Disclosure of Invention
The invention aims to overcome the defect of single structure of sedative drugs in the prior art. Therefore, the invention provides a benzodihydrofuran compound with a novel structure, a pharmaceutical composition and application thereof. The compound has a sedative effect and is helpful for relieving mania symptoms of patients suffering from mental diseases.
The invention provides a compound shown as a formula I or pharmaceutically acceptable salt thereof;
;
Wherein ring A is "a 5-10 membered heterocycloalkyl group having 1,2 or 3 heteroatoms selected from N, O and S, having 1,2 or 3 heteroatoms" or "a 5-10 membered heterocycloalkenyl group having 1,2 or 3 heteroatoms selected from N, O and S";
r1 is hydroxy;
Ring B isOr (b);
X1 is-NH-, oxygen, or-CH2 -;
X2 is-NR3 -or oxygen;
x3 is nitrogen;
R3 is C1-C6 alkyl or-C (O) -C1-C6 alkyl;
R2 is C1-C6 alkyl or oxo (=o);
n is 2, 3 or 4;
m and x are independently 0,1, 2 or 3.
In certain preferred embodiments of the present invention, certain groups in the compounds of formula I or pharmaceutically acceptable salts thereof are defined below, and the unrecited groups are as described in any of the embodiments of the present invention (referred to herein as "in one embodiment").
In one embodiment of the present invention, the 5-10 membered heterocycloalkyl is a monocyclic or spiro ring.
In one embodiment of the present invention, the heteroatoms in the 5-to 10-membered heterocycloalkyl group are independently selected from N, 1 or 2 heteroatoms, e.g.,、、Or (b)。
In one embodiment of the present invention, the 5-10 membered heterocycloalkenyl is 6-8 membered heterocycloalkenyl.
In one embodiment of the present invention, the 5-to 10-membered heterocycloalkenyl group is independently selected from N, 1 heteroatom in number, for example,Or (b)。
In one embodiment of the invention, the C1-C6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, preferably methyl.
In one embodiment of the invention, ring A is a 5-10 membered heterocycloalkyl having 1,2 or 3 heteroatoms selected from 1,2 or 3 of N, O and S.
In one embodiment of the invention, ring B is。
In one embodiment of the invention, X1 is oxygen or-CH2 -, preferably oxygen.
In one embodiment of the invention, X2 is-NR3 -.
In one embodiment of the invention, R3 isOr methyl, preferably。
In one embodiment of the invention, R2 is oxo.
In one embodiment of the invention, n is 2 or 3, preferably 2.
In one embodiment of the invention, m is 0 or 1, preferably 0.
In one embodiment of the invention, x is 0 or 1, preferably 0.
In one embodiment of the invention, ring A is、、、、Or (b)It is preferable that the composition is a composition,、、Or (b)It is further preferable that the composition is,、Or (b)Wherein the a-terminal is connected with the ring B, and the B-terminal is connected withAre connected.
In one aspect of the present invention,Is that、、、、、Or (b)Preferably、、、Or (b)Further preferably、Or (b)Wherein the a-terminal is connected with the ring B, and the B-terminal is connected withAre connected.
In one embodiment of the invention, ring B is、、、Or (b)Preferably、、、、Or (b)Further preferably、、、Or (b)More preferablyOr (b)。
In one aspect of the present invention,Is that、、、、、Or (b)Preferably、、、Or (b)Further preferablyOr (b)。
In one embodiment of the present invention, the compound shown in formula I is a compound shown in formula I-1 or formula I-2:
Or (b);
Wherein the rings A, R1、X1、X2、X3、R2, n, m, and x are defined in any of the embodiments of the present invention.
In one embodiment of the present invention, the compound shown in formula I is a compound shown in formula I-1-1 or I-1-2:
Or (b);
Wherein Y is-CH-or N, and X2 and N are defined as in any one of the embodiments of the present invention.
In one embodiment of the present invention, the compound shown in formula I or a pharmaceutically acceptable salt thereof is any one of the following compounds:
。
The present invention provides a pharmaceutical composition comprising:
(1) A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of the present invention and
(2) Pharmaceutically acceptable auxiliary materials.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described hereinbefore, as claimed in any one of the present inventions, selected from:
(1) Preparing a 5-HT2A receptor agonist;
(2) Preparing a medicament for treating and/or preventing a disease associated with a 5-HT2A receptor;
(3) Preparing medicine for treating and/or preventing mania of mental disease patients.
In one embodiment of the invention, the disorder associated with the 5-HT2A receptor is mania in a psychotic disorder patient.
Description of the terms
Unless otherwise indicated, the terms used in the present invention have the following meanings:
the term "pharmaceutically acceptable" refers to those compositions which are relatively non-toxic, safe, and suitable for use by a patient.
The term "pharmaceutically acceptable salt" refers to a salt of a compound that is obtained by reaction with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, the base addition salt may be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, the acid addition salt may be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See in particular Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).
The term "-" at the end of a group means that the group is attached to the remainder of the molecule at that site and "in the end of a structural fragment"By "is meant that the structural fragment is attached to the remainder of the molecule via the site, e.g.,Refers to methoxy.
The term "oxo" is =o.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "heterocycloalkyl" refers to a cyclic group of a specified number of heteroatoms (e.g., 1, 2, or 3) of a specified number of ring atoms (e.g., 5-10 membered), of a specified heteroatom species (one, two, or three of N, O and S), which is a single ring, bridged ring, or spiro ring, and each ring is saturated. The heterocycloalkyl group is attached to the remainder of the molecule via a carbon atom or heteroatom. Heterocycloalkyl groups include, but are not limited to:、、、 Etc.
