CN116478059A

CN116478059A - Crystal form, eutectic crystal form and eutectic crystal form of dicyclic derivative regulator and preparation method thereof

Info

Publication number: CN116478059A
Application number: CN202310086631.9A
Authority: CN
Inventors: 陈金瑶; 呙临松
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Priority date: 2022-01-24
Filing date: 2023-01-18
Publication date: 2023-07-25

Abstract

The invention relates to a crystal form, eutectic crystal form and eutectic crystal form of a dicyclic derivative regulator and a preparation method thereof. In particular to a crystal form of a compound with a general formula (I), a eutectic crystal form, a preparation method, a pharmaceutical composition containing the crystal form or the eutectic crystal form with a therapeutically effective dose, and a preparation method of the pharmaceutical composition in the preparation of medicines for treating cardiovascular diseases, digestive system diseases, central nervous system diseases and/or mental diseasesIs provided.

Description

Crystal form, eutectic crystal form and eutectic crystal form of dicyclic derivative regulator and preparation method thereof

Technical Field

The invention belongs to the field of biological medicine, and in particular relates to a crystal form, a eutectic crystal form and a eutectic crystal form of a bicyclo derivative regulator, and a preparation method and application thereof.

Background

Depression is a common mental disorder that repeatedly attacks and severely impairs the patient's ability to live in daily life. Despite extensive research, the exact neurobiological processes leading to depression and the mechanisms by which antidepressants produce therapeutic effects are not completely understood. Approximately 20% of people will develop depression at various stages of life, and currently about 3.5 hundred million people suffer from depression, and the number is expanding. The existing medicine is often not ideal in treatment effect on major depressive disorder, at least 30% of depressed patients do not achieve satisfactory treatment effect, and only less than 50% of patients achieve remission. Thus, antidepressants have great market demands.

Clinical findings that depression is often associated with biological rhythms may have antidepressant effects by modulating circadian rhythms. Agomelatine developed by Servier is the only approved melatonin receptor agonist antidepressant, has strong agonism to melatonin MT1 and MT2 receptors and antagonism to 5-HT2C receptors. Melatonin receptors have the ability to regulate circadian rhythms, regulate sleep, and 5-HT2C receptors are involved in antidepressant function. Clinically, the traditional Chinese medicine composition has obvious antidepressant effect, better tolerance and compliance, can increase the sleep continuity and quality of patients with Major Depressive Disorder (MDD), and has obviously smaller sexual dysfunction than other antidepressants.

Agomelatine is a multi-target antidepressant with a brand new mechanism target, has good antidepressant effect, but has low bioavailability (about 5 percent), obvious first pass effect on liver, and 90 percent of the Agomelatine is metabolized by CYP1A2 enzyme after absorption, and 10 percent of Agomelatine is metabolized by CYP2C9 enzyme, so that individual differential liver injury can be caused. Clinically, agomelatine has adverse effect on liver enzymes, ALT/AST elevation (3 times higher than the normal upper limit) occurs in more than 1% of patients, and the elevation has dose dependency, and exposure of patients with slight and severe liver function injury is obviously increased, so that liver function is further damaged.

International application WO2019011279A1 reports the presence of MT1, MT2 agonists and 5-HT _2C Preclinical bioactivity data for the antagonist compounds show improved absolute bioavailability, but their practical effects remain to be validated. Therefore, development of a drug with low liver first pass effect, high absolute bioavailability, MT1 and MT2 receptor agonistic activity and 5-HT has been urgently needed _2C Antagonism of new antidepressants to meet huge market demands.

Application number: PCT/CN2021/108795 discloses a series of structures containing modulators of bicyclic derivatives, and in subsequent developments, the invention provides comprehensive researches on the crystal forms of the above substances in order to facilitate the processing, filtration, drying, storage, long-term stability, high bioavailability and the like of the products.

Disclosure of Invention

All that is referred to in patent application PCT/CN2021/108795 is incorporated herein by reference.

The invention aims to provide a crystal form of a compound shown in a general formula (I), which has the following structure:

wherein:

r is selected from C _1-3 Alkyl, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, cyano-substituted C _1-3 Alkyl or C _3-6 Cycloalkyl;

R ₁ or R is ₂ Independently selected from deuterium, halogenOf plain, cyano or C _1-3 Alkyl, preferably deuterium, fluorine, chlorine, bromine or methyl.

In a preferred embodiment of the present invention, the structure of the compound is represented by general formula (II):

wherein:

r is selected from C _1-3 Alkyl, C _1-3 Deuterated alkyl or C _3-6 Cycloalkyl;

methyl, deuterated methyl or cyclopropyl are preferred.

In a preferred embodiment of the invention, the crystalline form of the compound is the crystalline form of the following compound:

n- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide;

n- (2- (7-cyclopropoxy-4-fluoronaphthalen-1-yl) ethyl) acetamide;

n- (2- (7-isopropoxy-naphthalen-1-yl-3-d) ethyl) acetamide;

n- (2- (7-cyclopropoxy-naphthalen-1-yl-3-d) ethyl) acetamide;

n- (2- (7-cyclopropoxy-3-fluoronaphthalen-1-yl) ethyl) acetamide;

n- (2- (7-cyclopropoxy-3-chloronaphthalen-1-yl) ethyl) acetamide;

n- (2- (7-cyclopropoxy-3-bromonaphthalen-1-yl) ethyl) acetamide;

n- (2- (7-cyclopropoxy-3-methylnaphthalen-1-yl) ethyl) acetamide;

n- [2- [ 3-bromo-7- (cyanomethoxy) -1-naphthyl ] ethyl ] acetamide;

n- (2- (3-chloro-7- (cyanomethoxy) naphthalen-1-yl) ethyl) acetamide;

n- (2- (7- (cyanomethoxy) -3-methyl-1-naphthyl) ethyl) acetamide.

In a preferred embodiment of the invention, the crystalline form is N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide form a, wherein:

The X-ray powder diffraction pattern of the crystal form A has diffraction peaks at the position that 2 theta is 11.7 plus or minus 0.2 degrees; or a diffraction peak at 12.8±0.2°; or a diffraction peak at 15.3±0.2°; or a diffraction peak at 18.0±0.2°; or a diffraction peak at 21.2±0.2°; or a diffraction peak at 25.6±0.2°; or a diffraction peak at 26.4±0.2°; or a diffraction peak at 27.0±0.2°; or a diffraction peak at 17.4±0.2°; or a diffraction peak at 22.1±0.2°; preferably, any of the diffraction peaks described above is contained at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably any 6, 7 or 8 thereof.

In a further preferred embodiment of the present invention, the X-ray powder diffraction pattern of form a comprises at least one or more diffraction peaks in the range of 11.7±0.2°, 12.8±0.2°, 15.3±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 18.0±0.2°, 21.2±0.2°, 25.6±0.2°, 26.4±0.2°, 27.0±0.2°, preferably 2, 3, 4 or 5 thereof; for example, the number of the cells to be processed,

11.7±0.2°、12.8±0.2°；

11.7±0.2°、15.3±0.2°；

12.8±0.2°、15.3±0.2°；

12.8±0.2°、18.0±0.2°；

15.3±0.2°、21.2±0.2°；

11.7±0.2°、12.8±0.2°、15.3±0.2°、18.0±0.2°；

11.7±0.2°、12.8±0.2°、15.3±0.2°、21.2±0.2°；

11.7±0.2°、12.8±0.2°、21.2±0.2°、25.6±0.2°；

12.8±0.2°、15.3±0.2°、25.6±0.2°、26.4±0.2°；

18.0±0.2°、15.3±0.2°、26.4±0.2°、27.0±0.2°；

11.7±0.2°、12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°；

11.7±0.2°、12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、26.4±0.2°；

11.7±0.2°、12.8±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°；

12.8±0.2°、15.3±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°；

18.0±0.2°、15.3±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°；

11.7±0.2°、12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°；

11.7±0.2°、12.8±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°；

12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°；

11.7±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°。

In a further preferred embodiment of the present invention, the X-ray powder diffraction pattern of form a optionally further comprises one or more diffraction peaks at 17.4±0.2°, 22.1±0.2°, 30.8±0.2°, 8.4±0.2°, 20.0±0.2°, 21.6±0.2° or 23.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

17.4±0.2°、22.1±0.2°；

17.4±0.2°、30.8±0.2°；

22.1±0.2°、30.8±0.2°；

30.8±0.2°、8.4±0.2°；

17.4±0.2°、22.1±0.2°、30.8±0.2°、8.4±0.2°；

17.4±0.2°、22.1±0.2°、30.8±0.2°、20.0±0.2°；

22.1±0.2°、30.8±0.2°、8.4±0.2°、20.0±0.2°；

30.8±0.2°、8.4±0.2°、20.0±0.2°、21.6±0.2°；

17.4±0.2°、22.1±0.2°、30.8±0.2°、8.4±0.2°、20.0±0.2°、21.6±0.2°；

17.4±0.2°、22.1±0.2°、30.8±0.2°、8.4±0.2°、20.0±0.2°、23.7±0.2°；

22.1±0.2°、30.8±0.2°、8.4±0.2°、20.0±0.2°、21.6±0.2°、23.7±0.2°；

17.4±0.2°、22.1±0.2°、30.8±0.2°、8.4±0.2°、20.0±0.2°、21.6±0.2°、23.7±0.2°。

in a preferred embodiment of the present invention, the X-ray powder diffraction pattern of form A optionally comprises one or more diffraction peaks at 11.7.+ -. 0.2 °, 12.8.+ -. 0.2 °, 15.3.+ -. 0.2 °, 18.0.+ -. 0.2 °, 21.2.+ -. 0.2 °, 25.6.+ -. 0.2 °, 26.4.+ -. 0.2 °, 27.0.+ -. 0.2 °, 17.4.+ -. 0.2 °, 22.1.+ -. 0.2 °, 30.8.+ -. 0.2 °, 8.4.+ -. 0.2 °, 20.0.+ -. 0.2 °, 21.6.+ -. 0.2 ° or 23.7.+ -. 0.2 ℃,

preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally; for example, the X-ray powder diffraction pattern of a has diffraction peaks at 2θ:

11.7±0.2°、12.8±0.2°、15.3±0.2°、25.6±0.2°；

11.7±0.2°、12.8±0.2°、15.3±0.2°、26.4±0.2°；

21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°；

25.6±0.2°、26.4±0.2°、27.0±0.2°、17.4±0.2°；

11.7±0.2°、12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、27.0±0.2°；

11.7±0.2°、12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、17.4±0.2°；

12.8±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°、17.4±0.2°；

15.3±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°、17.4±0.2°、22.1±0.2°；

11.7±0.2°、12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、17.4±0.2°；

11.7±0.2°、12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、22.1±0.2°；

12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°、17.4±0.2°；

15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°、17.4±0.2°、22.1±0.2°；

11.7±0.2°、12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°、17.4±0.2°、22.1±0.2°；

11.7±0.2°、12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°、17.4±0.2°、8.4±0.2°；

12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°、17.4±0.2°、22.1±0.2°、30.8±0.2°；

15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、27.0±0.2°、17.4±0.2°、22.1±0.2°、30.8±0.2°、8.4±0.2°。

in a further preferred embodiment of the present invention, crystalline form a of the compound N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide, using Cu-ka radiation, has X-ray characteristic diffraction peaks expressed in terms of 2θ angles and interplanar spacings d values as shown in table 1.

