PYRIDINYL MORPHOLINE COMPOUND, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF

Abstract

Disclosed in the present invention are a pyridinyl morpholine compound, a preparation method therefor, and an application thereof. The present invention provides a pyridinyl morpholine compound as represented by formula I, a pharmaceutically acceptable salt thereof or a hydrate of the pharmaceutically acceptable salt thereof. The compound can be used as an antagonist for one or more of D.sub.2, D.sub.3 or 5-HT.sub.2A, and is used for preparing a drug for treating schizophrenia.

##STR00001##

Claims

1. A pyridinyl morpholine compound represented by formula I, a pharmaceutically acceptable salt thereof, or a hydrate of the pharmaceutically acceptable salt thereof: ##STR00064## wherein, R.sup.1 is ##STR00065## R.sup.3 is C.sub.1-C.sub.3 alkyl, “C.sub.1-C.sub.3 alkyl substituted by one C.sub.1-C.sub.3 alkoxy”, C.sub.3-C.sub.6 cycloalkyl, phenyl, “5- to 6-membered heteroaryl with 1 to 2 heteroatoms selected from one or more of N, O and S”, “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S”, or, “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S” substituted by one C.sub.1-C.sub.3 alkyl; the heterocycloalkyl is connected to the carbonyl in R.sup.1 by N atom; R.sup.4 and R.sup.5 are independently hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.2 is phenyl, “5- to 6-membered heteroaryl with 1 to 2 heteroatoms selected from one or more of N, O and S”, or, phenyl substituted by one or more R.sup.2-1; R.sup.2-1 is independently C.sub.1-C.sub.3 alkoxy or halogen.

2. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sup.3 is defined as any one of the definitions (1) to (6), definition (1), R.sup.3 is C.sub.1-C.sub.3 alkyl, ##STR00066## C.sub.3-C.sub.6 cycloalkyl, or “5- to 6-membered heteroaryl with one heteroatom selected from N, O and S”, “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S”, or, “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S” substituted by one C.sub.1-C.sub.3 alkyl; the heterocycloalkyl is connected to the carbonyl in R.sup.1 by N atom; definition (2), R.sup.3 is C.sub.1-C.sub.3 alkyl, ##STR00067## furanyl, pyridyl, tetrahydropyrrolyl, morpholinyl, piperidinyl or piperazinyl; definition (3), R.sup.3 is furanyl, pyridyl or tetrahydropyrrolyl; definition (4), R.sup.3 is C.sub.1-C.sub.3 alkyl, ##STR00068## furanyl, pyridyl, tetrahydropyrrolyl or piperazinyl; definition (5), R.sup.3 is “5- to 6-membered heteroaryl with 1 heteroatom selected from N and O” or tetrahydropyrrolyl; and, definition (6), R.sup.3 is C.sub.3 alkyl, “C.sub.1-C.sub.3 alkyl substituted by one C.sub.1-C.sub.3 alkoxy”, phenyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, piperazinyl or methylpiperazinyl; or, R.sup.2 is defined as definition (a) or definition (b); definition (a), phenyl, “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S” or phenyl substituted by one R.sup.2-1; definition (b), R.sup.2 is phenyl, “5- to 6-membered heteroaryl with 1 heteroatom selected from N and S” or phenyl substituted with one R.sup.2-1; or, R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.3 alkyl; or, R.sup.2-1 is independently C.sub.1-C.sub.3 alkoxy or fluorine.

3. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 2, wherein, the definitions of the groups of the pyridinyl morpholine compound represented by formula I are as described in scheme 1, scheme 2, scheme 3, scheme 4 or scheme 5; scheme 1: R.sup.3 is C.sub.1-C.sub.3 alkyl ##STR00069## C.sub.3-C.sub.6 cycloalkyl, “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S”, “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S”, or, “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S” substituted by one C.sub.1-C.sub.3 alkyl; the heterocycloalkyl is connected to the carbonyl in R.sup.1 by N atom; R.sup.2 is phenyl, “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S”, or phenyl substituted by one or more R.sup.2-1; R.sup.2-1 is independently C.sub.1-C.sub.3 alkoxy or halogen; scheme 2: R.sup.3 is C.sub.1-C.sub.3 alkyl, ##STR00070## furanyl, pyridyl, tetrahydropyrrolyl, morpholinyl, piperidinyl or piperazinyl; R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.3 alkyl; R.sup.2 is phenyl, “5- to 6-membered heteroaryl with 1 heteroatom selected from N and S”, or phenyl substituted by one or more R.sup.2-1; R.sup.2-1 is independently C.sub.1-C.sub.3 alkoxy or halogen; scheme 3: R.sup.3 is furanyl, pyridyl or tetrahydropyrrolyl; R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.3 alkyl; R.sup.2 is phenyl, “5- to 6-membered heteroaryl with 1 heteroatom selected from N and S”, or phenyl substituted by one or more R.sup.2-1; R.sup.2-1 is independently C.sub.1-C.sub.3 alkoxy or halogen; scheme 4: R.sup.3 is C.sub.1-C.sub.3 alkyl, ##STR00071## furanyl, pyridyl, tetrahydropyrrolyl or piperazinyl; R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.3 alkyl; R.sup.2 is phenyl, “5- to 6-membered heteroaryl with 1 heteroatom selected from N and S”, or phenyl substituted by one or more R.sup.2-1; R.sup.2-1 is independently C.sub.1-C.sub.3 alkoxy or halogen; scheme 5: R.sup.3 is C.sub.3 alkyl, “C.sub.1-C.sub.3 alkyl substituted by one C.sub.1-C.sub.3 alkoxy”, phenyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, piperazinyl or methylpiperazinyl; R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.3 alkyl; R.sup.2 is phenyl, “5- to 6-membered heteroaryl with 1 heteroatom selected from N and S”, or phenyl substituted by one or more R.sup.2-1.

4. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 1, wherein, the pyridinyl morpholine compound represented by formula I is the pyridinyl morpholine compound represented by formula I-1 or the pyridinyl morpholine compound represented by formula I-2: ##STR00072## or, in the pharmaceutically acceptable salt, the salt is hydrochloride, hydrobromide, sulfate, methanesulfonate or trifluoroacetate; or, in the pharmaceutically acceptable salt, relative to the pyridinyl morpholine compound represented by formula I, the number of acid molecular contained in the salt is 0.5 to 2; or, in the hydrate of the pharmaceutically acceptable salt, the salt is hydrochloride, bromate, sulfate, trifluoroacetate, methanesulfonate or palmitate; or, in the hydrate of the pharmaceutically acceptable salt, relative to the pyridinyl morpholine compound represented by formula I, the number of acid molecular contained in the hydrate of the salt is 0.5 to 2; or, in the hydrate of the pharmaceutically acceptable salt, relative to the pyridinyl morpholine compound represented by formula I, the number of water molecular contained in the hydrate of the salt is 0.5 to 2.

5. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 4, wherein, the pyridinyl morpholine compound represented by formula I is the pyridinyl morpholine compound represented by formula I-1: ##STR00073## when R.sup.3 is C.sub.1-C.sub.3 alkyl substituted by one C.sub.1-C.sub.3 alkoxy, the C.sub.1-C.sub.3 alkyl substituted by one C.sub.1-C.sub.3 alkoxy is ##STR00074## when R.sup.3 is “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S”, the “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S” is furanyl or pyridyl; when R.sup.3 is “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S substituted by one C.sub.1-C.sub.3 alkyl”, the C.sub.1-C.sub.3 alkyl is methyl; when R.sup.3 is “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S substituted by one C.sub.1-C.sub.3 alkyl”, the “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S substituted by one C.sub.1-C.sub.3 alkyl is ##STR00075##

6. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 5, wherein, when R.sup.3 is “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S”, the “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S” is or ##STR00076## or, when R.sup.2 is “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S”, the “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S” is ##STR00077##

7. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 6, wherein, R.sup.1 is ##STR00078## or, R.sup.2 is ##STR00079##

8. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 1, wherein, the pyridinyl morpholine compound represented by formula I is any one of the following compounds: TABLE-US-00007 No. Structure I-1 embedded image I-2 I-3 I-4 I-5 I-6 I-7 II-1 II-2 II-3 II-4 II-5 II-6 III-1 III-2 III-3 III-4 IV-1 IV-2 IV-3 IV-4 V-1 V-2 V-3 V-4 V-5 VI-1 VI-2 VI-3 VI-4 VI-5 VII-1 VII-2 VII-3 VII-4 VII-5

9. A preparation method of the pyridinyl morpholine compound represented by formula I according to claim 1, wherein, comprising conducting an amidation reaction as shown below with a compound represented by formula 6 and substance Y to obtain the pyridinyl morpholine compound represented by formula I; the substance Y is a compound represented by formula A or formula B; ##STR00116##

10. A pharmaceutical composition, wherein, comprising substance X and pharmaceutical excipients; the substance X is the pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 1.

11. A method for treating or antagonizing schizophrenia in a subject in need thereof, comprising administering an effective amount of substance X to the subject, wherein, the substance X is the pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 1.

12. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 4, wherein, when R.sup.3 is C.sub.1-C.sub.3 alkyl, the C.sub.1-C.sub.3 alkyl is methyl, ethyl, n-propyl, or isopropyl; when R.sup.3 is C.sub.1-C.sub.3 alkyl substituted by one C.sub.1-C.sub.3 alkoxy, the C.sub.1-C.sub.3 alkoxy is methoxy; when R.sup.3 is C.sub.1-C.sub.3 alkyl substituted by one C.sub.1-C.sub.3 alkoxy, the C.sub.1-C.sub.3 alkyl is methyl; when R.sup.3 is C.sub.1-C.sub.3 alkoxy, the C.sub.1-C.sub.3 alkoxy is ethoxy; when R.sup.3 is C.sub.3-C.sub.6 cycloalkyl, the C.sub.3-C.sub.6 cycloalkyl is cyclopropyl or cyclohexyl; when R.sup.3 is “5- to 6-membered heteroaryl with 1 to 2 heteroatoms selected from one or more of N, O and S”, the “5- to 6-membered heteroaryl with 1 to 2 heteroatoms selected from one or more of N, O and S” is “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S”; when R.sup.3 is “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S”, the “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S” is ##STR00117## when R.sup.3 is “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S substituted by one C.sub.1-C.sub.3 alkyl”, the C.sub.1-C.sub.3 alkyl is methyl, ethyl, n-propyl, or isopropyl; when R.sup.3 is “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S substituted by one C.sub.1-C.sub.3 alkyl”, the “5- to 6-membered heterocycloalkyl with one heteroatom of N, and 0 or 1 heteroatom selected from N, O and S” is ##STR00118##

13. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 4, wherein, when R.sup.4 is C.sub.1-C.sub.3 alkyl, the C.sub.1-C.sub.3 alkyl is methyl, ethyl, n-propyl, or isopropyl; or, when R.sup.5 is C.sub.1-C.sub.3 alkyl, the C.sub.1-C.sub.3 alkyl is methyl, ethyl, n-propyl, or isopropyl; or, when R.sup.2 is “5- to 6-membered heteroaryl with 1 to 2 heteroatoms selected from one or more of N, O and S”, the “5- to 6-membered heteroaryl with 1 to 2 heteroatoms selected from one or more of N, O and S” is “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S”.

14. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 4, wherein, when R.sup.2-1 is C.sub.1-C.sub.3 alkoxy, the C.sub.1-C.sub.3 alkoxy is methoxy, ethoxy, propoxy or isopropoxy; or, when R.sup.2-1 is halogen, the halogen is fluorine, chlorine, bromine or iodine.

15. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 5, wherein, when R.sup.2-1 is C.sub.1-C.sub.3 alkoxy, the C.sub.1-C.sub.3 alkoxy is methoxy; or, when R.sup.2 is “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S”, the “5- to 6-membered heteroaryl with 1 heteroatom selected from N, O and S” is furanyl, thienyl, pyrrolyl or pyridyl.

16. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 1, wherein, the pharmaceutically acceptable salt of the pyridinyl morpholine compound represented by formula I is any one of the following compounds: ##STR00119## ##STR00120##

17. The pyridinyl morpholine compound represented by formula I, the pharmaceutically acceptable salt thereof, or the hydrate of the pharmaceutically acceptable salt thereof according to claim 1, wherein, the hydrate of the pharmaceutically acceptable salt of the pyridinyl morpholine compound represented by formula I is the following compound: ##STR00121##

18. The method according to claim 11, wherein, the antagonizing refers to antagonizing one or more than one of D.sub.2, D.sub.3 and 5-HT.sub.2A.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0125] The present disclosure is further described below by way of embodiments, but the present disclosure is not thereby limited to the scope of the described embodiments. The experimental methods not specified in the specific conditions in the following embodiments are selected according to the conventional methods and conditions, or according to the commodity instructions.

[0126] The compounds of the present disclosure can be prepared by the following general synthetic method. Further, the present disclosure also refers to the methods reported in WO2010070370 and WO2011073705 to synthesize the compound cariprazine hydrochloride reported in the literature, which is used as a control sample for in vitro and in vivo activity screening.

[0127] General Synthetic Method:

##STR00062## ##STR00063##

Synthesis of Intermediate 2

[0128] Compound 1 (25.7 g, 0.1 mol) was added to dichloromethane (200 mL), and then the mixture was cooled to 0° C. in an ice bath, and triethylamine (0.25 mol) was added dropwise, and isopropyl chloroformate (0.12 mol) was slowly added dropwise. The mixture was stirred at room temperature for 3 to 5 hours, cooled to 5° C., and then cold water (1 L) was added thereto, and the mixture was stirred for 0.5 hours, and the layers was separated. The organic layer was washed with saturated brine, evaporated to dryness. Under the protection of N.sub.2, anhydrous THF was added thereto, and the temperature was lowered to 0° C., and then KBH.sub.4 (8.1 g, 0.15 mol) was slowly added in batches. The mixture was stirred at room temperature for 4 to 5 hours, then cooled to 5° C. or less, and saturated ammonium chloride solution was slowly added dropwise until bubbles were not formed. The system was concentrated under reduced pressure to near dryness, and water/dichloromethane were added thereto, and the layers were separated, and then the organic layer was washed with saturated Na.sub.2CO.sub.3 solution, water, and saturated brine successively, then evaporated to dryness to obtain intermediate 2.

Synthesis of Intermediate 3

[0129] Intermediate 2 (9.7 g, 0.04 mol) and triethylamine (0.12 mol) were added to dichloromethane (100 mL), and a solution of methanesulfonyl chloride (0.048 mol) in dichloromethane (40 mL) was slowly added dropwise at about 0° C., and then the mixture was stirred at room temperature for 2 to 4 hours. The reaction solution was washed with water, 1% aqueous sodium hydroxide solution, water, and saturated brine successively, evaporated to dryness, and recrystallized with 95% ethanol to obtain intermediate 3.

Synthesis of Intermediate 4

[0130] 2,6-Dichloro-4-iodopyridine (5 g, 18.33 mmol), arylboronic acid compound (18.33 mmol), Pd(dppf)Cl.sub.2 (0.68 g, 1.83 mmol), toluene (120 mL), sodium carbonate (7.74 g, 55.21 mmol) were added to a 250 mL single-necked flask. Under the protection of nitrogen, the mixture was reacted at external temperature of 80° C. for 14 to 18 hours, and the completion of reaction was detected by TLC. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated and purified by column chromatography to obtain product 8.

[0131] The product 8 (15.47 mmol), N-Boc-piperazine (2.88 g, 15.47 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (0.9 g, 1.55 mmol), Pd.sub.2(dba).sub.3 (0.35 g, 0.39 mmol), sodium tert-butanol (2.97 g, 23.21 mmol) and toluene (80 mL) were added to a 250 mL single-necked flask. Under the protection of nitrogen, the mixture was reacted at external temperature of 80° C. for 10 to 16 hours, and the completion of reaction was detected by TLC. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated and purified by column chromatography to obtain product 10. The product 10 (3.75 mmol), morpholine (0.34 g, 3.75 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (0.21 g, 0.37 mmol), Pd.sub.2(dba).sub.3 (0.09 g, 0.1 mmol), sodium tert-butanol (0.72 g, 7.5 mmol) and toluene (20 mL) were added to a 100 mL single-necked flask. Under the protection of nitrogen, the mixture was reacted at external temperature of 80° C. for 10 to 15 hours, and the completion of reaction was detected by TLC. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated and purified by column chromatography to obtain product 12. The product was dissolved in CH.sub.2Cl.sub.2 (50 mL), and then 5 equivalents of trifluoroacetic acid was added, and the reaction solution was stirred at room temperature for 8 to 10 hours, and the completion of reaction was detected by TLC. The pH of the reaction solution was adjusted to 10 to 12 with 20% NaOH aqueous solution, and the reaction solution was stirred for 10 min, and then the layers were separated. The organic layer was washed with H.sub.2O (30 mL×2) and saturated brine (50 mL×2) successively, dried over anhydrous Na.sub.2SO.sub.4 for 1 hour, filtered and concentrated to obtain intermediate 4.

Synthesis of Intermediate 5

[0132] Intermediates 3 (6.4 g, 0.02 mol), intermediate 4 (0.018 mol), anhydrous potassium carbonate (5.5 g, 0.04 mol) were added to acetonitrile (100 mL), and the reaction was refluxed overnight, filtered. The filter cake was washed twice with acetonitrile, and the filtrate was combined, evaporated to dryness, and then the residue was recrystallized with anhydrous ethanol to obtain intermediates 5.

Synthesis of Intermediate 6

[0133] Intermediate 5 (10 mmol) was added to dichloromethane (40 mL), and then trifluoroacetic acid (7 mL) was slowly added dropwise, and the mixture was stirred at room temperature overnight. The system was washed with water, 5% NaOH aqueous solution, and saturated brine successively, and the organic layer was concentrated to dryness to obtain intermediate 6.

Synthesis of Compound Represented by General Formula (I)

[0134] Intermediate 6 (5 mmol), triethylamine (6 mmol), and dichloromethane (10 mL) were added to a 50 mL three-necked flask, and a solution of acyl chloride (5.5 mmol) in dichloromethane (10 mL) was added dropwise at 0 to 5° C. After the dropwise addition was completed, the mixture was stirred at room temperature for 2-5 hours, and the system was washed with water and saturated brine successively. The organic layer was concentrated to dryness, and recrystallized with anhydrous ethanol to obtain the compound of the present disclosure.

Synthesis of the Salt of Compound Represented by General Formula (I)

[0135] The compound represented by general formula (I) was placed in 5% acid/ethanol and refluxed to dissolve, and the mixture was cooled to precipitate the salt of the compound, and the acid can be hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid.

[0136] In the above general method, R.sup.3 is C.sub.1-C.sub.3 alkyl, “C.sub.1-C.sub.3 alkyl substituted by one C.sub.1-C.sub.3 alkoxy”, C.sub.3-C.sub.6 cycloalkyl, phenyl, “5- to 6-membered heteroaryl with 1 to 2 heteroatoms selected from one or more of N, O and S”, “5- to 6-membered heterocycloalkyl with one of N atom, and 0 or 1 heteroatom selected from N, O and S”, or, “5- to 6-membered heterocycloalkyl with one of N atom, and 0 or 1 heteroatom selected from N, O and S” substituted by one C.sub.1-C.sub.3 alkyl; the heterocycloalkyl is connected to the carbonyl in R.sup.1 by N atom;

[0137] R.sup.4 and R.sup.5 are independently hydrogen or C.sub.1-C.sub.3 alkyl.

Example 1

Preparation of N-(trans-4-(2-(4-(6-morpholino-4-phenylpyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)acetamide (I-1) and the salt thereof

trans-4-(2-(4-(6-Morpholino-4-phenylpyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-amine (intermediate 6-1, prepared according to the general synthetic method)

[0138] (1.0 g, 2.2 mmol) [ custom-character 1] and triethylamine (3.3 mmol) were added to CH.sub.2Cl.sub.2 (20 mL), and the mixture was stirred, and a solution of acetyl chloride (0.2 g, 2.4 mmol) in CH.sub.2Cl.sub.2 (5 mL) was added dropwise at 0 to 5° C. After the dropwise addition was completed, the mixture was stirred at room temperature for 2-4 hours, and the system was washed with water and saturated brine successively, and then the organic layer was concentrated to dryness, and recrystallized with anhydrous ethanol to obtain 0.8 g of white solid with a yield of 74%.

[0139] .sup.1H NMR (CDCl.sub.3 δ:ppm) δ 7.52-7.51 (m, 2H), 7.46 (d, J=4.2 Hz, 2H), 7.36-7.35 (m, 2H), 7.08-7.06 (m, 1H), 6.25 (s, 2H), 3.88-3.86 (m, 1H), 3.85-3.79 (m, 4H), 3.59 (brs, 4H), 3.54-3.48 (m, 4H), 2.56 (brs, 4H), 2.48-2.35 (m, 2H), 2.12-2.03 (m, 2H), 2.01 (s, 3H), 1.85 (d, J=12.6 Hz, 2H), 1.53-1.43 (m, 2H), 1.22-1.20 (m, 5H). ESI-MS:492[M+H.sup.+].

Preparation of the Hydrochloride of Compound I-1

[0140] Compound I-1 (0.5 g, 1.0 mmol) and 5% hydrochloric acid aqueous solution (1.1 mmol) were added to ethanol (10 mL), refluxed to dissolve, cooled to precipitate a white solid, and filtered to obtain 0.4 g of white solid with a yield of 75.7%.

[0141] Element analysis: C.sub.29H.sub.41N.sub.5O.sub.2.Math.HCl (theoretical value %: C, 65.95; H, 8.02; N, 13.26; experimental value %: C, 65.90; H, 8.13; N, 13.21).

Preparation of the Methanesulfonate Hemihydrate of Compound I-1

[0142] Compound I-1 (0.5 g, 1.0 mmol) and methanesulfonic acid aqueous solution (1.1 mmol) were added to ethanol (10 mL), refluxed to dissolve, cooled to precipitate a white solid, and filtered to obtain 0.41 g of white solid with a yield of 77.6%.

[0143] Element analysis: C.sub.29H.sub.41N.sub.5O.sub.2.Math.CH.sub.4O.sub.3S.Math.½H.sub.2O (theoretical value %: C, 60.38; H, 7.77, N, 11.74; experimental value %: C, 60.29; H, 7.83; N, 11.57).

Example 2

Preparation of N-(trans-4-(2-(4-(6-morpholino-4-phenylpyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)butyramide (I-2) and the salt thereof

[0144] Intermediate 6-1 (5.0 mmol) (prepared according to the general synthetic method) and butyryl chloride (5.5 mmol) were used as raw materials, and 2.1 g of compound I-2 as white solid with a yield of 80% was obtained according to the preparation method of compound I-1.

[0145] .sup.1H NMR (CDCl.sub.3 δ:ppm) δ 7.53-7.52 (m, 2H), 7.44 (d, J=4.2 Hz, 2H), 7.35-7.34 (m, 2H), 7.07-7.05 (m, 1H), 6.23 (s, 2H), 3.84-3.82 (m, 1H), 3.81-3.75 (m, 4H), 3.56 (brs, 4H), 3.51-3.45 (m, 4H), 2.53 (brs, 4H), 2.46-2.33 (m, 2H), 2.31 (t, J=5.6 Hz, 2H) 2.10-2.01 (m, 2H), 1.84 (d, J=12.6 Hz, 2H), 1.50-1.42 (m, 2H), 1.34-1.32 (m, 2H), 1.21-1.19 (m, 5H), 0.58 (s, 3H). ESI-MS:520[M+H.sup.+].