The term "heterocycloalkenyl" refers to a cyclic group of a specified number of heteroatoms (e.g., 1, 2, or 3) with a specified number of ring atoms (e.g., 5-10 members), of a specified heteroatom class (one, two, or three of N, O and S), which is a monocyclic, bridged, or spiro unsaturated alkyl group. The heterocycloalkenyl group is attached to the remainder of the molecule via a carbon atom or heteroatom. Heterocycloalkenyl groups include, but are not limited to:、 Etc.
The term "alkyl" refers to a straight or branched, saturated monovalent hydrocarbon radical having the indicated number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl and the like.
The term "pharmaceutically acceptable excipients" refers to all substances contained in a pharmaceutical formulation, except for the active pharmaceutical ingredient, which generally fall into two broad categories, excipients and additives. See in particular the pharmacopoeia of the people's republic of China (2020 edition) ）"、Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).
The term "treatment" refers to the elimination of etiology or alleviation of symptoms.
The term "preventing" refers to reducing the risk of developing a disease.
The term "patient" refers to any animal, typically a mammal, such as a human, in need of treatment or prevention of a disease. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effect that the invention provides the benzodihydrofuran compound with novel structure, the pharmaceutical composition and the application thereof. The compound has a sedative effect and is helpful for relieving mania symptoms of patients suffering from mental diseases.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The following abbreviations represent the following reagents, respectively:
Preparation of intermediates
Intermediate A3- (2, 3-Dihydrobenzofuran-7-yl) propanal
Step 12, 3-Dihydrobenzofuran-7-carbaldehyde (1.0 g, 6.7 mmol) and methyl (triphenylphosphine) acetate (3.36 g, 10.05 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL) at room temperature. The reaction solution was stirred at 80 ℃ for 2 h. The reaction solution was cooled to room temperature and concentrated in vacuo to give crude product. Purification of the crude product by column chromatography (EtOAc/pe=0-10%) gave a-1 (1.18 g, yield: 76.1%) as a white solid. MS M/z (ESI): 205.1 [ M+H ]+
Step 2A-1 (1.18 g, 5.8 mmol) was dissolved in methanol (10 mL) at room temperature and 10% wet palladium on carbon (310 mg, 0.29 mmol) was added. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 1 h a. The reaction solution was filtered through celite, washed with methanol, and the filtrates were combined and concentrated in vacuo to give A-2 (1.15 g, yield: 96.6%) as a colorless viscous oil. The crude product was used directly in the next reaction without purification. MS M/z (ESI): 207.1 [ M+H ]+
Step 3, dissolving A-2 (500 mg, 2.4 and mmol) in tetrahydrofuran (8 and mL) at room temperature, cooling to zero under nitrogen atmosphere, adding a 1M lithium aluminum hydride tetrahydrofuran solution (8 and mL), and stirring at room temperature for 1 hour. The reaction was stirred at zero degrees, diluted with ethyl acetate (20 mL) and sodium sulfate decahydrate was added, filtered through celite, washed with methanol and concentrated in vacuo to give the crude product. Purification of the crude product by column chromatography (EtOAc/pe=0-15%) afforded a-3 (340 mg, yield: 78.7%) as a colorless oily liquid. MS M/z (ESI): 179.1 [ M+H ]+
Step 4. Dissolving A-3 (3 g, 16.9 mmol) in dichloromethane (100 mL) at room temperature, placing under nitrogen atmosphere, adding Dwjamaican reagent (DMP) (21.4 g, 50.6 mmol), and stirring at room temperature for 5 hours. The reaction solution was filtered through celite, the filtrate was washed with saturated aqueous sodium bicarbonate solution, and the organic phase was concentrated in vacuo to give the crude product. Purification of the crude product by column chromatography (EtOAc/pe=0-20%) afforded a (2.5 g, yield: 84.2%) as a colorless oily liquid.
Intermediate B2- (2, 3-Dihydrobenzofuran-7-yl) acetaldehyde
Step 1) the compound 7-bromo-2, 3-dihydrobenzofuran (5.0 g, 25.1 mmol), potassium vinylfluoroborate (6.7 g, 50.2 mmol), pd (dppf) Cl2 dichloromethane complex (0.8 g, 1.25 mmol) and potassium carbonate (7.0 g, 50.2 mmol) were added together in a 100mL single-necked flask followed by dioxane/water (45 mL, V1/V2 =8:1) and slowly warmed to 110℃under nitrogen overnight with stirring. After completion of TLC detection, the reaction mixture was cooled to room temperature, suction filtered under reduced pressure, water (30 mL) was added to the filtrate, extracted with ethyl acetate (50 ml×2), the organic phases were combined, washed with saturated brine (50 ml×1), dried over anhydrous sodium sulfate, dried under reduced pressure, and the crude product was purified by column chromatography (EtOAc/pe=0-2%) to give B-1 (3.20: 3.20 g, yield: 87%) as a pale yellow oil.
Step 2, compound B-1 (1.0 g, 6.8 mmol) and anhydrous THF (10 mL) were added together into a 100 mL three-necked flask, N2 and a solution of 2M B2H6/dimethyl sulfide (6 mL) were slowly added dropwise under ice water bath, and after the addition, stirring was allowed at room temperature for 3 h. Subsequently, 10% aqueous NaOH (7 mL) and 30% H2O2 (1 mL) were slowly added dropwise, respectively, under an ice-water bath, and after the addition, the mixture was allowed to stir overnight at room temperature. After completion of the TLC detection, water (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL. Times.1), dried over anhydrous sodium sulfate, dried under reduced pressure, and the crude product was purified by column chromatography (EtOAc/PE=0-30%) to give B-2 (0.6 g, yield) as a pale yellow oil : 54%）.1H NMR (500 MHz, CDCl3) δ 7.09 (dd, J = 7.3, 0.9 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.80 (t, J = 7.4 Hz, 1H), 4.56 (t, J = 8.7 Hz, 2H), 3.86 (t, J = 6.3 Hz, 2H), 3.22 (t, J = 8.7 Hz, 2H), 2.86 (t, J = 6.3 Hz, 2H). MS m/z (ESI): 164.5 [M+H]+.