TABLE 1 XRPD ray diffraction data for crystalline form A of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide

The compound N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide in the invention has an X-ray powder diffraction pattern shown in figure 1 or a DSC pattern shown in figure 2.

The invention also relates to a co-crystal of a compound according to any of the above embodiments, characterized in that the co-crystal of the compound is selected from the group consisting of sulfuric acid co-crystal, nitric acid co-crystal, phosphoric acid co-crystal, formic acid co-crystal, benzenesulfonic acid co-crystal, benzoic acid co-crystal, gentisic acid co-crystal, camphoric acid co-crystal, tartaric acid co-crystal, malonic acid co-crystal, succinic acid co-crystal, dodecylsulfuric acid co-crystal, 1, 5-naphthalene disulfonic acid co-crystal, ethanesulfonic acid co-crystal, fumaric acid co-crystal, isethionic acid co-crystal, pamoic acid co-crystal, maleic acid co-crystal, oxalic acid co-crystal, p-toluenesulfonic acid co-crystal, p-aminobenzoic acid co-crystal, glycine co-crystal, lysine co-crystal, sarcosine co-crystal, citric acid co-crystal, L-proline co-crystal, isonicotinamide co-crystal or urea co-crystal; preferably phosphoric acid co-crystal, benzenesulfonic acid co-crystal, fumaric acid co-crystal, oxalic acid co-crystal, 1, 5-naphthalene disulfonic acid co-crystal, p-aminobenzoic acid co-crystal, L-proline co-crystal or urea co-crystal.

In a preferred embodiment of the invention, the number of ligands in the co-crystal of the compound is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3; further preferably 1.

In a preferred embodiment of the invention, the co-crystals of the compounds are in the form of crystals,

preferably N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide, more preferably N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide, wherein:

n- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphoric acid eutectic A, wherein the number of phosphoric acid is 1, and an X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphoric acid eutectic A has diffraction peaks at the positions of 10.9+/-0.2 degrees; or a diffraction peak at 13.0±0.2°; or a diffraction peak at 16.9±0.2°; or a diffraction peak at 19.5±0.2°; or a diffraction peak at 20.4±0.2°; or a diffraction peak at 21.2±0.2°; or a diffraction peak at 21.7±0.2°; or a diffraction peak at 26.5±0.2°; or a diffraction peak at 8.4±0.2°; or a diffraction peak at 17.9±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

Or N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphoric acid eutectic B, wherein the number of phosphoric acid is 1, and the X-ray powder diffraction pattern has diffraction peaks at the position of 11.5+/-0.2 DEG of 2 theta; or a diffraction peak at 12.8±0.2°; or a diffraction peak at 17.9±0.2°; or a diffraction peak at 19.7±0.2°; or a diffraction peak at 21.3±0.2°; or a diffraction peak at 22.4 + -0.2 deg.; or a diffraction peak at 23.2±0.2°; or a diffraction peak at 28.6±0.2°; or a diffraction peak at 9.0±0.2°; or a diffraction peak at 10.6 + -0.2 deg.; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

or N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide benzenesulfonic acid eutectic, wherein the X-ray powder diffraction pattern of the eutectic has diffraction peaks at the 2 theta of 12.1+/-0.2 degrees; or a diffraction peak at 12.7±0.2°; or a diffraction peak at 14.0±0.2°; or a diffraction peak at 18.7±0.2°; or a diffraction peak at 21.1±0.2°; or a diffraction peak at 22.1±0.2°; or a diffraction peak at 24.5±0.2°; or a diffraction peak at 25.0±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 16.9±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

Or N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide fumaric acid eutectic, wherein the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide fumaric acid eutectic has diffraction peaks at the position of 8.1+/-0.2 DEG; or a diffraction peak at 13.1±0.2°; or a diffraction peak at 16.3±0.2°; or a diffraction peak at 19.3±0.2°; or a diffraction peak at 20.5±0.2°; or a diffraction peak at 22.0 + -0.2 deg.; or a diffraction peak at 24.9±0.2°; or a diffraction peak at 25.6±0.2°; or a diffraction peak at 9.2±0.2°; or a diffraction peak at 12.4±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

or N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide oxalic acid eutectic A, wherein an X-ray powder diffraction pattern of the eutectic A has diffraction peaks at the positions of 5.6+/-0.2 DEG of 2 theta; or a diffraction peak at 11.1±0.2°; or a diffraction peak at 11.7±0.2°; or a diffraction peak at 12.7±0.2°; or a diffraction peak at 16.9±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 21.1±0.2°; or a diffraction peak at 22.6 + -0.2 deg.; or a diffraction peak at 12.1±0.2°; or a diffraction peak at 14.9±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

Or N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide oxalic acid eutectic B, wherein an X-ray powder diffraction pattern of the eutectic B has diffraction peaks at the positions of 13.0+/-0.2 DEG of 2 theta; or a diffraction peak at 14.9±0.2°; or a diffraction peak at 16.9±0.2°; or a diffraction peak at 19.9±0.2°; or a diffraction peak at 24.1±0.2°; or a diffraction peak at 26.9±0.2°; or a diffraction peak at 27.9±0.2°; or a diffraction peak at 29.0±0.2°; or a diffraction peak at 9.3±0.2°; or a diffraction peak at 14.2±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

or, N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide 1, 5-naphthalene disulfonic acid crystal form, wherein the X-ray powder diffraction pattern has diffraction peaks at the position of 12.7+/-0.2 DEG of 2 theta; or a diffraction peak at 15.5±0.2°; or a diffraction peak at 22.1±0.2°; or a diffraction peak at 23.3±0.2°; or a diffraction peak at 24.0±0.2°; or a diffraction peak at 25.7±0.2°; or a diffraction peak at 29.3±0.2°; or a diffraction peak at 39.3±0.2°; or a diffraction peak at 12.1±0.2°; or a diffraction peak at 16.1±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

Or N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide para aminobenzoic acid eutectic, wherein the X-ray powder diffraction pattern of the eutectic has diffraction peaks at 9.5+/-0.2 degrees of 2 theta; or a diffraction peak at 11.0 + -0.2 deg.; or a diffraction peak at 13.9±0.2°; or a diffraction peak at 15.4±0.2°; or a diffraction peak at 16.9±0.2°; or a diffraction peak at 19.2±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 21.9±0.2°; or a diffraction peak at 5.6±0.2°; or a diffraction peak at 14.8±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

or N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide L-proline co-crystal A, wherein an X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide L-proline co-crystal A has diffraction peaks at the positions of 5.6+/-0.2 DEG of 2 theta; or a diffraction peak at 8.6±0.2°; or a diffraction peak at 11.1±0.2°; or a diffraction peak at 16.9±0.2°; or a diffraction peak at 17.3±0.2°; or a diffraction peak at 19.2±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 26.1±0.2°; or a diffraction peak at 9.6±0.2°; or a diffraction peak at 14.7±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

Or N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide L-proline co-crystal B, wherein an X-ray powder diffraction pattern of the co-crystal B has diffraction peaks at 15.2+/-0.2 DEG of 2 theta; or a diffraction peak at 18.1±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 22.7±0.2°; or a diffraction peak at 24.8±0.2°; or a diffraction peak at 30.6±0.2°; or a diffraction peak at 32.2±0.2°; or a diffraction peak at 36.6±0.2°; or a diffraction peak at 18.5±0.2°; or a diffraction peak at 21.1±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

or N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide urea eutectic A, wherein an X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide urea eutectic A has diffraction peaks at the position of 5.7+/-0.2 DEG; or a diffraction peak at 11.0 + -0.2 deg.; or a diffraction peak at 16.9±0.2°; or a diffraction peak at 19.2±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 20.7±0.2°; or a diffraction peak at 22.3 + -0.2 deg.; or a diffraction peak at 35.5±0.2°; or a diffraction peak at 11.2±0.2°; or a diffraction peak at 14.9±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

Or N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide urea eutectic B, wherein an X-ray powder diffraction pattern of the eutectic B has diffraction peaks at the positions of 4.6+/-0.2 DEG of 2 theta; or a diffraction peak at 9.3±0.2°; or a diffraction peak at 12.3±0.2°; or a diffraction peak at 13.9±0.2°; or a diffraction peak at 14.9±0.2°; or a diffraction peak at 18.0±0.2°; or a diffraction peak at 19.2±0.2°; or a diffraction peak at 23.2±0.2°; or a diffraction peak at 12.9±0.2°; or a diffraction peak at 18.6±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

in a preferred embodiment of the present invention,

the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphoric acid eutectic A at least comprises one or more diffraction peaks positioned in the degrees 2 theta of 10.9+/-0.2 degrees, 13.0+/-0.2 degrees and 16.9+/-0.2 degrees, preferably comprises two of the diffraction peaks, more preferably comprises three diffraction peaks; optionally, it may further comprise at least one of 19.5±0.2°, 20.4±0.2°, 21.2±0.2°, 21.7±0.2°, 26.5±0.2°, preferably 2, 3, 4 or 5 thereof; for example, the number of the cells to be processed,

10.9±0.2°、13.0±0.2°、16.9±0.2°、19.5±0.2°、20.4±0.2°、21.2±0.2°、21.7±0.2°、26.5±0.2°；

The X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphoric acid eutectic B at least comprises one or more diffraction peaks positioned in the angles of 11.5+/-0.2 DEG, 12.8+/-0.2 DEG and 17.9+/-0.2 DEG, preferably comprises two of the diffraction peaks, more preferably comprises three diffraction peaks; optionally, it may further comprise at least one of 19.7±0.2°, 21.3±0.2°, 22.4±0.2°, 23.2±0.2°, 28.6±0.2°, preferably 2, 3, 4 or 5 thereof; for example, the number of the cells to be processed,