Preparation of the Methanesulfonate of Compound I-2

[0146] Compound I-2 (1.0 mmol) and methanesulfonic acid aqueous solution (1.0 mmol) were used as raw materials, and 0.45 g of white solid with a yield of 73% was obtained according to the synthetic method of the hydrochloride of compound I-1.

[0147] Element analysis: C.sub.31H.sub.45N.sub.5O.sub.2.Math.CH.sub.4O.sub.3S (theoretical value %: C, 62.41; H, 8.02; N, 11.37; experimental value %: C, 62.58; H, 7.89; N, 11.44).

Example 3

Preparation of ethyl ((trans)-4-(2-(4-(6-morpholino-4-phenylpyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (I-3) and the salt thereof

[0148] Intermediate 6-1 (5.0 mmol) (prepared according to the general synthetic method) and ethyl chloroformate (5.5 mmol) were used as raw materials, and 1.9 g of compound I-3 as white solid with a yield of 72.8% was obtained according to the preparation method of compound I-1.

[0149] .sup.1H NMR (CDCl.sub.3, δ:ppm) δ 7.55-7.54 (m, 2H), 7.47 (d, J=4.2 Hz, 2H), 7.37-7.36 (m, 2H), 7.06-7.04 (m, 1H), 6.25 (s, 2H), 3.94 (q, J=7.0 Hz, 2H), 3.83-3.81 (m, 1H), 3.80-3.74 (m, 4H), 3.55 (brs, 4H), 3.50-3.44 (m, 4H), 2.55 (brs, 4H), 2.47-2.34 (m, 2H), 2.11-2.02 (m, 2H), 1.86 (d, J=12.6 Hz, 2H), 1.51-1.43 (m, 2H), 1.22-1.20 (m, 5H), 1.06 (t, J=7.0 Hz, 3H). ESI-MS:522[M+H.sup.+].

Preparation of the Hydrobromide of Compound I-3

[0150] Compound I-3 (1 mmol) and 5% hydrobromic acid aqueous solution (1 mmol) were used as raw materials, and 0.48 g of white solid with a yield of 80% was obtained according to the synthetic method of the hydrochloride of compound I-1.

[0151] Element analysis: C.sub.30H.sub.43N.sub.5O.sub.3.Math.HBr (theoretical value %: C, 59.79; H, 7.36; N, 11.62; experimental value %: C, 59.84; H, 7.27; N, 11.69).

Example 4

Preparation of N-((trans)-4-(2-(4-(6-morpholino-4-phenylpyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)cyclopropanecarboxamide (I-4)

[0152] Intermediate 6-1 (5.0 mmol) (prepared according to the general synthetic method), cyclopropanecarbonyl chloride (5.5 mmol) were used as raw materials, and 2.2 g of compound I-4 as white solid with a yield of 84.6% was obtained according to the preparation method of compound I-1.

[0153] .sup.1H NMR (CDCl.sub.3, δ:ppm) δ 7.55-7.54 (m, 2H), 7.48 (d, J=4.2 Hz, 2H), 7.39-7.38 (m, 2H), 7.11-7.09 (m, 1H), 6.27 (s, 2H), 3.90-3.88 (m, 1H), 3.87-3.81 (m, 4H), 3.61 (brs, 4H), 3.56-3.50 (m, 4H), 2.58 (brs, 4H), 2.49-2.34 (m, 2H), 2.14-2.05 (m, 2H), 1.91 (d, J=12.6 Hz, 2H), 1.48-1.41 (m, 3H), 1.26-1.24 (m, 5H), 0.83-0.81 (m, 2H), 0.54-0.52 (m, 2H).

[0154] ESI-MS:518[M+H.sup.+].

Example 5

Preparation of N-((trans)-4-(2-(4-(6-morpholino-4-phenylpyridin-2-yl)piperazin-1-yl)cyclohexyl)cyclohexanecarboxamide (I-5) and the salt thereof

[0155] Intermediate 6-1 (5.0 mmol) (prepared according to the general synthetic method) and cyclohexanecarbonyl chloride (5.5 mmol) were used as raw materials, and 2.0 g of compound I-5 as white solid with a yield of 71% was obtained according to the preparation method of compound I-1.

[0156] .sup.1H NMR (CDCl.sub.3, δ:ppm) δ 7.51-7.50 (m, 2H), 7.45 (d, J=4.2 Hz, 2H), 7.35-7.34 (m, 2H), 7.07-7.05 (m, 1H), 6.24 (s, 2H), 3.89-3.87 (m, 1H), 3.84-3.78 (m, 4H), 3.58 (brs, 4H), 3.53-3.47 (m, 4H), 2.54 (brs, 4H), 2.46-2.33 (m, 3H), 2.11-2.02 (m, 2H), 1.87 (d, J=12 Hz, 2H), 1.68-1.59 (m, 5H), 1.51-1.41 (m, 7H), 1.21-1.19 (m, 5H). ESI-MS:560[M+H.sup.+].

Preparation of the Hydrochloride of Compound I-5

[0157] Compound I-5 (1 mmol) and 5% hydrochloric acid aqueous solution (1 mmol) were used as raw materials, and 0.48 g of white solid with a yield of 81% was obtained according to the synthetic method of the hydrochloride of compound I-1.

[0158] Element analysis: C.sub.34H.sub.49N.sub.5O.sub.2.Math.HCl (theoretical value %: C, 68.49; H, 8.45; N, 11.75; experimental value %: C, 68.38; H, 8.39; N, 11.86).

Preparation of the Trifluoroacetate of Compound I-5

[0159] Compound I-5 (1 mmol) and 5% trifluoroacetic acid aqueous solution (1 mmol) were used as raw materials, and 0.56 g of white solid with a yield of 83% was obtained according to the synthetic method of the hydrochloride of compound I-1.

[0160] Element analysis: C.sub.34H.sub.49N.sub.5O.sub.2.Math.CF.sub.3CO.sub.2H (theoretical value %: C, 64.17; H, 7.48; N, 10.39; experimental value %: C, 64.29; H, 7.27; N, 10.55).

Example 6

Preparation of N-((trans)-4-(2-(4-(6-morpholino-4-phenylpyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)furan-2-carboxamide (I-6)

[0161] Intermediate 6-1 (5.0 mmol) and furan-2-carbonyl chloride (5.5 mmol) were used as raw materials, and 2.3 g of target compound I-6 as off-white solid with a yield of 85% was obtained according to the preparation method of compound I-1.

[0162] .sup.1H NMR (CDCl.sub.3, δ:ppm) δ 7.58-7.56 (m, 2H), 7.46-7.35 (m, 4H), 7.09 (d, J=3.4 Hz, 1H), 6.49 (dd, J=3.4, 1.8 Hz, 1H), 6.23 (s, 1H), 6.17 (d, J=10.5 Hz, 2H), 3.92-3.91 (m, 1H), 3.86-3.80 (m, 4H), 3.60 (brs, 4H), 3.55-3.49 (m, 4H), 2.58 (brs, 4H), 2.49-2.36 (m, 2H), 2.13-2.03 (m, 2H), 1.83 (d, J=12.6 Hz, 2H), 1.54-1.44 (m, 2H), 1.23-1.20 (m, 5H).

[0163] ESI-MS:544[M+H.sup.+].

Example 7

Preparation of 1,1-dimethyl-3-(trans-4-(2-(4-(6-morpholino-4-phenylpyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)urea (I-7)

[0164] Intermediate 6-1 (5.0 mmol) and dimethylcarbamoyl chloride (5.5 mmol) were used as raw materials, and 2.0 g of target compound I-7 as white solid with a yield of 77% was obtained according to the preparation method of compound I-1.

[0165] .sup.1H NMR (CDCl.sub.3, δ:ppm) δ 7.54-7.53 (m, 2H), 7.48 (d, J=4.2 Hz, 2H), 7.38-7.37 (m, 2H), 7.10-7.08 (m, 1H), 6.27 (s, 2H), 3.89-3.87 (m, 1H), 3.86-3.80 (m, 4H), 3.61 (brs, 4H), 3.56-3.50 (m, 4H), 3.01 (s, 6H), 2.58 (brs, 4H), 2.50-2.37 (m, 2H), 2.14-2.05 (m, 2H), 1.87 (d, J=12.6 Hz, 2H), 1.55-1.45 (m, 2H), 1.24-1.22 (m, 5H). ESI-MS:521[M+H.sup.+].

Example 8

Preparation of N-(trans-4-(2-(4-(4-(4-fluorophenyl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)benzamide (II-1)

[0166] trans-4-(2-(4-(4-(4-Fluorophenyl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (intermediate 6-2, prepared according to the general synthetic method) (5.0 mmol) and benzoyl chloride (5.5 mmol) were used as raw materials, and 2.1 g of target compound II-1 as off-white solid with a yield of 73% was obtained according to the preparation method of compound I-1.

[0167] .sup.1H NMR (CDCl.sub.3, δ:ppm) δ 7.84-7.82 (m, 3H), 7.80 (dd, J=8.7, 5.6 Hz, 2H), 7.56-7.54 (m, 3H), 7.30 (d, J=8.7 Hz, 2H), 6.46 (s, 1H), 6.41 (s, 1H), 3.74-3.70 (m, 8H), 3.48-3.46 (m, 4H), 3.13 (brs, 4H), 2.97 (t, J=7.6 Hz, 2H), 1.75-1.73 (m, 4H), 1.56-1.55 (m, 2H), 1.21-1.19 (m, 3H), 1.07-0.91 (m, 2H). ESI-MS:572[M+H.sup.+].

Example 9

Preparation of N-(trans-4-(2-(4-(4-(4-fluorophenyl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)nicotinamide (II-2)

[0168] Intermediate 6-2 (5.0 mmol) and nicotinoyl chloride (5.5 mmol) were used as raw materials, and 2.4 g of target compound II-2 as white solid with a yield of 84% was obtained according to the preparation method of compound I-1.

[0169] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 8.13-8.11 (m, 3H), 7.78-7.76 (m, 3H), 7.64 (d, J=7.9 Hz, 1H), 7.30 (d, J=8.7 Hz, 2H), 6.48 (s, 1H), 6.43 (s, 1H), 3.76-3.62 (m, 8H), 3.51-3.49 (m, 4H), 3.16 (brs, 4H), 3.03 (t, J=7.6 Hz, 2H), 1.78-1.76 (m, 4H), 1.59-1.58 (m, 2H), 1.24-1.22 (m, 3H), 1.10-0.93 (m, 2H).

[0170] ESI-MS:573[M+H.sup.+].

Example 10

Preparation of N-(trans-4-(2-(4-(4-(4-fluorophenyl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)furan-2-carboxamide (II-3)

[0171] Intermediate 6-2 (5.0 mmol) and furan-2-carbonyl chloride (5.5 mmol) were used as raw materials, and 2.0 g of target compound II-3 as white solid with a yield of 71% was obtained according to the preparation method of compound I-1.

[0172] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.81 (dd, J=8.7, 5.6 Hz, 2H), 7.30-7.28 (m, 4H), 7.18 (d, J=7.9 Hz, 1H), 6.61-6.60 (m, 1H), 6.46 (s, 1H), 6.41 (s, 11H), 3.73-3.69 (m, 8H), 3.49-3.47 (m, 4H), 3.13 (brs, 4H), 3.00 (t, J=7.6 Hz, 2H), 1.75-1.73 (m, 4H), 1.56-1.55 (m, 2H), 1.21-1.19 (m, 3H), 1.07-0.90 (m, 2H). ESI-MS:562[M+H.sup.+].