Step 3C-2 (600 mg, 3.7 mmol) was added to a 50 mL single vial at room temperature with anhydrous DCM (10 mL), followed by the addition of Dess Martin reagent (Dess-MARTIN REAGENT) (2.3 g, 5.5 mmol) in portions and stirring at room temperature for 1 hour. After completion of TLC detection, the reaction was filtered, the filtrate was slowly added dropwise to a saturated NaHCO3 solution to adjust the pH of the system to basic, DCM was extracted (20 mL x 2), the organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, dried under reduced pressure and spun-dried, and the crude product was purified by column chromatography (EtOAc/pe=0-10%) to give colorless oil B (0.4 g, yield: 67%).
EXAMPLE 1- (8- (1- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -1,2,3, 6-tetrahydropyridin-4-yl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) ethan-1-one
Step 1 8-bromo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine (330 mg, 1.54 mmol) and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (480 mg, 1.56 mmol) were dissolved in 8 mL dioxane, aqueous potassium phosphate solution (816 mg, 3.85 mmol, 2 mL H2O),N2 replaced and Pd (dppf) Cl2 DCM (63 mg, 0.077 mmol) was added, heated to 90o C for 16 h.TLC to detect completion of reaction, water and EtOAc were added, the aqueous phase was extracted with EtOAc, the organic phase was combined, washed three times with saturated sodium chloride solution, dried and concentrated and column-packed with normal phase silica gel (PE/EtOAc=3/1) to give compound 1-1 (mg, off-white solid, 88 z (MS: 38.38+38).
Step 2-1 (430 mg, 1.36 mmol) was dissolved in 10 mL DCM, DIEA (0.67 mL, 4.1 mmol) was added, cooled to 0o C, acetyl chloride (128 mg, 1.63 mmol) was added, stirred at room temperature for 16h, concentrated and then purified by normal phase silica gel chromatography (PE/EtOAc=3/1) to afford compound 1-2 (410 mg, off-white solid, 84% yield). MS M/z (ESI): 359.2 [ M+H ]+.
Step 3. 1-2 (95 mg, 0.265 mmol) was dissolved in 2mL DCM, TFA (0.5 mL, 6.73 mmol) was added, stirred at room temperature for 1h, and concentrated to give compound 1-3, the crude product was used directly in the next reaction. MS M/z (ESI): 259.3 [ M+H ]+.
Step 4 dissolving Compounds 1-3 (99 mg, 0.265 mmol) in 2 mL DCM, adding 3- (2, 3-dihydrobenzofuran-7-yl) propanal (47 mg, 0.265 mmol) at room temperature, stirring at room temperature for 5min, adding NaBH (OAc)3 (170 mg, 0.8 mmol), stirring at room temperature for 16h, adding water and DCM to separate layers, washing the organic phase, and passing through a normal phase silica gel column (DCM/MeOH=10/1) to give Compound E1 (55 mg, off-white solid, yield 50%）.1H NMR (500 MHz, CD3OD) δ 7.09-7.07 (m, 2H), 7.00-6.98 (m, 3H), 6.78 (t, J = 5.0 Hz, 1H), 5.78 (s, 1H), 4.54 (t, J = 10.0 Hz, 2H), 4.31 (t, J = 5.0 Hz, 2H), 3.92 (t, J = 10.0 Hz, 2H), 3.75 (t, J = 5.0 Hz, 2H), 3.34 (t, J = 5.0 Hz, 2H), 3.20 (t, J = 10.0 Hz, 2H), 3.12-3.08 (m, 2H), 2.77 (t, J = 5.0 Hz, 2H), 2.68 (t, J = 10.0 Hz, 2H), 2.29 (s, 3H), 2.10-2.03 (m, 2H).MS m/z (ESI): 419.8 [M+H]+.
EXAMPLE 2 1- (8- (1- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) piperidin-4-yl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) ethan-1-one
Compound E1 (20 mg, 0.048 mmol) was dissolved in MeOH (3 mL), 10% pd/C (15 mg) was added, and hydrogenation was carried out at room temperature for 2 hours with stirring, and prep-HPLC purification and isolation (eluent (v/v): acetonitrile/(water+0.05% NH4HCO 3) =30% -70%) gave compound E2 (10.0 mg, white solid, yield 50%）.1H NMR (500 MHz, CD3OD) δ 7.06-7.04 (m, 3H), 7.00-6.98 (m, 2H), 6.75 (t, J = 5.0 Hz, 1H), 4.53 (t, J = 10.0 Hz, 2H), 4.33 (t, J = 5.0 Hz, 2H), 3.91 (t, J = 10.0 Hz, 2H), 3.28-3.26 (m, 2H), 3.19 (t, J = 10.0 Hz, 2H), 3.08-3.01 (m, 1H), 2.69 (t, J = 5.0 Hz, 2H), 2.61 (t, J = 10.0 Hz, 2H), 2.49-2.45 (m, 2H), 2.29 (s, 3H), 1.96-1.79 (m, 6H).MS m/z (ESI): 421.9 [M+H]+.