11.5±0.2°、12.8±0.2°、17.9±0.2°、19.7±0.2°、21.3±0.2°、22.4±0.2°、23.2±0.2°、28.6±0.2°；

the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide benzene sulfonic acid eutectic at least comprises one or more diffraction peaks positioned in the degrees 2 theta of 12.1+/-0.2 degrees, 12.7+/-0.2 degrees and 14.0+/-0.2 degrees, preferably comprises two of the diffraction peaks, more preferably comprises three diffraction peaks; optionally, it may further comprise at least one of 18.7±0.2°, 21.1±0.2°, 22.1±0.2°, 24.5±0.2°, 25.0±0.2°, preferably 2, 3, 4 or 5 thereof; for example, the number of the cells to be processed,

12.1±0.2°、12.7±0.2°、14.0±0.2°、18.7±0.2°、21.1±0.2°、22.1±0.2°、24.5±0.2°、25.0±0.2°；

the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide fumaric acid eutectic at least comprises one or more diffraction peaks positioned in the degrees 2 theta of 8.1+/-0.2 degrees, 13.1+/-0.2 degrees and 16.3+/-0.2 degrees, preferably comprises two of the diffraction peaks, more preferably comprises three diffraction peaks; optionally, it may further comprise at least one of 19.3±0.2°, 20.5±0.2°, 22.0±0.2°, 24.9±0.2°, 25.6±0.2°, preferably 2, 3, 4 or 5 thereof; for example, the number of the cells to be processed,

8.1±0.2°、13.1±0.2°、16.3±0.2°、19.3±0.2°、20.5±0.2°、22.0±0.2°、24.9±0.2°、25.6±0.2°；

The X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide oxalic acid eutectic A at least comprises one or more diffraction peaks positioned in the degrees 2 theta of 5.6+/-0.2 degrees, 11.1+/-0.2 degrees and 11.7+/-0.2 degrees, preferably comprises two of the diffraction peaks, more preferably comprises three diffraction peaks; optionally, it may further comprise at least one of 12.7±0.2°, 16.9±0.2°, 19.6±0.2°, 21.1±0.2°, 22.6±0.2°, preferably 2, 3, 4 or 5 thereof; for example, the number of the cells to be processed,

5.6±0.2°、11.1±0.2°、11.7±0.2°、12.7±0.2°、16.9±0.2°、19.6±0.2°、21.1±0.2°、22.6±0.2°；

the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide oxalic acid co-crystal B optionally further comprises one or more diffraction peaks at 9.3±0.2°, 14.2±0.2°, 16.4±0.2°, 19.5±0.2°, 22.0±0.2°, 23.1±0.2° or 24.9±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

9.3±0.2°、14.2±0.2°、16.4±0.2°、19.5±0.2°、22.0±0.2°、23.1±0.2°；

the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide 1, 5-naphthalene disulfonic acid eutectic at least comprises one or more diffraction peaks positioned in the degrees 2 theta of 12.7+/-0.2 degrees, 15.5+/-0.2 degrees and 22.1+/-0.2 degrees, preferably comprises two of the diffraction peaks, more preferably comprises three diffraction peaks; optionally, it may further comprise at least one of 23.3±0.2°, 24.0±0.2°, 25.7±0.2°, 29.3±0.2°, 39.3±0.2°, preferably 2, 3, 4 or 5 thereof; for example, the number of the cells to be processed,

12.7±0.2°、15.5±0.2°、22.1±0.2°、23.3±0.2°、24.0±0.2°、25.7±0.2°、29.3±0.2°、39.3±0.2°；

The X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide-para-aminobenzoic acid eutectic at least comprises one or more diffraction peaks positioned in 9.5+/-0.2 DEG, 11.0+/-0.2 DEG and 13.9+/-0.2 DEG, preferably comprises two of the diffraction peaks, more preferably comprises three diffraction peaks; optionally, it may further comprise at least one of 15.4±0.2°, 16.9±0.2°, 19.2±0.2°, 19.6±0.2°, 21.9±0.2°, preferably 2, 3, 4 or 5 thereof; for example, the number of the cells to be processed,

9.5±0.2°、11.0±0.2°、13.9±0.2°、15.4±0.2°、16.9±0.2°、19.2±0.2°、19.6±0.2°、21.9±0.2°；

the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide L-proline co-crystal A at least comprises one or more diffraction peaks positioned in the degrees 2 theta of 5.6+/-0.2 degrees, 8.6+/-0.2 degrees and 11.1+/-0.2 degrees, preferably comprises two of the diffraction peaks, more preferably comprises three diffraction peaks; optionally, it may further comprise at least one of 16.9±0.2°, 17.3±0.2°, 19.2±0.2°, 19.6±0.2°, 26.1±0.2°, preferably 2, 3, 4 or 5 thereof; for example, the number of the cells to be processed,

5.6±0.2°、8.6±0.2°、11.1±0.2°、16.9±0.2°、17.3±0.2°、19.2±0.2°、19.6±0.2°、26.1±0.2°；

the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide L-proline co-crystal B at least comprises one or more diffraction peaks positioned in 15.2+/-0.2 DEG, 18.1+/-0.2 DEG and 19.6+/-0.2 DEG of 2 theta, preferably comprises two of the diffraction peaks, more preferably comprises three diffraction peaks; optionally, it may further comprise at least one of 22.7±0.2°, 24.8±0.2°, 30.6±0.2°, 32.2±0.2°, 36.6±0.2°, preferably 2, 3, 4 or 5 thereof; for example, the number of the cells to be processed,

15.2±0.2°、18.1±0.2°、19.6±0.2°、22.7±0.2°、24.8±0.2°、30.6±0.2°、32.2±0.2°、36.6±0.2°；

The X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide urea eutectic A at least comprises one or more diffraction peaks positioned in the degrees 2 theta of 5.7+/-0.2 degrees, 11.0+/-0.2 degrees and 16.9+/-0.2 degrees, preferably comprises two of the diffraction peaks, more preferably comprises three diffraction peaks; optionally, it may further comprise at least one of 19.2±0.2°, 19.6±0.2°, 20.7±0.2°, 22.3±0.2°, 35.5±0.2°, preferably 2, 3, 4 or 5 thereof; for example, the number of the cells to be processed,

5.7±0.2°、11.0±0.2°、16.9±0.2°、19.2±0.2°、19.6±0.2°、20.7±0.2°、22.3±0.2°、35.5±0.2°；

the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide urea eutectic B at least comprises one or more diffraction peaks positioned in the degrees 2 theta of 4.6+/-0.2 degrees, 9.3+/-0.2 degrees and 12.3+/-0.2 degrees, preferably comprises two of the diffraction peaks, and more preferably comprises three diffraction peaks; optionally, it may further comprise at least one of 13.9±0.2°, 14.9±0.2°, 18.0±0.2°, 19.2±0.2°, 23.2±0.2°, preferably 2, 3, 4 or 5 thereof; for example, the number of the cells to be processed,

4.6±0.2°、9.3±0.2°、12.3±0.2°、13.9±0.2°、14.9±0.2°、18.0±0.2°、19.2±0.2°、23.2±0.2°。

in a further preferred embodiment of the present invention,

the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal a optionally further comprises one or more diffraction peaks at 2θ of 8.4±0.2°, 17.9±0.2°, 19.8±0.2°, 22.7±0.2°, 25.0±0.2°, 27.3±0.2° or 27.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

8.4±0.2°、17.9±0.2°、19.8±0.2°、22.7±0.2°、25.0±0.2°、27.3±0.2°；

The X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal B optionally further comprises one or more diffraction peaks at 9.0±0.2°, 10.6±0.2°, 20.3±0.2°, 21.5±0.2°, 25.6±0.2°, 26.2±0.2° or 27.8±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

9.0±0.2°、10.6±0.2°、20.3±0.2°、21.5±0.2°、25.6±0.2°、26.2±0.2°；

the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide benzenesulfonic acid co-crystal optionally further comprises one or more diffraction peaks at 16.0±0.2°, 16.9±0.2°, 17.3±0.2°, 21.4±0.2°, 27.1±0.2°, 28.0±0.2° or 29.8±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

16.0±0.2°、16.9±0.2°、17.3±0.2°、21.4±0.2°、27.1±0.2°、28.0±0.2°；

the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide fumaric acid co-crystal optionally further comprises one or more diffraction peaks at 9.2±0.2°, 12.4±0.2°, 14.9±0.2°, 17.4±0.2°, 18.8±0.2°, 24.4±0.2° or 26.5±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

9.2±0.2°、12.4±0.2°、14.9±0.2°、17.4±0.2°、18.8±0.2°、24.4±0.2°；

The X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide oxalic acid co-crystal a optionally further comprises one or more diffraction peaks at 2θ of 12.1±0.2°, 14.9±0.2°, 15.3±0.2°, 16.3±0.2°, 17.9±0.2°, 20.8±0.2° or 25.6±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

12.1±0.2°、14.9±0.2°、15.3±0.2°、16.3±0.2°、17.9±0.2°、20.8±0.2°；

the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide 1, 5-naphthalenedisulfonic acid co-crystal optionally further comprises one or more diffraction peaks at 12.1±0.2°, 16.1±0.2°, 17.1±0.2°, 21.5±0.2°, 22.5±0.2°, 25.3±0.2° or 33.5±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

12.1±0.2°、16.1±0.2°、17.1±0.2°、21.5±0.2°、22.5±0.2°、25.3±0.2°；

The X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide to aminobenzoic acid co-crystal optionally further comprises one or more diffraction peaks at 5.6±0.2°, 14.8±0.2°, 20.7±0.2°, 22.5±0.2°, 25.5±0.2°, 31.0±0.2° or 35.9±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

5.6±0.2°、14.8±0.2°、20.7±0.2°、22.5±0.2°、25.5±0.2°、31.0±0.2°；

the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal a optionally further comprises one or more diffraction peaks at 9.6±0.2°, 14.7±0.2°, 14.9±0.2°, 20.8±0.2°, 22.9±0.2°, 33.7±0.2° or 35.1±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

