FUSED RING COMPOUND, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

The present invention relates to a fused ring compound represented by general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition and use thereof. The compound provided in the present invention is useful for treating, preventing and/or controlling various nervous system disorders. The compound provided in the present invention modulates one or more monoamine transporters, inhibits the reuptake of endogenous monoamines such as dopamine, 5-hydroxytryptamine, and norepinephrine (e.g., from the synaptic cleft), and/or modulates the 5-HT.sub.3 receptor.

##STR00001##

Claims

1. A compound represented by formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof: ##STR00134## wherein R.sub.1 is hydrogen or C1 to C20 alkyl; preferably hydrogen or C1 to C10 alkyl; more preferably hydrogen or C1 to C6 alkyl; m, n, p, q are each independently 0 or 1 or 2 or 3; preferably, m, n, p, q are each independently 1 or 2; provided that m+p is 1, 2, 3 or 4, N+q is 1, 2, 3 or 4, and m+p+n+q is 3, 4, 5, 6 or 7; X is CR.sub.2, N or C; when X is CR.sub.2 or N, “” connected with X represents a single bond, R.sub.2 is hydrogen, hydroxyl or C1 to C6 alkoxy; when X is C, “” connected with X represents a double bond; G ring is phenyl, biphenyl group, naphthyl, tetrahydronaphthyl, dihydroindenyl, monocyclic heterocyclyl or benzoheterocyclyl; further, G ring is optionally substituted by one or more identical or different substituents; the substituent on G ring is halogen, oxo (═O), hydroxy, halo-C1 to C6 alkyl, C1 to C6 alkanoyl, C1 to C6 alkyl substituted by C1 to C6 alkoxy, C1 to C6 alkyl or C1 to C6 alkoxy, preferably, the substituent on the G ring is halogen, oxo (═O), hydroxy, halo-C1 to C4 alkyl, C1 to C4 alkanoyl, C1 to C4 alkyl substituted by C1 to C6 alkoxy, C1 to C4 alkyl or C1 to C4 alkoxy, more preferably, the substituent on the G ring is halogen, oxo (═O), hydroxy, acetyl, trifluoromethyl, methoxymethyl, methyl, ethyl, methoxy or ethoxy.

2. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the G ring is ##STR00135## ##STR00136## and the G ring is optionally substituted by one or more identical or different substituents, and the substituent on the G ring is defined the same as that defined in claim 1.

3. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the G ring is ##STR00137## and the G ring is optionally substituted by one or more identical or different substituents, the substituent on the G ring is defined the same as that defined in claim 1.

4. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein ##STR00138## ##STR00139## ##STR00140## is a group selected from the group consisting of formulae S-1 to S-41: wherein, X and R.sub.1 are defined the same as those defined in claim 1.

5. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein ##STR00141## is a group selected from the group consisting of formulae S-1a to S-41a: ##STR00142## ##STR00143## wherein, R.sub.1 is defined the same as that defined in claim 1.

6. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds: ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156##

7. A method for preparing a fused ring compound according to claim 1, wherein the method is carried out by one of the following methods 1-7, Method 1: a compound represented by formula (II-a) is coupled with a compound represented by formula (III) to obtain a compound represented by formula (Ia), as shown in Scheme 1: ##STR00157## wherein, G ring, m, n, p, q, R.sub.1 are defined the same as those defined in claim 1; L.sub.1 represents halogen, C1 to C6 alkylsulfonyloxy, benzenesulfonyloxy or naphthalenesulfonyloxy, the above C1 to C6 alkylsulfonyloxy, benzenesulfonyloxy and naphthalenesulfonyloxy may be optionally further substituted with one or more substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 alkoxy, nitro, hydroxy, amino and C1 to C6 alkanoyl; L.sub.1 is preferably halogen, C1 to C4 alkylsulfonyloxy, benzenesulfonyloxy or naphthalenesulfonyloxy, the above C1 to C4 alkylsulfonyloxy, benzenesulfonyloxy and naphthalenesulfonyloxy may be optionally further substituted by one or more substituents selected from the group consisting of halogen, C1 to C4 alkyl, C1 to C4 alkoxy, nitro, hydroxyl, amino and C1 to C4 alkanoyl; L.sub.1 is most preferably chlorine, bromine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, naphthalenesulfonyloxy, methylbenzenesulfonyloxy, nitrobenzenesulfonyloxy, aminobenzenesulfonyloxy, chlorobenzenesulfonyloxy, bromobenzenesulfonyloxy or methoxybenzenesulfonyloxy; Method 2: a compound represented by formula (II-b) is coupled with a compound represented by formula (III) to obtain a compound represented by formula (IV), and then the amino protecting group is removed to obtain a compound of formula (Ib), which is optionally alkylated or reductive aminated to obtain a compound represented by formula (Ia), as shown in Scheme 2: ##STR00158## wherein, G ring, m, n, p, q are defined the same as those defined in claim 1; R.sub.1 is C1 to C20 alkyl, L.sub.1 represents halogen, C1 to C6 alkylsulfonyloxy, benzenesulfonyloxy or naphthalenesulfonyloxy, the above C1 to C6 alkylsulfonyloxy, benzenesulfonyloxy and naphthalenesulfonyloxy may be optionally further substituted with one or more substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 alkoxy, nitro, hydroxy, amino and C1 to C6 alkanoyl; Li is preferably halogen, C1 to C4 alkylsulfonyloxy, benzenesulfonyloxy or naphthalenesulfonyloxy, the above C1 to C4 alkylsulfonyloxy, benzenesulfonyloxy and naphthalenesulfonyloxy may be optionally further substituted by one or more substituents selected from the group consisting of halogen, C1 to C4 alkyl, C1 to C4 alkoxy, nitro, hydroxyl, amino and C1 to C4 alkanoyl; Li is most preferably chlorine, bromine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, naphthalenesulfonyloxy, methylbenzenesulfonyloxy, nitrobenzenesulfonyloxy, aminobenzenesulfonyloxy, chlorobenzenesulfonyloxy, bromobenzenesulfonyloxy or methoxybenzenesulfonyloxy; PG is a substituted or unsubstituted benzyl group, acyl type amino protecting group or alkoxycarbonyl type amino protecting group, and the substituent on the benzyl group is one or more independently selected from the group consisting of halogen, trifluoromethyl, C1 to C6 alkyl, C1 to C6 alkoxy and nitro, preferably the acyl type amino protecting group is formyl, acetyl, propionyl, benzoyl, haloacetyl or phthaloyl, and the alkoxycarbonyl type amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl, Method 3: a compound represented by formula (V) is coupled with a compound represented by formula (III), and then the amino protecting group is removed to obtain a compound of formula (Ic), which is optionally alkylated or reductive aminated to obtain a compound represented by formula (If), as shown in Scheme 3: ##STR00159## wherein, G ring, m, n, p, q are defined the same as those defined in claim 1; R.sub.1 is C1 to C20 alkyl, L.sub.1 represents halogen, C1 to C6 alkylsulfonyloxy, benzenesulfonyloxy or naphthalenesulfonyloxy, the above C1 to C6 alkylsulfonyloxy, benzenesulfonyloxy and naphthalenesulfonyloxy may be optionally further substituted with one or more substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 alkoxy, nitro, hydroxy, amino and C1 to C6 alkanoyl; L.sub.1 is preferably halogen, C1 to C4 alkylsulfonyloxy, benzenesulfonyloxy or naphthalenesulfonyloxy, the above C1 to C4 alkylsulfonyloxy, benzenesulfonyloxy and naphthalenesulfonyloxy may be optionally further substituted by one or more substituents selected from the group consisting of halogen, C1 to C4 alkyl, C1 to C4 alkoxy, nitro, hydroxyl, amino and C1 to C4 alkanoyl; L.sub.1 is most preferably chlorine, bromine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, naphthalenesulfonyloxy, methylbenzenesulfonyloxy, nitrobenzenesulfonyloxy, aminobenzenesulfonyloxy, chlorobenzenesulfonyloxy, bromobenzenesulfonyloxy or methoxybenzenesulfonyloxy; PG is a substituted or unsubstituted benzyl group, acyl type amino protecting group or alkoxycarbonyl type amino protecting group, and the substituent on the benzyl group is one or more independently selected from the group consisting of halogen, trifluoromethyl, C1 to C6 alkyl, C1 to C6 alkoxy and nitro, preferably the acyl type amino protecting group is formyl, acetyl, propionyl, benzoyl, haloacetyl or phthaloyl, and the alkoxycarbonyl type amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl, Method 4: a compound represented by formula (II-a) is reacted with a compound represented by formula (X) through carbonyl addition to obtain a compound represented by formula (VIII), and then the amino protecting group is removed to obtain a compound of formula (Id), as shown in Scheme 4: ##STR00160## wherein, G ring, m, n, p, q are defined the same as those defined in claim 1; L.sub.2 represents Li, MgBr, MgCl, MgI, ZnBr, ZnCl or ZnI; PG is an acyl type amino protecting group or alkoxycarbonyl type amino protecting group, preferably the acyl type amino protecting group is formyl, acetyl, propionyl, benzoyl, haloacetyl or phthaloyl, and the alkoxycarbonyl type amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl, Method 5: a compound represented by formula (VII-a) is reacted with a compound represented by formula (X) through carbonyl addition to obtain a compound of formula (VIII), and then dehydration and amino deprotection are simultaneously performed to obtain a compound of formula (Ie), which is optionally alkylated or reductive aminated to obtain a compound represented by formula (Ig), as shown in Scheme 5: ##STR00161## wherein, G ring, m, n, p, q are defined the same as above; R.sub.1 is C1-C20 alkyl; L.sub.2 represents Li, MgBr, MgCl, MgI, ZnBr, ZnCl or ZnI; PG is an acyl type amino protecting group or alkoxycarbonyl type amino protecting group, preferably the acyl type amino protecting group is formyl, acetyl, propionyl, benzoyl, haloacetyl or phthaloyl, and the alkoxycarbonyl type amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl, Method 6: a compound represented by formula (VII-b) is reacted with a compound represented by formula (X) through carbonyl addition to obtain a compound represented by formula (Ih), which is then dehydrated to obtain a compound of formula (Ig), as shown in Scheme 6: ##STR00162## wherein, G ring, m, n, p, q are defined the same as above; R.sub.1 is C1-C20 alkyl; L.sub.2 represents Li, MgBr, MgCl, MgI, ZnBr, ZnCl or ZnI; Method 7: a compound represented by formula (Ie) or (Ig) is subjected to hydrogenation reduction to obtain a compound represented by formula (Ic) or (If) respectively: ##STR00163## wherein, G ring, m, n, p, q are defined the same as above.

8. A pharmaceutical composition, comprising a therapeutically effective amount of one or more compounds according to claim 1, the stereoisomers thereof and the pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier.

9. A method for the prevention and/or treatment of a central nervous system disease, comprising administering to a subject in need thereof one or more compounds according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

10. The method according to claim 9, wherein the central nervous system disease is selected from the group consisting of affective disorder; mental disorder; mood disorder; depression; intrinsic depression; major depression; uncontrollable depression; dysthymic disorder; cyclic affective disorder; panic attack; panic disorder; social phobia; obsessive-compulsive and behavioral disorders; impulsive disorders; post-traumatic stress disorders; anxiety disorders; acute stress disorders; hysteria; anorexia nervosa; sleep disorders; adaptive disorders; autism; neuropathic headache; mania; hyperactivity; fibromyalgia; neuropathic pain; attention deficit/hyperactivity diseases and tics.

11. The method of claim 10, wherein the sleep disorder is selected from sleep apnea, insomnia, narcolepsy, or cataplexy.

12. The method of claim 10, wherein the neuropathic pain is selected from postherpetic neuralgia, reflex sympathetic dystrophy/causalgia, nerve trauma, prosthetic pain, peripheral neuropathy or herpes zoster.

13. The method of claim 12, wherein the peripheral neuropathy is diabetic neuropathy or neuropathy caused by long-term drinking of alcohol.

Description

BEST MODE FOR CARRYING OUT THE INVENTION

[0103] The present invention is further illustrated by the following preparation examples, examples and pharmacological activity test examples, but the scope of the present invention is not limited thereto.