Example 11

Preparation of 1-(trans-4-(2-(4-(4-(4-fluorophenyl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-methylurea (II-4)

[0173] Intermediate 6-2 (5.0 mmol) and N-methylcarbamoyl chloride (5.5 mmol) were used as raw materials, and 2.2 g of target compound II-4 as off-white solid with a yield of 84% was obtained according to the preparation method of compound I-1.

[0174] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.90 (s, 1H), 7.80 (dd, J=8.7, 5.6 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 6.45 (s, 11H), 6.40 (s, 11H), 5.86 (d, J=7.9 Hz, 11H), 3.72-3.68 (m, 8H), 3.47-3.45 (m, 4H), 3.12 (brs, 4H), 2.99 (t, J=7.6 Hz, 2H), 2.70 (s, 3H), 1.74-1.72 (m, 4H), 1.55-1.54 (m, 2H), 1.20-1.18 (m, 3H), 1.06-0.89 (m, 2H).

[0175] ESI-MS:525[M+H.sup.+].

Example 12

Preparation of 3-(trans-4-(2-(4-(4-(4-fluorophenyl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea (II-5)

[0176] Intermediate 6-2 (5.0 mmol) and N,N-dimethylcarbamoyl chloride (5.5 mmol) were used as raw materials, and 1.9 g of target compound II-5 as white solid with a yield of 70% was obtained according to the preparation method of compound I-1.

[0177] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.79 (dd, J=8.7, 5.6 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 6.45 (s, 1H), 6.40 (s, 1H), 5.87 (d, J=7.9 Hz, 1H), 3.72-3.68 (m, 8H), 3.47-3.45 (m, 4H), 3.12 (brs, 4H), 2.99 (t, J=7.6 Hz, 2H), 2.74 (s, 6H), 1.74-1.72 (m, 4H), 1.55-1.54 (m, 2H), 1.20-1.18 (m, 3H), 1.06-0.89 (m, 2H). ESI-MS:539[M+H.sup.+].

Example 13

Preparation of 3-(trans-4-(2-(4-(4-(4-fluorophenyl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methyl-1-propylurea (II-6)

[0178] Intermediate 6-2 (5.0 mmol), N-methyl-N-propanecarbonyl chloride (5.5 mmol) were used as raw materials, and 2.4 g of target compound II-6 as off-white solid with a yield of 85% was obtained according to the preparation method of compound I-1.

[0179] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.79 (dd, J=8.7, 5.6 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 6.45 (s, 1H), 6.40 (s, 1H), 5.87 (d, J=7.9 Hz, 1H), 3.72-3.68 (m, 8H), 3.47-3.45 (m, 4H), 3.20 (t, J=7.6 Hz, 2H), 3.12 (brs, 4H), 3.10 (s, 6H), 2.99 (t, J=7.6 Hz, 2H), 1.74-1.72 (m, 4H), 1.63-1.61 (m, 2H), 1.55-1.54 (m, 2H), 1.20-1.18 (m, 3H), 1.06-0.89 (m, 2H), 0.86 (t, J=7.6 Hz, 2H).

[0180] ESI-MS:567[M+H.sup.+].

Example 14

Preparation of N-(trans-4-(2-(4-(4-(4-methoxyphenyl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)tetrahydropyrrole-1-carboxamide (III-1)

[0181] trans-4-(2-(4-(4-(4-Methoxyphenyl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (intermediate 6-3, prepared according to the general synthetic method) (5.0 mmol) and pyrrolidine-1-carbonyl chloride (5.5 mmol) were used as raw materials, and 2.0 g of target compound III-1 as white solid with a yield of 71% was obtained according to the preparation method of compound I-1.

[0182] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.69 (d, J=8.7 Hz, 2H), 7.05-6.97 (m, 2H), 6.45 (s, 1H), 6.39 (s, 1H), 5.88 (d, J=7.8 Hz, 1H), 3.95-3.74 (m, 5H), 3.70-3.67 (m, 6H), 3.45-3.42 (m, 4H), 3.40-3.29 (m, 1H), 3.19 (brs, 4H), 3.15-3.12 (m, 4H), 3.07 (t, J=8.1 Hz, 2H), 1.84-1.82 (m, 4H), 1.74-1.72 (m, 4H), 1.63-1.49 (m, 2H), 1.20-1.18 (m, 3H), 0.98-0.96 (m, 2H). ESI-MS:577[M+H.sup.+].

Example 15

Preparation of N-(trans-4-(2-(4-(4-(4-methoxyphenyl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)morpholine-4-carboxamide (III-2)

[0183] Intermediate 6-3 (5.0 mmol) and morpholine-4-carbonyl chloride (5.5 mmol) were used as raw materials, and 2.7 g of target compound III-2 as off-white solid with a yield of 91% was obtained according to the preparation method of compound I-1.

[0184] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.70 (d, J=8.7 Hz, 2H), 7.06-6.98 (m, 2H), 6.46 (s, 1H), 6.40 (s, 1H), 5.87 (d, J=7.8 Hz, 1H), 3.95-3.74 (m, 5H), 3.70-3.67 (m, 6H), 3.60-3.68 (m, 4H), 3.45-3.42 (m, 4H), 3.35-3.34 (m, 4H), 3.40-3.29 (m, 1H), 3.19 (brs, 4H), 3.07 (t, J=8.1 Hz, 2H), 1.74-1.72 (m, 4H), 1.63-1.49 (m, 2H), 1.20-1.18 (m, 3H), 0.98-0.96 (m, 2H).

[0185] ESI-MS:593[M+H.sup.+].

Example 16

Preparation of N-(trans-4-(2-(4-(4-(4-methoxyphenyl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)piperidine-1-carboxamide (III-3)

[0186] Intermediate 6-3 (5.0 mmol) and piperidine-1-carbonyl chloride (5.5 mmol) were used as raw materials, and 2.1 g of target compound III-3 as off-white solid with a yield of 71% was obtained according to the preparation method of compound I-1.

[0187] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.69 (d, J=8.7 Hz, 2H), 7.05-6.97 (m, 2H), 6.45 (s, 1H), 6.39 (s, 1H), 5.88 (d, J=7.8 Hz, 1H), 3.93-3.72 (m, 9H), 3.69-3.66 (m, 6H), 3.44-3.41 (m, 4H), 3.39-3.28 (m, 11H), 3.18 (brs, 4H), 3.06 (t, J=8.1 Hz, 2H), 1.75-1.71 (m, 8H), 1.64-1.50 (m, 4H), 1.18-1.16 (m, 3H), 0.97-0.95 (m, 2H). ESI-MS:591[M+H.sup.+].

Example 17

Preparation of N-(trans-4-(2-(4-(4-(4-methoxyphenyl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)-4-methylpiperazine-1-carboxamide (III-4)

[0188] Intermediate 6-3 (5.0 mmol) and 4-methylpiperazine-1-carbonyl chloride (5.5 mmol) were used as raw materials, and 2.6 g of target compound III-4 as off-white solid with a yield of 86% was obtained according to the preparation method of compound I-1.

[0189] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.69 (d, J=8.7 Hz, 2H), 7.05-6.97 (m, 2H), 6.45 (s, 11H), 6.39 (s, 11H), 5.88 (d, J=7.8 Hz, 1H), 3.95-3.74 (m, 5H), 3.70-3.67 (m, 6H), 3.45-3.42 (m, 4H), 3.39-3.29 (m, 5H), 3.19 (brs, 4H), 3.07 (t, J=8.1 Hz, 2H), 2.32-2.30 (m, 4H), 2.22 (s, 3H), 1.74-1.72 (m, 4H), 1.63-1.49 (m, 2H), 1.20-1.18 (m, 3H), 0.98-0.96 (m, 2H). ESI-MS:606[M+H.sup.+].

Example 18

Preparation of N-(trans-4-(2-(4-(6′-morpholino-[2,4′-bipyridin]-2′-yl)piperazin-1-yl)ethyl)cyclohexyl)propionamide (IV-1)

[0190] trans-4-(2-(4-(6′-Morpholino-[3,4′-bipyridin]-2′-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (intermediate 6-4, prepared according to the general synthetic method) (5.0 mmol) and pyridine-2-carbonyl chloride (5.5 mmol) were used as raw materials, and 1.9 g of target compound IV-1 as off-white solid with a yield of 75% was obtained according to the preparation method of compound I-1.

[0191] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 8.94 (dd, J=2.4, 0.8 Hz, 1H), 8.62 (dd, J=4.8, 1.6 Hz, 1H), 8.13 (dt, J=8.0, 1.9 Hz, 1H), 7.52-7.44 (m, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 5.87 (d, J=7.8 Hz, 1H), 3.71-3.69 (m, 8H), 3.49-3.47 (m, 4H), 3.38-3.30 (m, 1H), 3.10 (brs, 4H), 2.97 (t, J=7.6 Hz, 2H), 2.35 (q, J=7.6 Hz, 2H), 1.75-1.73 (m, 4H), 1.53-1.52 (m, 2H), 1.20-1.18 (m, 3H), 1.05 (t, J=7.6 Hz, 3H), 0.98-0.96 (m, 2H).

[0192] ESI-MS:507[M+H.sup.+].

Example 19

Preparation of N-(trans-4-(2-(4-(6′-morpholino-[2,4′-bipyridin]-2′-yl)piperazin-1-yl)ethyl)cyclohexyl)furan-2-carboxamide (IV-2) and the salt thereof

[0193] Intermediate 6-4 (5.0 mmol) and furan-2-carbonyl chloride (5.5 mmol) were used as raw materials, and 2.3 g of target compound IV-2 as white solid with a yield of 85% was obtained according to the preparation method of compound I-1.

[0194] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 8.95 (dd, J=2.4, 0.8 Hz, 1H), 8.61 (dd, J=4.8, 1.6 Hz, 1H), 8.14 (dt, J=8.0, 1.9 Hz, 1H), 7.53-7.45 (m, 1H), 7.22-7.20 (m, 3H), 6.60-6.59 (m, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 3.71-3.69 (m, 8H), 3.49-3.47 (m, 4H), 3.38-3.30 (m, 1H), 3.10 (brs, 4H), 2.97 (t, J=7.6 Hz, 2H), 1.75-1.73 (m, 4H), 1.53-1.52 (m, 2H), 1.20-1.18 (m, 3H), 0.98-0.96 (m, 2H).

[0195] ESI-MS:545[M+H.sup.+].

Preparation of the Hydrochloride of Compound IV-2

[0196] Compound IV-2 (1 mmol), 5% hydrochloric acid aqueous solution (1 mmol) were used as raw materials, and 0.49 g of white solid with a yield of 84% was obtained according to the preparation method of the hydrochloride of compound I-1.

[0197] Element analysis: C.sub.31H.sub.40N.sub.6O.sub.3.Math.HCl (theoretical value %: C, 64.07; H, 7.11; N, 14.46; experimental value %: C, 64.21; H, 7.00; N, 14.69).

Example 20

Preparation of 1,1-dimethyl-3-(trans-4-(2-(4-(6′-morpholino-[2,4′-bipyridin]-2′-yl)piperazin-1-yl)ethyl)cyclohexyl)urea (IV-3)

[0198] Intermediate 6-4 (5.0 mmol) and dimethylcarbamoyl chloride (5.5 mmol) were used as raw materials, and 2.1 g of target compound IV-3 as white solid with a yield of 81% was obtained according to the preparation method of compound I-1.

[0199] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 8.95 (dd, J=2.4, 0.8 Hz, 1H), 8.61 (dd, J=4.8, 1.6 Hz, 1H), 8.14 (dt, J=8.0, 1.9 Hz, 1H), 7.53-7.45 (m, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 5.87 (d, J=7.8 Hz, 1H), 3.71-3.69 (m, 8H), 3.49-3.47 (m, 4H), 3.38-3.30 (m, 1H), 3.10 (brs, 4H), 2.97 (t, J=7.6 Hz, 2H), 2.74 (s, 6H), 1.75-1.73 (m, 4H), 1.53-1.52 (m, 2H), 1.20-1.18 (m, 3H), 0.98-0.96 (m, 2H). ESI-MS:522[M+H.sup.+].