9.6±0.2°、14.7±0.2°、14.9±0.2°、20.8±0.2°、22.9±0.2°、33.7±0.2°；

the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal B optionally further comprises one or more diffraction peaks at 18.5±0.2°, 21.1±0.2°, 26.0±0.2°, 27.1±0.2°, 30.3±0.2°, 34.0±0.2° or 34.8±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

18.5±0.2°、21.1±0.2°、26.0±0.2°、27.1±0.2°、30.3±0.2°、34.0±0.2°；

The X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal a optionally further comprises one or more diffraction peaks at 11.2±0.2°, 14.9±0.2°, 24.2±0.2°, 25.5±0.2°, 28.0±0.2°, 29.4±0.2° or 31.7±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

11.2±0.2°、14.9±0.2°、24.2±0.2°、25.5±0.2°、28.0±0.2°、29.4±0.2°；

the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal B optionally further comprises one or more diffraction peaks at 2θ of 12.9±0.2°, 18.6±0.2°, 25.5±0.2°, 27.1±0.2°, 27.7±0.2°, 28.0±0.2° or 37.6±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included; for example, the number of the cells to be processed,

12.9±0.2°、18.6±0.2°、25.5±0.2°、27.1±0.2°、27.7±0.2°、28.0±0.2°

in a preferred embodiment of the present invention,

the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal a optionally comprises one or more diffraction peaks at 10.9±0.2°, 13.0±0.2°, 16.9±0.2°, 19.5±0.2°, 20.4±0.2°, 21.2±0.2°, 21.7±0.2°, 26.5±0.2°, 8.4±0.2°, 17.9±0.2°, 19.8±0.2°, 22.7±0.2°, 25.0±0.2°, 27.3±0.2° or 27.7±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of the optional positions; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal a has diffraction peaks at 2θ:

10.9±0.2°、13.0±0.2°、16.9±0.2°、19.5±0.2°、20.4±0.2°、21.2±0.2°、21.7±0.2°、26.5±0.2°、8.4±0.2°、17.9±0.2°；

The X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal B optionally comprises one or more diffraction peaks at 11.5±0.2°, 12.8±0.2°, 17.9±0.2°, 19.7±0.2°, 21.3±0.2°, 22.4±0.2°, 23.2±0.2°, 28.6±0.2°, 9.0±0.2°, 10.6±0.2°, 20.3±0.2°, 21.5±0.2°, 25.6±0.2°, 26.2±0.2° or 27.8±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of the optional positions; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal B has diffraction peaks at 2θ:

11.5±0.2°、12.8±0.2°、17.9±0.2°、19.7±0.2°、21.3±0.2°、22.4±0.2°、23.2±0.2°、28.6±0.2°、9.0±0.2°、10.6±0.2°；

the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide benzenesulfonic acid co-crystal optionally comprises one or more diffraction peaks at 2θ of 12.1±0.2°, 12.7±0.2°, 14.0±0.2°, 18.7±0.2°, 21.1±0.2°, 22.1±0.2°, 24.5±0.2°, 25.0±0.2°, 16.0±0.2°, 16.9±0.2°, 17.3±0.2°, 21.4±0.2°, 27.1±0.2°, 28.0±0.2° or 29.8±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of the optional positions; for example, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide benzenesulfonic acid co-crystal has diffraction peaks at the following positions in 2θ:

12.1±0.2°、12.7±0.2°、14.0±0.2°、18.7±0.2°、21.1±0.2°、22.1±0.2°、24.5±0.2°、25.0±0.2°、16.0±0.2°、16.9±0.2°；

The X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide fumarate co-crystal optionally comprises one or more diffraction peaks at 8.1±0.2°, 13.1±0.2°, 16.3±0.2°, 19.3±0.2°, 20.5±0.2°, 22.0±0.2°, 24.9±0.2°, 25.6±0.2°, 9.2±0.2°, 12.4±0.2°, 14.9±0.2°, 17.4±0.2°, 18.8±0.2°, 24.4±0.2° or 26.5±0.2°, preferably comprising one or more diffraction peaks at 4, 5, 6, 8 or 10 of the optional positions; for example, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide fumarate co-crystal has diffraction peaks at the following positions of 2θ:

8.1±0.2°、13.1±0.2°、16.3±0.2°、19.3±0.2°、20.5±0.2°、22.0±0.2°、24.9±0.2°、25.6±0.2°、9.2±0.2°、12.4±0.2°；

the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide oxalic acid co-crystal a optionally comprises one or more diffraction peaks at 5.6±0.2°, 11.1±0.2°, 11.7±0.2°, 12.7±0.2°, 16.9±0.2°, 19.6±0.2°, 21.1±0.2°, 22.6±0.2°, 12.1±0.2°, 14.9±0.2°, 15.3±0.2°, 16.3±0.2°, 17.9±0.2°, 20.8±0.2° or 25.6±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of the optional positions; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal a has diffraction peaks at 2θ:

5.6±0.2°、11.1±0.2°、11.7±0.2°、12.7±0.2°、16.9±0.2°、19.6±0.2°、21.1±0.2°、22.6±0.2°、12.1±0.2°、14.9±0.2°；

The X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide oxalic acid co-crystal B optionally comprises one or more diffraction peaks at 13.0±0.2°, 14.9±0.2°, 16.9±0.2°, 19.9±0.2°, 24.1±0.2°, 26.9±0.2°, 27.9±0.2°, 29.0±0.2°, 9.3±0.2°, 14.2±0.2°, 16.4±0.2°, 19.5±0.2°, 22.0±0.2°, 23.1±0.2° or 24.9±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of the optional positions; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal B has diffraction peaks at 2θ:

13.0±0.2°、14.9±0.2°、16.9±0.2°、19.9±0.2°、24.1±0.2°、26.9±0.2°、27.9±0.2°、29.0±0.2°、9.3±0.2°、14.2±0.2°；

the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide 1, 5-naphthalene disulfonic acid co-crystal optionally comprises one or more diffraction peaks at 2θ of 12.7±0.2°, 15.5±0.2°, 22.1±0.2°, 23.3±0.2°, 24.0±0.2°, 25.7±0.2°, 29.3±0.2°, 39.3±0.2°, 12.1±0.2°, 16.1±0.2°, 17.1±0.2°, 21.5±0.2°, 22.5±0.2°, 25.3±0.2° or 33.5±0.2°, preferably comprises a diffraction peak at 4, 5, 6, 8 or 10 ° in which the diffraction peak is selected; for example, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide 1, 5-naphthalene disulfonic acid co-crystal has diffraction peaks at the following positions in 2θ:

12.7±0.2°、15.5±0.2°、22.1±0.2°、23.3±0.2°、24.0±0.2°、25.7±0.2°、29.3±0.2°、39.3±0.2°、12.1±0.2°、16.1±0.2°；

The X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide to aminobenzoic acid co-crystal optionally comprises one or more diffraction peaks at 9.5±0.2°, 11.0±0.2°, 13.9±0.2°, 15.4±0.2°, 16.9±0.2°, 19.2±0.2°, 19.6±0.2°, 21.9±0.2°, 5.6±0.2°, 14.8±0.2°, 20.7±0.2°, 22.5±0.2°, 25.5±0.2°, 31.0±0.2° or 35.9±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of the optional positions; for example, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide para-aminobenzoic acid co-crystal has diffraction peaks at 2θ:

9.5±0.2°、11.0±0.2°、13.9±0.2°、15.4±0.2°、16.9±0.2°、19.2±0.2°、19.6±0.2°、21.9±0.2°、5.6±0.2°、14.8±0.2°；

the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal a optionally comprises one or more diffraction peaks at 5.6±0.2°, 8.6±0.2°, 11.1±0.2°, 16.9±0.2°, 17.3±0.2°, 19.2±0.2°, 19.6±0.2°, 26.1±0.2°, 9.6±0.2°, 14.7±0.2°, 14.9±0.2°, 20.8±0.2°, 22.9±0.2°, 33.7±0.2° or 35.1±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of the optional positions; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal a has diffraction peaks at 2θ:

5.6±0.2°、8.6±0.2°、11.1±0.2°、16.9±0.2°、17.3±0.2°、19.2±0.2°、19.6±0.2°、26.1±0.2°、9.6±0.2°、14.7±0.2°；

The X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal B optionally comprises one or more diffraction peaks at 15.2±0.2°, 18.1±0.2°, 19.6±0.2°, 22.7±0.2°, 24.8±0.2°, 30.6±0.2°, 32.2±0.2°, 36.6±0.2°, 18.5±0.2°, 21.1±0.2°, 26.0±0.2°, 27.1±0.2°, 30.3±0.2°, 34.0±0.2° or 34.8±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of the optional positions; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal B has diffraction peaks at 2θ:

15.2±0.2°、18.1±0.2°、19.6±0.2°、22.7±0.2°、24.8±0.2°、30.6±0.2°、32.2±0.2°、36.6±0.2°、18.5±0.2°、21.1±0.2°；

the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal a optionally comprises one or more diffraction peaks at 5.7±0.2°, 11.0±0.2°, 16.9±0.2°, 19.2±0.2°, 19.6±0.2°, 20.7±0.2°, 22.3±0.2°, 35.5±0.2°, 11.2±0.2°, 14.9±0.2°, 24.2±0.2°, 25.5±0.2°, 28.0±0.2°, 29.4±0.2° or 31.7±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of the optional positions; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal a has diffraction peaks at 2θ:

5.7±0.2°、11.0±0.2°、16.9±0.2°、19.2±0.2°、19.6±0.2°、20.7±0.2°、22.3±0.2°、35.5±0.2°、11.2±0.2°、14.9±0.2°；

The X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal B optionally comprises one or more diffraction peaks at 2θ of 4.6±0.2°, 9.3±0.2°, 12.3±0.2°, 13.9±0.2°, 14.9±0.2°, 18.0±0.2°, 19.2±0.2°, 23.2±0.2°, 12.9±0.2°, 18.6±0.2°, 25.5±0.2°, 27.1±0.2°, 27.7±0.2°, 28.0±0.2° or 37.6±0.2°, preferably comprising one or more diffraction peaks at optional 4, 5, 6, 8 or 10; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal B has diffraction peaks at 2θ:

4.6±0.2°、9.3±0.2°、12.3±0.2°、13.9±0.2°、14.9±0.2°、18.0±0.2°、19.2±0.2°、23.2±0.2°、12.9±0.2°、18.6±0.2°。

in a preferred embodiment of the present invention, the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal A, the number of phosphoric acid is 1, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angle and d-plane spacing using Cu-K alpha radiation are shown in Table 2. The X-ray powder diffraction pattern is substantially as shown in figure 3.