EXAMPLE 1

2-(naphthalen-2-yl)octahydropyrrolo[3,4-c]pyrrole

[0104] ##STR00041##

[0105] Step 1:

[0106] 2-Bromonaphthalene (1-a, 10.7 g, 52 mmol, 1.1 eq) and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10 g, 47 mmol, 1 eq) were added to 150 mL of toluene. The toluene solution was added with Pd.sub.2(dba).sub.3 (2.16 g, 2.36 mmol, 0.05 eq), BINAP (2.35 g, 3.78 mmol, 0.08 eq) and potassium tert-butoxide (7.9 g, 70.8 mmol, 1.5 eq), and heated under N.sub.2 protection at an external temperature of 105° C. for 10 h. The reaction solution was diluted with 150 ml of ethyl acetate and filtered, and the filter cake was washed with a small amount of ethyl acetate. The filtrate was washed with 300 ml of a saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and rotary evaporated to dryness to obtain 16 g of a brown oil. The oil was slurried in 100 ml of ethanol to precipitate out a large amount of solids, stirred for 2 h at room temperature to disperse the solids evenly, and filtered. The filter cake was heated at 50° C. for 3 h to obtain 1-b as a gray solid (15.2 g, yield 95.3%).

[0107] Step 2:

[0108] 1-b (15.2 g) was added to 100 ml of methanol, added with 80 ml of a concentrated hydrochloric acid, and stirred at room temperature for 2 h. The reaction solution was diluted with 500 ml of water, and extracted with 400 ml of methyl tert-butyl ether to remove less polar impurities. The aqueous phase was adjusted pH with 200 ml of a 5M NaOH solution to 9 and extracted with 600 ml of dichloromethane. The organic phase was washed with 300 ml of a saturated sodium chloride solution, dried with anhydrous sodium sulfate and rotary evaporated to dryness to obtain 10.8 g of a yellow solid. ESI-MS (m/z): 239.17 [M+H].sup.+. HPLC>95%.

EXAMPLE 2

2-methyl-5-(naphthalen-2-yl)octahydropyrrolo[3,4-c]pyrrole

[0109] ##STR00042##

[0110] Step 1:

[0111] The product of Example 1 (7.5 g, 31.6 mmol) was added to 120 ml of ethyl formate, and added with triethylamine (17.6 ml, 126.6 mmol, 4 eq). The system was heated at an external temperature of 60° C. for 3 h, and diluted with 100 ml of ethyl acetate. The organic phase was washed with 200 ml of a saturated ammonium chloride solution and then with 200 ml of a saturated sodium chloride solution, dried over anhydrous sodium sulfate and rotary evaporated to dryness to obtain 2-a as a yellowish solid (8.4g, yield 99.8%).

[0112] Step 2:

[0113] 2-a (8.4 g, 31.6 mmol) was added to 120 ml of dry tetrahydrofuran, and added with a 1M borane tetrahydrofuran solution (63.2 ml, 63.2 mmol, 2 eq). The reaction solution was gradually cleared, and kept under N2 protection at an outer temperature of 68° C. for 2 h. The reaction solution was put in an ice bath, added dropwise with 7.9 ml of hydrochloric acid (3 eq) dissolved in 100 ml of methanol to produce a large number of bubbles, heated at an external temperature of 68° C. for 10 h, and rotary evaporated to dryness. The residue was added with 80 ml of water. The aqueous phase was adjusted pH with 20 ml of a 5M NaOH solution to 9, and extracted with 200 ml of DCM. The organic phase was washed with 200 ml of a saturated sodium chloride solution, dried over anhydrous sodium sulfate and rotary evaporated to dryness to obtain 8 g of a solid. ESI-MS (m/z): 253.35 [M+H].sup.+. HPLC>95%.

EXAMPLE 3

5-(Benzo[b]thiophen-4-yl)octahydrocyclopenta[c]pyrrole hydrochloride

[0114] ##STR00043##

[0115] Step 1:

[0116] Thionyl chloride (1.2 g, 10 mmol) was added dropwise to a solution of 3-a (2.27 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in dichloromethane (30 mL) at 0° C. After the addition, the mixture was raised to 20° C. to react for 5 h, added with water to quench the reaction, and layered. The organic layer was concentrated and subjected to column chromatography (EA:PE=1:15 to 1:5) to obtain 3-b (1.25 g, yield 60%).

[0117] Step 2:

[0118] Potassium tert-butoxide (1.12 g, 10 mmol) was added to a solution of bis(pinacolato)diboron (2.54 g, 10 mmol), cuprous chloride (25 mg, 0.25 mmol) and the ligand xantphos (145 mg, 0.25 mmol) in THF (30 mL) at 0° C. under nitrogen protection. After the addition, the mixture was raised to 20° C. and reacted for 30 min, added dropwise with a solution of 3-b (1.23 g, 5 mmol) in THF (2 mL), and reacted at room temperature overnight. The reaction solution was directly mixed with silica gel and subjected to column chromatography (EA:PE=1:15 to 1:5) to obtain 3-c (800 mg, yield 48%).

[0119] Step 3:

[0120] A solution of 3-c (340 mg, 1 mmol), 4-bromobenzothiophene (213 mg, 1 mmol), cesium carbonate (326 mg, 1 mmol) and dppfPdCl.sub.2 (73.2 mg, 0.1 mmol) in dioxane (10 mL) was reacted at 80° C. under nitrogen protection overnight. The reaction solution was directly mixed with silica gel and subjected to column chromatography (EA:PE=1:15 to 1:5) to obtain 3-d (40 mg, yield 12%).

[0121] Step 4:

[0122] 3-d (66 mg, 0.2 mmol) was dissolved in methanol (1 mL), added with a 4N HCl methanol solution (1 mL), and reacted at room temperature for 1 h. The reaction solution was concentrated to dryness, and slurried in methyl tert-butyl ether to obtain the title compound as an off-white solid (40 mg). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.88 (d, 1H), 7.69 (d, 1H), 7.54 (d, 1H), 7.46 (d, 1H), 7.23 (t, 1H), 3.28 (m, 2H), 3.20 (m, 2H), 3.08 (m, 1H), 2.90 (m, 2H), 2.39 (m, 2H), 1.37 (m, 2H). ESI-MS (m/z): 244.20 [M+H].sup.+.

EXAMPLE 4

5-(Benzothiophen-5-yl)octahydrocyclopenta[c]pyrrole hydrochloride

[0123] ##STR00044##

[0124] Step 1:

[0125] 4-a (340 mg, 1 mmol), 5-bromobenzothiophene (213 mg, 1 mmol), cesium carbonate (326 mg, 1 mmol) and dppfPdCl.sub.2 (73.2 mg, 0.1 mmol) were added in dioxane (10 mL), and reacted at 80° C. under nitrogen protection overnight. The reaction solution was directly mixed with silica gel and subjected to column chromatography (EA:PE=1:15 to 1:5) to obtain 4-b (43 mg, yield 14%).

[0126] Step 2:

[0127] 4-b (66 mg, 0.2 mmol) was dissolved in methanol (1 mL), added with a 4N HCl methanol solution (1 mL), and reacted at room temperature for 1 h. The reaction solution was concentrated to dryness, and slurried in methyl tert-butyl ether to obtain the title compound as an off-white solid (38 mg). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.00 (d, 1H), 7.81 (d, 1H), 7.62 (d, 1H), 7.43 (dd, 1H), 7.33 (d, 1H), 3.28 (m, 2H), 3.20 (m, 2H), 3.09 (m, 1H), 2.90 (m, 2H), 2.40 (m, 2H), 1.37 (m, 2H). ESI-MS (m/z): 244.20 [M+H].sup.+.

EXAMPLE 5

6-(Benzo[b]thiophen-4-yl)decahydrocyclohepta[c]pyrrole hydrochloride

[0128] ##STR00045##

[0129] Step 1:

[0130] Thionyl chloride (1.2 g, 10 mmol) was added dropwise to a solution of 5-a (2.55 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in dichloromethane (30 mL) at 0° C. After the addition, the reaction mixture was raised to 20° C. to react for 5 h, added with water to quench the reaction, and layered. The organic layer was concentrated and subjected to column chromatography (EA:PE=1:15 to 1:5) to obtain 5-b (1.5 g, yield 55%).

[0131] Step 2:

[0132] Potassium tert-butoxide (1.12 g, 10 mmol) was added to a solution of bis(pinacolato)diboron (2.54 g, 10 mmol), cuprous chloride (25 mg, 0.25 mmol) and the ligand xantphos (145 mg, 0.25 mmol) in THF (30 mL) at 0° C. under nitrogen protection. After the addition, the reaction solution was raised to 20° C. and reacted for 30 min, added dropwise with a solution of 5-b (1.37 g, 5 mmol) in THF (2 mL), and reacted at room temperature overnight. The reaction solution was directly mixed with silica gel and subjected to column chromatography (EA:PE=1:15 to 1:5) to obtain 5-c (900 mg, yield 50%).

[0133] Step 3:

[0134] A solution of 5-c (360 mg, 1 mmol), 4-bromobenzothiophene (213 mg, 1 mmol), cesium carbonate (326 mg, 1 mmol) and dppfPdCl.sub.2 (73.2 mg, 0.1 mmol) in dioxane (10 mL) was reacted at 80° C. under nitrogen protection overnight. The reaction solution was directly mixed with silica gel and subjected to column chromatography (EA:PE=1:15 to 1:5) to obtain 5-d (45 mg, yield 13%).

[0135] Step 4:

[0136] 5-d (74mg, 0.2 mmol) was dissolved in methanol (1 mL), added with a 4N HCl methanol solution (1 mL), and reacted at room temperature for 1 h. The reaction solution was concentrated to dryness, and slurried in methyl tert-butyl ether to obtain the title compound as an off-white solid (48 mg). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.90 (d, 1H), 7.70 (d, 1H), 7.56 (d, 1H), 7.47 (d, 1H), 7.24 (t, 1H), 3.52 (m, 3H), 2.87 (dd, 2H), 2.53 (m, 2H), 1.89 (m, 6H), 1.56 (m, 2H). ESI-MS (m/z): 272.28 [M+H].sup.+.

EXAMPLE 6

2-(naphthalen-2-yl)decahydropyrrolo[3,4-d]azepine maleate

[0137] ##STR00046##

[0138] Step 1:

[0139] 6-a (200 mg, 0.66 mmol, 1 eq), 2-bromonaphthalene (137 mg, 0.66 mmol, 1 eq), Pd.sub.2(dba).sub.3 (30 mg, 0.033 mmol, 0.05 eq), BINAP (33 mg, 0.053 mmol, 0.08 eq), potassium tert-butoxide (222 mg, 1.98 mmol, 3 eq) were added to 5 ml of dioxane under nitrogen protection, and heated at an external temperature of 105° C. for 8 h. The resultant was filtered, and the filter cake was washed with ethyl acetate. The filtrate was washed with water and then with saturated sodium chloride, dried, and rotary evaporated to dryness. The residue was subjected to silica gel column chromatography to obtain crude 6-b as an oil (153 mg).

[0140] Step 2 and Step 3:

[0141] 6-b (153 mg, 0.43 mmol, 1 eq) was dissolved in chloroform, added with ethyl 1-chloroethylchloroformate (93 μl, 0.86 mmol, 2 eq), and heated at an external temperature of 70° C. for 4 h. The reaction solution was rotary evaporated to dryness, added with methanol, and heated to reflux at 70° C. for 1 h. The resultant was added with water and then with 1 ml of concentrated hydrochloric acid. Methyl tert ether was added to remove impurities. The aqueous phase was adjusted pH to 9, and extracted with DCM. The organic phase was washed with saturated brine, dried, rotary evaporated to dryness, and subjected to column chromatography to obtain a solid (95 mg), which formed a maleate in THF, and dried to obtain the title compound as a white solid (98 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.46 (br, 2H), 7.73 (d, 1H), 7.70 (d, 1H), 7.63 (d, 1H), 7.34 (t, 1H), 7.15 (t, 1H), 7.06 (dd, 1H), 6.79 (d, 1H), 6.02 (s, 2H), 3.70 (dd, 2H), 3.37 (m, 2H), 3.00 (m, 4H), 2.70 (br, 2H), 2.00-1.79 (m, 4H). ESI-MS (m/z): 267.37 [M+H].sup.+.

EXAMPLE 7

6-(Benzothiophen-5-yl)decahydropyrrolo[3,4-d]azepine maleate

[0142] ##STR00047##

[0143] Step 1:

[0144] 820 mg of 7-a, 1.1 eq of 5-bromobenzothiophene, 0.05 eq of Pd.sub.2(dba).sub.3 and 0.08 eq of BINAP were mixed in toluene, stirred at room temperature for 5 min, and added with 2 eq of potassium tert-butoxide. The atmosphere was replaced with nitrogen for three times and the reaction mixture was reacted at 80° C. overnight. The insoluble matter was filtered off, and the filter cake was washed with ethyl acetate. The filtrate was combined, washed with brine, dried and concentrated, and then subjected to silica gel column chromatography to obtain 870 mg of a product, which was slurried in a small amount of dichloromethane to obtain 7-b as a white solid (780 mg).