EXAMPLE 3 1- (8- (1- (2, 3-Dihydrobenzofuran-7-yl) ethyl) -1,2,3, 6-tetrahydropyridin-4-yl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) ethan-1-one
Preparation of E3 Synthesis method of step 4 with reference to E1 .1H NMR (500 MHz, CD3OD) δ 7.12 (t, J = 10.0 Hz, 1H), 7.01 (t, J = 10.0 Hz, 1H), 6.99 (t, J = 5.0 Hz, 1H), 6.93-6.89 (m, 2H), 6.80 (t, J = 5.0 Hz, 1H), 5.80 (s, 1H), 4.52 (t, J = 10.0 Hz, 2H), 4.26 (t, J = 5.0 Hz, 2H), 3.95 (t, J = 10.0 Hz, 2H), 3.76 (t, J = 5.0 Hz, 2H), 3.32-3.15 (m, 6H), 2.98 (t, J = 5.0 Hz, 2H), 2.77 (t, J = 10.0 Hz, 2H), 2.30 (s, 3H).MS m/z (ESI): 405.8 [M+H]+.
EXAMPLE 4 1- (8- (1- (2, 3-Dihydrobenzofuran-7-yl) ethyl) piperidin-4-yl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) ethan-1-one
Synthesis method of E4 preparation reference E2 .1H NMR (500 MHz, CD3OD) δ 7.08-7.04 (m, 3H), 6.95-6.88 (m, 2H), 6.76 (t, J = 5.0 Hz, 1H), 4.53 (t, J = 10.0 Hz, 2H), 4.34 (t, J = 5.0 Hz, 2H), 3.91 (t, J = 10.0 Hz, 2H), 3.25-3.17 (m, 4H), 3.04-3.00 (m, 1H), 2.85-2.82 (m, 2H), 2.75-2.72 (m, 2H), 2.38 (t, J = 10.0 Hz, 2H), 2.33 (s, 3H), 1.87-1.77 (m, 4H).MS m/z (ESI): 407.8 [M+H]+.
EXAMPLE 5 1- (8- (1- (2- (2-3-dihydrobenzofuran-7-yl) ethyl) -1,2,5, 6-tetrahydropyridin-3-yl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) acetic acid-1-one
Step 1 the compound 8-bromo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine (1.0 g, 4.67 mmol), tert-butyl 5- (4, 5-tetramethyl-1, 3, 2-dioxaboro-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (1.7 g, 5.61 mmol), pd (dppf) Cl2 dichloromethane complex (0.19 g, 0.23 mmol) and potassium carbonate (1.9 g, 14.01 mmol) were added together in a 100mL single-necked flask followed by 1, 4-Dioxane)/water (12 ml, v1/V2 =5:1) and slowly warmed to 80 ℃ under nitrogen atmosphere and stirred overnight. After completion of LCMS detection, the reaction was cooled to room temperature, suction filtered under reduced pressure, water (30 mL) was added to the filtrate, extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, dried under reduced pressure, and the crude product was purified by column chromatography (EtOAc/pe=0-50%) to give compound 5-1 (pale yellow oil, 1.4 g, yield: 95%). MS M/z (ESI): 261.3 [ M+H-tBu ]+.
Step 2) Compound 5-1 (0.7 g, 2.21 mmol) was added to a 100mL single-port flask, followed by dichloromethane (15 mL) and triethylamine (0.68 g, 6.72 mmol) respectively, then acetyl chloride (0.2 g, 2.43 mmol) was added dropwise, the reaction mixture was stirred at room temperature for reaction 1 h, dried under reduced pressure, and crude product was purified by column chromatography (EtOAc/PE=0-50%) to give Compound 5-2 (yellow oil, 0.7g, yield: 88%). MS M/z (ESI): 303.4 [ M+H-tBu ]+.
Step 3 Compound 5-2 (200 mg, 0.56 mmol) was added to a 10mL single vial with anhydrous DCM (2 mL), followed by HCl/Dioxane (1 mL) and stirring at room temperature for 12h. After completion of the reaction by LCMS, the reaction mixture was dried under reduced pressure to give crude compound 5-3 (gray solid, 0.13 g, yield 90%). The crude product was used directly in the next reaction without further purification. MS M/z (ESI): 259.4 [ M+H ]+.
Step 4 preparation of E5 reference is made to the fourth step of the synthetic method of example 1 .1H NMR (500 MHz, CDCl3) δ 7.11-6.94 (m, 4H), 6.85 (t, J = 7.8 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 5.85 (s, 1H), 4.54 (t, J = 8.7 Hz, 2H), 4.34-4.29 (m, 2H), 3.95 (s, 2H), 3.40 (d, J = 28.3 Hz, 2H), 3.22-3.18 (m, 2H), 2.85 (d, J = 41.4 Hz, 6H), 2.42 (s, 2H), 2.32 (s, 3H). MS m/z (ESI): 405.8 [M+H]+.
EXAMPLE 6 1- (8- (1- (2- (2-) 2-dihydrobenzofuran-7-yl) ethyl) piperidin-3-yl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) ethan-1-one
Compound E5 (30 mg, 0.074 mmol) and methanol (3 mL) were added to a 100mL single-necked flask, followed by Pd/C (2 mg, 0.015) and stirred at room temperature under hydrogen atmosphere for 5 h. After the LCMS detection reaction is completed, vacuum suction filtration is performed, and the filtrate is directly purified and separated by Prep-HPLC (eluent (v/v): acetonitrile/(water+0.05% NH4HCO3) =30% -70%) to obtain compound E6 (white solid, 11 mg, yield) 37%).1H NMR (500 MHz, CDCl3) δ 7.12-6.89 (m, 4H), 6.86 (t, J = 7.8 Hz, 1H), 6.77 (t, J = 7.4 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 4.33 (t, J = 4.9 Hz, 2H), 3.95 (s, 2H), 3.20 (t, J = 8.7 Hz, 5H), 2.74 (d, J = 81.5 Hz, 4H), 2.32 (s, 3H), 2.15-1.61 (m, 6H).MS m/z (ESI): 407.8 [M+H]+.
EXAMPLE 7 4- (1- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) piperidin-4-yl) -1-methyl-3, 4-dihydroquinoxalin-2 (1H) -one
Step 1. Compound 8-3 (200 mg, 0.6 mmol) and potassium carbonate (414 mg, 3 mmol) were added together in a 50 mL single-necked flask, followed by DMF (10 mL) and finally methyl iodide (0.4 ml, 6 mmol) and slowly warmed to 800 C under nitrogen and stirred overnight. LCMS detected completion of the reaction, the reaction was cooled to room temperature, filtered, concentrated and passed through a column to afford product 7-1 (yellow solid, 150 mg, 72.4% yield). MS m/z (ESI): 290.5[ M+H-tBu ]+
The preparation method of the step 2:7-2 is referred to as the method for preparing E2. MS M/z (ESI): 246.3 [ M+H ]+.
Step 3 preparation of E7 with reference to the Synthesis method of the fourth step of example 1 .1H NMR (500 MHz, CD3OD) δ 7.15–7.03 (m, 3H), 6.99 (d, J = 7.2 Hz, 1H), 6.97–6.92 (m, 2H), 6.78 (t, J = 7.4 Hz, 1H), 4.59–4.51 (m, 2H), 3.99–3.92 (m, 1H), 3.68 (d, J = 13.1 Hz, 4H), 3.49–3.41 (m, 1H), 3.36–3.33 (m, 3H), 3.23–3.10 (m, 7H), 2.68 (q, J = 7.2 Hz, 2H), 2.08 (ddd, J = 12.3, 9.7, 6.4 Hz, 4H). MS m/z (ESI): 406.7 [M+H]+.
EXAMPLE 8 1- (4- (1- (3- (2, 3-dihydrobenzofuran-7-yl) propyl) piperidin-4-yl) -3, 4-dihydroquinoxalin-1 (2H) -yl) ethan-1-one
Step 1. The compound 1-fluoro-2-nitrobenzene (2 g, 14.2 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (5.6 g, 28.4 mmol), potassium carbonate (7.8 g, 56.8 mmol) were added together in a single-necked flask of 100mL followed by acetonitrile (100 mL) separately, and after addition, slowly warmed to reflux under nitrogen and stirred overnight. LCMS detected completion of the reaction, the reaction was cooled to room temperature, filtered, concentrated and passed through a column to afford product 8-1 (yellow solid, 3 g, 65.5% yield). MS M/z (ESI): 266.0 [ M+H-tBu ]+
The preparation method of the step 2:8-2 is referred to as the method for preparing E2. MS M/z (ESI): 292.3 [ M+H ]+.
Step 3, compound 8-2 (1.6 g, 5.5 mmol) was dissolved in DCM (20 mL), then chloroacetyl chloride (807 mg, 7.1 mmol) was slowly added at 00 C, this reaction was reacted at 00 C for 1H, then the reaction solution was dried, acetonitrile (20 mL) and sodium bicarbonate ((2.3 g, 27.5 mmol)) were then added, respectively, slowly warmed to reflux under nitrogen protection and stirred overnight, LCMS was performed to detect completion of the reaction, the reaction solution was cooled to room temperature, filtered, concentrated, and passed through a column to give product 8-3 (yellow solid, 800 mg, yield 43.6%) MS M/z (ESI 276.4 [ M+H-tBu ]+).
Step 4 preparation method 8-4 reference is made to the synthesis of the third step of intermediate A. MS M/z (ESI): 318.2 [ M+H ]+.
Step 5 preparation method 8-5 reference is made to the synthesis method of the second step of example 1. MS M/z (ESI): 260.4 [ M+H-100]+
Step 6 preparation method 8-6 reference is made to the synthesis method of the third step of example 1. MS M/z (ESI): 260.4 [ M+H ]+
Step 7 preparation of E8 reference is made to the fourth step of the synthetic method of example 1 .1H NMR (500 MHz, CDCl3) δ 7.06 (d, J = 7.2 Hz, 2H), 7.00 (s, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.76 (dd, J = 21.0, 13.6 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.64 (s, 1H), 4.55 (t, J = 8.7 Hz, 2H), 3.82 (s, 2H), 3.71 (s, 1H), 3.36 (s, 3H), 3.21 (t, J = 8.7 Hz, 3H), 2.49 (d, J = 135.1 Hz, 6H), 2.22 (s, 3H), 1.97 (d, J = 127.4 Hz, 6H). MS m/z (ESI): 420.8 [M+H]+.
EXAMPLE 9 1- (4- (1- (2, 3-dihydrobenzofuran-7-yl) ethyl) piperidin-4-yl) -3, 4-dihydroquinoxalin-1 (2H) -yl) ethan-1-one
Preparation of E9 with reference to the fourth step of the synthesis of example 1 .1H NMR (500 MHz, CDCl3) δ 7.06 (t, J = 7.4 Hz, 2H), 6.95 (dd, J = 17.1, 7.5 Hz, 2H), 6.78 (dd, J = 14.1, 6.6 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.63 (t, J = 7.5 Hz, 1H), 4.55 (td, J = 8.7, 3.5 Hz, 2H), 3.83 (s, 2H), 3.68 (s, 1H), 3.36 (s, 2H), 3.21 (t, J = 8.7 Hz, 4H), 2.91-2.57 (m, 4H), 2.36-2.15 (m, 5H), 1.79 (t, J = 33.5 Hz, 4H). MS m/z (ESI): 406.7 [M+H]+.