TABLE 2 XRPD ray diffraction data for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal A

In a preferred embodiment of the present invention, the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal B, the number of phosphoric acids being 1, is shown in Table 3 using Cu-K alpha radiation, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angle and interplanar spacing d values are shown in Table 3. The X-ray powder diffraction pattern is substantially as shown in figure 4.

TABLE 3 XRPD ray diffraction data for cocrystal B of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphate

In a preferred embodiment of the present invention, the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide benzenesulfonic acid co-crystal was irradiated with Cu-K alpha, and the X-ray characteristic diffraction peaks expressed in terms of 2-theta angle and interplanar spacing d values are shown in Table 4. The X-ray powder diffraction pattern is substantially as shown in figure 5.

Table 4 XRPD ray diffraction data for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide benzenesulfonic acid co-crystals

In a preferred embodiment of the present invention, the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide fumarate co-crystals were irradiated with Cu-K alpha, and the X-ray characteristic diffraction peaks expressed in terms of 2-theta angle and interplanar spacing d values are shown in Table 5. The X-ray powder diffraction pattern is substantially as shown in figure 6.

TABLE 5 XRPD ray diffraction data for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide fumaric acid co-crystals

In a preferred embodiment of the present invention, the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal A was irradiated with Cu-K alpha, and the X-ray characteristic diffraction peaks expressed in terms of 2-theta angle and interplanar spacing d values are shown in Table 6. The X-ray powder diffraction pattern is substantially as shown in figure 7.

TABLE 6 XRPD ray diffraction data for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal A

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In a preferred embodiment of the present invention, the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid cocrystal B is irradiated with Cu-K alpha, and the X-ray characteristic diffraction peaks expressed in terms of 2-theta angle and interplanar spacing d are shown in Table 7. The X-ray powder diffraction pattern is substantially as shown in figure 8.

TABLE 7 XRPD ray diffraction data for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid cocrystal B

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In a preferred embodiment of the present invention, the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide 1, 5-naphthalenedisulfonic acid cocrystal was irradiated with Cu-K alpha, and the X-ray characteristic diffraction peaks expressed in terms of 2-theta angle and d-plane spacing are shown in Table 8. The X-ray powder diffraction pattern is substantially as shown in figure 9.

TABLE 8 XRPD ray diffraction data for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide 1, 5-naphthalenedisulfonic acid cocrystals

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In a preferred embodiment of the present invention, the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide para-aminobenzoic acid co-crystal was irradiated with Cu-K alpha, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angle and d-plane spacing are shown in Table 9. The X-ray powder diffraction pattern is substantially as shown in figure 10.

TABLE 9 XRPD ray diffraction data for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide para-aminobenzoic acid co-crystals

In a preferred embodiment of the present invention, the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal A was irradiated with Cu-K alpha, and the X-ray characteristic diffraction peaks expressed in terms of 2-theta angle and interplanar spacing d values are shown in Table 10. The X-ray powder diffraction pattern is substantially as shown in figure 11.

TABLE 10 XRPD ray diffraction data for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal A

In a preferred embodiment of the present invention, the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal B was irradiated with Cu-K alpha, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angle and interplanar spacing d values are shown in Table 11. The X-ray powder diffraction pattern is substantially as shown in figure 12.

TABLE 11 XRPD ray diffraction data for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal B

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In a preferred embodiment of the present invention, the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal A was irradiated with Cu-K alpha, and the X-ray characteristic diffraction peaks expressed in terms of 2-theta angle and interplanar spacing d values are shown in Table 12. The X-ray powder diffraction pattern is substantially as shown in figure 13.

Table 12 XRPD ray diffraction data for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal a

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In a preferred embodiment of the present invention, the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal B was irradiated with Cu-K alpha, and the X-ray characteristic diffraction peaks expressed in terms of 2-theta angle and interplanar spacing d values are shown in Table 13. The X-ray powder diffraction pattern is substantially as shown in figure 14.

TABLE 13 XRPD ray diffraction data for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal B

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In a further preferred embodiment of the present invention, the 2 theta error of the diffraction peak position of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide crystal form a, which has a relative peak intensity of the first decade, and the diffraction peak at the corresponding position in fig. 1 is + -0.2 deg. to + -0.5 deg., preferably + -0.2 deg. to + -0.3 deg., most preferably + -0.2 deg..

In a further preferred embodiment of the present invention, the 2 θ error of the diffraction peak at the position of the preceding ten diffraction peaks corresponding to the positions of fig. 3, fig. 4, fig. 5, fig. 6, fig. 7, fig. 8, fig. 9, fig. 10, fig. 11, fig. 12, fig. 13 and fig. 14 in the X-ray powder diffraction patterns of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide in the form of phosphoric acid co-crystal a, phosphoric acid co-crystal B, benzenesulfonic acid co-crystal, fumaric acid co-crystal, oxalic acid co-crystal a, oxalic acid co-crystal B, 1, 5-naphthalenedisulfonic acid co-crystal, p-aminobenzoic acid co-crystal, L-proline co-crystal A, L-proline co-crystal B, urea co-crystal a and urea co-crystal B is ±0.2° ±0.5°, preferably ±0.2° ±0.3°, most preferably ±0.2°.

In a further preferred embodiment of the present invention, any of the above crystalline forms is an anhydrous or hydrated form, and when the crystalline form is a hydrated form, the number of water is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3;

preferably, the crystalline form is an anhydrate.

In a further preferred embodiment of the present invention, the preparation method of the above-mentioned compound crystal form specifically comprises the following steps:

1) Weighing a proper amount of compound or crystal form thereof, and dissolving the compound or crystal form thereof by using a benign solvent, wherein the temperature is preferably 0-50 ℃;

2) Adding a poor solvent, and naturally cooling to room temperature;

3) Stirring to separate out, filtering and drying the obtained solid;

the benign solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, acetonitrile, isopropanol, isopropyl acetate, butanone, tetrahydrofuran or 2-methyl-tetrahydrofuran; ethanol is preferred;

the poor solvent is selected from one or more of water, methyl tertiary butyl ether, n-heptane, benzene, toluene or chlorobenzene; preferably water.

In a further preferred embodiment of the present invention, the preparation method of the compound eutectic crystal form specifically includes the following steps:

1) Weighing a proper amount of compound, and dissolving the compound with a benign solvent;

2) Adding a proper amount of ligand into the mixture at room temperature; the amount of ligand is preferably 1.2 equivalents;

3) Stirring to separate out, filtering and drying the obtained solid;

the benign solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, acetonitrile, isopropanol, isopropyl acetate, butanone, tetrahydrofuran or 2-methyl-tetrahydrofuran; preferably ethyl acetate

The ligand is selected from sulfuric acid, nitric acid, phosphoric acid, formic acid, benzenesulfonic acid, benzoic acid, gentisic acid, camphoric acid, tartaric acid, malonic acid, succinic acid, dodecylsulfuric acid, 1, 5-naphthalene disulfonic acid, ethanesulfonic acid, fumaric acid, hydroxyethylsulfonic acid, pamoic acid, maleic acid, oxalic acid, p-toluenesulfonic acid, p-aminobenzoic acid, glycine, lysine, sarcosine, citric acid, L-proline, L-malic acid, isonicotinamide or urea; phosphoric acid, benzenesulfonic acid, fumaric acid, oxalic acid, 1, 5-naphthalenedisulfonic acid, p-aminobenzoic acid, L-proline or urea are preferred.

It is also an object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of any of the above compounds or a crystalline form of any of the above compounds co-crystals, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

The invention also aims at providing the application of the crystal form of any one of the compounds, the crystal form of any one of the compound eutectic or the pharmaceutical composition in preparing melatonin receptor agonist medicines.

The invention also aims to provide a crystal form of any one of the compounds, a crystal form of any one of the compound eutectic or the pharmaceutical composition for preparingMT1 and MT2 receptor agonists and 5-HT _2C Use of receptor antagonist medicaments.

The invention also aims to provide the application of the crystal form of any one of the compounds, the crystal form of any one of the compound eutectic or the pharmaceutical composition in preparing medicines for treating or preventing cardiovascular diseases, digestive system diseases, central nervous system diseases and/or mental diseases; preferably, the central nervous system and/or psychiatric disorder is selected from melatonin system disorders, stress, anxiety disorders, seasonal affective disorders, schizophrenia, phobia, depression, major depressive disorder, sleep disorders, insomnia or fatigue caused by jet lag, weight disorders, mood disorders, schizophrenic lineage disorders, spasticity disorders, memory disorders and/or cognitive disorders, movement disorders, personality disorders, autism lineage disorders, pain, traumatic brain injury, substance abuse disorders and/or withdrawal syndromes, tinnitus, autism, alzheimer's disease, epileptic seizures, neuralgia or drug addiction withdrawal symptoms major depressive disorder or manic disorder.

Detailed description of the invention

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "ligand" refers to atoms, molecules and ions that can create a bond with a central atom (metal or metalloid).

Drawings

FIG. 1 is an XRPD pattern for crystalline form A of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide.

FIG. 2 is a DSC plot of crystalline form A of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide.

FIG. 3 is an XRPD pattern for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal A.

FIG. 4 is an XRPD pattern for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal B.

FIG. 5 is an XRPD pattern for a co-crystal of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide benzenesulfonic acid.

FIG. 6 is an XRPD pattern for an N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide fumarate co-crystal.

FIG. 7 is an XRPD pattern for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal A.

FIG. 8 is an XRPD pattern for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal B.

FIG. 9 is an XRPD pattern for a co-crystal of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide 1, 5-naphthalenedisulfonic acid.

FIG. 10 is an XRPD pattern for a co-crystal of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide in para-aminobenzoic acid.

FIG. 11 is an XRPD pattern for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal A.

FIG. 12 is an XRPD pattern for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal B.

FIG. 13 is an XRPD pattern for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal A.

FIG. 14 is an XRPD pattern for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal B.

Interpretation of the terms

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 8 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, and most preferably an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, with methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred.

The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means-CH ₂ - "ethylene" means- (CH) ₂ ) ₂ - "propylene" means- (CH) ₂ ) ₃ "butylene" means- (CH) ₂ ) ₄ -and the like. The term "alkenyl" means a radical composed of at least two groupsAlkyl groups as defined above consisting of a number of carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and even more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.

"hydroxy" refers to an-OH group.