[0145] Step 2:

[0146] 7-b was dissolved in methanol, added with hydrochloric acid, and stirred at room temperature for 1 h. After the reaction, the reaction mixture was added with water and MTBE, and the organic phase was discarded. The aqueous phase was separated and adjusted pH to be weakly alkaline, and extracted with DCM. The organic phase was washed with brine, dried and concentrated to obtain an oil, which formed maleate in THF, and dried to obtain the title compound as a yellowish solid (920 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.66 (d, 2H), 7.75 (d, 1H), 7.62 (d, 1H), 7.26 (d, 1H), 7.19 (d, 1H), 6.99 (dd, 1H), 6.09 (s, 2H), 3.83 (dd, 2H), 3.35 (brs, 2H), 3.18 (ddd, 2H), 2.77 (d, 2H), 2.56 (q, 2H), 1.66-1.85 (m, 4H). ESI-MS (m/z): 273.28 [M+H].sup.+.

EXAMPLE 8

5-(naphthalen-1-yl)octahydrocyclopenta[c]pyrrole hydrochloride

[0147] ##STR00048##

[0148] Step 1:

[0149] 500 mg of 1-bromonaphthalene was dissolved in 5 mL of THF under nitrogen protection, cooled at an external temperature of −80° C. to control the internal temperature to be less than −70° C. 1.05 eq of n-BuLi (2.5M) was added dropwise to the THF solution of 1-bromonaphthalene, stirred at −70° C. for 1 h to form 8-b. The internal temperature was controlled to be less than −70° C., the reaction mixture was added dropwise with 0.8 eq of 8-a (dissolved in 3 mL THF) as a raw material, and slowly raised to −40° C. to be stirred for 12 h. After quenched with an ammonium chloride aqueous solution, the reaction mixture was layered with ethyl acetate/water layers, and the ethyl acetate phase was concentrated to obtain a crude 8-c.

[0150] Step 2:

[0151] The crude 8-c was dissolved in 5 mL of methanol, added with 2 mL of concentrated hydrochloric acid, and refluxed at 65° C. for 1 h. After cooled to room temperature, the reaction mixture was concentrated and replaced with acetone twice, slurried in acetone, filtered and dried to obtain 140 mg of 8-d.

[0152] Step 3:

[0153] 90 mg of 8-d was dissolved in 5 mL of acetic acid, added with 20 mg of 10% Pd/C, purged with hydrogen, and reacted at 25° C. for 24 h. The reaction solution was filtered, and the acetic acid phase was alkalized with 5 ml of a 20% NaOH and layered with 10 ml of DCM. The organic phase was concentrated. The residue was added with 3 mL of HCl-dioxane in an ice-water bath to form a salt. The solid was filtered, slurried in 5 mL of petroleum ether, filtered and dried to obtain 26 mg of the title compound as a white solid. ESI-MS m/z 238.32 [M+H].sup.+.

EXAMPLE 9

5-(3,4-chlorophenyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole hydrochloride

[0154] ##STR00049##

[0155] Step 1:

[0156] 500 mg of 3,4-dichlorobromobenzene 9-b (1 eq) was added to 5 ml of a freshly distilled THF, decreased to −80° C. under nitrogen protection, and added dropwise with a butyl lithium solution (2.5M, 1.1 eq), and the system is dissolved clearly. At this temperature, the resultant was added with 2 ml of a THF solution containing 300 mg of 9-a (0.6 eq), and then naturally warmed to room temperature for reaction. The reaction system was quenched with ammonium chloride, extracted with ethyl acetate and water, dried, concentrated and subjected to column chromatography to obtain 90 mg of the intermediate 9-c.

[0157] Step 2:

[0158] The intermediate 9-c was added to 2 ml of methanol, added with 1 ml of concentrated hydrochloric acid, and heated to reflux for 3 h. The system was concentrated to dryness, and slurried in acetone to obtain 42 mg of the title compound as a white flaky crystal. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.66 (d, 1H), 7.51 (d, 1H), 7.45 (dd, 1H), 6.17 (m, 1H), 3.81 (m, 1H), 3.57-3.26 (m, 4H), 3.15 (m, 2H), 2.74 (m, 1H).

EXAMPLE 10

2-(Benzo[b]thiophen-7-yl)octahydropyrrolo[3,4-c]pyrrole maleate

[0159] ##STR00050##

[0160] 2-(Benzo[b]thiophen-7-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 7-bromo-benzo[b]thiophene instead of 2-bromonaphthalene.

[0161] The basic product was dissolved in methanol. 1.05 eq of maleic acid was dissolved in tetrahydrofuran, added dropwise into the methanol solution of the basic product, stirred at room temperature for 5 min, concentrated, slurried in tetrahydrofuran, stirred at room temperature for 3 h and filtered. The filter cake was heated at 50° C. for 3 h to obtain the title compound.

[0162] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.77 (s, 2H), 7.72 (d, 1H), 7.46 (d, 1H), 7.43 (d, 1H), 7.29 (t, 1H), 6.77 (d, 1H), 6.02 (s, 2H), 3.47-3.60 (m, 4H), 3.27-3.37 (m, 2H), 3.03-3.15 (m, 4H). ESI-MS (m/z): 245.22 [M+H].sup.+.

EXAMPLE 11

2-(Benzo[b]thiophen-7-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole oxalate

[0163] ##STR00051##

[0164] 2-(Benzo[b]thiophen-7-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 10 instead of the product of Example 1.

[0165] The basic product was dissolved in methanol. 1.05 eq of oxalic acid was dissolved in tetrahydrofuran, added dropwise to the methanol solution of the basic product, stirred at room temperature for 5 min, concentrated, slurried in tetrahydrofuran, stirred at room temperature for 3 h and filtered. The filter cake was heated at 50° C. for 3 h to obtain the title compound.

[0166] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.59 (brs, 2H), 7.72 (d, 1H), 7.47 (d, 1H), 7.44 (d, 1H), 7.29 (t, 1H), 6.79 (d, 1H), 3.64 (dd, 2H), 3.52 (dd, 2H), 3.24 (t, 2H), 3.13 (m, 2H), 3.01 (m, 2H), 2.80 (s, 3H). ESI-MS (m/z): 259.27 [M+H].sup.+.

EXAMPLE 12

2-(Benzo[b]thiophen-4-yl)octahydropyrrolo[3,4-c]pyrrole maleate

[0167] ##STR00052##

[0168] The basic product was prepared in the same manner as that in Example 1, except using 4-bromo-benzo[b]thiophene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain 2-(Benzo[b] thiophen-4-yl)octahydropyrrolo[3,4-c]pyrrole maleate.

[0169] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.78 (s, 2H), 7.67 (d, 1H), 7.64 (d, 1H), 7.55 (d, 1H), 7.24 (t, 1H), 6.76 (d, 1H), 6.02 (s, 2H), 3.51 (dd, 2H), 3.43 (dd, 2H), 3.23 (dd, 2H), 3.04-3.20 (m, 4H). ESI-MS (m/z): 245.21 [M+H].sup.+.

EXAMPLE 13

2-(Benzo[b]thiophen-4-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole hydrobromide

[0170] ##STR00053##

[0171] 2-(Benzo [b]thiophen-4-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 12 instead of the product of Example 1, and the hydrobromide was formed in accordance with Example 10 by using a 40% aqueous hydrobromic acid instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0172] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.80 (d, 1H), 7.56-7.72 (m, 3H), 7.26 (t, 1H), 6.82 (dd, 1H), 3.89 (td, 1H), 3.61 (dd, 1H), 3.20-3.55 (m, 5H), 2.92-3.11 (m, 3H), 2.87 (dd, 3H). ESI-MS (m/z): 259.30 [M+H].sup.+.

EXAMPLE 14

2-(Benzo[b]thiophen-5-yl)octahydropyrrolo[3,4-c]pyrrole maleate

[0173] ##STR00054##

[0174] The basic product was prepared in the same manner as that in Example 1, except using 5-bromo-benzo[b]thiophene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain 2-(Benzo[b]thiophen-5 -yl)octahydropyrrolo[3,4-c]pyrrole maleate.

[0175] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.78 (s, 2H), 7.79 (d, 1H), 7.65 (d, 1H), 7.29 (d, 1H), 7.08 (d, 1H), 6.88 (dd, 1H), 6.01 (s, 2H), 3.44-3.52 (m, 2H), 3.39 (dd, 2H), 3.26-3.30 (m, 2H), 3.07-3.17 (m, 4H). ESI-MS (m/z): 245.18 [M+H].sup.+.

EXAMPLE 15

2-(Benzo[b]thiophen-5-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole hydrochloride

[0176] ##STR00055##

[0177] 2-(Benzo[b]thiophen-5 -yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 14 instead of the product of Example 1, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0178] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.06 (m, 3H), 7.73 (t, 1H), 7.63 (dd, 1H), 7.43 (t, 1H), 3.97 (m, 4H), 3.85 (d, 1H), 3.75 (m, 1H), 3.65-3.46 (m, 3H), 3.43 (dd, 1H), 3.01 (d, 3H). ESI-MS (m/z): 259.23 [M+H].sup.+.

EXAMPLE 16

2-(3,4-dichlorophenyl)octahydropyrrolo[3,4-c]pyrrole

[0179] ##STR00056##

[0180] 2-(3,4-dichlorophenyl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 1-bromo-3,4-dichlorobenzene instead of 2-bromonaphthalene.

[0181] .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 7.29 (d, 1H), 6.84 (d, 1H), 6.65 (dd, 1H), 3.59 (m, 2H), 3.42 (m, 2H), 3.33 (m, 2H), 3.27-3.18 (m, 4H). ESI-MS (m/z): 257.29 [M+H].sup.+.

EXAMPLE 17

2-(3,4-dichlorophenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole

[0182] ##STR00057##

[0183] 2-(3,4-dichlorophenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the product of Example 16 instead of the product of Example 1.

[0184] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.20 (d, 1H), 6.67 (d, 1H), 6.44 (dd, 1H), 3.37 (t, 2H), 3.14 (dd, 2H), 2.97 (m, 2H), 2.70 (t, 2H), 2.46 (dd, 2H), 2.33 (s, 3H). ESI-MS (m/z): 271.24 [M+H].sup.+.

EXAMPLE 18

2-(Benzofuran-4-yl)octahydropyrrolo[3,4-c]pyrrole hydrochloride

[0185] ##STR00058##

[0186] 2-(Benzofuran-4-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 4-bromobenzofuran instead of 2-bromonaphthalene, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0187] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.46 (d, 2H), 7.84 (d, 1H), 7.16 (d, 1H), 7.13 (t, 1H), 6.98 (d, 1H), 6.41 (d, 1H), 3.40-3.60 (m, 6H), 3.06-3.15 (m, 4H). ESI-MS (m/z): 229.19 [M+H].sup.+.

EXAMPLE 19

2-(Benzo[b]thiophen-6-yl)octahydropyrrolo[3,4-c]pyrrole maleate

[0188] ##STR00059##

[0189] 2-(Benzo[b]furan-4-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 6-bromo-benzo[b]thiophene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.83 (s, 2H), 7.69 (d, 1H), 7.35 (d, 1H), 7.25 (d, 1H), 7.18 (d, 1H), 6.85 (dd, 1H), 6.02 (s, 2H), 3.48 (m, 2H), 3.40 (dd, 2H), 3.33 (m, 2H), 3.05-3.17 (m, 4H). ESI-MS (m/z): 245.39 [M+H].sup.+.

EXAMPLE 20

2-(Benzofuran-7-yl)octahydropyrrolo[3,4-c]pyrrole

[0190] ##STR00060##

[0191] 2-(Benzofuran-7-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 7-bromo-benzofuran instead of 2-bromonaphthalene.

[0192] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (d, 1H), 7.03 (m, 2H), 6.86 (d, 1H), 6.51 (d, 1H), 3.56 (m, 2H), 3.24 (dd, 2H), 2.94 (m, 2H), 2.78 (m, 2H), 2.62 (m, 2H). ESI-MS (m/z): 229.34 [M+H].sup.+.