Example 21

Preparation of 1,1-diisopropyl-3-(trans-4-(2-(4-(6′-morpholino-[2,4′-bipyridin]-2′-yl)piperazin-1-yl)ethyl)cyclohexyl)urea (IV-4)

[0200] Intermediate 6-4 (5.0 mmol) and diisopropylcarbamoyl chloride (5.5 mmol) were used as raw materials, and 2.0 g of target compound IV-4 as white solid with a yield of 69% was obtained according to the preparation method of compound I-1.

[0201] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) S 8.95 (dd, J=2.4, 0.8 Hz, 1H), 8.61 (dd, J=4.8, 1.6 Hz, 1H), 8.14 (dt, J=8.0, 1.9 Hz, 1H), 7.53-7.45 (m, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 5.87 (d, J=7.8 Hz, 1H), 3.91-3.90 (m, 2H), 3.71-3.69 (m, 8H), 3.49-3.47 (m, 4H), 3.38-3.30 (m, 1H), 3.10 (brs, 4H), 2.97 (t, J=7.6 Hz, 2H), 1.75-1.73 (m, 4H), 1.53-1.52 (m, 2H), 1.45-1.42 (m, 12H), 1.20-1.18 (m, 3H), 0.98-0.96 (m, 2H). ESI-MS:578[M+H.sup.+].

Example 22

Preparation of N-(trans-4-(2-(4-(4-(furan-2-yl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)acetamide (V-1)

[0202] trans-4-(2-(4-(4-(Furan-2-yl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (intermediate 6-5, prepared according to the general synthetic method) (5.0 mmol) and acetyl chloride (5.5 mmol) were used as raw materials, and 2.1 g of target compound V-1 as white solid with a yield of 87% was obtained according to the preparation method of compound I-1.

[0203] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.79 (d, J=1.7 Hz, 1H), 7.16 (d, J=3.4 Hz, 1H), 6.63 (dd, J=3.4, 1.8 Hz, 1H), 6.49-6.47 (m, 2H), 5.90 (d, J=7.8 Hz, 1H), 3.71-3.69 (m, 8H), 3.45-3.43 (m, 4H), 3.36-3.32 (m, 1H), 3.11 (brs, 4H), 2.98 (t, J=7.6 Hz, 2H), 2.01 (s, 3H), 1.74-1.72 (m, 4H), 1.55-1.54 (m, 2H), 1.20-1.18 (m, 3H), 0.98-0.96 (m, 2H). ESI-MS:482[M+H.sup.+].

Example 23

Preparation of N-(trans-4-(2-(4-(4-(furan-2-yl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-methoxyacetamide (V-2)

[0204] Intermediate 6-5 (5.0 mmol) and 2-methoxyacetyl chloride (5.5 mmol) were used as raw materials, and 2.2 g of target compound V-2 as white solid with a yield of 86% was obtained according to the preparation method of compound I-1.

[0205] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.78 (d, J=1.7 Hz, 1H), 7.15 (d, J=3.4 Hz, 1H), 6.63 (dd, J=3.4, 1.8 Hz, 1H), 6.49-6.47 (m, 2H), 5.96 (d, J=7.8 Hz, 1H), 4.46 (s, 2H), 3.70-3.68 (m, 8H), 3.44-3.42 (m, 4H), 3.45 (s, 3H), 3.36-3.32 (m, 1H), 3.11 (brs, 4H), 2.98 (t, J=7.6 Hz, 2H), 1.74-1.72 (m, 4H), 1.55-1.54 (m, 2H), 1.20-1.18 (m, 3H), 0.98-0.96 (m, 2H). ESI-MS:512[M+H.sup.+].

Example 24

Preparation of 3-(trans-4-(2-(4-(4-(furan-2-yl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea (V-3)

[0206] Intermediate 6-5 (5.0 mmol) and dimethylcarbamoyl chloride (5.5 mmol) were used as raw materials, and 2.1 g of target compound V-3 as white solid with a yield of 82% was obtained according to the preparation method of compound I-1.

[0207] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.78 (d, J=1.7 Hz, 1H), 7.15 (d, J=3.4 Hz, 1H), 6.63 (dd, J=3.4, 1.8 Hz, 11H), 6.49-6.47 (m, 2H), 5.87 (d, J=7.8 Hz, 1H), 3.70-3.68 (m, 8H), 3.44-3.42 (m, 4H), 3.36-3.32 (m, 1H), 3.11 (brs, 4H), 2.98 (t, J=7.6 Hz, 2H), 2.74 (s, 6H), 1.74-1.72 (m, 4H), 1.55-1.54 (m, 2H), 1.20-1.18 (m, 3H), 0.98-0.96 (m, 2H). ESI-MS:511[M+H.sup.+].

Example 25

Preparation of N-(trans-4-(2-(4-(4-(furan-2-yl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)piperidine-1-carboxamide (V-4) and the salt thereof

[0208] Intermediate 6-5 (5.0 mmol) and piperidine-1-carbonyl chloride (5.5 mmol) were used as raw materials, and 2.4 g of target compound V-4 as white solid with a yield of 87% was obtained according to the preparation method of compound I-1.

[0209] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.77 (d, J=1.7 Hz, 1H), 7.14 (d, J=3.4 Hz, 1H), 6.62 (dd, J=3.4, 1.8 Hz, 1H), 6.48-6.46 (m, 2H), 5.87 (d, J=7.8 Hz, 1H), 3.92-3.88 (m, 4H), 3.70-3.68 (m, 8H), 3.44-3.42 (m, 4H), 3.36-3.32 (m, 1H), 3.11 (brs, 4H), 2.98 (t, J=7.6 Hz, 2H), 1.82-1.80 (m, 4H), 1.74-1.72 (m, 4H), 1.62-1.60 (m, 2H), 1.55-1.54 (m, 2H), 1.20-1.18 (m, 3H), 0.99-0.97 (m, 2H). ESI-MS:551[M+H.sup.+].

Preparation of the Hydrobromide of Compound V-4

[0210] Compound V-4 (1 mmol) and 5% hydrobromic acid aqueous solution (1 mmol) were used as raw materials, and 0.5 g of white solid with a yield of 79% was obtained according to the preparation method of the hydrochloride of compound I-1.

[0211] Element analysis: C.sub.31H.sub.46N.sub.6O.sub.3.Math.HBr (theoretical value %: C, 58.95; H, 7.50; N, 13.30; experimental value %: C, 58.79; H, 7.58; N, 13.47).

Preparation of the Sulfate of Compound V-4

[0212] Compound V-4 (1 mmol) and 5% sulfuric acid (0.5 mmol) were used as raw materials, and 0.28 g of white solid with a yield of 60% was obtained according to the preparation method of the hydrochloride of compound I-1.

[0213] Element analysis: C.sub.31H.sub.46N.sub.6O.sub.3.Math.½H.sub.2SO.sub.4 theoretical value %: C, 62.08; H, 7.90; N, 14.01; experimental value %: C, 62.30; H, 7.72; N, 14.14).

Example 26

Preparation of N-(trans-4-(2-(4-(4-(furan-2-yl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)morpholine-4-carboxamide (V-5)

[0214] Intermediate 6-5 (5.0 mmol) and morpholine-4-carbonyl chloride (5.5 mmol) were used as raw materials, and 2.4 g of target compound V-5 as white solid with a yield of 87% was obtained according to the preparation method of compound I-1.

[0215] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.78 (d, J=1.7 Hz, 1H), 7.15 (d, J=3.4 Hz, 1H), 6.63 (dd, J=3.4, 1.8 Hz, 1H), 6.49-6.47 (m, 2H), 5.87 (d, J=7.8 Hz, 1H), 3.70-3.68 (m, 8H), 3.59-3.56 (m, 4H), 3.44-3.42 (m, 4H), 3.37-3.31 (m, 5H), 3.11 (brs, 4H), 2.98 (t, J=7.6 Hz, 2H), 1.74-1.72 (m, 4H), 1.55-1.54 (m, 2H), 1.20-1.18 (m, 3H), 0.98-0.96 (m, 2H). ESI-MS:553[M+H*].

Example 27

Preparation of N-(trans-4-(2-(4-(6-morpholino-4-(thiophen-2-yl)pyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)acetamide (VI-1)

[0216] trans-4-(2-(4-(4-(Thiophen-2-yl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (intermediate 6-6, prepared according to the general synthetic method) (5.0 mmol) and acetyl chloride (5.5 mmol) were used as raw materials, and 2.2 g of target compound VI-1 as white solid with a yield of 88% was obtained according to the preparation method of compound I-1.

[0217] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 7.82 (d, J=1.7 Hz, 1H), 7.44 (d, J=3.4 Hz, 1H), 6.73 (dd, J=3.4, 1.8 Hz, 1H), 6.49-6.47 (m, 2H), 5.97 (d, J=7.8 Hz, 1H), 3.75-3.73 (m, 8H), 3.49-3.47 (m, 4H), 3.40-3.36 (m, 1H), 3.15 (brs, 4H), 3.02 (t, J=7.6 Hz, 2H), 2.01 (s, 3H), 1.76-1.74 (m, 4H), 1.57-1.56 (m, 2H), 1.22-1.20 (m, 3H), 1.01-0.99 (m, 2H). ESI-MS:498[M+H.sup.+].

Example 28

Preparation of N-(trans-4-(2-(4-(6-morpholino-4-(thiophen-2-yl)pyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)cyclopropanecarboxamide (VI-2)

[0218] Intermediate 6-6 (5.0 mmol) and cyclopropanecarbonyl chloride (5.5 mmol) were used as raw materials, and 2.4 g of target compound VI-2 as white solid with a yield of 92% was obtained according to the preparation method of compound I-1.

[0219] .sup.1H NMR (Chloroform-d, 6:ppm) δ 7.82 (d, J=1.7 Hz, 1H), 7.44 (d, J=3.4 Hz, 1H), 6.73 (dd, J=3.4, 1.8 Hz, 1H), 6.49-6.47 (m, 2H), 5.95 (d, J=7.8 Hz, 1H), 3.75-3.73 (m, 8H), 3.49-3.47 (m, 4H), 3.40-3.36 (m, 1H), 3.15 (brs, 4H), 3.02 (t, J=7.6 Hz, 2H), 1.76-1.74 (m, 4H), 1.57-1.54 (m, 3H), 1.22-1.20 (m, 3H), 1.01-0.99 (m, 2H), 0.81-0.79 (m, 2H), 0.60-0.58 (m, 2H). ESI-MS:524[M+H.sup.+].

Example 29

Preparation of N-(trans-4-(2-(4-(6-morpholino-4-(thiophen-2-yl)pyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)nicotinamide (VI-3) and the salt thereof

[0220] Intermediate 6-6 (5.0 mmol) and nicotinoyl chloride (5.5 mmol) were used as raw materials, and 1.9 g of target compound VI-3 as white solid with a yield of 68% was obtained according to the preparation method of compound I-1.

[0221] .sup.1H NMR ((CDCl.sub.3, δ:ppm) δ 8.87 (dd, J=2.4, 1.2 Hz, 1H) 8.56-8.55 (m, 1H), 8.16 (dd, J=7.6, 2.4 Hz, 1H), 7.83-7.81 (m, 2H), 7.46-7.44 (m, 2H), 6.73 (dd, J=3.4, 1.8 Hz, 1H), 6.49-6.47 (m, 2H), 3.75-3.73 (m, 8H), 3.49-3.47 (m, 4H), 3.40-3.36 (m, 1H), 3.15 (brs, 4H), 3.02 (t, J=7.6 Hz, 2H), 1.76-1.74 (m, 4H), 1.57-1.56 (m, 2H), 1.22-1.20 (m, 3H), 1.01-0.99 (m, 2H).