"halogen" means fluorine, chlorine, bromine or iodine.

"amino" means-NH ₂ 。

"cyano" refers to-CN.

"nitro" means-NO ₂ 。

"carboxy" means-C (O) OH.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N, N-dimethylformamide.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetonitrile.

"DMA" refers to N, N-dimethylacetamide.

“Et ₂ O "refers to diethyl ether.

"DCE" refers to 1,2 dichloroethane.

"DIPEA" refers to N, N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

“Pd ₂ (dba) ₃ "means tris (dibenzylideneacetone) dipalladium.

"Dppf" refers to 1,1' -bis-diphenylphosphino ferrocene.

"HATU" refers to 2- (7-oxo-benzotriazol) -N, N' -tetramethylurea hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bis (trimethylsilylamide).

"MeLi" refers to lithium-based.

"n-BuLi" refers to n-butyllithium.

“NaBH(OAc) ₃ "means sodium triacetoxyborohydride.

"t-BuONO" refers to t-butyl nitrite.

"EA" refers to ethyl acetate.

"PE" refers to petroleum ether.

"DCM" refers to dichloromethane.

"STAB" refers to sodium triacetoxyborohydride.

“Pd(dcypf)Cl ₂ "refers to dichloro [1,1' -bis (dicyclohexyl-phosphorus) ferrocene]Palladium.

The terms "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc. all express the same meaning, that is, X may be any one or several of A, B, C.

The hydrogen atoms of the invention can be replaced by the isotope deuterium thereof, and any hydrogen atom in the compound of the embodiment of the invention can be replaced by deuterium atoms.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

Detailed Description

The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.

Examples

The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated methanol (CD) ₃ OD) and deuterated chloroform (CDCl) ₃ ) The internal standard is Tetramethylsilane (TMS).

An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18X 4.6mm column).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.

All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific explanation.

Example 1A

Preparation of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide

The first step: preparation of 5-amino-8-bromonaphthalene-2-ol

5-Aminonaphthalene-2-ol (10 g,62.9 mmol) was dissolved in DMF (100 mL), NBS (12.3 g,69.2 mmol) was added, the mixture was reacted at 110℃for 3 hours, cooled to room temperature, water and ethyl acetate were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 5-amino-8-bromonaphthalene-2-ol (10.8 g, yield 72%).

MS m/z(ESI):238.1[M+H] ⁺ ,240.1[M+H+2] ⁺ .

And a second step of: preparation of 8-bromo-5-fluoronaphthalene-2-ol

5-amino-8-bromonaphthalene-2-ol (5 g,21.0 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0deg.C, and HBF was added ₄ (40 mL, 48%) solution, then NaNO was added ₂ (4.4 g,63.8 mmol) in water (10 mL) and stirring at 0deg.C was continued for 1 hour, naBF was added ₄ (11.5 g,104.5 mmol). Gradually heating to room temperature, filtering to obtain solid, washing with water and diethyl ether. And (5) vacuum drying. The resulting solid was dissolved in xylene (100 mL) and heated at reflux for 2 hours. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 8-bromo-5-fluoronaphthalene-2-ol (3.5 g, 69% yield).

MS m/z(ESI):240.1[M+H] ⁺ ,243.1[M+H+2] ⁺ .

And a third step of: preparation of 4-bromo-1-fluoro-6-methoxynaphthalene

8-bromo-5-fluoronaphthalen-2-ol (3H) -one (3.4 g,14.2 mmol) was added to DMF (30 mL) and K was added ₂ CO ₃ Methyl iodide (2.4 g,16.9 mmol) was added dropwise at room temperature (5.8 g,42.0 mmol), and stirring was continued for 2 hours. Extraction with water and ethyl acetate, washing the combined organic phases with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration, and column chromatography purification gave 4-bromo-1-fluoro-6-methoxynaphthalene (3.4 g, 94% yield).

¹ H NMR(400MHz,Chloroform-d)δ8.06(d,J＝9.0Hz,1H),7.93-7.90(m,2H),7.15(d,J＝9.0Hz,1H),6.92(dd,J＝12,7.8Hz,1H),4.01(s,3H).

Fourth step: preparation of 2- (4-fluoro-7-methoxynaphthalen-1-yl) acetylnitrile

4-bromo-1-fluoro-6-methoxynaphthalene (3.3 g,13.0 mmol) was dissolved in anhydrous THF (50 mL), magnesium powder (1.6 g,66.7 mmol) and elemental iodine (2 particles) were added, nitrogen was replaced three times, and the temperature was raised to 50℃and stirred for 0.5 hours. Bromoacetonitrile (2.0 g,16.8 mmol) in THF (20 mL) was added dropwise to the mixture in an ice-water bath, gradually warmed to room temperature, stirred for 1 hour, quenched with water, extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 2- (4-fluoro-7-methoxynaphthalen-1-yl) acetylnitrile (1.8 g, 64% yield).

¹ H NMR(400MHz,Chloroform-d)δ8.02(d,J＝9.0Hz,1H),7.63(s,1H),7.08(d,J＝9.0Hz,1H),6.92(m,2H),5.05(s,2H),3.99(s,3H).

Fifth step: preparation of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide

2- (4-fluoro-7-methoxynaphthalen-1-yl) acetylnitrile (1.7 g,7.9 mmol) and acetic anhydride (2.0 g,19.8 mmol) were dissolved in dichloromethane/methanol (30 mL/15 mL) solution and NiCl was added at 0deg.C ₂ ·6H ₂ O (1.1 g,4.7 mmol), sodium borohydride (1.3 g,34.2 mmol) was added in portions and stirred at room temperature for 5 hours. 6N HCl was added, water was added, the mixture was filtered, extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography purification gave N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide (1.5 g, 73% yield).

MS m/z(ESI):262.1[M+H] ⁺ .

¹ H NMR(400MHz,Chloroform-d)δ8.02(d,J＝8.0Hz,1H),7.47(s,1H),7.21-7.15(m,2H),6.93-6.88(m,1H),5.73(s,1H),3.99(s,3H),3.58-3.53(m,2H),3.20-3.16(t,J＝8.0Hz,2H),1.95(s,3H).

Example 1

Preparation of N- (2- (7-cyclopropyloxy-4-fluoronaphthalen-1-yl) ethyl) acetamide

The first step: preparation of N- (2- (4-fluoro-7-hydroxynaphthalen-1-yl) ethyl) acetamide

N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide (1.4 g,5.4 mmol) was dissolved in dichloromethane (20 mL), cooled to 0deg.C under nitrogen protection, and BBr was added dropwise ₃ (2.7 g,10.8 mmol) was stirred at room temperature for 3 hours. Adding NaHCO ₃ The mixture was washed with an aqueous solution and extracted with dichloromethane/methanol (10/1). The organic layer was washed with water and 10% aqueous sodium bicarbonate. Dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give N- (2- (4-fluoro-7-hydroxynaphthalen-1-yl) ethyl) acetamide (980 mg, 75% yield).

MS m/z(ESI):248.1[M+H] ⁺ .

And a second step of: preparation of N- (2- (7-cyclopropyloxy-4-fluoronaphthalen-1-yl) ethyl) acetamide

N- (2- (4-fluoro-7-hydroxynaphthalen-1-yl) ethyl) acetamide (100 mg,0.41 mmol) was dissolved in DMF (5 mL), cyclopropyl bromide (150 mg,1.24 mmol) was added, cs ₂ CO ₃ (400 mg,1.22 mmol) was reacted for 4 hours with microwaves at 160℃and extracted with water and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative HPLC to give N- (2- (7-cyclopropoxy-4-fluoronaphthalen-1-yl) ethyl) acetamide (44 mg, 38% yield).

MS m/z(ESI):288.1[M+H] ⁺ .

Example 2

Preparation of N- (2- (7-isopropoxy-naphthalen-1-yl-3-d) ethyl) acetamide

The first step: preparation of N- (2- (7-methoxy-3-bromonaphthalen-1-yl) ethyl) acetamide

The substrate N- (2- (7-methoxy-1-naphthyl) ethyl) acetamide (5 g,20.6 mmol) was dissolved in glacial acetic acid (50 mL), heated to 85deg.C (oil bath temperature), and a solution of bromine (4.0 g,25.0 mmol) in AcOH (30 mL) was added dropwise. After the completion of the dropwise addition, the mixture was heated and stirred for 3 hours. The reaction solution was cooled to room temperature, which was then poured into water (150 mL), extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by column chromatography to give N- (2- (7-methoxy-3-bromonaphthalen-1-yl) ethyl) acetamide (4.5 g, yield 68%).

MS m/z(ESI):322.1[M+H] ⁺ ,324.1[M+H+2] ⁺ .

And a second step of: preparation of N- (2- (7-methoxynaphthalen-1-yl-3-d) ethyl) acetamide

N- (2- (7-methoxy-3-bromonaphthalen-1-yl) ethyl) acetamide (200 mg,0.62 mmol) was dissolved in anhydrous THF (20 mL), cooled to-78deg.C under nitrogen, and a solution of N-BuLi (1.6 mL,1.6 mmol) in THF (10 mL) was added dropwise and stirred for 0.5 h. Dropwise adding D ₂ O (1 mL) and stirring was continued for 1 hour. Quenching with water, regulating pH to 6 with dilute hydrochloric acid, and extracting with ethyl acetate. Dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give N- (2- (7-methoxynaphthalen-1-yl-3-d) ethyl) acetamide (87 mg, yield 57%).

MS m/z(ESI):245.1[M+H] ⁺ .

And a third step of: preparation of N- (2- (7-hydroxynaphthalen-1-yl-3-d) ethyl) acetamide

N- (2- (7-Methoxynaphthalen-1-yl-3-d) ethyl) acetamide (80 mg,0.33 mmol) was dissolved in dichloromethane (10 mL), cooled to 0deg.C under nitrogen protection, and BBr was added dropwise ₃ (270mg，1.1mmol)Stirring for 2 hours at room temperature. Adding NaHCO ₃ The aqueous solution was quenched and extracted with dichloromethane. Washed with water and 10% aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give N- (2- (7-hydroxynaphthalen-1-yl-3-d) ethyl) acetamide (55 mg, yield 73%).

MS m/z(ESI):231.1[M+H] ⁺ .