EXAMPLE 21

2-(Benzofuran-5-yl)octahydropyrrolo[3,4-c]pyrrole maleate

[0193] ##STR00061##

[0194] 2-(Benzofuran-7-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 5-bromo-benzofuran instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0195] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.78 (s, 2H), 7.86 (d, 1H), 7.43 (d, 1H), 6.86 (d, 1H), 6.81 (dd, 1H), 6.76 (dd, 1H), 6.02 (s, 2H), 3.47 (m, 2H), 3.37 (m, 2H), 3.22 (m, 2H), 3.05-3.15 (m, 4H). ESI-MS (m/z): 229.27 [M+H].sup.+.

EXAMPLE 22

2-(Benzo[b]thiophen-2-yl)octahydropyrrolo[3,4-c]pyrrole maleate

[0196] ##STR00062##

[0197] 2-(Benzo[b]thiophen-2-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 2-bromo-benzo[b]thiophene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0198] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.81 (s, 2H), 7.68 (d, 1H), 7.45 (d, 1H), 7.21 (td, 1H), 7.03 (t, 1H), 6.09 (s, 1H), 6.02 (s, 2H), 3.37-3.49 (m, 4H), 3.33 (m, 2H), 3.09-3.20 (m, 4H). ESI-MS (m/z): 245.18 [M+H].sup.+.

EXAMPLE 23

2-(Benzo[b]thiophen-3-yl)octahydropyrrolo[3,4-c]pyrrole maleate

[0199] ##STR00063##

[0200] 2-(Benzo[b]thiophen-3-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 3-bromo-benzo[b]thiophene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0201] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.73 (s, 2H), 7.96 (dd, 1H), 7.91 (dd, 1H), 7.38 (m, 2H), 6.78 (s, 1H), 6.02 (s, 2H), 3.50 (m, 2H), 3.26-3.46 (m, 2H), 3.17 (d, 2H), 3.01-3.11 (m, 4H). ESI-MS (m/z): 245.18 [M+H].sup.+.

EXAMPLE 24

2-(naphthalen-1-yl)octahydropyrrolo[3,4-c]pyrrole maleate

[0202] ##STR00064##

[0203] 2-(naphthalen-1-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 1-bromonaphthalene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0204] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.73 (s, 2H), 8.15 (m, 1H), 7.89 (m, 1H), 7.59 (d, 1H), 7.52 (m, 2H), 7.42 (t, 1H), 7.11 (d, 1H), 6.01 (s, 2H), 3.57 (m, 2H), 3.28 (d, 2H), 3.19 (dd, 2H), 3.09 (d, 4H). ESI-MS m/z 239.27 [M+H].sup.+.

EXAMPLE 25

2-ethyl-5-(naphthalen-2-yl)octahydropyrrolo[3,4-c]pyrrole oxalate

[0205] ##STR00065##

[0206] 2-ethyl-5-(naphthalen-2-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using ethyl acetate instead of ethyl formate, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0207] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.75 (d, 1H), 7.72 (d, 1H), 7.68 (d, 1H), 7.36 (m, 1H), 7.18 (m, 2H), 6.92 (d, 1H), 3.59 (br, 2H), 3.51 (m, 2H), 3.32 (m, 2H), 3.13 (m, 6H), 1.2 (t, 3H). ESI-MS m/z 267.40[M+H].sup.+.

EXAMPLE 26

2-methyl-5-(naphthalen-1-yl)octahydropyrrolo[3,4-c]pyrrole oxalate

[0208] ##STR00066##

[0209] 2-methyl-5-(naphthalen-1-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 24 instead of the product of Example 1, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0210] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.18 (m, 1H), 7.88 (m, 1H), 7.59 (d, 1H), 7.52 (m, 2H), 7.41 (t, 1H), 7.11 (d, 1H), 3.62 (br, 2H), 3.28 (d, 2H), 3.08 (m, 6H), 2.86 (s, 3H). ESI-MS m/z 253.33 [M+H].sup.+.

EXAMPLE 27

2-(2,3-dichlorophenyl)octahydropyrrolo[3,4-c]pyrrole maleate

[0211] ##STR00067##

[0212] 2-(2,3-dichlorophenyl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 1-bromo-2,3-dichlorobenzene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0213] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.67 (s, 2H), 7.29 (m, 2H), 7.10 (dd, 1H), 6.01 (s, 2H), 3.53 (m, 2H), 3.34 (d, 2H), 3.00 (m, 6H). ESI-MS m/z 257.23 [M+H].sup.+.

EXAMPLE 28

2-(2,3-dichlorophenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole oxalate

[0214] ##STR00068##

[0215] 2-(2,3-dichlorophenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 27 instead of the product of Example 1, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0216] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.29 (m, 2H), 7.10 (dd, 1H), 3.58 (m, 2H), 3.32 (d, 2H), 3.00 (m, 6H), 2.77 (s, 3H). ESI-MS m/z 271.23 [M+H].sup.+.

EXAMPLE 29

2-(6-fluoronaphthalen-2-yl)octahydropyrrolo[3,4-c]pyrrole maleate

[0217] ##STR00069##

[0218] 2-(6-fluoronaphthalen-2-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 2-bromo-6-fluoronaphthalene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0219] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.88 (s, 2H), 7.76 (d, 1H), 7.74 (d, 1H), 7.52 (dd, 1H), 7.28 (td, 1H), 7.19 (dd, 1H), 6.95 (d, 1H), 6.02 (s, 2H), 3.43 (m, 6H), 3.12 (m, 4H). ESI-MS m/z 257.31 [M+H].sup.+.

EXAMPLE 30

2-(6-fluoronaphthalen-2-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole maleate

[0220] ##STR00070##

[0221] 2-(6-fluoronaphthalen-2-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 29 instead of the product of Example 1, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0222] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.76 (dt, 2H), 7.53 (dd, 1H), 7.29 (td, 1H), 7.24 (dd, 1H), 7.01 (d, 1H), 6.02 (s, 2H), 3.54 (m, 4H), 3.24 (m, 6H), 2.84 (s, 3H). ESI-MS m/z 271.29 [M+H].sup.+.

EXAMPLE 31

2-(1-fluoronaphthalen-2-yl)octahydropyrrolo[3,4-c]pyrrole maleate

[0223] ##STR00071##

[0224] 2-(1-fluoronaphthalen-2-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 2-bromo-1-fluoronaphthalene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0225] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.83 (s, 2H), 7.86 (m, 2H), 7.67 (d, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 7.25 (t, 1H), 6.02 (s, 2H), 3.49 (m, 6H), 3.10 (m, 4H). ESI-MS m/z 257.25 [M+H].sup.+.

EXAMPLE 32

2-(1-fluoronaphthalen-2-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole maleate

[0226] ##STR00072##

[0227] 2-(1-fluoronaphthalen-2-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 31 instead of the product of Example 1, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0228] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.89 (d, 1H), 7.86 (d, 1H), 7.68 (d, 1H), 7.52 (m, 1H), 7.37 (m, 1H), 7.28 (t, 1H), 6.02 (s, 2H), 3.60 (m, 2H), 3.31 (br, 6H), 3.13 (br, 2H), 2.85 (s, 3H). ESI-MS m/z 271.33 [M+H].sup.+.

EXAMPLE 33

3-(hexahydropyrrolo[3,4-c] pyrrole-2(1H)-yl)isoquinoline maleate

[0229] ##STR00073##

[0230] 3-(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)isoquinoline was prepared in the same manner as that in Example 1, except using 3-bromoisoquinoline instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0231] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.96 (s, 1H), 8.85 (s, 2H), 7.86 (d, 1H), 7.66 (d, 1H), 7.53 (m, 1H), 7.24 (m, 1H), 6.69 (s, 1H), 6.07 (s, 2H), 3.52 (m, 6H), 3.14 (m, 4H). ESI-MS m/z 240.32 [M+H].sup.+.

EXAMPLE 34

3-(5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)isoquinoline maleate

[0232] ##STR00074##

[0233] 3-(5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)isoquinoline was prepared in the same manner as that in Example 2, except using the basic product of Example 33 instead of the product of Example 1, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0234] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.98 (s, 1H), 7.87 (d, 1H), 7.67 (d, 1H), 7.54 (t, 1H), 7.26 (t, 1H), 6.75 (s, 1H), 6.06 (s, 2H), 3.48 (m, 6H), 2.85 (s, 3H), 2.77 (m, 2H), 2.50 (m, 2H). ESI-MS m/z 254.41 [M+H].sup.+.

EXAMPLE 35

6-(3,4-dichlorophenyl)decahydropyrrolo[3,4-d]azepine

[0235] ##STR00075##

[0236] Step 1:

[0237] 800 mg of 7-a as a raw material, 1.1 eq of 3,4-dichlorobromobenzene as a raw material, 0.05 eq of Pd.sub.2(dba).sub.3, 0.08 eq of BINAP were mixed in toluene, stirred at room temperature for 5 min, and added with 2 eq of potassium tert-butoxide. The atmosphere was replaced with nitrogen for three times and the reaction mixture was reacted at 80° C. overnight. The insoluble matter was filtered off, and the filter cake was washed with ethyl acetate. The filtrate was combined, washed with brine, dried and concentrated, and then subjected to silica gel column chromatography to obtain 850 mg of 35-a.

[0238] Step 2:

[0239] The 35-a was dissolved in methanol, added with hydrochloric acid, and stirred at room temperature for 1 h. After the reaction, the reaction mixture was added with water and MTBE, and the organic phase was discarded. The aqueous phase was separated and adjusted pH to be weakly alkaline, added with DCM to extract. The organic phase was washed with brine, dried and concentrated, and then subjected to silica gel column chromatography to obtain the title compound as a white solid. ESI-MS (m/z): 285.22 [M+H].sup.+.

EXAMPLE 36

6-(Benzo[b]thiophen-7-yl)decahydropyrrolo[3,4-d]azepine maleate

[0240] ##STR00076##

[0241] 6-(Benzo[b]thiophen-7-yl)decahydropyrrolo[3,4-d]azepine maleate was prepared in the same manner as that in Example 7, except using 7-bromo-benzo[b]thiophene instead of 5-bromobenzothiophene.

[0242] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.69 (s, 2H), 7.71 (d, 1H), 7.50 (d, 1H), 7.43 (d, 1H), 7.30 (t, 1H), 6.94 (d, 1H), 6.02 (s, 2H), 3.49 (m, 4H), 3.08 (m, 2H), 2.85 (m, 2H), 2.66 (m, 2H), 1.90 (m, 4H). ESI-MS m/z 273.29 [M+H].sup.+.

EXAMPLE 37

6-(2,3-dichlorophenyl)decahydropyrrolo[3,4-d]azepine maleate

[0243] ##STR00077##

[0244] 6-(2,3-dichlorophenyl)decahydropyrrolo[3,4-d]azepine maleate was prepared in the same manner as that in Example 7, except using 1-bromo-2,3-dichlorobenzene instead of 5-bromobenzothiophene.

[0245] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.66 (s, 2H), 7.26 (m, 2H), 7.13 (dd, 1H), 6.02 (s, 2H), 3.43 (m, 2H), 3.23 (m, 2H), 2.91 (m, 2H), 2.81 (m, 2H), 2.63 (m, 2H), 1.86 (m, 4H). ESI-MS m/z 285.38 [M+H].sup.+.

EXAMPLE 38

6-(Benzo[b]thiophen-4-yl)decahydropyrrolo[3,4-d]azepine maleate

[0246] ##STR00078##

[0247] 6-(Benzo[b]thiophen-4-yl)decahydropyrrolo [3,4-d] azepine maleate was prepared in the same manner as that in Example 7, except using 4-bromo-benzo[b]thiophene instead of 5-bromobenzothiophene.

[0248] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.69 (s, 2H), 7.69 (d, 1H), 7.55 (d, 1H), 7.37 (d, 1H), 7.24 (t, 1H), 6.87 (d, 1H), 6.02 (s, 2H), 3.45 (m, 4H), 3.05 (m, 2H), 2.85 (m, 2H), 2.66 (m, 2H), 1.93 (m, 4H). ESI-MS m/z 273.47 [M+H].sup.+.

EXAMPLE 39

6-(naphthalen-2-yl)decahydropyrrolo[3,4-d]azepine maleate

[0249] ##STR00079##

[0250] 6-(naphthalen-2-yl)decahydropyrrolo[3,4-d]azepine maleate was prepared in the same manner as that in Example 7, except using 2-bromonaphthalene instead of 5-bromobenzothiophene.