[0222] ESI-MS:561[M+H.sup.+].

Preparation of the Hydrochloride of Compound VI-3

[0223] Compound VI-3 (1 mmol) and 5% hydrochloric acid aqueous solution (1 mmol) were used as raw materials, and 0.48 g of white solid with a yield of 80% was obtained according to the preparation method of the hydrochloride of compound I-1.

[0224] Element analysis: C.sub.31H.sub.40N.sub.6O.sub.2S.Math.HCl (theoretical value %: C, 62.35; H, 6.92; N, 14.07; experimental value %: C, 62.45; H, 6.55; N, 14.26).

Preparation of the Trifluoroacetate of Compound VI-3

[0225] Compound VI-3 (1 mmol) and 5% trifluoroacetic acid aqueous solution (1 mmol) were used as raw materials, and 0.57 g of white solid with a yield of 85% was obtained according to the preparation method of the hydrochloride of compound I-1.

[0226] Element analysis: C.sub.31H.sub.40N.sub.6O.sub.2S.Math.CF.sub.3CO.sub.2H (theoretical value %: C, 58.74; H, 6.12; N, 12.45; experimental value %: C, 58.59; H, 6.34; N, 12.66).

Example 30

Preparation of 1,1-dimethyl-3-(trans-4-(2-(4-(6-morpholino-4-(thiophen-2-yl)pyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)urea (VI-4)

[0227] Intermediate 6-6 (5.0 mmol) and dimethylcarbamoyl chloride (5.5 mmol) were used as raw materials, and 1.8 g of target compound VI-4 as white solid with a yield of 68% was obtained according to the preparation method of compound I-1.

[0228] .sup.1H NMR (CDCl.sub.3, δ:ppm) δ 7.83 (d, J=1.7 Hz, 1H), 7.46 (d, J=3.4 Hz, 1H), 6.75 (dd, J=3.4, 1.8 Hz, 1H), 6.49-6.47 (m, 2H), 5.93 (d, J=7.8 Hz, 1H), 3.75-3.73 (m, 8H), 3.49-3.47 (m, 4H), 3.40-3.36 (m, 1H), 3.15 (brs, 4H), 3.02 (t, J=7.6 Hz, 2H), 2.71 (s, 6H), 1.76-1.74 (m, 4H), 1.57-1.56 (m, 2H), 1.22-1.20 (m, 3H), 1.01-0.99 (m, 2H). ESI-MS:527[M+H.sup.+].

Example 31

Preparation of N-(trans-4-(2-(4-(6-morpholino-4-(thiophen-2-yl)pyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)tetrahydropyrrole-1-carboxamide (VI-5)

[0229] Intermediate 6-6 (5.0 mmol) and pyrroline-4-carbonyl chloride (5.5 mmol) were used as raw materials, and 2.0 g of target compound VI-5 as white solid with a yield of 72% was obtained according to the preparation method of compound I-1.

[0230] .sup.1H NMR (CDCl.sub.3, δ:ppm) δ 7.82 (d, J=1.7 Hz, 1H), 7.44 (d, J=3.4 Hz, 1H), 6.73 (dd, J=3.4, 1.8 Hz, 1H), 6.49-6.47 (m, 2H), 5.97 (d, J=7.8 Hz, 1H), 3.75-3.73 (m, 8H), 3.49-3.47 (m, 4H), 3.40-3.36 (m, 1H), 3.31-3.29 (m, 4H), 3.15 (brs, 4H), 3.02 (t, J=7.6 Hz, 2H), 1.78-1.74 (m, 8H), 1.57-1.56 (m, 2H), 1.22-1.20 (m, 3H), 1.00-0.98 (m, 2H). ESI-MS:553[M+H.sup.+].

Example 32

Preparation of N-(trans-4-(2-(4-(6-morpholino-4-(1H-pyrrol-2-yl)pyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)propionamide (VII-1)

[0231] trans-4-(2-(4-(4-(Pyrrol-2-yl)-6-morpholinopyridin-2-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (intermediate 6-7, prepared according to the general synthetic method) (5.0 mmol) and propionyl chloride (5.5 mmol) were used as raw materials, and 2.1 g of target compound VII-1 as white solid with a yield of 85% was obtained according to the preparation method of compound I-1.

[0232] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 12.02 (brs, 1H), 7.02 (d, J=1.7 Hz, 1H), 6.89 (d, J=3.4 Hz, 1H), 6.43 (dd, J=3.4, 1.8 Hz, 1H), 6.26-6.24 (m, 2H), 5.85 (d, J=7.8 Hz, 1H), 3.71-3.69 (m, 8H), 3.45-3.43 (m, 4H), 3.37-3.33 (m, 1H), 3.12 (brs, 4H), 2.99 (t, J=7.6 Hz, 2H), 2.35 (q, J=7.6 Hz, 2H), 1.75-1.73 (m, 4H), 1.56-1.55 (m, 2H), 1.21-1.19 (m, 3H), 1.01-0.97 (m, 5H). ESI-MS:495[M+H.sup.+].

Example 33

Preparation of N-(trans-4-(2-(4-(6-morpholino-4-(1H-pyrrol-2-yl)pyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)furan-2-carboxamide (VII-2)

[0233] Intermediate 6-7 (5.0 mmol) and furan-2-carbonyl chloride (5.5 mmol) were used as raw materials, and 1.9 g of target compound VII-2 as white solid with a yield of 71% was obtained according to the preparation method of compound I-1.

[0234] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 12.02 (brs, 1H), 7.25-7.23 (m, 2H), 7.20 (d, J=7.8 Hz, 1H), 7.02 (d, J=1.7 Hz, 1H), 6.89-6.87 (m, 2H), 6.43 (dd, J=3.4, 1.8 Hz, 1H), 6.26-6.24 (m, 2H), 3.71-3.69 (m, 8H), 3.45-3.43 (m, 4H), 3.37-3.33 (m, 1H), 3.12 (brs, 4H), 2.98 (t, J=7.6 Hz, 2H), 1.75-1.73 (m, 4H), 1.56-1.55 (m, 2H), 1.21-1.19 (m, 3H), 0.99-0.98 (m, 2H). ESI-MS:533[M+H.sup.+].

Example 34

Preparation of N-(trans-4-(2-(4-(6-morpholino-4-(1H-pyrrol-2-yl)pyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)cyclohexanecarboxamide (VII-3)

[0235] Intermediate 6-7 (2.0 mmol) and cyclohexanecarbonyl chloride (2.4 mmol) were used as raw materials, and 0.8 g of target compound VII-3 as white solid with a yield of 73% was obtained according to the preparation method of compound I-1.

[0236] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 12.02 (brs, 1H), 7.02 (d, J=1.7 Hz, 1H), 6.89 (d, J=3.4 Hz, 1H), 6.43 (dd, J=3.4, 1.8 Hz, 1H), 6.26-6.24 (m, 2H), 5.85 (d, J=7.8 Hz, 1H), 3.71-3.69 (m, 8H), 3.45-3.43 (m, 4H), 3.37-3.33 (m, 1H), 3.12 (brs, 4H), 2.99 (t, J=7.6 Hz, 2H), 2.48-2.46 (m, 1H), 1.75-1.70 (m, 6H), 1.56-1.55 (m, 2H), 1.51-1.41 (m, 8H), 1.21-1.19 (m, 3H), 0.98-0.96 (m, 2H). ESI-MS:549[M+H.sup.+].

Example 35

Preparation of 1,1-dimethyl-3-(trans-4-(2-(4-(6-morpholino-4-(1H-pyrrol-2-yl)pyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)urea (VII-4)

[0237] Intermediate 6-7 (2.0 mmol) and dimethylcarbamoyl chloride (2.4 mmol) were used as raw materials, and 0.8 g of target compound VII-4 as white solid with a yield of 78% was obtained according to the preparation method of compound I-1.

[0238] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 12.02 (brs, 1H), 7.03 (d, J=1.7 Hz, 1H), 6.90 (d, J=3.4 Hz, 1H), 6.44 (dd, J=3.4, 1.8 Hz, 1H), 6.27-6.25 (m, 2H), 5.86 (d, J=7.8 Hz, 1H), 3.71-3.69 (m, 8H), 3.45-3.43 (m, 4H), 3.37-3.33 (m, 1H), 3.12 (brs, 4H), 2.99 (t, J=7.6 Hz, 2H), 2.74 (s, 6H), 1.75-1.73 (m, 4H), 1.56-1.55 (m, 2H), 1.21-1.19 (m, 3H), 0.99-0.97 (m, 2H).

[0239] ESI-MS:510[M+H.sup.+].

Example 36

Preparation of N-(trans-4-(2-(4-(6-morpholino-4-(1H-pyrrol-2-yl)pyridin-2-yl)piperazin-1-yl)ethyl)cyclohexyl)piperidine-1-carboxamide (VII-5) and the salts thereof

[0240] Intermediate 6-7 (2.0 mmol) and piperidine-1-carbonyl chloride (2.4 mmol) were used as raw materials, and 0.9 g of target compound VII-5 as white solid with a yield of 82% was obtained according to the preparation method of compound I-1.

[0241] .sup.1H NMR (DMSO-d.sub.6, δ:ppm) δ 12.02 (brs, 1H), 7.03 (d, J=1.7 Hz, 1H), 6.90 (d, J=3.4 Hz, 1H), 6.44 (dd, J=3.4, 1.8 Hz, 1H), 6.27-6.25 (m, 2H), 5.86 (d, J=7.8 Hz, 1H), 3.71-3.69 (m, 8H), 3.62-3.60 (m, 4H), 3.45-3.43 (m, 4H), 3.37-3.33 (m, 1H), 3.12 (brs, 4H), 2.99 (t, J=7.6 Hz, 2H), 1.75-1.73 (m, 4H), 1.56-1.51 (m, 6H), 1.39-1.37 (m, 2H), 1.21-1.19 (m, 3H), 0.99-0.97 (m, 2H). ESI-MS:550[M+H.sup.+].

Preparation of the Hydrobromide of Compound VII-5

[0242] Compound VII-5 (1.0 mmol) and 5% hydrobromic acid aqueous solution (1.0 mmol) were used as raw materials, and 0.51 g of white solid with a yield of 81% was obtained according to the preparation method of the hydrochloride of compound I-1.

[0243] Element analysis: C.sub.31H.sub.47N.sub.7O.sub.2.Math.HBr (theoretical value %: C, 59.04; H, 7.67; N, 15.55; experimental value %: C, 59.18; H, 7.82; N, 15.31).

Example 37

[0244] 1. Tablet:

[0245] All of the compounds in the examples of the present disclosure 20 mg

[0246] Sucrose 150 mg

[0247] Corn starch 27 mg

[0248] Magnesium stearate 3 mg

[0249] Preparation method: The active ingredients were mixed with sucrose and corn starch, and then water was added thereto for moistening. The mixture was stirred evenly, dried, crushed and sieved, and magnesium stearate was added thereto, and then the mixture was mixed evenly, and pressed into tablets. 200 mg of each tablet was weighed and contained 20 mg of active ingredient.

Example 38

[0250] 2. Injection:

[0251] All of the compounds in the examples of the present disclosure 2 mg

[0252] Water for injection 98 mg

[0253] Preparation method: The active ingredient was dissolved in water for injection, mixed evenly, filtered, and the obtained solution was sub-packed in ampoule bottle under sterile conditions with 10 mg in each bottle, and the active ingredient content was 0.2 mg/bottle.

Example 39

[0254] Dopamine D.sub.2 Receptor Binding Test

[0255] 1. Experimental Materials

[0256] (1) Transfection of D.sub.2 Receptor Cells:

[0257] In this experiment, HEK293 cells were transfected with plasmid vector containing D.sub.2 receptor protein gene, and calcium phosphate transfection method was used and after transfection, the cells were cultured in a culture solution containing G418, and the cell monoclonal and radioligand binding experiments were selected, and finally a stable cell line which could stably express D.sub.2 receptor protein was obtained.

[0258] (2) Receptor Binding Experimental Materials:

[0259] Isotope ligand [.sup.3H]Spiperone (113.0 Ci/mmol); purchased from Sigma company; (+)spiperone, purchased from RBI company; GF/B glass fiber filter paper, purchased from Whatman company; Tris imported and sub-packed; PPO, POPOP purchased from Shanghai Reagent No. 1 Factory; lipid-soluble scintillation fluid. Beckman LS-6500 multifunctional liquid scintillation counter.

[0260] 2. Experimental Method:

[0261] (1) Cells:

[0262] HeK-293 cells were infected with recombinant viruses containing the above various genes respectively, and after 48-72 hours, the receptor proteins were expressed in large quantities on the membrane, and the cells were centrifuged at 1000 rpm for 5 min and then the culture solution was discarded, and the cells were collected, and stored in a −20° C. refrigerator for later use. Tris-HCl reaction buffer (pH=7.5) was used to resuspend in the experiment.

[0263] (2) Receptor Competitive Binding Experiment:

[0264] 20 μL of the test compound, 20 μL of the radioactive ligand and 160 μL of the receptor protein were added to the reaction tube, so that the final concentration of the test compound and the positive drug cariprazine were both, and after incubation for 50 min in a 30° C. water bath, and the mixture was immediately transferred to an ice bath to terminate the reaction. On the Millipore cell sample collector, the mixture was quickly filtrated under reduced pressure through GF/C glass fiber filter paper, and eluted with 3 mL of eluent (50 mMTris-HCl, pH 7.5) for 3 times, then dried under microwave for 5 to 6 min. The filter paper was moved into a 0.5 mL centrifuge tube, and 500 μL of lipid-soluble scintillation solution was added. The mixture was kept in the dark for more than 30 min, and the radioactivity intensity was determined by counting. The inhibition rate percentage of each compound to isotopic ligand binding was calculated according to the following formula:

Inhibition rate (I%)=(total binding tube CPM−compound CPM)/(total binding tube CPM−non-specific binding tube CPM)×100%.

Two replicate tubes were made for each experiment of compound, and two separate experiments were performed.

[0265] The inhibition rate of the all compounds of the present disclosure was higher than 95%, and receptor binding tests in a series of concentrations were then performed on the compound of the present disclosure to determine the half inhibition amount (IC.sub.50, concentration of compound required to inhibit 50% [.sup.3H] Spiperone binding to D.sub.2 receptor). Two tubes were tested for each concentration and two independent tests were performed for each compound.

Ki=IC.sub.50/(1+[L]/K.sub.D)

(Ki: affinity of the drug and the receptor, L: concentration of radioactive ligands, K.sub.D: affinity value of the radioactive ligand and the receptor)

[0266] D.sub.2 receptor binding test results of the compound of the present disclosure are shown in table 1. The test results in table 1 show that the compound of the present disclosure has strong or moderate affinity for dopamine D.sub.2 receptor.

Example 40

[0267] Dopamine D.sub.3 Receptor Binding Test

[0268] The experimental method was performed with reference to Journal of Pharmacology and Experimental Therapeutics 2010, 333(1): 328. [.sup.3H]methyl-spiperone (0.3 nM) was used as the ligand, and (+)-butaclamol (10 μM) was used to determine the non-specific binding, and the binding assay was performed on human recombinant D.sub.3 receptor (expressed in CHO cells).

[0269] D.sub.3 receptor binding test results of the compound of the present disclosure are shown in table 1. It can be seen from table 1 that the compounds of the present disclosure all have strong affinity for D.sub.3 receptors, which are comparable to the positive drug cariprazine, and combined with the results of example 39, this series of compounds also have appropriate selectivity for D.sub.3/D.sub.2 receptor, that is, the selectivity is between 10 and 60 times.

Example 41

[0270] 5-HT.sub.2A Receptor Binding Test

[0271] 1. Experimental Materials

[0272] (1) Transfection of 5-HT.sub.2A Cell:

[0273] In this experiment, HEK293 cells were transfected with plasmid vector containing 5-HT.sub.2A receptor protein gene, and calcium phosphate transfection method was used and after transfection, the cells were cultured in a culture solution containing G418, and the cell monoclonal and radioligand binding experiments were selected, and finally a stable cell line which could stably express 5-HT.sub.2A receptor protein was obtained.

[0274] (2) Receptor Binding Experimental Materials:

[0275] Isotope ligand [.sup.3H]-Ketanserin (67.0 Ci/mmol); purchased from PerkinElmer company; (+)spiperone, purchased from RBI company; GF/B glass fiber filter paper, purchased from Whatman company; Tris imported and sub-packed; PPO, POPOP purchased From Shanghai Reagent No. 1 Factory; lipid-soluble scintillation fluid. Beckman LS-6500 multifunctional liquid scintillation counter.

[0276] 2. Experimental Method

[0277] HeK-293 cells were infected with recombinant viruses containing the above various genes respectively, and after 48-72 hours, the receptor proteins were expressed in large quantities on the membrane, and the cells were centrifuged at 1000 rpm for 5 min and then the culture solution was discarded, and the cells were collected, and stored in a −20° C. refrigerator for later use. Tris-HCl reaction buffer (pH 7.7) was used to resuspend in the experiment.

[0278] Receptor competitive binding experiment: 10 μL of the test compound, 10 μL of the radioactive ligand and 80 μL of the receptor protein were added to the reaction tube, so that the final concentration of the test compound and the positive drug were both 10 μmol/L, and after incubation for 15 min in a 37° C. water bath, and the mixture was immediately transferred to an ice bath to terminate the reaction. On the Millipore cell sample collector, the mixture was quickly filtrated under reduced pressure through GF/B glass fiber filter paper, and eluted with 3 mL of eluent (50 mM Tris-HCl, PH 7.7) for 3 times, then dried under microwave for 8 to 9 min. The filter paper was moved into a 0.5 mL centrifuge tube, and 500 μL of lipid-soluble scintillation solution was added. The mixture was kept in the dark for more than 30 min, and the radioactivity intensity was determined by counting. The inhibition rate percentage of each compound to isotopic ligand binding was calculated according to the following formula:

Inhibition rate (I%)=(total binding tube CPM−compound CPM)/(total binding tube CPM−non-specific binding tube CPM)×100%

[0279] Two replicate tubes were made for each experiment of compound, and two separate experiments were performed.

[0280] The compounds with an inhibition rate greater than 95% were subjected to receptor binding tests in a series of concentrations to determine the half inhibition amount (IC.sub.50, concentration of compound required to inhibit [.sup.3H]-Ketanserin binding to 5-HT.sub.2A receptor).

[0281] Two tubes were tested for each concentration and two independent tests were performed for each compound.

Ki=IC.sub.50/(1+[L]/K.sub.D)

(Ki: affinity of the drug and the receptor, L: concentration of radioactive ligands, K.sub.D: affinity value of the radioactive ligand and the receptor)

[0282] 5-HT.sub.2A receptor binding test results of the compound of the present disclosure are shown in table 1.

[0283] The test results in table 1 show that the compounds of the present disclosure have strong affinity for 5-HT.sub.2A receptors, and most of the compound have stronger affinity for 5-HT.sub.2A than that of the positive drug cariprazine.

TABLE-US-00002 TABLE 1 Affinity of the compound for each receptor (Ki value, nM) No. D.sub.2 D.sub.3 5-HT.sub.2A I-1 3.1 0.2 1.7 I-2 1.2 0.1 1.9 I-3 2.5 0.08 2.1 I-4 2.0 0.05 3.9 I-5 8.6 0.9 1.1 I-6 0.14 0.02 1.0 I-7 0.12 0.01 0.2 II-1 1.7 0.2 2.3 II-2 0.9 0.07 2.4 II-3 1.4 0.09 1.2 II-4 2.8 0.3 0.9 II-6 1.0 0.04 1.3 III-1 3.2 0.2 10.8 III-2 1.9 0.07 5.1 III-3 4.6 0.5 12.5 III-4 11.8 1.2 6.6 IV-1 2.5 0.05 2.7 IV-2 0.9 0.03 1.1 IV-3 2.0 0.1 3.6 IV-4 1.7 0.08 8.7 V-1 8.1 0.7 1.6 V-2 15.2 1.2 8.8 V-3 7.1 0.07 5.0 V-4 10.6 0.3 2.8 V-5 1.0 0.04 2.9 VI-1 0.8 0.05 1.6 VI-2 1.3 0.08 2.1 VI-3 1.9 0.8 1.7 VI-4 2.0 0.1 0.9 VI-5 1.0 0.07 1.1 VII-1 4.5 0.28 3.2 VII-2 2.6 0.1 0.7 VII-3 5.1 1.2 3.8 VII-4 0.6 0.03 1.1 VII-5 4.0 0.3 7.9 Cariprazine 0.8 0.08 22.1

[0284] Therefore, it can be seen from the results in table 1 that the compounds of the present disclosure have strong affinity for D.sub.3 and 5-HT.sub.2A receptors, and strong or moderate affinity for D.sub.2 receptors. In addition, most of the compounds have appropriate selectivity to D.sub.2/D.sub.3 receptor, and the selectivity is between 10 to 60 times, which is better than that of cariprazine (the selectivity is less than 10 times). The affinity of most compounds for 5-HT.sub.2A receptor is significantly better than that of positive control drugs. Therefore, such compounds have the potential of simultaneously improving cognitive impairment effects and low EPS side effects.

Example 42

[0285] H.sub.1 Receptor Binding Test

[0286] HEK-293 cell membrane homogenate (12.5 μg/point) infected with recombinant virus containing H.sub.1 receptor protein gene and 1 nM [.sup.3H]pyrilamine (purchased from Sigma Company) were incubated in buffer solution containing 37 mM NaCl, 2.68 mM KCl, 8.1 mM Na.sub.2HPO.sub.4 and 1.47 mM KH.sub.2PO.sub.4 (pH 7.4) for 60 min in the presence or absence of test compound. Non-specific binding was determined in the presence of 1 μM pyrilamine. After the incubation, the mixture was quickly filtered under reduced pressure through GF/B glass fiber filter paper, and eluted with 3 mL of eluent (50 mM Tris-HCl, PH 7.7) for 3 times, and dried under microwave for 8 to 9 minutes. The filter paper was moved into a 0.5 mL centrifuge tube and 500 μL lipid-soluble scintillation solution was added. The mixture was kept in the dark for more than 30 min, and the radioactivity intensity was determined by counting. The inhibition rate percentage of each compound to isotopic ligand binding was calculated according to the following formula:

Inhibition rate (I%)=(total binding tube CPM−compound CPM)/(total binding tube CPM−non-specific binding tube CPM)×100%

[0287] Two replicate tubes were made for each experiment of compound, and two separate experiments were performed.

[0288] The inhibition rate of the all compounds of the present disclosure was higher than 95%, and then receptor binding tests in a series of concentrations were then performed on the compound of the present disclosure to determine the half inhibition amount (IC.sub.50, concentration of compound required to inhibit 50% [.sup.3H] pyrilamine binding to H.sub.1 receptor). Two tubes were tested for each concentration and two independent tests were performed for each compound.

Ki=IC.sub.50/(1+[L]/K.sub.D)

(Ki: affinity of the drug and the receptor, L: concentration of radioactive ligands, K.sub.D: affinity value of the radioactive ligand and the receptor)

[0289] H.sub.1 receptor binding test results of the compound of the present disclosure are shown in table 2. The test results of table 2 show that most of the compounds of the present disclosure have weak or no affinity for H.sub.1 receptors, and the affinity is more than 100 times lower than the efficacy target (the affinity of the efficacy target is between 0.03 and 12 nM), which is significantly lower than the marketed drug cariprazine. Therefore, the series of compounds of the present disclosure have low side effects of potential sedation and weight gain.