Fourth step: preparation of N- (2- (7-isopropoxy-naphthalen-1-yl-3-d) ethyl) acetamide

N ₂ Cs was added to DMF (3 mL) of N- (2- (7-hydroxynaphthalen-1-yl-3-d) ethyl) acetamide (50 mg,217.13 mol), 2-iodopropane (110.7 mg,651.4 mol) ₂ CO ₃ (141.1 mg, 434.2. Mu. Mol), potassium iodide (18 mg, 108.56. Mu. Mol) and stirred at 50℃for 12 hours. The reaction mixture was extracted with water and dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give N- (2- (7-isopropoxyhnaphthalen-1-yl-3-d) ethyl) acetamide (3 mg, yield 5%) by preparative HPLC purification.

MS m/z(ESI):273.1[M+H] ⁺ .

¹ H NMR(400MHz,Chloroform-d)δ8.04(d,J＝9.0Hz,1H),7.81(s,1H),7.75(s,1H),7.41(s,1H),7.35-7.26(m,1H),5.66(s,1H),4.75-4.70(m,1H),3.60(q,J＝6.8Hz,2H),3.20(t,J＝7.2Hz,2H),2.05(s,3H),1.30-1.28(d,J＝8.0Hz,6H).

Example 3

Preparation of N- (2- (7-cyclopropoxy-naphthalen-1-yl-3-d) ethyl) acetamide

Preparation of N- (2- (7-Cyclopropyloxynaphthalen-1-yl-3-d) ethyl) acetamide reference example 2.

MS m/z(ESI):271.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO)δ8.01(s,1H),7.93(dd,J＝9.9,2.3Hz,1H),7.80(m,J＝13.3,5.4Hz,1H),7.72(d,J＝3.1Hz,1H),7.44(s,1H),7.01-6.94(m,1H),4.05–3.99(m,1H),3.37(d,J＝8.0Hz,2H),3.14(t,J＝7.4Hz,2H),1.81(s,3H),0.91(q,J＝5.7Hz,2H),0.72(d,J＝7.1Hz,2H).

Example 4

Preparation of N- (2- (7-cyclopropyloxy-3-fluoronaphthalen-1-yl) ethyl) acetamide

The substrate N- (2- (7-methoxy-1-naphthyl) ethyl) acetamide (14.6 g,60.0 mmol) was dissolved in glacial acetic acid (120 mL), heated to 85deg.C (oil bath temperature), and a solution of bromine (11.51 g,72.0mmol,3.69 mL) in AcOH (30 mL) was added dropwise. After the completion of the dropwise addition, the mixture was heated and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (500 mL), extracted with ethyl acetate (200 mL. Times.3), the organic layers were combined, washed with saturated NaCl (150 mL. Times.3), and the organic layer Na ₂ SO ₄ Drying, concentration gave a crude product which was purified by reverse phase to give N- (2- (7-methoxy-3-bromonaphthalen-1-yl) ethyl) acetamide as a white solid (12.0 g, 62% yield).

MS m/z(ESI):322.1[M+H] ⁺ ,324.1[M+H+2] ⁺ .

And a second step of: preparation of N- (2- (7-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethyl) acetamide

The substrate N- [2- (3-bromo-7-methoxy-1-naphthyl) ethyl]Acetamide (1.61 g,5.0 mmol), pinacol borate (2.54 g,7.9 mmol) and potassium acetate (1.47 g,15.0 mmol) were dissolved in anhydrous dioxane (45 mL)) In the process, nitrogen is replaced three times, pd (dppf) Cl is added ₂ (731 mg,1.0 mmol) was heated to 90℃and reacted for 2 hours. The reaction solution was concentrated to obtain a crude product, and the target compound N- (2- (7-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethyl) acetamide (1.6 g, yield 87%) was obtained as a yellow solid by column chromatography purification.

MS m/z(ESI):370.1[M+H] ⁺ .

And a third step of: preparation of N- (2- (7-methoxy-3- (boronic acid) naphthalen-1-yl) ethyl) acetamide

The substrate N- (2- (7-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethyl) acetamide (1.4 g,3.8 mmol) was dissolved in acetone (40 mL) and water (40 mL) and ammonium acetate (1.46 g,19.0 mmol) and NaIO were added ₄ (4.05 g,19.0 mmol). Heated to 25℃and reacted for 4 hours. The reaction solution was concentrated to obtain a crude product, the mixed solvent (THF: ea=1:1) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by column chromatography to obtain the objective compound N- (2- (7-methoxy-3- (boronic acid) naphthalen-1-yl) ethyl) acetamide (766 mg, yield 70%) as a yellow solid.

MS m/z(ESI):286.1[M-H] ^- .

Fourth step: preparation of N- [2- (3-fluoro-7-methoxy-1-naphthyl) ethyl ] acetamide

Reagent NaOH (121 mg,3.0 mmol) was dissolved in MeOH (10 mL) at room temperature, after which substrate N- (2- (7-methoxy-3- (boronic acid) naphthalen-1-yl) ethyl) acetamide (720 mg,2.5 mmol) was added and then stirred at 25℃for 15 min. Then, the reaction mixture was cooled to 0℃and AgOTf (1.94 g,7.5 mmol) was added thereto, followed by stirring at 0℃for 30 minutes. Then, the reaction solution was concentrated in solvent at 0℃with an oil pump, and azeotropically removed with acetone (5 mL. Times.3) by solventResidual methanol to obtain crude product. The crude product was dissolved in acetone (10 mL) and activated 3A molecular sieve (350 mg) was added followed by F-TEDA-BF ₄ (935 mg,2.6 mmol). Then stirred at 0℃for 1 hour. The reaction solution was slowly added to 100mL of water, extracted with ethyl acetate (150 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by column chromatography to give N- [2- (3-fluoro-7-methoxy-1-naphthyl) ethyl group]Acetamide (214 mg, 33% yield).

MS m/z(ESI):262.1[M+H] ⁺ .

Fifth step: preparation of N- [2- (3-fluoro-7-hydroxy-1-naphthyl) ethyl ] acetamide

The substrate N- [2- (3-fluoro-7-methoxy-1-naphthyl) ethyl]Acetamide (241 mg, 922.3. Mu. Mol) was dissolved in anhydrous dichloromethane (10 mL), cooled to 0deg.C under nitrogen substitution protection, and BBr was added dropwise ₃ (1.84 mmol,3.0 mL) and stirring was continued for 30 min after the addition. The reaction was quenched by dropwise addition to 100mL of water followed by addition of 100mL of saturated NaHCO ₃ The aqueous solution was extracted with dichloromethane (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the crude product. Purifying by column chromatography to obtain target compound N- [2- (3-fluoro-7-hydroxy-1-naphthyl) ethyl]Acetamide (204 mg, 89% yield).

MS m/z(ESI):248.1[M+H] ⁺ .

Sixth step: preparation of N- (2- (7-cyclopropyl-3-fluoronaphthalen-1-yl) ethyl) acetamide

The substrate N- [2- (3-fluoro-7-hydroxy-1-naphthyl) ethyl]Acetamide (49 mg,0.2 mmol) and cyclopropyl bromide (121 mg,1.0 mmol) were dissolved in NMP (1 mL), placed in a 5.0mL microwave tube, and Cs was added ₂ CO ₃ (98 mg, 300. Mu. Mol) and KI (50 mg, 300. Mu. Mol). The reaction was carried out at 180℃for 2 hours with microwaves. Concentrating the reaction solution, and removing the solvent to obtain a crude productThe product N- (2- (7-cyclopropyl-3-fluoronaphthalen-1-yl) ethyl) acetamide (10 mg, 17% yield) was a yellow liquid.

MS m/z(ESI):288.1[M+H] ⁺ .

1H NMR(400MHz,DMSO)δ8.07(s,1H),7.82(dd,J＝13.3,5.4Hz,2H),7.52(dd,J＝9.9,2.3Hz,1H),7.28–7.21(m,2H),4.05–3.99(m,1H),3.37(d,J＝8.0Hz,2H),3.14(t,J＝7.4Hz,2H),1.81(s,3H),0.91(q,J＝5.7Hz,2H),0.72(d,J＝7.1Hz,2H).

Example 5

Preparation of N- (2- (7-cyclopropyloxy-3-chloronaphthalen-1-yl) ethyl) acetamide

The first step: preparation of N- (2- (7-cyclopropyl-3-chloronaphthalen-1-yl) ethyl) acetamide

To a solution of N- (2- (7-cyclopropyl-3-bromonaphthalen-1-yl) ethyl) acetamide (20 mg, 57. Mu. Mol) in DMF (2 mL) under nitrogen was added CuCl (113 mg,1.14 mmol), and the mixture was stirred at 140℃for 3 hours under nitrogen to complete the reaction. The reaction mixture was extracted with saturated brine and dichloromethane (3×10 ml). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and then subjected to acid treatment to give N- (2- (7-cyclopropyl-3-chloronaphthalen-1-yl) ethyl) acetamide (7 mg, yield 38%).

MS m/z(ESI):304.1[M+H] ⁺ ,306.1[M+H+2] ⁺ .

¹ H NMR(400MHz,DMSO)δ8.07(s,1H),7.84(dd,J＝5.4,3.4Hz,2H),7.80(s,1H),7.35(d,J＝2.0Hz,1H),7.26(dd,J＝9.0,2.3Hz,1H),4.07–4.00(m,1H),3.37(s,2H),3.16–3.09(m,2H),1.81(s,3H),0.92(d,J＝7.3Hz,2H),0.73(d,J＝7.1Hz,2H).

Example 6

Preparation of N- (2- (7-cyclopropyloxy-3-bromonaphthalen-1-yl) ethyl) acetamide

The first step: preparation of N- (2- (7-hydroxy-3-bromonaphthalen-1-yl) ethyl) acetamide

To a solution of N- (2- (7-methoxy-3-bromonaphthalen-1-yl) ethyl) acetamide (3.3 g,10.24 mmol) in dichloromethane (30 mL) at 0deg.C under nitrogen was added dropwise BBr ₃ (1M, 20.48 mL), stirred at 30deg.C for 1 hour, and reacted completely. Pouring the mixture into saturated NaHCO at 0deg.C ₃ In aqueous solution, dichloromethane-methanol (10/1) was extracted. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give N- (2- (7-hydroxy-3-bromonaphthalen-1-yl) ethyl) acetamide (3 g, 95% yield).

MS m/z(ESI):308.1[M+H] ⁺ ,310.1[M+H+2] ⁺ .