EXAMPLE 10 1- (8- (1- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -1,2,5, 6-tetrahydropyridin-3-yl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) ethan-1-one
Preparation method of E10 reference to the synthetic method of E5 .1H NMR (500 MHz, DMSO-d6) δ 7.09 (d, J = 7.3 Hz, 1H), 6.93 (dt, J = 38.6, 7.6 Hz, 3H), 6.77 (t, J = 7.4 Hz, 1H), 5.99 (s, 1H), 4.50 (t, J = 8.7 Hz, 2H), 4.29 (t, J = 4.8 Hz, 2H), 4.02 (s, 2H), 3.86–3.84 (m, 3H), 3.52 (dd, J = 11.9, 5.8 Hz, 1H), 3.17 (dd, J = 11.0, 6.3 Hz, 5H), 2.57 (q, J = 7.7, 7.1 Hz, 3H), 2.48-2.39 (m, 1H), 2.24 (s, 3H), 2.06-1.95 (m, 2H). MS m/z (ESI): 419.7 [M+H]+.
EXAMPLE 11 1- (8- (1- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) piperidin-3-yl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) ethan-1-one
The preparation method of step 1:11-1 refers to the second step synthesis method of intermediate A.
Step 2 preparation method 11-2 reference is made to the third synthetic procedure of example E10.
Step 3 preparation of E11 with reference to the fourth Synthesis procedure of example E10 .1H NMR (500 MHz, CDCl3) δ 7.14-6.79 (m, 5H), 6.76 (t, J = 7.4 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 4.33 (s, 2H), 3.93 (s, 2H), 3.49-3.14 (m, 4H), 2.99 (s, 2H), 2.60 (s, 5H), 2.31 (s, 3H), 1.86 (s, 6H). MS m/z (ESI): 421.6 [M+H]+.
EXAMPLE 12 4- (2, 3-Dihydrobenzo [ b ] [1,4] dioxin-5-yl) -1- (2, 3-Dihydrobenzofuran-7-yl) ethyl) piperidine
Step 1:12-1 preparation method reference is made to the first step synthesis method of example 5. MS M/z (ESI): 262.2 [ M+H-tBu ]+
Step 2:12-2 preparation method reference is made to the synthetic method of example 6. MS M/z (ESI): 264.2 [ M+H-tBu ]+
Step 3 preparation method 12-3 reference is made to the third synthetic step of example 5. MS M/z (ESI): 220.2 [ M+H ]+.
Step 4 preparation of E12 with reference to the Synthesis method of example 1 in the fourth step .1H NMR (500 MHz, CDCl3) δ 7.07 (t, J = 9.4 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.84-6.73 (m, 4H), 4.55 (t, J = 8.7 Hz, 2H), 4.33-4.17 (m, 4H), 3.29 (d, J = 54.1 Hz, 2H), 3.21 (t, J = 8.2 Hz, 2H), 2.98 (s, 5H), 2.58-2.14 (m, 2H), 1.91 (s, 2H), 1.62 (s, 2H).MS m/z (ESI): 366.7 [M+H]+.
EXAMPLE 13 8- (1- (2, 3-Dihydrobenzofuran-7-yl) ethyl) piperidin-4-yl) -4-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine
Step 1 Compound 1-1 (150 mg, 0.48 mmol) was dissolved in 8 mL acetonitrile, cesium carbonate (315 mg, 0.96 mmol) was added, methyl iodide (204 mg, 1.44 mmol) was added, and heated to reflux 16 h. TLC checked completion of the reaction, water and EtOAc were added to separate the layers, the aqueous phase was extracted with EtOAc, the organic phases were combined, washed three times with saturated sodium chloride solution, and dried and concentrated to give compound 13-1 (115 mg, colorless oil, yield 72%) by column chromatography on normal phase silica gel (PE/etoac=3/1). MS M/z (ESI): 331.2 [ M+H ]+.
The preparation method of the step 2:13-2 refers to the synthesis method of the step 3 of the E1. MS M/z (ESI): 231.4 [ M+H ]+
The preparation method of step 3:13-3 refers to the synthesis method of step 4 of E1. MS M/z (ESI): 377.8 [ M+H ]+
Step 4 preparation method of E13 reference E2 Synthesis method .1H NMR (500 MHz, CD3OD) δ 7.14 (d, J = 10.0 Hz, 1H), 7.01 (d, J = 5.0 Hz, 1H), 6.83-6.76 (m, 2H), 6.62 (d, J = 5.0 Hz, 1H), 6.53 (d, J = 10.0 Hz, 1H), 4.58 (t, J = 10.0 Hz, 2H), 4.29 (t, J = 5.0 Hz, 2H), 3.67 (d, J = 10.0 Hz, 2H), 3.26-3.00 (m, 10H), 2.86 (s, 3H), 2.06-1.93 (m, 5H).MS m/z (ESI): 379.6 [M+H]+.
EXAMPLE 14 1- (2, 3-Dihydrobenzofuran-7-yl) ethyl) -4- (4-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-8-yl) piperidin-3-ol
Compound 13-3 (20 mg, 0.053 mmol) was dissolved in 2 mL THF, borane dimethyl sulfide (0.11 mL, 0.11 mmol) was added, stirred at room temperature for reaction 16 h, naOH aqueous solution (0.13 mL, 0.13 mmol) was added, and hydrogen peroxide solution (0.015 mL, 0.13 mmol) was added, stirred at room temperature for reaction 3h. TLC detection of completion of the reaction, delamination of the aqueous and EtOAc, extraction of the aqueous phase with EtOAc, washing of the combined organic phases with saturated sodium chloride solution, concentration and filtration followed by prep-HPLC purification and separation (eluent (v/v): acetonitrile/(water+0.05% NH4HCO 3) =30% -70%) gives Compound E14 (4.0 mg, white solid, yield) 18%).1H NMR (500 MHz, CD3OD) δ 7.09 (d, J = 10.0 Hz, 1H), 6.96 (d, J = 5.0 Hz, 1H), 6.80-6.76 (m, 2H), 6.62-6.58 (m, 2H), 4.58 (t, J = 10.0 Hz, 2H), 4.41-4.24 (m, 2H), 3.28-3.15 (m, 6H), 3.13-3.03 (m, 4H), 2.88 (s, 3H), 2.65-2.60 (m, 2H), 2.21-2.15 (m, 1H), 1.84-1.68 (m, 3H).MS m/z (ESI): 395.6 [M+H]+.
EXAMPLE 15 1- (5- (1- (2- (2-3-dihydrobenzofuran-7-yl) ethyl) piperidin-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) ethan-1-one
Step 1:15-1 preparation method reference is made to the synthesis of the second step of example E5.
Step 2:15-2 preparation method reference is made to the synthetic method of the first step of example E5.
Step 3 preparation method 15-3 reference is made to the synthetic method of example 6.
Step 4:15-4 preparation method reference is made to the synthetic method of the third step of example E5.
Step 5 preparation of E15 reference is made to the synthetic method of example 3 .1H NMR (500 MHz, CDCl3) δ 7.24-6.90 (m, 5H), 6.80 (t, J = 7.4 Hz, 1H), 4.56 (t, J = 8.7 Hz, 2H), 3.79 (t, J = 6.5 Hz, 2H), 3.22 (t, J = 8.7 Hz, 4H), 3.11-2.46 (m, 8H), 2.19 (s, 5H), 1.96 (p, J = 6.7 Hz, 3H), 1.83 (s, 2H). MS m/z (ESI): 405.8 [M+H]+.
EXAMPLE 16 1- (8- (5- (2, 3-Dihydrobenzofuran-7-yl) ethyl) -5-azaspiro [2.5] oct-8-yl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) ethan-1-one
Step 1. The compound tert-butyl 8-oxo-5-aza [2.5] octane-5-carboxylate (100 mg, 0.44 mmol) was added to a 25mL single-necked flask with 4-methylbenzenesulfonyl hydrazide (83 mg, 0.44 mmol), followed by anhydrous methanol (10 mL), and stirred overnight at room temperature under nitrogen. LCMS detected completion of the reaction and the reaction was dried under reduced pressure to give crude compound 16-1 (white solid, 170 mg, 98% yield). The crude product was used directly in the next reaction without further purification. MS M/z (ESI): 394.7 [ M+H ]+.
Step 2. Compound 16-1 (130 mg, 0.33 mmol), 8-bromo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine (0.36 g, 0.36 mmol),Pd2(dba)3(30 mg, 0.03 mmol),X-Phos (15 mg, 0.1 mmol),t-BuOLi (80 mg, 1.00 mmol) , were added together in a 100 mL single vial followed by the addition of anhydrous dioxane (5 mL), and after addition, slowly warmed to 110℃under nitrogen and stirred overnight. LCMS checked the completion of the reaction, cooled the reaction to room temperature, water (20 mL), etOAc extraction (2×20 mL), combined organic phases, washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, dried under reduced pressure, and the crude purified by column chromatography (EtOAc/pe=0-30%) to give compound 16-2 (pale yellow solid, 100 mg, yield: 88%). MS M/z (ESI): 243.6 [ M-Boc ]+
Step 3 Compound 16-2 (60 mg,0.18 mmol), TEA (40 mg,0.54 mmol) and anhydrous DCM (5 mL) were added together in a 25mL single-port bottle, acetyl chloride (12 mg) was slowly added dropwise under ice-water bath, and after the dropwise addition, stirring was allowed for 1h at room temperature. LCMS checked the completion of the reaction, and saturated NH4 Cl solution (10 mL), DCM extraction (2×10 mL), combined organic phases, washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to give compound 16-3 (pale yellow solid, 30mg, yield: 45%) as crude product purified by column chromatography (EtOAc/pe=0-30%). MS M/z (ESI): 285.7 [ M-Boc ]+.
Step 4. Compound 16-3 (30 mg, 0.08 mmol) was added to a 25 mL single-necked flask with methanol (10 mL), followed by 10% Pd/C (wet, 30 mg), and then stirred under hydrogen atmosphere with slow warming to 40℃for 5h. LCMS detected the end of the reaction, the reaction was filtered and the filtrate was dried under reduced pressure to give crude compound 16-4 (pale yellow oil, 25 mg, 83% yield). The crude product was used directly in the next reaction without further purification. MS M/z (ESI): 387.6 [ M+H ]+.
Step 5 Compound 16-4 (25 mg, 0.09 mmol) and anhydrous DCM (5 mL) were added together in a single vial of 25mL followed by TFA (1 mL) and stirred at room temperature for 1h. After completion of LCMS detection, the reaction mixture was dried under reduced pressure to give crude compound 16-5 (pale yellow oil, 20 mg). The crude product was used directly in the next reaction without further purification. MS M/z (ESI): 287.5 [ M+H ]+.
Step 6 preparation of E16 reference example E1 Synthesis method of step 4 .1H NMR (500 MHz, CDCl3) δ 7.06 (d, J = 7.1 Hz, 1H), 6.98 (d, J = 7.3 Hz, 3H), 6.84 (t, J = 7.9 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 4.55 (t, J = 8.7 Hz, 2H), 4.36-4.28 (m, 2H), 4.02 - 3.84 (m, 2H), 3.44 - 3.34 (m, 1H), 3.21 (t, J = 8.7 Hz, 3H), 3.03-2.09 (m, 9H), 2.30 (s, 3H), 1.83 - 1.75 (m, 1H), 0.50-0.15 (m, 3H). MS m/z (ESI): 433.7 [M+H]+.
EXAMPLE 17 1- (8- (4- (2- (2-) 2-dihydrobenzofuran-7-yl) ethyl) piperazin-1-yl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) acetic acid 1-one
Step 1 8-bromo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine (500 mg, 2.34 mmol) and TEA (473 mg, 4.68 mmol) were dissolved in DCM (10 mL) at room temperature, replaced three times with N2, and acetyl chloride (220 mg, 2.80 mmol) was added. The reaction solution was stirred at room temperature for 10 min a. LC-MS monitors the reaction to be complete, adds sat.NaCl solution, separates liquid, dries and concentrates in vacuum to obtain crude product. Purification of the crude product by column chromatography (EtOAc/pe=0-30%) afforded 17-1 (550 mg, yield: 91.6%) as a yellow solid. MS M/z (ESI): 255.9, 257.9 [ M+H ]+.
Step 2-17-1 (500 mg, 1.95 mmol), t-butylpiperazine-1-carboxylate (550 mg, 2.93 mmol), pd (OAc)2 (50 mg, 0.195 mmol), BINAP (120 mg, 0.195 mmol) and NaOt-Bu (570 mg, 5.95 mmol) were added to a three-necked flask containing 1,4-dioxane (15 mL) at room temperature, the N2 was replaced three times, and the reaction mixture was stirred at 100o C for 16h. LC-MS monitors the generation of 40% of the product, water and EA are added, liquid separation is carried out, the water phase is extracted twice by EA, and the crude product is obtained by drying and vacuum concentration. Purification of the crude product by column chromatography (EtOAc/pe=0-30%) afforded 17-2 (400 mg, yield: 64.3%) as a brown solid. MS M/z (ESI): 320.3 [ M+H ]+.
Preparation of step 3:17-3 reference is made to the synthetic method of step 1. MS M/z (ESI): 362.2 [ M+H ]+.
Step 4 17-3 (300 mg, 0.83 mmol) was dissolved in DCM (6 mL) at room temperature and TFA (2 mL) was added. The reaction solution was stirred at room temperature for 1h. LC-MS monitors that the reaction is complete, concentrates most TFA, adds sat NaHCO3 solution to adjust pH=7-8, then extracts water phase with mixed solvent of DCM/MeOH=10/1, dries and concentrates in vacuum to obtain crude product. Purification of the crude product by column chromatography (EtOAc/pe=0-30%) gave 17-4 (140 mg, yield: 64.6%) as a brown oil. MS m/z (ESI): 262.2[ M+H ]+.
Step 5 preparation of E17 reference is made to the fourth Synthesis procedure of example 1 .1H NMR (500 MHz, CDCl3) δ 7.06 (d, J = 7.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.87-6.77 (m, 4H), 4.55 (t, J = 8.5 Hz, 2H), 4.39 (m, J = 4.5 Hz, 2H), 3.96 (s, 2H), 3.21 (t, J = 8.5 Hz, 2H), 3.14 (s, 4H), 2.90-2.55 (m, 8H), 2.31 (s, 3H). MS m/z (ESI):408.2 [M+H]+.
Effect example 1 downstream beta-arestin functional Activity test of 5-HT2A receptor
The method is mainly carried out by using a Promega company NanoBret kit. Specifically, a 5HT2A receptor plasmid with Nanoluc at the C end, a beta-arestin plasmid with Halo-tag at the C end and a pcDNA3.1 plasmid for expressing GRK2 are respectively constructed. HEK293 cells (ATCC, CRL-1573) were seeded in 6-well plates before transfection, and after overnight incubation, plasmids of Nanoluc-5HT2AR, GRK2, beta-arestin-halotag were mixed at a ratio of 1:1:10 and added to 6-well plates together with the transfection reagent at a transfection amount of 2ug per well. After 4 hours, cells were transferred to 384 well plates after digestion, 20000 cells per well, and the test compound or 5-HT was added as positive control and incubation was continued overnight at 37 ℃,5% co2. After the next day removal, diluted NanoBRETTMNano-Glo substrate (10 ul per well after dilution according to instructions) was added and read on a microplate reader at 618nm/460 nm. The data were analyzed using Prism software with the read at the highest concentration of 5-HT as 100% of downstream pathway activation, and the data were fitted using the "log (ag) vs. response-Variable slope (four parameters)" model to give EC50 and Emax.
TABLE 1
Effect example 2 animal behavioural test
The experiment is a forced swimming experiment of mice, and animals are C57BL/6J male mice 7-8 weeks old, and each group comprises 12 animals. The mice were placed in a 5L glass beaker with a water level of 15cm for 15 minutes 24hr before testing. On the day of testing, mice were placed in the same beaker for 6 minutes after 30 minutes of intraperitoneal injection of either blank vehicle (5% DMSO,10% polyethylene glycol-15-hydroxystearate, 85% physiological saline) ketamine (20 mpk) or test subject (15 mpk). Four minutes after the software (Shanghai Ji amount, JLBehv-FSG-4) analysis, mice were stationary. And calculating the immobility time of each administration group and the immobility time of the solvent control group in the same batch for statistical analysis, wherein if the data meet normal distribution, a statistical method adopts parameter test, namely independent sample t test, and if the data do not meet normal distribution, a statistical method adopts non-parameter test, as shown in table 2 and figure 1. Bar graph expressed as mean ± standard error, (×p <0.05, ×p < 0.01). Bar graph expressed as mean ± standard error, (×p <0.05, ×p < 0.01). Experimental results show that compared with a solvent control group under the same experimental conditions, the control compound ketamine can obviously reduce the immobility time of mice, and the compounds 16 and 17 of the embodiment of the invention can obviously increase the immobility time of mice and play a sedative role on the mice.
TABLE 2
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