TABLE-US-00003 TABLE 2 Affinity of the compound for H.sub.1 receptor (Ki value, nM) No. H.sub.1 I-1 760 I-2 950 I-3 >1000 I-4 550 I-5 >1000 I-6 >1000 I-7 420 II-1 670 II-2 >1000 II-3 980 II-4 540 II-5 300 II-6 >1000 III-1 >1000 III-2 >1000 III-3 >1000 III-4 980 IV-1 >1000 IV-2 >1000 IV-3 790 IV-4 670 V-1 530 V-2 740 V-3 800 V-4 >1000 V-5 >1000 VI-1 >1000 VI-2 >1000 VI-3 740 VI-4 590 VI-5 >1000 VII-1 460 VII-2 600 VII-3 870 VII-4 >1000 VII-5 >1000 Cariprazine 30

Example 43

[0290] In vivo anti-schizophrenia activity test of the compound of the present disclosure

[0291] In this example, the compound with D.sub.2/D.sub.3 receptor selectivity between 10 and 60 times, with strong affinity for D.sub.2/D.sub.3/5-HT.sub.2A receptor and weak affinity for H.sub.1 receptor were selected for in vivo anti-schizophrenia activity test.

[0292] 1. Apomorphine Model Experiment

[0293] (1) Test Method

[0294] An acute mode of administration was used in the experiment.

[0295] The experimental mice were randomly divided into groups, and after the control or test compound was administrated by gavage for 30 minutes, apomorphine (5 mg/kg) was injected intraperitoneally to induce a stereotyped motion model. The following symptoms were observed in the first 30 seconds of every 10 minutes (0-10 minutes, 11-20 minutes, 21-30 minutes, 31-40 minutes, 41-50 minutes, 51-60 minutes, 61-70 minutes) within 70 minutes after the apomorphine solution was administered to mice, and scored according to the following standards:

[0296] 1) 4 point, continuous biting;

[0297] 2) 3 point, the cage lid was bit at least once during observation;

[0298] 3) 2 point, the cage chassis or cage wall was licked at least once during observation;

[0299] 4) 1 point, compulsive sniffing and bowing activities were appeared;

[0300] 5) 0 point, no of the above activities.

[0301] The total score of the mice was calculated for the above behaviors within 70 min, and the improvement rate was calculated according to the following formula. The data were expressed as mean±standard error (Mean±SEM), and were analyzed using GraphPad Prism software, and data analysis was performed using t-test, and a significant difference was considered to exist when P<0.05.

[00001] $Improvement rate = \frac{\begin{matrix} Stereotyped motion scoring \\ in model control group \end{matrix} - \begin{matrix} Stereotyped motion scoring \\ in administration group \end{matrix}}{Stereotyped motion scoring in model control group} \times 100 %$

[0302] (2) Experimental Grouping and Administration Design

[0303] C57BL/6 mice were randomly divided into 6 groups with at least 9 mice in each group, namely model control group (apomorphine, dissolved in normal saline), cariprazine (positive control drug), the compound of the present disclosure, respectively.

[0304] (3) Administration and Observation after Administration

[0305] The compound claimed in the present disclosure and the positive drug cariprazine were administered with gradient doses of 0.05, 0.10, 0.20, 0.60, 1.20, 1.50 mg.Math.kg.sup.−1 (oral gavage). During the experiment, the clinical response symptoms of the animals were recorded.

[0306] (4) Statistical Methods

[0307] All data were expressed as x±SEM, processed with the 11.5 software statistical package, and t-test and one-way analysis of variance were performed for the comparison of the means of the two samples, with P<0.05 as a significant difference.

[0308] (5) Experimental Results

[0309] The specific experimental results are shown in table 3.

TABLE-US-00004 TABLE 3 Inhibition of total stereotyped motion of mouse schizophrenic model induced by Apo. with single oral administration of compound I-3 and other compounds (ED.sub.50) Compound ED.sub.50 (mg/kg) I-3 0.19 I-6 0.43 II-2 0.08 II-6 0.13 IV-2 0.10 V-5 0.78 VI-1 0.55 VI-5 0.16 VII-4 0.20 Cariprazine 0.30

[0310] The results of this test show that: Compared with the positive control drug cariprazine, the compounds of the present disclosure can significantly improve the stereotyped behavior of mice, and the schizophrenia model induced by apomorphine is a classic model of schizophrenia, so the series of the compounds of the present disclosure have good anti-schizophrenia effect. Compound I-3, II-2, II-6, IV-2, VI-5, VII-4 have better effects (ED.sub.50) on the stereotyped behavior of mice than the positive control drug cariprazine.

[0311] 2. MK-801 model Experiment

[0312] (1) Test Method

[0313] An acute mode of administration was used in the experiment. The experimental mice were randomly divided into groups and put into a spontaneous activity box to adapt for 5-10 minutes before the experiment. After 10 minutes of intragastric administration, the animals were intraperitoneally injected with MK-801 (0.5 mg/kg), and put back into the spontaneous activity box to start infrared monitoring, and the video of animal activities was continuously collected for 90 minutes. After the experiment, the video files were analyzed with SPSS 11.5 software statistical package, and the total distance of activities within 90 minutes was obtained. The data were expressed as mean±standard error (Mean±SEM), and were analyzed using GraphPad Prism software, and data analysis was performed using t-test, and a significant difference was considered to exist when P<0.05.

[0314] (2) Experimental Grouping and Administration Design

[0315] 57BL/6 mice were randomly divided into 6 groups with at least 12 mice in each group, namely blank control group, model control group (MK-801, dissolved in normal saline), cariprazine group and compound group of the present disclosure. Cariprazine was used as a positive drug control, and MK-801 was a tool drug for modeling.

[0316] (3) Experimental Results

[0317] The specific results are shown in table 4.

TABLE-US-00005 TABLE 4 Effect of single oral administration on the total distance of open-field motion in mouse model of schizophrenia induced by MK-801 (ED.sub.50) Compound ED.sub.50 (mg/kg) I-3 0.33 I-6 0.20 II-2 0.07 II-6 0.10 IV-2 0.05 V-5 0.51 VI-1 0.12 VI-5 0.08 VII-4 0.25 Cariprazine 0.15

[0318] The experimental results show that the cariprazine group and the compounds of the present disclosure can obviously improve the total distance of open-field motion in mice, because the open-field motion model induced by MK-801 is a common model of negative symptoms of schizophrenia, so the series of the compounds of the present disclosure have good anti-negative symptoms effect of schizophrenia. The improvement rate of compound II-2, II-6, IV-2, II-2, VI-1 on open-field motion of mice is better than that of the positive drug control cariprazine, indicating that the activity of compound II-2, II-6, IV-2, II-2, VI-1 is better than that of carilazine in this model.

Example 44

[0319] Acute Toxicity Experiments of the Compound

[0320] In this example, 10 compounds of the present disclosure (I-3, I-6, II-2, II-6, IV-2, V-5, VI-1, VI-5 and VII-4) and cariprazine (positive control drug) were selected for acute toxicity experiments.

[0321] (1) Experimental Protocol

[0322] 1) The toxicity symptoms and death conditions were observed after the oral administration of cariprazine and compound I-3 and other compounds of the present disclosure in ICR mice, and the acute toxicity was compared.

[0323] 2) Solvent preparation: An appropriate amount of Tween-80 was weighed and diluted with deionized water to a concentration of 5% (g/v) Tween-80.

[0324] 3) Preparation for administration: The required test samples were weighed respectively, and prepared into suspensions with concentrations of 6.25, 12.50, 25.00, 50.00 and 100.00 mg/mL (equivalent to 125, 250, 500, 1000 and 2000 mg/kg, respectively) with 5% Tween-80 solution.

[0325] 4) Route of administration: The administration route of the test samples and the solvent control group (0.5% Tween-80) was oral administration.

[0326] 5) Frequency of administration: Single administration, fasting overnight before administration.

[0327] 6) Dosing capacity: 20 mL/kg.

[0328] General symptom observation: On the day of administration, the observation was performed once about 0.5, 1, 2, 4 and 6 hours after the first administration; the observation period was 2 to 6 days, twice a day, once in the morning and once in the afternoon.

[0329] The observation content includes, but is not limited to, general condition, behavioral activity, gait posture, eye, mouth, nose, gastrointestinal tract, skin hair, urogenital tract.

[0330] (2) Statistical Analysis

[0331] Body weight data were expressed as mean±standard deviation, and were compared between groups using Levene's test and one-way ANOVA. If there were differences, Dunnet t test was used.

[0332] (3) Experimental Results

[0333] 10 compounds of the present disclosure and cariprazine (positive control drug) were selected for acute toxicity experiments as described above. The experimental results are shown in table 5.

[0334] In the MTD test, the tolerance of the animals to the drug was investigated, and the maximum tolerated dose was reached when the animals were dying frequently.

TABLE-US-00006 TABLE 5 Acute toxicity test results of single oral administration of compound I-3 and other compounds and cariprazine positive drug Test sample MTD (mg/kg) I-3 800 mg/kg I-6 >2000 mg/kg II-2 450 mg/kg II-6 1100 mg/kg IV-2 >2000 mg/kg V-5 450 mg/kg VI-1 900 mg/kg VI-5 >2000 mg/kg VII-4 400 mg/kg Cariprazine 320 mg/kg Note: MTD maximum tolerance.

[0335] The results show that the MTD (maximum tolerance) of compounds I-6, IV-2 and VI-5 of the present disclosure in the above test samples are greater than 2000 mg/kg, and the acute toxicity is much lower than that of carlirazine; compounds I-3, II-2, II-6, V-5, VI-1 and VII-4 have MTD values greater than or equal to 400 mg/kg, which are better than that of cariprazine.

[0336] Although the specific embodiments of the present disclosure have been described above, those skilled in the art should understand that these are only embodiments, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present disclosure. Accordingly, the scope of protection of the present disclosure is defined by the claims.

PYRIDINYL MORPHOLINE COMPOUND, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF

Inventors

Cpc classification

Classification Explorer

C07D401/14

CHEMISTRY; METALLURGY

Classification Explorer

C07D405/12

CHEMISTRY; METALLURGY

Classification Explorer

A61P25/18

HUMAN NECESSITIES

Classification Explorer

C07D417/14

CHEMISTRY; METALLURGY

Classification Explorer

C07D409/04

CHEMISTRY; METALLURGY

Classification Explorer

C07D413/14

CHEMISTRY; METALLURGY

Classification Explorer

C07D213/74

CHEMISTRY; METALLURGY

Classification Explorer

C07D471/04

CHEMISTRY; METALLURGY

Classification Explorer

C07D405/04

CHEMISTRY; METALLURGY

Classification Explorer

A61K31/5377

HUMAN NECESSITIES

Classification Explorer

C07D213/87

CHEMISTRY; METALLURGY

Classification Explorer

C07D409/14

CHEMISTRY; METALLURGY

Classification Explorer

C07D405/14

CHEMISTRY; METALLURGY

Classification Explorer

C07D401/04

CHEMISTRY; METALLURGY

International classification

Classification Explorer

C07D213/74

CHEMISTRY; METALLURGY

Classification Explorer

C07D213/87

CHEMISTRY; METALLURGY

Classification Explorer

C07D401/04

CHEMISTRY; METALLURGY

Classification Explorer

C07D405/14

CHEMISTRY; METALLURGY

Classification Explorer

C07D405/12

CHEMISTRY; METALLURGY

Classification Explorer

C07D405/04

CHEMISTRY; METALLURGY

Classification Explorer

C07D409/04

CHEMISTRY; METALLURGY

Classification Explorer

C07D409/14

CHEMISTRY; METALLURGY

Abstract

Claims

Description