And a second step of: preparation of N- (2- (7-cyclopropyl-3-bromonaphthalen-1-yl) ethyl) acetamide

N- (2- (7-hydroxy-3-bromonaphthalen-1-yl) ethyl) acetamide (2.5 g,8.11 mmol), potassium iodide (134 mg,0.81 mmol) and Cs under nitrogen ₂ CO ₃ Bromocyclopropane (1.96 g,16.22 mmol) was added to DMF (10 mL) (5.27 g,16.2 mmol) and the mixture was stirred with microwaves at 170℃for 4 hours to complete the reaction. The reaction solution was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [ dichloromethane/methanol=1/0 to 50/1 ] ]N- (2- (7-cyclopropyl-3-bromonaphthalen-1-yl) ethyl) acetamide (1.3 g, 46% yield) was obtained as a yellow oil.

MS m/z(ESI):348.1[M+H] ⁺ ,350.1[M+H+2] ⁺ .

¹ H NMR(400MHz,DMSO)δ8.08(s,1H),8.00(s,1H),7.86–7.78(m,2H),7.46(s,1H),7.25(dd,J＝8.9,2.0Hz,1H),4.08–3.99(m,1H),3.35(d,J＝7.6Hz,2H),3.16–3.07(m,2H),1.81(s,3H),0.92(q,J＝6.1Hz,2H),0.72(s,2H).

Example 7

Preparation of N- (2- (7-cyclopropyloxy-3-methylnaphthalen-1-yl) ethyl) acetamide

The first step: preparation of N- (2- (7-cyclopropyl-3-methylnaphthalen-1-yl) ethyl) acetamide

Substrate N- (2- (7-cyclopropyl-3-bromonaphthalen-1-yl) ethyl) acetamide (104 mg,0.3 mmol), cs ₂ CO ₃ (293 mg, 900. Mu. Mol) and trimethyl borate (75 mg, 720. Mu. Mol, 83.87. Mu.L) were dissolved in anhydrous dioxane (5 mL) and water (1 mL), nitrogen was replaced three times, and Pd (dppf) Cl was added ₂ (44 mg, 60. Mu. Mol) was heated to 110℃for 4 hours. The reaction solution was concentrated to obtain a crude product, which was extracted with water, ethyl acetate (80 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, which was purified by column chromatography to obtain N- (2- (7-cyclopropyl-3-methylnaphthalen-1-yl) ethyl) acetamide (24 mg, yield 27%) as a white solid product, which was purified by preparative HPLC.

MS m/z(ESI):284.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl3)δ7.65(dd,J＝17.5,5.3Hz,2H),7.46(s,1H),7.16(dd,J＝10.7,3.9Hz,2H),3.93–3.87(m,1H),3.64(dd,J＝13.2,6.7Hz,2H),3.22(t,J＝7.0Hz,2H),2.46(s,3H),1.94(s,3H),0.92–0.87(m,2H),0.82(t,J＝6.3Hz,2H).

Example 8

Preparation of N- [2- [ 3-bromo-7- (cyanomethoxy) -1-naphthyl ] ethyl ] acetamide

The first step: preparation of N- [2- [ 3-bromo-7- (cyanomethoxy) -1-naphthyl ] ethyl ] acetamide

N- [2- (3-bromo-7-hydroxy-1-naphthyl) ethyl ] acetamide (50 mg, 162.25. Mu. Mol), bromoacetonitrile (58 mg, 486. Mu. Mol) and potassium carbonate (67 mg, 486. Mu. Mol) were stirred in acetonitrile (5 mL) at 80℃for 1 hour. The reaction solution was filtered, washed with ethyl acetate, and the organic phase was concentrated and purified by flash column chromatography (dichloromethane/methanol=15/1) to give N- [2- [ 3-bromo-7- (cyanomethoxy) -1-naphthyl ] ethyl ] acetamide as a white solid (40 mg, yield 68%).

MS m/z(ESI):347.0[M+H] ⁺ ，349.0[M+H+2] ⁺ .

¹ H NMR(400MHz,DMSO)δ8.18–8.10(m,1H),8.06(s,1H),7.93(d,J＝9.0Hz,1H),7.83-7.82(m,1H),7.52-7.51(m,1H),7.38–7.29(m,1H),5.39(s,2H),3.36–3.25(m,2H),3.14(t,J＝8Hz,2H),1.83(s,3H).

Example 9

Preparation of N- (2- (3-chloro-7- (cyanomethoxy) naphthalen-1-yl) ethyl) acetamide

The first step: preparation of N- (2- (3-chloro-7-hydroxynaphthalen-1-yl) ethyl) acetamide

N- [2- (3-bromo-7-hydroxy-1-naphthyl) ethyl ] acetamide (130 mg, 422. Mu. Mol) and cuprous chloride (418 mg,4.22 mmol) were stirred in N, N-dimethylformamide (3 mL) at 140℃for 1 hour with microwaves. To the reaction solution were added 30mL of water and ethyl acetate (20 mL), filtered, extracted with ethyl acetate (20 mL. Times.2), and the organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate and concentrated to give N- (2- (3-chloro-7-hydroxynaphthalen-1-yl) ethyl) acetamide as a yellow oil (70 mg, yield 63%).

MS m/z(ESI):264.1[M+H] ⁺ ，266.1[M+H+2] ⁺ .

And a second step of: preparation of N- (2- (3-chloro-7- (cyanomethoxy) naphthalen-1-yl) ethyl) acetamide

N- [2- (3-chloro-7-hydroxy-1-naphthyl) ethyl ] acetamide (70 mg, 265. Mu. Mol), bromoacetonitrile (95 mg, 796. Mu. Mol) and potassium carbonate (110 mg, 796. Mu. Mol) were stirred in acetonitrile (3 mL) at 80℃for 1 hour. The reaction solution was filtered, washed with ethyl acetate, and the organic phase was concentrated and purified by flash column chromatography (dichloromethane/methanol=15/1) to give N- (2- (3-chloro-7- (cyanomethoxy) naphthalen-1-yl) ethyl) acetamide as a white solid (30 mg, yield 35%).

MS m/z(ESI):303.1[M+H] ⁺ ,305.1[M+H+2] ⁺ .

¹ H NMR(400MHz,DMSO)δ8.20–8.09(m,1H),7.96–7.88(m,2H),7.86–7.80(m,1H),7.43–7.38(m,1H),7.37–7.30(m,1H),5.39(s,2H),3.43–3.33(m,2H),3.15(t,J＝8Hz,2H),1.83(s,3H).

Example 10

Preparation of N- (2- (7- (cyanomethoxy) -3-methyl-1-naphthyl) ethyl) acetamide

The first step: preparation of N- (2- (7-hydroxy-3-methyl-naphthalen-1-yl) ethyl) acetamide

N- [2- (3-bromo-7-hydroxy-1-naphthyl) ethyl group]Acetamide (100 mg, 324. Mu. Mol), trimethylboroxine (122 mg, 973. Mu. Mol), cs ₂ CO ₃ (211mg，649μmol)，Pd(dppf)Cl ₂ DCM (27 mg, 32. Mu. Mol) in dioxane (3 mL) and water (0.3 mL) under nitrogen was stirred for 1 h at 100deg.C. LC-MS showed the reaction was complete. The reaction solution was directly used for the next reaction.

MS m/z(ESI):244.1[M+H] ⁺ .

And a second step of: preparation of N- (2- (7- (cyanomethoxy) -3-methyl-1-naphthyl) ethyl) acetamide

To the reaction solution of the above step, bromoacetonitrile (117 mg, 974. Mu. Mol) and potassium carbonate (135 mg, 974. Mu. Mol) were added, and the mixture was stirred at 80℃for 1 hour. The reaction solution was filtered, washed with ethyl acetate, and the organic phase was concentrated and purified by flash column chromatography (dichloromethane/methanol=0% -3%) to give the crude product as a white solid of N- (2- (7- (cyanomethoxy) -3-methyl-1-naphthyl) ethyl) acetamide (23 mg, 24% yield).

MS m/z(ESI):283.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO)δ8.18–8.07(m,1H),7.82(d,J＝8Hz,1H),7.79–7.74(m,1H),7.54(s,1H),7.29–7.18(m,2H),5.35(s,2H),3.47–3.27(m,2H),3.18–3.01(m,2H),2.42(s,3H),1.85(s,3H).

Biological test evaluation

The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.

Test example 1 determination of the Effect of the Compounds of the invention on calcium flux in cells stably expressing the MT1/MT2 receptor

1. The purpose of the experiment is as follows:

The compounds were tested for agonism of HEK293-MT1/HEK293-MT2 cell activity.

2. Laboratory instruments and reagents:

2.1 instrument:

384 well-assay plate (Corning: 3764);

384 well-Echo compound plate (Labcyte: LP-0200);

384 well-compound plates (PE: 6008590);

Bravo Tip(Agilent：10734-202)；

FLIPR Tip(Molecular Device：9000-0764)；

plate reader FLIPR Tetra (Molecular Device);

pipetting stations Bravo (Agilent) and ECHO 550 (labcytoe);

liquid applicator Multidrop Combi (ThermoFisher).

2.2 reagents:

DMEM,high glucose(Gibco：12100)；

fetal bovine serum (Biosera: FB-1058/500);

P/S(Biosera：XC-A4122)；

5X Matrigel(Corning：354230)；

HBSS(Sigma：H1387)；

HEPES(Invitrogen：15630080)；

Fluo-8 AM(AAT Bioquest：21080)；

Probenecid(Sigma：P8761)；

Pluronic F-127(Sigma：P2443-250G)；

1000X Fluo-8 AM (2 mM): dissolving Fluo-8 AM in DMSO, oscillating for 1-2min, packaging, and storing at-20deg.C;

complete medium: dmem+10% fbs+1X P/S;

cell inoculation medium: dmem+10% fbs+1xps;

experiment buffer 1:1X HBSS+20mM HEPES+1mM Probenecid+0.025%Pluronic F-127;

experiment buffer 2:1X HBSS+20mM HEPES+0.075% Pluronic F-127;1X Matrigel: diluting 5X Matrigel with DMEM;

cell lines:

HDB HEK293-MT1；

HDB HEK293-MT2。

3. the experimental method comprises the following steps:

1) HEK293-MT1/HEK293-MT2 cell line was cultured in complete medium at 37℃with 5% CO ₂ To 70 to 90 percent of fusion degree.

2) 384 well-cell plates were coated with 1X Matrigel, 5uL per well, and room temperature for 10-30 min.

3) The cell digestion treatment was resuspended in cell seeding medium, seeded with 8,000 cells/well/20. