heating to 50 deg.C, stirring for 4 hours, monitoring the reaction by TLC, removing acetic acid under reduced pressure after the reaction is finished, adding water (50mL) to quench the reaction, extracting with ethyl acetate (2X 50mL), combining organic layers, drying, concentrating, and separating by column chromatography to obtain off-white solid 3.6g (compound 4f) with yield 54.5%.
And a sixth step: compound 4f (3.0g, 4.5mmol) was dissolved in methanol (30mL), palladium on carbon (500mg) was added at room temperature, hydrogen was substituted for 3 times, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, filtration was carried out, and the filtrate was concentrated to give 1.8g (compound 4g) of an off-white solid with a yield of 69.5%.
The seventh step: compound 4g (571mg, 1.0mmol), CDI (194mg, 1.2mmol), DIPEA (387mg, 3.0mmol) were dissolved in DMF (30mL), stirred at room temperature for 2 hours, then O-methylhydroxylamine hydrochloride (88mg, 1.0mmol) was added, stirred for 8 hours, monitored by TLC, after the reaction was completed, 50mL of water was added to quench the reaction, extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 508mg (compound 4) as an off-white solid in 78.9% yield and ESI (+) m/z 645.2.
Example 5
A compound of formula 5: 1- (4- (4- (cyclopropyl (2- (dimethylamino) -6-fluorophenyl) amino) -6- (2-fluoro-4-methoxyphenyl) -7-methoxy-1H-indol-2-yl) -3-fluorophenyl) -3-methoxyurea; the synthesis reaction formula is as follows:
Figure BDA0003151255180000141
the first step is as follows: compound 1a (37.9g, 100.0mmol), compound 5a (19.4g, 100.0mmol), Pd (dppf) Cl2(3.7g, 5.0mmol) and potassium carbonate (20.7g, 150.0mmol) are dissolved in DMF (200mL), the temperature is raised to 100 ℃ and the reaction is kept for 8 hours, TLC monitors the reaction, after the reaction is finished, water (200mL) is added to quench the reaction, ethyl acetate (200mL multiplied by 2) is used for extraction, organic layers are combined, dried, concentrated and separated by column chromatography to obtain 33.1g (compound 5b) of light yellow solid, and the yield is 67.1%.
The second step is that: compound 5b (32.0g, 64.9mmol), compound 1d (11.0g, 64.9mmol), Pd (PPh)3)4(5.8g, 5.0mmol) and cesium carbonate (42.1g, 129.8mmol)) were dissolved in dioxane (300mL) and purified water (200mL), the temperature was raised to 80 ℃ and the reaction was stirred for 8 hours, the reaction was monitored by TLC, after completion of the reaction, extraction was performed with ethyl acetate (500 mL. times.2), the organic layer was concentrated and column chromatography was performed to obtain 28.7g of an off-white solid (Compound 5c) in 82.0% yield.
The third step: compound 5c (28.0g, 51.9mmol) was dissolved in dichloromethane (200mL), trifluoroacetic acid (50mL) was added at room temperature, the reaction was stirred at room temperature for 4 hours, TLC monitored, after the reaction was completed, the solvent was removed under reduced pressure, then pH was adjusted to 8-9 with saturated sodium carbonate solution, extraction was performed with ethyl acetate (200mL × 2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 14.8g of off-white solid (compound 5d) with a yield of 64.9%.
The fourth step: dissolving the compound 5d (13.2g, 30.0mmol) in hydrochloric acid solution (4mol/L, 200mL), adding sodium nitrite (4.1g, 60.0mmol) under ice bath, keeping the temperature and stirring for reaction for 3 hours, then adding stannic chloride (22.8g, 120.0mmol), heating to 30 ℃ for reaction for 5 hours, monitoring the reaction by TLC, after the reaction is finished, adding saturated sodium carbonate solution to adjust the pH to 8-9, extracting with ethyl acetate (300 mL. times.2), combining organic layers, drying, filtering, and separating by column chromatography to obtain 9.8g of off-white solid (compound 5e), wherein the yield is 72.1%.
The fifth step: dissolving compound 5e (4.5g, 10.0mmol) and compound 1h (2.4g, 10.0mmol) in acetic acid (50mL), heating to 50 deg.C, stirring for 4 hr, monitoring the reaction by TLC, removing acetic acid under reduced pressure after the reaction is finished, adding water (50mL) to quench the reaction, extracting with ethyl acetate (2X 50mL), combining organic layers, drying, concentrating, and separating by column chromatography to obtain off-white solid 5.1g (compound 5f) with yield of 77.0%.
And a sixth step: compound 5f (3.0g, 4.5mmol) was dissolved in methanol (30mL), palladium on carbon (500mg) was added at room temperature, hydrogen was substituted for 3 times, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, filtration was carried out, and the filtrate was concentrated to give 2.2g (compound 5g) of an off-white solid with a yield of 85.6%.
The seventh step: compound 5g (572mg, 1.0mmol), CDI (194mg, 1.2mmol), DIPEA (387mg, 3.0mmol) were dissolved in DMF (30mL), stirred at room temperature for 2 hours, then O-methylhydroxylamine hydrochloride (88mg, 1.0mmol) was added, stirred for 12 hours, monitored by TLC, after the reaction was completed, 50mL of water was added to quench the reaction, extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 458mg (compound 5) as an off-white solid with a yield of 71.0% and ESI (+) m/z 646.2.
Example 6
A compound of formula 6: 1- (4- (4- (cyclopropyl (2, 6-difluorophenyl) amino) -7-methoxy-6- (4-methoxyphenyl) -1H-indol-2-yl) -3-fluorophenyl) -3-methoxyurea; the synthesis reaction formula is as follows:
Figure BDA0003151255180000161
the first step is as follows: compound 1c (4.68g, 10.0mmol), compound 6a (1.5g, 10.0mmol), Pd (PPh)3)4(1.1g, 1.0mmol) and cesium carbonate (6.5g, 20.0mmol) were dissolved in dioxane (100mL) and purified water (100mL), the temperature was raised to 80 ℃ and the reaction was stirred for 5 hours, the reaction was monitored by TLC, after completion of the reaction, extraction was performed with ethyl acetate (500 mL. times.2), the organic layer was concentrated and column chromatography was performed to obtain 3.8g of an off-white solid (Compound 6b) with a yield of 76.6%.
The second step is that: compound 6b (3.8g, 7.7mmol) was dissolved in dichloromethane (20mL), trifluoroacetic acid (10mL) was added at room temperature, the reaction was stirred at room temperature for 4 hours, TLC monitored, after the reaction was completed, the solvent was removed under reduced pressure, then pH was adjusted to 8-9 with saturated sodium carbonate solution, extraction was performed with ethyl acetate (100mL × 2), organic layers were combined, dried, filtered, and column chromatography separated to give 1.8g of off-white solid (compound 6c) in 59.0% yield.
The third step: dissolving compound 6c (1.8g, 4.5mmol) in hydrochloric acid solution (4mol/L, 20mL), adding sodium nitrite (621mg, 9.0mmol) under ice bath, reacting for 3 hours under stirring at constant temperature, then adding tin dichloride (3.4g, 18.0mmol), heating to 30 ℃ for 8 hours, monitoring the reaction by TLC, after the reaction is finished, adding saturated sodium carbonate solution to adjust pH to 8-9, extracting with ethyl acetate (30 mL. times.2), combining organic layers, drying, filtering, and separating by column chromatography to obtain 1.4g of off-white solid (compound 6d) with yield of 75.8%.
The fourth step: compound 6d (1.2g, 2.9mmol) and compound 1h (709mg, 10.0mmol) were dissolved in acetic acid (20mL), the temperature was raised to 50 ℃ and the reaction was stirred for 4 hours, TLC monitored the reaction, after the reaction was completed, the acetic acid was removed under reduced pressure, water (50mL) was added to quench the reaction, extraction was performed with ethyl acetate (2 × 50mL), the organic layers were combined, dried, concentrated, and separated by column chromatography to give 1.2g of off-white solid (compound 6e) with a yield of 66.8%.
The fifth step: compound 6e (1.2g, 1.9mmol) was dissolved in methanol (30mL), palladium on carbon (200mg) was added at room temperature, hydrogen was substituted for 3 times, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, filtration was carried out, and the filtrate was concentrated to give 850mg of an off-white solid (Compound 6f) with a yield of 85.0%.
And a sixth step: compound 6f (529mg, 1.0mmol), CDI (194mg, 1.2mmol), DIPEA (387mg, 3.0mmol) were dissolved in DMF (30mL), stirred at room temperature for 2 hours, then O-methylhydroxylamine hydrochloride (88mg, 1.0mmol) was added, stirred for 12 hours, monitored by TLC, after the reaction was completed, 50mL of water was added to quench the reaction, extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried, filtered, and isolated by column chromatography to give 411mg (compound 6) as an off-white solid in 68.3% yield and ESI (+) m/z 603.2.
Example 7
A compound of formula 7: 1- (4- (4- (cyclopropyl (2, 6-difluorophenyl) amino) -7-methoxy-6- (6-methoxypyridin-3-yl) -1H-indol-2-yl) -3-fluorophenyl) -3-methoxyurea; the synthesis reaction formula is as follows:
Figure BDA0003151255180000171
the first step is as follows: compound 1c (4.68g, 10.0mmol), compound 7a (1.5g, 10.0mmol), Pd (PPh)3)4(1.1g, 1.0mmol), cesium carbonate (6.5g, 20.0mmol) were dissolved in dioxane (100mL) and purified water (100mL), the temperature was raised to 80 ℃ and the reaction was stirred for 5 hours, the reaction was monitored by TLC, after completion of the reaction, extraction was performed with ethyl acetate (500 mL. times.2), the organic layer was concentrated, and column chromatography was performed to obtain 4.2g of an off-white solid (Compound 7b) with a yield of 84.5%.
The second step is that: compound 7b (4.2g, 8.5mmol) was dissolved in dichloromethane (20mL), trifluoroacetic acid (10mL) was added at room temperature, the reaction was stirred at room temperature for 4 hours, TLC monitored, after the reaction was completed, the solvent was removed under reduced pressure, then pH was adjusted to 8-9 with saturated sodium carbonate solution, extraction was performed with ethyl acetate (100mL × 2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 2.4g of off-white solid (compound 7c) with a yield of 71.6%.
The third step: dissolving compound 7c (2.0g, 5.0mmol) in hydrochloric acid solution (4mol/L, 20mL), adding sodium nitrite (660mg, 10.0mmol) under ice bath, keeping the temperature and stirring for reaction for 3 hours, then adding tin dichloride (3.8g, 20.0mmol), heating to 30 ℃ for reaction for 6 hours, monitoring the reaction by TLC, after the reaction is finished, adding saturated sodium carbonate solution to adjust the pH to 8-9, extracting with ethyl acetate (30mL multiplied by 2), combining organic layers, drying, filtering, and separating by column chromatography to obtain 1.5g of off-white solid (compound 7d) with the yield of 72.8%.
The fourth step: compound 7d (1.4g, 3.4mmol) and compound 1h (825mg, 3.4mmol) were dissolved in acetic acid (20mL), the temperature was raised to 50 ℃ and the reaction was stirred for 4 hours, TLC monitored, after the reaction was completed, acetic acid was removed under reduced pressure, water (50mL) was added to quench the reaction, extraction was performed with ethyl acetate (2 × 50mL), the organic layers were combined, dried, concentrated, and separated by column chromatography to give 1.7g (compound 7e) as an off-white solid with a yield of 80.9%.
The fifth step: compound 7e (1.7g, 2.7mmol) was dissolved in methanol (30mL), palladium on carbon (200mg) was added at room temperature, hydrogen gas was substituted for 3 times, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, filtration was carried out, and the filtrate was concentrated to give 1.0g of an off-white solid (Compound 7f) with a yield of 69.0%.
And a sixth step: compound 7f (530mg, 1.0mmol), CDI (194mg, 1.2mmol), DIPEA (387mg, 3.0mmol) were dissolved in DMF (30mL), stirred at room temperature for 2 hours, then O-methylhydroxylamine hydrochloride (88mg, 1.0mmol) was added, stirred for 8 hours, the reaction was monitored by TLC, after completion of the reaction, quenched by addition of 50mL of water, extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried, filtered, and isolated by column chromatography to give 424mg of off-white solid (compound 7) in 70.3% yield and ESI (+) m/z ═ 604.2.
Example 8
A compound according to formula 8: 4- (4- (cyclopropyl (2, 6-difluorophenyl) amino) -2- (2-fluoro-4- (3-methoxyureido) phenyl) -7-methoxy-1H-indol-6-yl) -3-fluorobenzamide; the synthesis reaction formula is as follows:
Figure BDA0003151255180000191
the first step is as follows: compound 1c (4.68g, 10.0mmol), compound 8a (1.8g, 10.0mmol), Pd (PPh)3)4(1.1g, 1.0mmol), cesium carbonate (6.5g, 20.0mmol) were dissolved in dioxane (100mL) and purified water (100mL), the temperature was raised to 100 ℃ and the reaction was stirred for 8 hours, the reaction was monitored by TLC, after completion of the reaction, extraction was performed with ethyl acetate (50 mL. times.2), the organic layer was concentrated, and column chromatography was performed to obtain 3.9g of an off-white solid (Compound 8b) in 74.0% yield.
The second step is that: compound 8b (3.5g, 6.6mmol) was dissolved in dichloromethane (20mL), trifluoroacetic acid (10mL) was added at room temperature, the reaction was stirred at room temperature for 4 hours, TLC monitored, after the reaction was completed, the solvent was removed under reduced pressure, then pH was adjusted to 8-9 with saturated sodium carbonate solution, extraction was performed with ethyl acetate (100mL × 2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 2.2g (compound 8c) as an off-white solid in 78.1% yield.
The third step: dissolving the compound 8c (2.0g, 4.7mmol) in hydrochloric acid solution (4mol/L, 20mL), adding sodium nitrite (620mg, 9.4mmol) under ice bath, keeping the temperature and stirring for reaction for 3 hours, then adding tin dichloride (3.6g, 18.8mmol), heating to 30 ℃ for reaction for 6 hours, monitoring the reaction by TLC, after the reaction is finished, adding saturated sodium carbonate solution to adjust the pH to 8-9, extracting with ethyl acetate (80mL multiplied by 2), combining organic layers, drying, filtering, and carrying out column chromatography separation to obtain 1.2g of off-white solid (compound 8d) with the yield of 57.8%.
The fourth step: compound 8d (1.2g, 2.7mmol) and compound 1h (656mg, 2.7mmol) were dissolved in acetic acid (20mL), the temperature was raised to 50 ℃ and the reaction was stirred for 6 hours, TLC monitored, after the reaction was completed, the acetic acid was removed under reduced pressure, water (50mL) was added to quench the reaction, extraction was performed with ethyl acetate (2 × 50mL), the organic layers were combined, dried, concentrated, and separated by column chromatography to give 1.3g (compound 8e) of an off-white solid with a yield of 74.1%.
The fifth step: compound 8e (1.3g, 2.0mmol) was dissolved in methanol (30mL), palladium on carbon (200mg) was added at room temperature, hydrogen was substituted for 3 times, the reaction was stirred at room temperature for 6 hours, monitored by TLC, filtered after completion of the reaction, and the filtrate was concentrated to give 940mg of off-white solid (compound 8f) in 83.9% yield.
And a sixth step: compound 8f (560mg, 1.0mmol), CDI (194mg, 1.2mmol), DIPEA (387mg, 3.0mmol) were dissolved in DMF (30mL), stirred at room temperature for 2 hours, then O-methylhydroxylamine hydrochloride (88mg, 1.0mmol) was added, stirred for 10 hours, monitored by TLC, quenched with 50mL water after completion of the reaction, extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried, filtered, and isolated by column chromatography to give 510mg (compound 8) as an off-white solid in 80.6% yield, ESI (+) m/z ═ 634.2.
Example 9
A compound of formula 9: 4- (4- (cyclopropyl (2, 6-difluorophenyl) amino) -2- (2-fluoro-4- (3-methoxyureido) phenyl) -7-methoxy-1H-indol-6-yl) benzamide; the synthesis reaction formula is as follows:
Figure BDA0003151255180000201
the first step is as follows: compound 1c (4.68g, 10.0mmol), compound 9a (1.7g, 10.0mmol), Pd (PPh)3)4(1.1g, 1.0mmol), cesium carbonate (6.5g, 20.0mmol) were dissolved in dioxane (100mL) and purified water (100mL), the temperature was raised to 90 ℃ and the reaction was stirred for 10 hours, the reaction was monitored by TLC, after completion of the reaction, extraction was performed with ethyl acetate (50 mL. times.2), the organic layer was concentrated, and column chromatography was performed to obtain 3.4g of an off-white solid (compound 9b) in a yield of 66.8%.
The second step is that: compound 9b (3.4g, 6.7mmol) was dissolved in dichloromethane (20mL), trifluoroacetic acid (10mL) was added at room temperature, the reaction was stirred at room temperature for 4 hours, TLC monitored, after the reaction was completed, the solvent was removed under reduced pressure, then pH was adjusted to 8-9 with saturated sodium carbonate solution, extraction was performed with ethyl acetate (100mL × 2), the organic layers were combined, dried, filtered, and separated by column chromatography to give 2.3g of off-white solid (compound 9c) with a yield of 84.2%.
The third step: dissolving the compound 9c (2.3g, 5.6mmol) in hydrochloric acid solution (4mol/L, 20mL), adding sodium nitrite (739mg, 11.2mmol) under ice bath, stirring for reaction for 3 hours while maintaining the temperature, then adding tin dichloride (4.3g, 22.4mmol), heating to 30 ℃ for 6 hours, monitoring the reaction by TLC, after the reaction is finished, adding saturated sodium carbonate solution to adjust the pH to 8-9, extracting with ethyl acetate (80 mL. times.2), combining the organic layers, drying, filtering, and separating by column chromatography to obtain 1.7g of off-white solid (compound 9d) with the yield of 71.7%.
The fourth step: compound 9d (1.5g, 3.5mmol) and compound 1h (859mg, 3.5mmol) were dissolved in acetic acid (20mL), the temperature was raised to 50 ℃ and the reaction was stirred for 6 hours, TLC monitored, after the reaction was completed, acetic acid was removed under reduced pressure, water (50mL) was added to quench the reaction, extraction was performed with ethyl acetate (2 × 50mL), the organic layers were combined, dried, concentrated, and separated by column chromatography to give 1.4g of off-white solid (compound 9e) with a yield of 63.3%.
The fifth step: compound 9e (1.4g, 2.2mmol) was dissolved in methanol (30mL), palladium on carbon (200mg) was added at room temperature, hydrogen was substituted for 3 times, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, filtration was carried out, and the filtrate was concentrated to give 778mg of an off-white solid (Compound 9f) in 65.3% yield.
And a sixth step: compound 9f (542mg, 1.0mmol), CDI (194mg, 1.2mmol), DIPEA (387mg, 3.0mmol) were dissolved in DMF (30mL), stirred at room temperature for 2 hours, then O-methylhydroxylamine hydrochloride (88mg, 1.0mmol) was added, stirred for 5 hours, monitored by TLC, quenched with 50mL water after completion of the reaction, extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried, filtered, and isolated by column chromatography to give 464mg (compound 9) as an off-white solid in 75.4% yield, ESI (+) m/z 616.2.
Example 10
A compound according to formula 10: 1- (4- (4- (cyclopropyl (2, 6-difluorophenyl) amino) -6- (4- (dimethylamino) -2-fluorophenyl) -7-methoxy-1H-indol-2-yl) -3-fluorophenyl) -3-methoxyurea; the synthesis reaction formula is as follows:
Figure BDA0003151255180000221
the first step is as follows: compound 1c (4.68g, 10.0mmol), compound 10a (1.8g, 10.0mmol), Pd (PPh)3)4(1.1g, 1.0mmol), cesium carbonate (6.5g, 20.0mmol) were dissolved in dioxane (100mL) and purified water (100mL), the temperature was raised to 80 ℃ and the reaction was stirred for 10 hours, the reaction was monitored by TLC, after completion of the reaction, extraction was performed with ethyl acetate (50 mL. times.2), the organic layer was concentrated, and column chromatography was performed to obtain 3.3g of an off-white solid (compound 10b) with a yield of 62.6%.
The second step: compound 10b (3.0g, 5.7mmol) was dissolved in dichloromethane (20mL), trifluoroacetic acid (10mL) was added at room temperature, the reaction was stirred at room temperature for 4 hours, TLC monitored, after the reaction was completed, the solvent was removed under reduced pressure, then pH was adjusted to 8-9 with saturated sodium carbonate solution, extraction was performed with ethyl acetate (100mL × 2), organic layers were combined, dried, filtered, and column chromatography separated to give 1.8g of off-white solid (compound 10c) with a yield of 74.1%.
The third step: dissolving the compound 10c (1.8g, 4.2mmol) in hydrochloric acid solution (4mol/L, 20mL), adding sodium nitrite (554mg, 8.4mmol) under ice bath, keeping the temperature and stirring for reaction for 3 hours, then adding tin dichloride (3.2g, 16.8mmol), heating to 30 ℃ for reaction for 6 hours, monitoring the reaction by TLC, after the reaction is finished, adding saturated sodium carbonate solution to adjust the pH to 8-9, extracting with ethyl acetate (50mL multiplied by 2), combining organic layers, drying, filtering, and carrying out column chromatography to obtain 1.4g of off-white solid (compound 10d), wherein the yield is 75.4%.
The fourth step: compound 10d (1.3g, 2.9mmol) and compound 1h (715mg, 3.5mmol) were dissolved in acetic acid (20mL), the temperature was raised to 50 ℃ and the reaction was stirred for 6 hours, TLC monitored, after the reaction was completed, acetic acid was removed under reduced pressure, water (50mL) was added to quench the reaction, extraction was performed with ethyl acetate (2 × 50mL), the organic layers were combined, dried, concentrated, and separated by column chromatography to give 1.3g (compound 10e) of an off-white solid with a yield of 69.0%.
The fifth step: compound 10e (1.3g, 2.0mmol) was dissolved in methanol (30mL), palladium on carbon (200mg) was added at room temperature, hydrogen was substituted for 3 times, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, filtration was carried out, and the filtrate was concentrated to give 810mg of an off-white solid (compound 10f) with a yield of 72.3%.
And a sixth step: compound 10f (560mg, 1.0mmol), CDI (194mg, 1.2mmol), DIPEA (387mg, 3.0mmol) were dissolved in DMF (30mL), stirred at room temperature for 3 hours, then O-methylhydroxylamine hydrochloride (88mg, 1.0mmol) was added, stirred for 6 hours, monitored by TLC, quenched with 50mL water after completion of the reaction, extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried, filtered, and isolated by column chromatography to give 412mg (compound 10) as an off-white solid in 65.1% yield and ESI (+) m/z 634.2.
Example 11
Biological evaluation
The prepared CHO cell membrane site containing human GnRH receptor was diluted to 20. mu.g/mL with buffer, 20mM HEPES, 0.1% BSA (bovine serum albumin), 100. mu.g/mL (bacitracin), dispensed into tubes of 148. mu.l each, and then 2. mu.L of test compound dissolved in DMSO at various concentrations and 0.1nM125I-Trp6LHRH (50uL) was started, and in addition, a reaction solution to which DMSO (2. mu.L) was added was prepared instead of the test compound for the measurement of the maximum binding amount, and a reaction solution to which 100. mu.L of LHRH (2. mu.L) was added for the measurement of the non-specific binding amountThe reaction was stopped by incubating the reaction solutions at 4 ℃ for 3 hours instead of the test compound and then by pipetting the reaction solution through a Whatman glass funnel treated with 0.5% polyethyleneimine. Measuring the radioactivity remaining on the filter paper with a counter to obtain IC of the target compound50The specific data are shown in the following table:
A＜50nM，50nM≤B≤500nM，500nM≤C
examples IC50(GnRH) Examples IC50(GnRH)
Compound 1 B Compound 6 B
Compound 2 B Compound 7 B
Compound 3 A Compound 8 C
Compound 4 A Compound 9 A
Compound 5 C Compound 10 B
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 (9)

  1. A 7-methoxy-1H-indole compound or a pharmaceutically acceptable salt thereof, wherein the 7-methoxy-1H-indole compound is selected from any one of the following formulas 1-10, and has the following structural formula:
    Figure DEST_PATH_IMAGE002
    formula 1
    Figure DEST_PATH_IMAGE004
    Formula 2
    Figure DEST_PATH_IMAGE006
    Formula 3
    Figure DEST_PATH_IMAGE008
    Formula 4
    Figure DEST_PATH_IMAGE010
    Formula 5
    Figure DEST_PATH_IMAGE012
    Formula 6
    Figure DEST_PATH_IMAGE014
    Formula 7
    Figure DEST_PATH_IMAGE016
    Formula 8
    Figure DEST_PATH_IMAGE018
    Formula 9
    Figure DEST_PATH_IMAGE020
    Formula 10.
  2. 2. The method for preparing 7-methoxy-1H-indoles or their pharmaceutically acceptable salts as claimed in claim 1, comprising the steps of:
    Figure DEST_PATH_IMAGE022
    step 1), Synthesis of Compound IV
    Reacting a compound II, a compound III, alkali and a catalyst in a reaction solvent to obtain a compound IV;
    step 2), Synthesis of Compound VI
    Reacting the compound IV, the compound V, alkali and a catalyst in a reaction solvent to obtain a compound VI;
    step 3), Synthesis of Compound VII
    Reacting the compound VI with acid in a reaction solvent to obtain a compound VII;
    step 4), Synthesis of Compound VIII
    Reacting a compound VII under the action of hydrochloric acid and sodium nitrite at the temperature of-10-30 ℃; then reacting under the action of tin dichloride at the reaction temperature of 0-30 ℃ to obtain a compound VIII;
    step 5), Synthesis of Compound X
    Reacting a compound VIII, a compound IX and an acid in a reaction solvent to obtain a compound X;
    step 6), Synthesis of Compound XI
    Carrying out hydrogenation reaction on the compound X in a reaction solvent under the action of palladium carbon to obtain a compound XI;
    step 7), Synthesis of Compound I
    Reacting a compound XI, O-methylhydroxylamine hydrochloride, N' -carbonyldiimidazole and alkali in a reaction solvent to obtain a compound I;
    wherein R is1The 7-methoxy-1H-indoles of claim 1 or their pharmaceutically acceptable salts wherein R is as defined above2The 7-methoxy-1H-indole compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the definition of the corresponding groups is the same.
  3. 3. The method for preparing 7-methoxy-1H-indole compounds or pharmaceutically acceptable salts thereof according to claim 2, wherein in step 1), the reaction temperature is 40-120 ℃; the base is at least one selected from triethylamine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium phosphate and sodium acetate; the catalyst is at least one selected from bis (triphenylphosphine) palladium dichloride (II), tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) palladium, palladium acetate and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride; the reaction solvent is at least one selected from toluene, acetonitrile, dioxane, dimethyl sulfoxide, N-dimethylformamide and dimethylacetamide;
    in the step 2), the reaction temperature is 80-120 ℃, and the alkali is selected from at least one of cesium carbonate, sodium tert-butoxide, potassium tert-butoxide and potassium carbonate; the catalyst is at least one of tetrakis (triphenylphosphine) palladium, palladium acetate, tris (dibenzylideneacetone) dipalladium and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride; the reaction solvent is at least one selected from dioxane, N-dimethylformamide and toluene.
  4. 4. The method for preparing 7-methoxy-1H-indole compounds or pharmaceutically acceptable salts thereof according to claim 2, wherein in step 3), the reaction temperature is 20-80 ℃; the acid is at least one of trifluoroacetic acid, ethyl acetate solution of hydrogen chloride and ethanol solution of hydrogen chloride; the reaction solvent is at least one of dichloromethane, ethanol and ethyl acetate;
    in the step 5), the reaction temperature is 0-100 ℃; the acid is at least one of acetic acid, formic acid, phosphoric acid, polyphosphoric acid, sulfuric acid, zinc chloride, ferric chloride, aluminum chloride and boron trifluoride; the reaction solvent is at least one of methanol, ethanol and acetic acid.
  5. 5. The method for preparing 7-methoxy-1H-indole compounds or pharmaceutically acceptable salts thereof according to claim 2, wherein in step 6), the reaction temperature is 20-40 ℃; the reaction solvent is at least one of methanol, ethanol, tetrahydrofuran and dioxane.
  6. 6. The method for preparing 7-methoxy-1H-indole compound or pharmaceutically acceptable salt thereof according to claim 2, wherein in step 7), the reaction temperature is 20-100 ℃; the base is at least one of triethylamine, diisopropylethylamine and N-methylmorpholine; the reaction solvent is at least one of N, N-dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran and dioxane.
  7. 7. A pharmaceutical composition, comprising: the 7-methoxy-1H-indoles of claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents.
  8. 8. The use of a 7-methoxy-1H-indole compound according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of sex hormone related disorders.
  9. 9. Use of a 7-methoxy-1H-indole compound or a pharmaceutically acceptable salt thereof according to claim 8 for the manufacture of a medicament for the treatment or prevention of a sex hormone related disorder selected from any one of uterine leiomyoma, prostate cancer, breast cancer, ovarian cancer, endometriosis, assisted reproductive therapy and precocious puberty.
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WO1997021707A1 (en) * 1995-12-14 1997-06-19 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone
US5985901A (en) * 1997-06-05 1999-11-16 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone
CN101163691A (en) * 2005-01-14 2008-04-16 Cgi药学股份有限公司 1,3-diaryl substituted ureas as modulators of kinase activity
EP1858879B1 (en) * 2005-01-14 2012-06-06 Gilead Connecticut, Inc. 1,3-diaryl substituted ureas as modulators of kinase activity
EP1903037A1 (en) * 2006-09-07 2008-03-26 Bayer Schering Pharma Aktiengesellschaft 1-(hetero)aryl-3-[heteroaryl-piperidin-4yl]-thiourea derivatives as modulators of EP2 receptors
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