[0251] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.75 (s, 2H), 7.72 (d, 1H), 7.68 (d, 1H), 7.63 (d, 1H), 7.33 (td, 1H), 7.26 (dd, 1H), 7.16 (td, 1H), 7.00 (d, 1H), 6.01 (s, 2H), 3.90 (m, 2H), 3.30 (m, 4H), 2.78 (m, 2H), 2.56 (m, 2H), 1.76 (m, 4H). ESI-MS (m/z): 267.27 [M+H].sup.+.

EXAMPLE 40

2-methyl-6-(naphthalen-2-yl)decahydropyrrolo[3,4-d]azepine oxalate

[0252] ##STR00080##

[0253] 2-methyl-6-(naphthalen-2-yl)decahydropyrrolo[3,4-d]azepine was prepared in the same manner as that in Example 2, except using the basic product of Example 39 instead of the product of Example 1, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0254] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.69 (m, 3H), 7.31 (m, 2H), 7.17 (t, 1H), 7.04 (d, 1H), 4.01 (m, 2H), 3.52 (m, 2H), 3.17 (m, 2H), 2.72(m, 7H), 1.78 (m, 4H). ESI-MS (m/z): 281.36 [M+H].sup.+.

EXAMPLE 41

2-(Benzo[b]thiophen-4-yl)decahydropyrrolo[3,4-d]azepine maleate

[0255] ##STR00081##

[0256] 2-(Benzo [b]thiophen-4-yl)decahydropyrrolo [3,4-d] azepine maleate was prepared in the same manner as that in Example 6, except using 4-bromo-benzo[b]thiophene instead of 2-bromonaphthalene.

[0257] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.73 (s, 1H), 8.37 (s, 1H), 7.62 (d, 1H), 7.58 (d, 1H), 7.40 (d, 1H), 7.19 (t, 1H), 6.60 (d, 1H), 6.04 (s, 2H), 3.72 (m, 2H), 3.38 (m, 2H), 3.01 (m, 4H), 2.65 (m, 2H), 1.90 (m, 4H). ESI-MS m/z 273.39 [M+H].sup.+.

EXAMPLE 42

2-(3,4-dichlorophenyl)decahydropyrrolo[3,4-d]azepine maleate

[0258] ##STR00082##

[0259] 2-(3,4-dichlorophenyl)decahydropyrrolo[3,4-d]azepine maleate was prepared in the same manner as that in Example 6, except using 1-bromo-3,4-dichlorobenzene instead of 2-bromonaphthalene.

[0260] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.31 (br, 1H), 7.34 (d, 1H), 6.70 (d, 1H), 6.52 (dd, 1H), 6.02 (s, 2H), 3.53 (m, 2H), 3.33 (m, 2H), 2.94 (m, 4H), 2.65 (m, 2H), 1.85 (m, 4H). ESI-MS m/z 285.38 [M+H].sup.+.

Example 43

2-(Benzo[b]thiophen-7-yl)decahydropyrrolo[3,4-d]azepine maleate

[0261] ##STR00083##

[0262] 2-(Benzo [b]thiophen-7-yl)decahydropyrrolo [3,4-d] azepine maleate was prepared in the same manner as that in Example 6, except using 7-bromo-benzo[b]thiophene instead of 2-bromonaphthalene.

[0263] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.73 (s, 1H), 8.39 (s, 1H), 7.68 (d, 1H), 7.40 (d, 1H), 7.36 (d, 1H), 7.24 (t, 1H), 6.64 (d, 1H), 6.03 (s, 2H), 3.79 (m, 2H), 3.38 (m, 2H), 3.00 (m, 4H), 2.67 (m, 2H), 1.89 (m, 4H). ESI-MS m/z 273.40 [M+H].sup.+.

EXAMPLE 44

5-(Benzo[b]thiophen-6-yl)octahydrocyclopenta[c]pyrrole hydrochloride

[0264] ##STR00084##

[0265] 5-(Benzo[b]thiophen-6-yl)octahydrocyclopenta[c]pyrrole hydrochloride was prepared in the same manner as that in Example 3, except using 6-bromo-benzothiophene instead of 4-bromo-benzothiophene.

[0266] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.07 (d, 1H), 7.73 (d, 1H), 7.57 (d, 1H), 7.47 (dd, 1H), 7.35 (d, 1H), 3.28 (m, 2H), 3.20 (m, 2H), 3.09 (m, 1H), 2.90 (m, 2H), 2.40 (m, 2H), 1.37 (m, 2H). ESI-MS m/z 244.20 [M+H].sup.+.

EXAMPLE 45

5-(Benzo[b]thiophen-7-yl)octahydrocyclopenta[c]pyrrole hydrochloride

[0267] ##STR00085##

[0268] 5-(Benzo[b]thiophen-7-yl)octahydrocyclopenta[c]ipyrrole hydrochloride was prepared in the same manner as that in Example 3, except using 7-bromo-benzothiophene instead of 4-bromo-benzothiophene.

[0269] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.83 (d, 1H), 7.65 (d, 1H), 7.50 (m, 2H), 7.28 (t, 1H), 3.28 (m, 2H), 3.20 (m, 2H), 3.09 (m, 1H), 2.90 (m, 2H), 2.40 (m, 2H), 1.37 (m, 2H). ESI-MS m/z 244.22 [M+H].sup.+.

EXAMPLE 46

6-(Benzo[b]thiophen-5-yl)decahydrocyclohepta[c]pyrrole hydrochloride

[0270] ##STR00086##

[0271] 6-(Benzo[b]thiophen-5-yl)decahydrocyclohepta[c]pyrrole hydrochloride was prepared in the same manner as that in Example 5, except using 5-bromo-benzothiophene instead of 4-bromo-benzothiophene.

[0272] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.02 (d, 1H), 7.82 (d, 1H), 7.64 (d, 1H), 7.45 (dd, 1H), 7.35 (d, 1H), 3.52 (m, 3H), 2.87 (dd, 2H), 2.53 (m, 2H), 1.89 (m, 6H), 1.56 (m, 2H). ESI-MS m/z 272.27 [M+H].sup.+.

EXAMPLE 47

6-(Benzo[b]thiophen-6-yl)decahydrocyclohepta[c]pyrrole hydrochloride

[0273] ##STR00087##

[0274] 6-(Benzo[b]thiophen-6-yl)decahydrocyclohepta[c]pyrrole hydrochloride was prepared in the same manner as that in Example 5, except using 6-bromo-benzothiophene instead of 4-bromo-benzothiophene.

[0275] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.08 (d, 1H), 7.75 (d, 1H), 7.58 (d, 1H), 7.48 (dd, 1H), 7.36 (d, 1H), 3.53 (m, 3H), 2.87 (dd, 2H), 2.52 (m, 2H), 1.89 (m, 6H), 1.56 (m, 2H). ESI-MS m/z 272.29 [M+H].sup.+.

EXAMPLE 48

5-(Benzothiophen-7-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole hydrochloride

[0276] ##STR00088##

[0277] 5-(Benzothiophen-7-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole hydrochloride was prepared in the same manner as that in Example 9, except using 7-bromo-benzothiophene instead of 3,4-dichlorobromobenzene.

[0278] ESI-MS m/z 242.27 [M+H].sup.+.

EXAMPLE 49

5-(benzo[b]thiophen-2-yl)octahydrocyclopenta[c]pyrrol-5-ol

[0279] ##STR00089##

[0280] The intermediate 49-a was prepared in the same preparation method as the 9-c in Example 9, except using 2-bromobenzothiophene instead of 3,4-dichlorobromobenzene.

[0281] 110 mg of the intermediate was added to 3 ml of toluene, added with 550 mg of an acidic silica gel, and heated to reflux overnight. The reaction mixture was concentrated to remove the solvent and subjected to column chromatography to obtain 50 mg of the product, which was slurried in petroleum ether to obtain 26 mg of the title compound as an off-white solid.

[0282] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.81 (d, 1H), 7.69 (d, 1H), 7.28 (m, 2H), 7.17 (s, 1H), 3.06 (d, 2H), 2.97-2.82 (m, 4H), 2.49 (dd, 2H), 2.07 (d, 2H). ESI-MS m/z 260.14 [M+H].sup.+.

EXAMPLE 50

5-(benzothiophen-2-yl)octahydrocyclopenta[c]pyrrole hydrochloride

[0283] ##STR00090##

[0284] 5-(benzothiophen-2-yl)octahydrocyclopenta[c]pyrrole hydrochloride was prepared in the same manner as that in Example 3, except using 2-bromo-benzothiophene instead of 4-bromo-benzothiophene.

[0285] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.78 (d, 1H), 7.70 (d, 1H), 7.28 (m, 2H), 7.15 (s, 1H), 3.46 (m, 1H), 3.40-3.24 (m, 4H), 3.08 (m, 2H), 2.55 (m, 2H), 1.69 (m, 2H). ESI-MS m/z 244.24 [M+H].sup.+.

EXAMPLE 51

5-(Benzothiophen-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole hydrochloride

[0286] ##STR00091##

[0287] 5-(Benzothiophen-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole hydrochloride was prepared in the same manner as that in Example 9, except using 2-bromo-benzothiophene instead of 3,4-dichlorobromobenzene.

[0288] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.62 (br, 1H), 9.15 (br, 1H), 7.91 (m, 1H), 7.81 (m, 1H), 7.35 (m, 3H), 5.99 (m, 1H), 3.67 (m, 1H), 3.43-3.24 (m, 2H), 3.17 (m, 2H), 3.10-2.93 (m, 2H), 2.77 (m, 1H). ESI-MS m/z 242.25 [M+H].sup.+.

EXAMPLE 52

5-(Benzofuran-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole hydrochloride

[0289] ##STR00092##

[0290] 5-(Benzofuran-2-yl)-1,2,3,3 a,4,6a-hexahydrocyclopenta[c]pyrrole hydrochloride was prepared in the same manner as that in Example 9, except using 2-bromo-benzofuran instead of 3,4-dichlorobromobenzene.

[0291] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.30 (br, 2H), 7.63 (d, 1H), 7.56 (d, 1H), 7.31 (t, 1H), 7.24 (t, 1H), 6.88 (s, 1H), 6.18 (m, 1H), 3.71 (m, 1H), 3.34 (m, 2H), 3.18 (m, 2H), 2.99 (m, 2H), 2.69 (m, 1H). ESI-MS m/z 226.21 [M+H].sup.+.

EXAMPLE 53

5-(benzofuran-2-yl)octahydrocyclopenta[c]pyrrol-5-ol

[0292] ##STR00093##

[0293] The intermediate 53-a was prepared in the same preparation method as the 9-c in Example 9, except using 2-bromobenzofuran instead of 3,4-dichlorobromobenzene.

[0294] 120 mg of the intermediate and 600 mg of an acidic silica gel was dissolved in 3.5 mL of toluene, heated to 90° C. and reacted for 1 h, and subjected to column chromatography to obtain a pure product, which was slurried in petroleum ether at 50° C., filtered and dried to obtain 15 mg of the title compound as a yellowish solid.

[0295] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.53 (d, 1H), 7.43 (d, 1H), 7.21 (m, 2H), 6.69 (s, 1H), 3.23 (d, 2H), 3.01 (d, 4H), 2.57 (dd, 2H), 2.03 (d, 2H). ESI-MS m/z 244.14 [M+H].sup.+.

EXAMPLE 54

5-(naphthalen-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole hydrochloride

[0296] ##STR00094##

[0297] 5-(naphthalen-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole hydrochloride was prepared in the same manner as that in Example 9, except using 2-bromo-naphthalene instead of 3,4-dichlorobromobenzene.

[0298] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.85 (m, 4H), 7.76 (dd, 1H), 7.48 (m, 2H), 6.24 (m, 1H), 3.86 (m, 1H), 3.60-3.24 (m, 5H), 3.20 (dd, 1H), 2.91 (d, 1H).

EXAMPLE 55

5-(naphthalen-2-yl)octahydrocyclopenta[c]pyrrole hydrochloride

[0299] ##STR00095##

[0300] 5-(naphthalen-2-yl)octahydrocyclopenta[c]pyrrole hydrochloride was prepared in the same manner as that in Example 3, except using 2-bromo-naphthalene instead of 4-bromo-benzothiophene.

[0301] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.33 (br, 1H), 7.82 (m, 4H), 7.59 (dd, 1H), 7.47 (m, 2H), 3.32 (m, 1H), 3.15 (m, 4H), 2.92 (m, 2H), 2.29 (m, 2H), 1.72 (m, 2H). ESI-MS m/z 238.23 [M+H].sup.+.

EXAMPLE 56

5-(naphthalen-1-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole dihydrochloride

[0302] ##STR00096##

[0303] 5-(naphthalen-1-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole dihydrochloride was prepared in the same manner as that in Example 9, except using 1-bromo-naphthalene instead of 3,4-dichlorobromobenzene.

[0304] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.31 (br, 2H), 7.95-7.83 (m, 4H), 7.77 (dd, 1H), 7.50 (m, 2H), 6.28 (d, 1H), 3.70 (br, 1H), 3.40 (dd, 1H), 3.33 (dd, 1H), 3.23-3.05 (m, 3H), 2.99 (dd, 1H), 2.81 (d, 1H). ESI-MS m/z 236.32 [M+H].sup.+.

EXAMPLE 57

2-methyl-5-(naphthalen-2-yl)-1,2,3,3a,4,6a- hexahydrocyclopenta[c]pyrrole

[0305] ##STR00097##

[0306] The example 54 (60 mg) was dissolved in 1 mL of a formaldehyde solution (40%), stirred at 75° C. for 4 h, added with 2 eq of NaBH.sub.4 under ice-water bath, restored to room temperature to react for 10 h, and layered with dichloromethane/water layers. The organic phase was concentrated, and slurried in petroleum ether. After dried, 45 mg of the title compound as a white solid was obtained.

[0307] ESI-MS m/z 250.39 [M+H].sup.+.

EXAMPLE 58

2-methyl-5-(naphthalen-2-yl)octahydrocyclopenta[c]pyrrole hydrochloride

[0308] ##STR00098##

[0309] The example 57 (30 mg) was dissolved in 5mL of acetic acid, added with 5 mg of 10%

[0310] Pd/C, purged with hydrogen, and reacted at 25° C. for 24 h. Mass spectrometry showed that the raw material was reacted completely. The reaction solution was filtered, and the acetic acid phase was alkalized with 5 ml of 20% NaOH, and layered with 10 ml of DCM. The organic layer was concentrated, and added with 3 mL of HCl-dioxane in an ice-water bath to form a salt. The solid was filtered, slurried in 5 mL of petroleum ether, filtered and dried to obtain 8 mg of the title compound as a white solid.

[0311] ESI-MS m/z 252.43 [M+H].sup.+.

EXAMPLE 59

5-(Benzofuran-2-yl)-2-methyl-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole hydrochloride

[0312] ##STR00099##

[0313] 5-(Benzofuran-2-yl)-2-methyl-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole was prepared in the same manner as that in Example 57, except using the product of Example 52 instead of the product of Example 54, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0314] ESI-MS m/z 240.39 [M+H].sup.+.

EXAMPLE 60

5-(Benzofuran-2-yl)-2-methyloctahydrocyclopenta[c]pyrrole hydrochloride

[0315] ##STR00100##

[0316] The example 59 (50 mg) was dissolved in 5 mL of acetic acid, added with 5 mg of 10% Pd/C, purged with hydrogen, and reacted at 25° C. for 24 h. Mass spectrometry showed that the raw material was reacted completely. The reaction solution was filtered, and the acetic acid phase was alkalized with 5 ml of 20% NaOH, and layered with 10 ml of DCM. The organic layer was concentrated, and added with 3 mL of HCl-dioxane in an ice-water bath to form a salt. The solid was filtered, slurried in 5 mL of petroleum ether, filtered and dried to obtain 10 mg of the title compound as a white solid.

[0317] ESI-MS m/z 242.36 [M+H].sup.+.

EXAMPLE 61

5-(Benzothiophen-2-yl)-2-methyl-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole hydrochloride

[0318] ##STR00101##

[0319] 5-(Benzothiophen-2-yl)-2-methyl-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole was prepared in the same manner as that in Example 57, except using the product of Example 51 instead of the product of Example 54, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0320] ESI-MS m/z 256.23 [M+H].sup.+.

EXAMPLE 62

5-(benzothiophen-2-yl)-2-methyl-octahydrocyclopenta[c]pyrrole hydrochloride

[0321] ##STR00102##

[0322] The example 61 (45 mg) was dissolved in 5 mL of acetic acid, added with 20 mg of 10% Pd/C, purged with hydrogen, and reacted at 25° C. for 24 h. Mass spectrometry showed that the raw material was reacted completely. The reaction solution was filtered, and the acetic acid phase was alkalized with 5 ml of 20% NaOH, and layered with 10 ml of DCM. The organic layer was concentrated, added with 3 mL of HCl-dioxane in an ice-water bath to form a salt. The solid was filtered, slurried in 5 mL of petroleum ether, filtered and dried to obtain 5 mg of the title compound as a white solid.

[0323] ESI-MS m/z 258.31 [M+H].sup.+.

EXAMPLE 63

5-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole hydrochloride

[0324] ##STR00103##

[0325] 5-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole hydrochloride was prepared in the same manner as that in Example 3, except using 1-bromo-3,4-dichlorobenzene instead of 4-bromo-benzothiophene.

[0326] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.73 (d, 1H), 7.45 (m, 2H), 3.47 (m, 2H), 3.37 (m, 1H), 3.05 (m, 2H), 2.93 (m, 2H), 1.96 (m, 2H), 1.82 (m, 2H). ESI-MS m/z 256.27 [M+H].sup.+.

EXAMPLE 64

1-(Benzothiophen-5-yl)octahydropyrrolo[3,4-b]pyrrole maleate

[0327] ##STR00104##

[0328] 1-(Benzothiophen-5-yl)octahydropyrrolo[3,4-b]pyrrole was prepared in the same manner as that in Example 1, except using 5-bromo-benzothiophene instead of 2-bromonaphthalene and using t-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate instead of t-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0329] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.88 (s, 2H), 7.80 (d, 1H), 7.66 (d, 1H), 7.29 (d, 1H), 7.03 (d, 1H), 6.81 (d, 1H), 6.01 (s, 2H), 4.29 (t, 1H), 3.62 (m, 1H), 3.48 (m, 1H), 3.33 (m, 1H), 3.19 (m, 4H), 2.17 (m, 1H), 1.94 (m, 1H). ESI-MS (m/z): 245.21 [M+H].sup.+.

EXAMPLE 65

1-(Benzothiophen-5-yl)-5-methyloctahydropyrrolo[3,4-b]pyrrole oxalate

[0330] ##STR00105##

[0331] 1-(Benzothiophen-5-yl)-5-methyloctahydropyrrolo[3,4-b]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 64 instead of the product of Example 1, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0332] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.50 (brs, 2H), 7.79 (d, 1H), 7.65 (d, 1H), 7.29 (d, 1H), 7.02 (d, 1H), 6.80 (d, 1H), 4.34 (m, 1H), 3.59 (m, 1H), 3.47 (m, 1H), 3.24 (m, 5H), 2.72 (s, 3H), 2.15 (m, 1H), 1.95 (m, 1H). ESI-MS (m/z): 259.22 [M+H].sup.+.

EXAMPLE 66

2-(2,3-dimethylphenyl)octahydropyrrolo[3,4-c]pyrrole maleate

[0333] ##STR00106##

[0334] 2-(2,3-dimethylphenyeoctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 1-bromo-2,3-dimethylbenzene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0335] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.68 (s, 2H), 7.02 (t, 1H), 6.87 (m, 2H), 6.02 (s, 2H), 3.52 (m, 2H), 2.98 (m, 6H), 2.86 (m, 2H), 2.21 (s, 3H), 2.16 (s, 3H). ESI-MS (m/z): 217.23 [M+H].sup.+.

EXAMPLE 67

2-(2,3-dimethylphenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole oxalate

[0336] ##STR00107##

[0337] 2-(2,3-dimethylphenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 66 instead of the product of Example 1, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0338] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.02 (t, 1H), 6.87 (m, 2H), 3.59 (m, 2H), 2.82-3.06 (m, 8H), 2.80 (s, 3H), 2.21 (s, 3H), 2.17 (s, 3H). ESI-MS (m/z): 231.30 [M+H].sup.+.

EXAMPLE 68

2-(4-fluorobenzo[b]thiophen-6-yl)octahydropyrrolo[3,4-c]pyrrole dihydrochloride

[0339] ##STR00108##

[0340] 2-(4-fluorobenzo[b]thiophen-6-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 6-bromo-4-fluorobenzo[b]thiophene instead of 2-bromonaphthalene, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0341] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (brs, 2H), 7.40 (d, 1H), 7.27 (d, 1H), 6.99 (s, 1H), 6.65 (dd, 1H), 3.34-3.50 (m, 6H), 2.98-3.18 (m, 4H). ESI-MS (m/z): 263.18 [M+H].sup.+.

EXAMPLE 69

2-(6-fluorobenzothiophen-4-yl)octahydropyrrolo[3,4-c]pyrrole dihydrochloride

[0342] ##STR00109##

[0343] 2-(6-fluorobenzothiophen-4-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 4-bromo-6-fluorobenzothiophene instead of 2-bromonaphthalene, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0344] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.57 (d, 1H), 7.47 (d, 1H), 7.25 (dd, 1H), 6.63 (dd, 1H), 3.65 (m, 2H), 3.55 (m, 2H), 3.18-3.36 (m, 6H). ESI-MS (m/z): 263.13 [M+H].sup.+.

EXAMPLE 70

2-(6-fluorobenzothiophen-4-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole oxalate

[0345] ##STR00110##

[0346] 2-(6-fluorobenzothiophen-4-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 69 instead of the product of Example 1, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0347] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.63 (m, 2H), 7.41 (dd, 1H), 6.59 (dd, 1H), 3.57 (m, 2H), 3.49 (m, 2H), 3.24 (m, 2H), 3.12 (m, 4H), 2.81 (s, 3H). ESI-MS (m/z): 277.24 [M+H].sup.+.

EXAMPLE 71

2-methyl-5-(naphthalen-1-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole

[0348] ##STR00111##

[0349] The example 56 (50 mg) was dissolved in 1 mL of a formaldehyde solution (40%), stirred at 75° C. for 4 h, added with 2 eq of NaBH.sub.4 under ice-water bath, restored to room temperature to react for 10 h, and layered with dichloromethane/water layers. The organic phase was concentrated, slurried in petroleum ether. After dried, 40mg of the title compound as a white solid was obtained.

[0350] ESI-MS m/z 250.44 [M+H].sup.+.

EXAMPLE 72

2-(3,6-dimethoxynaphthalen-2-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole dihydrochloride

[0351] ##STR00112##

[0352] The intermediate 2-(3,6-dimethoxynaphthalen-2-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 2-bromo-3,6-dimethoxynaphthalene instead of 2-bromonaphthalene. Then, 2-(3,6-dimethoxynaphthalen-2-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2 by using the intermediate instead of the product of Example 1, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0353] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.13 (m, 1H), 7.77 (m, 1H), 7.45 (m, 1H), 7.25 (br, 1H), 7.08 (m, 1H), 4.10 (s, 3H), 4.15-3.96 (m, 4H), 3.91 (s, 3H), 3.84 (m, 2H), 3.65-3.38 (m, 4H), 3.02 (m, 3H). ESI-MS (m/z): 313.43 [M+H].sup.+.

EXAMPLE 73

2-(2,3-dimethoxyphenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole dihydrochloride

[0354] ##STR00113##

[0355] The intermediate 2-(2,3-dimethoxyphenyl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 1-bromo-2,3-dimethoxybenzene instead of 2-bromonaphthalene. Then, 2-(2,3-dimethoxyphenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2 by using the intermediate instead of the product of Example 1, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0356] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.40 (d, 1H), 7.19 (t, 1H), 7.11 (t, 1H), 6.96 (d, 1H), 4.05-3.81 (m, 10H), 3.76 (m, 2H), 3.55 (m, 1H), 3.40 (m, 2H), 3.19 (m, 1H), 2.99 (m, 3H). ESI-MS (m/z): 263.38 [M+H].sup.+.

EXAMPLE 74

2-(benzo[d][1,3]dioxol-4-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole dihydrochloride

[0357] ##STR00114##

[0358] The intermediate 2-(benzo[d][1,3]dioxol-4-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 4-bromobenzo[d][1,3]dioxolane instead of 2-bromonaphthalene. Then, 2-(benzo[d][1,3]dioxol-4-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2 by using the intermediate instead of the product of Example 1, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0359] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 6.83 (m, 1H), 6.70 (t, 1H), 6.63 (d, 1H), 5.97 (d, 2H), 3.95 (dd, 1H), 3.77 (t, 2H), 3.69 (d, 1H), 3.50-3.35 (m, 4H), 3.28 (m, 1H), 3.14 (m, 1H), 2.95 (m, 3H). ESI-MS (m/z): 247.31 [M+H].sup.+.

EXAMPLE 75

2-(1,3-difluoronaphthalen-2-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole dihydrochloride

[0360] ##STR00115##

[0361] The intermediate 2-(1,3-difluoronaphthalen-2-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 2-bromo-1,3-difluoronaphthalene instead of 2-bromonaphthalene. Then, 2-(1,3-difluoronaphthalen-2-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2 by using this intermediate instead of the product of Example 1, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0362] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.93 (d, 1H), 7.78 (d, 1H), 7.48 (m, 2H), 7.41 (d, 1H), 3.99 (m, 1H), 3.63-3.39 (m, 6H), 3.30 (m, 1H), 3.12 (m, 1H), 2.95 (m, 4H). ESI-MS (m/z): 289.32 [M+H].sup.+.

EXAMPLE 76

2-(3-fluoronaphthalen-2-yl)-5-methyloctahydropyrrolo [3,4-c]pyrrole dihydrochloride

[0363] ##STR00116##

[0364] The intermediate 2-(3-fluoronaphthalen-2-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 2-bromo-3-fluoronaphthalene instead of 2-bromonaphthalene. Then, 2-(3-fluoronaphthalen-2-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2 by using the intermediate instead of the product of Example 1 and using hydrochloride instead of maleic acid, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0365] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.75 (d, 1H), 7.71 (d, 1H), 7.49 (dd, 1H), 7.39 (t, 1H), 7.33 (t, 1H), 7.28 (dd, 1H), 4.00 (dd, 1H), 3.64 (m, 3H), 3.44 (dd, 1H), 3.34 (m, 1H), 3.22 (m, 2H), 3.06 (dd, 1H), 3.00-2.90 (m, 4H). ESI-MS (m/z): 271.32 [M+H].sup.+.

EXAMPLE 77

5-(Benzo[b]thiophen-4-yl)octahydropyrrolo[3,4-b]pyrrole hydrochloride

[0366] ##STR00117##

[0367] 5-(Benzo[b]thiophen-4-yl)octahydropyrrolo[3,4-b]pyrrole was prepared in the same manner as that in Example 1, except using 4-bromo-benzothiophene instead of 2-bromonaphthalene and using t-butyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate instead of t-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0368] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.79 (brs, 1H), 9.39 (brs, 1H),7.62 (m, 2H), 7.46 (d, 1H), 7.21 (t, 1H), 6.70 (d, 1H), 4.62 (m, 1H), 3.97 (m, 1H), 3.36 (m, 3H), 3.11 (m, 2H), 2.97 (m, 1H), 2.03 (m, 2H). ESI-MS (m/z): 245.17 [M+H].sup.+.

Example 78

2-([1,1′-biphenyl]-2-yl)octahydropyrrolo[3,4-c]pyrrole hydrochloride

[0369] ##STR00118##

[0370] 2-([1,1′-biphenyl]-2-yl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 2-bromo-1,1′-biphenyl instead of 2-bromonaphthalene, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0371] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.21 (brs, 1H), 9.09 (brs, 1H),7.49 (m, 4H), 7.35 (t, 1H), 7.28 (td, 1H), 7.15 (dd, 1H), 7.04 (m, 2H), 3.32 (m, 2H), 2.78 (m, 4H), 2.69 (m, 2H), 2.61 (m, 2H). ESI-MS (m/z): 265.26 [M+H].sup.+.

EXAMPLE 79

2-(2-(methoxymethyl)phenyl)octahydropyrrolo[3,4-c]pyrrole dihydrochloride

[0372] ##STR00119##

[0373] 2-(2-(methoxymethyl)phenyl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 1-bromo-2-(methoxymethyl)benzene instead of 2-bromonaphthalene, and the hydrochloride was formed in accordance with Example 10 by using a methanol solution of hydrochloride instead of the tetrahydrofuran solution of maleic acid in Example 10, to give the title compound.

[0374] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.23 (brs, 2H), 7.33 (m, 1H), 7.24 (m, 1H), 7.02 (m, 2H), 4.44 (s, 2H), 3.47 (m, 2H), 3.32 (s, 3H), 3.06 (m, 2H), 2.96 (m, 6H). ESI-MS (m/z): 233.29 [M+H].sup.+.

EXAMPLE 80

2-(3-methoxyphenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole oxalate

[0375] ##STR00120##

[0376] The intermediate 2-(3-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 1-bromo-3-methoxybenzene instead of 2-bromonaphthalene. 2-(3 -methoxyphenyl)-5 -methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the intermediate instead of the product of Example 1, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0377] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.08 (t, 1H), 6.29 (td, 2H), 6.20 (t, 1H), 3.71 (s, 3H), 3.53 (m, 2H), 3.35 (m, 2H), 3.14 (m, 4H), 3.02 (m, 2H), 2.76 (s, 3H). ESI-MS (m/z): 233.30 [M+H].sup.+.

EXAMPLE 81

2-methyl-5-(4-(trifluoromethyl)phenyl)octahydropyrrolo[3,4-c]pyrrole oxalate

[0378] ##STR00121##

[0379] The intermediate 2-(4-(trifluoromethyl)phenyl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 1-bromo-4-(trifluoromethyl)benzene instead of 2-bromonaphthalene. (ESI-MS (m/z): 257.32 [M+H]+). 2-methyl-5-(4-(trifluoromethyl)phenyeoctahydropyrrolo [3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the intermediate instead of the product of Example 1, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0380] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.50 (d, 2H), 6.75 (d, 2H), 3.50 (m, 2H), 3.42 (m, 2H), 3.36 (m, 2H), 3.17 (m, 2H), 3.08 (m, 2H), 2.76 (s, 3H). ESI-MS (m/z): 271.21 [M+H].sup.+.

EXAMPLE 82

2-(2-fluorophenyl)octahydropyrrolo[3,4-c]pyrrole maleate

[0381] ##STR00122##

[0382] 2-(2-fluorophenyl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 1-bromo-2-fluorobenzene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0383] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.72 (s, 2H), 7.11 (m, 1H), 7.06 (m, 1H), 6.85 (m, 2H), 6.01 (s, 2H), 3.48 (m, 2H), 3.35 (m, 2H), 3.20 (m, 2H), 3.02 (m, 4H). ESI-MS (m/z): 207.18 [M+H].sup.+.

EXAMPLE 83

2-(2-fluorophenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole oxalate

[0384] ##STR00123##

[0385] 2-(2-fluorophenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 82 instead of the product of Example 1, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0386] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.09 (m, 2H), 6.88 (m, 2H), 3.55 (m, 2H), 3.36 (d, 2H), 3.08 (m, 4H), 2.97 (m, 2H), 2.77 (s, 3H). ESI-MS (m/z): 221.28 [M+H].sup.+.

EXAMPLE 84

2-(2-ethoxyphenyl)octahydropyrrolo[3,4-c]pyrrole maleate

[0387] ##STR00124##

[0388] 2-(2-ethoxyphenyl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 1-bromo-2-ethoxybenzene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0389] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.66 (s, 2H), 6.88 (m, 3H), 6.77 (dd, 1H), 6.02 (s, 2H), 4.01 (m, 2H), 3.53 (m, 2H), 3.36 (d, 2H), 2.94 (m, 6H), 1.37 (t, 3H). ESI-MS (m/z): 233.26 [M+H].sup.+.

EXAMPLE 85

2-(2-ethoxyphenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole oxalate

[0390] ##STR00125##

[0391] 2-(2-ethoxyphenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 84 instead of the product of Example 1, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0392] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.89 (m, 2H), 6.85 (m, 1H), 6.78 (dd, 1H), 4.01 (m, 2H), 3.73 (m, 2H), 3.41 (m, 2H), 3.02 (m, 2H), 2.82 (s, 3H), 2.50 (m, 4H), 1.38 (t, 3H). ESI-MS (m/z): 247.30 [M+H].sup.+.

EXAMPLE 86

2-methyl-5-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole oxalate

[0393] ##STR00126##

[0394] The intermediate 2-methyl-5-(o-methylphenyl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using o-bromo-toluene instead of 2-bromonaphthalene. (ESI-MS (m/z): 203.34 [M+H].sup.+). 2-methyl-5-(o-tolyeoctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the intermediate instead of the product of Example 1, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0395] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.23 (brs, 2H), 7.12 (m, 2H), 6.95 (m, 2H), 3.62 (m, 2H), 3.08 (d, 2H), 2.97 (m, 4H), 2.85 (m, 2H), 2.79 (s, 3H), 2.28 (s, 3H). ESI-MS (m/z): 217.31 [M+H].sup.+.

EXAMPLE 87

2-(5-fluoro-2-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole maleate

[0396] ##STR00127##

[0397] 2-(5-fluoro-2-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 1, except using 1-bromo-2-methoxy-5-fluorobenzene instead of 2-bromonaphthalene, and the maleate was formed in accordance with Example 10 to obtain the title compound.

[0398] ESI-MS (m/z): 237.20 [M+H].sup.+.

EXAMPLE 88

2-(5-fluoro-2-methoxyphenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole oxalate

[0399] ##STR00128##

[0400] 2-(5-fluoro-2-methoxyphenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole was prepared in the same manner as that in Example 2, except using the basic product of Example 87 instead of the product of Example 1, and the oxalate was formed in accordance with Example 11 to obtain the title compound.

[0401] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.71 (brs, 2H), 6.90 (dd, 1H), 6.66 (ddd, 1H), 6.58 (dd, 1H), 3.76 (s, 3H), 3.59 (m, 2H), 3.38 (d, 2H), 2.97 (m, 6H), 2.77 (s, 3H). ESI-MS (m/z): 251.31 [M+H].sup.+.

EXAMPLE 89

6-(2,3-dichlorophenyl)decahydropyrrolo[3,4-d]azepine hydrochloride

[0402] ##STR00129##

[0403] 6-(2,3-dichlorophenyl)decahydropyrrolo[3,4-d]azepine was prepared in the same manner as that in Example 6, except using 2,3-dichloro-bromobenzene instead of 2-bromonaphthalene, and the hydrochloride was formed in accordance with Example 3 to obtain the title compound.

[0404] .sup.1H NMR (400 MHz, Methanol-d4): δ 7.66 (dd, J =8.1, 1.3 Hz, 1H), 7.54 (dd, J=8.1, 1.3 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 3.65 (d, J=7.7 Hz, 1H), 3.62 (d, J=7.7 Hz, 1H), 3.55 (d, J=6.6 Hz, 1H), 3.52 (d, J=6.6 Hz, 1H), 3.11-2.95 (m, 4H), 2.79 (m, 2H), 2.11-2.02 (m, 2H), 1.95 (m, 2H). ESI-MS(m/z): 285.35 [M+H].sup.+

EXAMPLE 90

6-(2,4-dichlorophenyl)decahydropyrrolo[3,4-d]azepine hydrochloride

[0405] ##STR00130##

[0406] 6-(2,4-dichlorophenyl)decahydropyrrolo[3,4-d] azepine was prepared in the same manner as that in Example 6, except using 2,4-dichloro-bromobenzene instead of 2-bromonaphthalene, and the hydrochloride was formed in accordance with Example 3 to obtain the title compound.

[0407] .sup.1H NMR (400 MHz, Methanol-d4): δ 7.68 (d, J=8.6 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.27 (dd, J=8.6, 2.4 Hz, 1H), 3.65 (d, J=7.7 Hz, 1H), 3.62 (d, J=7.7 Hz, 1H), 3.56 (d, J=6.5 Hz, 1H), 3.52 (d, J=6.5 Hz, 1H), 3.13-2.95 (m, 4H), 2.81 (m, 2H), 2.12-1.91 (m, 4H). ESI-MS (m/z): 285.35 [M+H].sup.+.

EXAMPLE 91

6-(3,4-dichlorophenyl)-2-methyldecahydropyrrolo[3,4-d]azepine hydrochloride

[0408] ##STR00131##

[0409] 6-(3,4-dichlorophenyl)-2-methyldecahydropyrrolo[3,4-d]azepine was prepared in the same manner as that in Example 2, except using the product of Example 35 instead of the product of Example 1, and the hydrochloride was formed in accordance with Example 3 to obtain the title compound.

[0410] ESI-MS (m/z): 299.30 [M+H].sup.+. HPLC: 95.99%.

EXAMPLE 92

7-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3,4-dihydroquinolin-2(1H)-one dihydrochloride

[0411] ##STR00132##

[0412] 7-(5-methylhexahydropyrrolo [3,4-c]pyrrol-2(1H)-yl)-3,4-dihydroquinolin-2(1H)-one was prepared in accordance with the steps in the method of Example 1 by using 5-bromo-3,4-dihydroquinolin-2(1H)-one and 2-methyloctahydropyrrolo[3,4-c]pyrrole as the raw materials, and the hydrochloride was formed in accordance with Example 3 to obtain the title compound. .sup.1H NMR (400 MHz, Methanol-d.sub.4): δ 7.06 (m, 3H), 3.94 (m, 1H), 3.73 (d, J=11.8 Hz, 1H), 3.70-3.30 (m, 8H), 3.03-2.89 (m, 5H), 2.56 (m, 2H).

[0413] ESI-MS (m/z): 272.34 [M+H].sup.+.

EXAMPLE 93

5-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3,4-dihydroquinolin-2(1H)-one dihydrochloride

[0414] ##STR00133##

[0415] 5-(5-methylhexahydropyrrolo [3,4-c]pyrrol-2(1H)-yl)-3,4-dihydroquinolin-2(1H)-one was prepared in accordance with the steps in the method of Example 1 by using 2-oxo-1,2,3,4-tetrahydroquinolin-5-yl trifluoromethanesulfonate and 2-methyloctahydropyrrolo[3,4-c]pyrrole as the raw materials, and the hydrochloride was formed in accordance with Example 3 to obtain the title compound. .sup.1H NMR (400 MHz, Methanol-d4): δ 6.95 (t, J=8.0 Hz, 1H), 6.49 (dd, J=8.2, 1.0 Hz, 1H), 6.37 (dd, J=7.9, 1.0 Hz, 1H), 3.93 (m, 1H), 3.73 (d, J=11.9 Hz, 1H), 3.70-3.34 (m, 8H), 2.97 (d, 3H), 2.89 (t, J=7.7 Hz, 2H), 2.52 (t, J=7.7 Hz, 2H). ESI-MS (m/z): 272.33 [M+H].sup.+.

[0416] Pharmacological Experiment 1. 5-HTT Reuptake Activity Assay

[0417] 5-HTT reuptake activity of the compound was conducted using a non-radioactive high-throughput screening system based on fluorescence according to the Reference (Journal of Neuroscience Methods, 2008, 169(1):168-176). The test was performed in accordance with the instructions of Molecular Devices on their Neurotransmitter transporter uptake assay kit.

[0418] The specific operations are as follows:

[0419] 1) On Day 1, HEK293-hSERT cells were seeded into a 384-well plate at 20000 cells/20 μl/well, and incubated at 37° C. overnight.

[0420] 2) On Day 2, the positive control compound and the test compound were diluted with 0.1% BSA buffer.

[0421] 3) The cell plate was taken out from the incubator, and the cell culture medium was drawn from the wells. Each well was added with 25 μl of the test solution. The negative control wells were added with 25 μl of BSA-containing buffer solution, and the positive control wells were added with 25 μl of the positive solution.

[0422] 4) After incubated at 37° C. for 30 min, each well was added with 25 μl of a dye solution, and incubated at 37° C. for 30 min.

[0423] 5) After the plate was read on a Flexstation 3 microplate reader, the data were processed by using Graphpad Prism software. The results are shown in Table 1.

TABLE-US-00001 TABLE 1 Compound IC.sub.50 1 <10 nM 2 <10 nM 6 <200 nM 7 <10 nM 8 <200 nM 9 <200 nM 10 <50 nM 11 <50 nM 12 <50 nM 13 <50 nM 14 <10 nM 15 <10 nM 16 <10 nM 17 <10 nM 19 <10 nM 21 <50 nM 22 <50 nM 23 <200 nM 26 <200 nM 27 <50 nM 28 <200 nM 29 <10 nM 30 <10 nM 31 <10 nM 32 <10 nM 35 <10 nM 36 <10 nM 37 <10 nM 38 <10 nM 39 <10 nM 41 <10 nM 42 <10 nM 43 <50 nM 48 <50 nM 50 <200 nM 51 <50 nM 52 <200 nM 54 <50 nM 55 <10 nM 56 <50 nM 57 <50 nM 59 <50 nM 61 <50 nM 62 <50 nM 64 <50 nM 65 <50 nM 66 <50 nM 67 <200 nM 68 <200 nM 69 <200 nM 70 <50 nM 71 <50 nM 75 <100 nM 76 <50 nM 81 <50 nM 89 <10 nM 90 <50 nM 93 <200 nM Positive control Citalopram 6.45 nM

[0424] In the above assay, preferred compounds of the present invention showed serotonin reuptake inhibitory concentrations less than 200 nM (IC.sub.50), more preferred compounds exhibited inhibitory concentrations below 100 nM, most preferred compounds exhibit inhibitory concentrations below 50 nM, and particularly interesting compounds exhibit serotonin reuptake inhibitory concentrations below 10 nM.

[0425] 2. 5-HT.sub.3 Receptor Affinity Activity Assay

[0426] The cell membrane was prepared from HEK293 cells expressing human recombinant 5-HT3 receptor, the membrane concentration was 2.2 μg per well, the concentration of the isotope ligand 3H-BRL 43694 was 0.5 nM, and the concentration of the non-specific binding compound MDL 72222 was 10 μM.

[0427] 1) 1 μl of the test compound as well as 1 μl of a serially diluted positive control MDL 72222 and 1 μl of DMSO negative control were transferred to the analysis plate.

[0428] 2) For cell plating, 100 μl of the membrane stock solution was added to the test plate.

[0429] 3) 100 μl of isotope-labeled ligand 3H-BRL 43694 was added.

[0430] 4) The test plate was sealed and incubated at room temperature for 1 h.

[0431] 5) 50 μl of a detergent, i.e. 0.3% polyethyleneimine was added to each well, and the Unifilter-96 GF/C filter plate was soaked at room temperature for at least 30 min.

[0432] 6) When the binding experiment was finished, the reaction mixture was filtered with the GF/C filter plate, and the GF/C filter plate and assay plate were then washed with a cold buffer 4 times.

[0433] 7) The filter plate was dried at 50° C.

[0434] 8) After dried, the filter plate was sealed at the bottom with a sealing tape, and added with 50 μl of scintillation fluid (Perkin Elmer Microscint 20 cocktail). The filter plate was sealed with a sealing film at the top.

[0435] 9) The 3H captured on the filter plate was counted on a Perkin Elmer MicroBeta2 reader, and the data was analyzed with GraphPad Prism 5 software. The results are shown in Table 2.

TABLE-US-00002 TABLE 2 Compound inhibition (%) at 1 μM 1 106%  2 97% 7 101%  10 86% 11 86% 12 101%  13 70% 14 99% 15 70% 16 96% 17 93% 26 76% 27 104%  28 82% 31 101%  32 103%  35 98% 36 89% 37 80% 38 103%  39 92% 41 86% 42 103%  50 83% 55 75% Positive control MDL72222 93% (IC.sub.50 = 9.28 nM)

[0436] It can be seen from table 2 that, the compounds of the present invention have high affinity to 5-HT.sub.3 receptor, and are capable of treating central nervous system diseases associated with 5-HT.sub.3 receptor. 5-HT.sub.3 receptor is located in the postsynaptic membrane, and regulates inhibitory GABA interneurons in different brain regions to regulate the release of various neurotransmitters. Serotonin acts on 5-HT.sub.3 receptor to reduce the release of various neurotransmitters. Therefore, antagonizing 5-HT.sub.3 receptors may cause de-inhibition, thereby increasing the release of neurotransmitters. 5-HT.sub.3 antagonists can enhance the effect of SSRIs antidepressants. Animal experiments showed that the combination of 5-HT.sub.3 antagonist ondansetron and paroxetine can enhance the antidepressant effect of paroxetine. Ondansetron can partially prevent the suppressant effect of paroxetine on 5-HT neuronal firing in the dorsal raphe nucleus, and enhance the paroxetine-induced increase of hippocampal extracellular 5-HT release (Pharmacology, Biochemistry and Behavior 2015, 131, 136-142).

[0437] Patients with depression often have chronic pain. Chronic physical pain is closely related to depression, and its severity is positively correlated with the severity of depression. Fibromyalgia is a chronic pain disease characterized by extensive pain. Clinical evidences showed that 5-HT.sub.3R antagonists granisetron, ondansetron and tropisetron can significantly reduce fibromyalgia (Arthritis Res Ther, 2006, 8(4), 212.), and therefore it is expected that antidepressant drugs with 5-HT.sub.3R antagonism can alleviate the pain condition of patients with depression.

[0438] A large amount of research evidences showed that the 5-HTergic system and other neurotransmitter systems such as cholinergic, dopaminergic, and glutamatergic systems interact in the control of learning and memory. Both the cerebral cortex and the dorsal hippocampus are important structures related to memory. The excitement of 5-HTergic neurons can stimulate cholinergic neurons to release acetylcholine. 5-HT.sub.3R antagonists can inhibit the regulated acetylcholine release of 5-HT without affecting the steady-state release of acetylcholine and prevent cognitive impairment. Overexpression of 5-HT.sub.3R in mice has been shown to enhance learning, memory and concentration. It has been reported in the literature that ondansetron can improve patients' memory and reduce cognitive impairment (Pharmacology & therapeutics, 2010, 128(1): 146-169.).

[0439] It can be seen according to the above examples that, some compounds of the present invention have 5-HTT/5-HT.sub.3 receptor multi-target effects, which are beneficial to balance neurotransmitters in the brain, and has good curative effect on the central nervous system diseases. Thus, it can act quickly through the synergistic action of multi-targeting and reduce the side effects caused by drugs.

[0440] 3. In Vivo Drug Efficacy Test (Mouse Forced Swimming Model)

[0441] Experimental animals: C57BL/6 mice (Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.), male, 6 weeks old, weighing 15-20 g. ICR mice (Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.), male, 6 weeks old, weighing 20-25 g. All the ordered mice were fed in a standard environment for 2-3 weeks before test.

[0442] Forced Swimming Test (FST): in the forced swimming apparatus, the water level is 45 cm, and the water temperature is 25° C. Before the experiment, the mice were placed in the experimental room for 1 h for adapting to the environment. At the beginning of the experiment, the mice were placed in the apparatus for 6min, and the whole process was recorded with a camera. When analyzing the data, only the immobility time of the mice in the last 4 min was counted, and the result was expressed by mean±SD.

[0443] Tail suspension test (TST): the mice were tail fixed to the apparatus with a medical tape for 6 min, the whole process was recorded by the camera. When analyzing the data, only the immobility time of the mice in the last 4 min was counted.

[0444] The results were analyzed by one-way analysis of variance. The test compounds at the following doses (Table 3) can significantly reduce the immobility time of mice, which has a significant difference compared with the blank control group. po: oral administration; ip: intraperitoneal administration. FST: Forced swimming test; TST: Tail suspension test.

TABLE-US-00003 TABLE 3 Test Compound Effective dose (mg/kg) Compound of Example 1 5 (po); FST Compound of Example 2 5 (po); FST Compound of Example 7 10 (ip); TST Compound of Example 10 10 (ip); FST Compound of Example 11 10 (ip); FST Compound of Example 12 3 (ip); FST Compound of Example 13 5 (ip); FST Compound of Example 14 3 (ip); FST Compound of Example 15 2.5 (po); FST Compound of Example 16 3 (ip); FST Compound of Example 17 5 (po); FST Compound of Example 19 10 (ip); FST Compound of Example 21 3 (ip); FST Compound of Example 22 10 (ip); TST Compound of Example 25 10 (ip); TST Compound of Example 28 10 (ip); TST Compound of Example 29 5 (po); FST Compound of Example 30 20 (po); FST Compound of Example 31 20 (po); FST Compound of Example 32 20 (po); FST Compound of Example 35 20 (po); FST Compound of Example 36 10 (ip); TST Compound of Example 37 10 (ip); FST Compound of Example 38 10 (ip); TST Compound of Example 39 10 (ip); TST Compound of Example 41 10 (ip); TST Compound of Example 50 10 (ip); FST Compound of Example 55 5 (po); FST Compound of Example 69 10 (ip); FST Compound of Example 81 10 (ip); FST Duloxetine 20 (po); FST Citalopram 20 (po); FST

[0445] The compounds of the present invention are not only strong in activity, but also effective after oral administration. They are characterized in low effective dose and low toxic and side effects, and have curative effect on the central nervous system diseases, especially have a good effect for major depression disorder (MDD), anxiety, obsessive-compulsive disorder, etc.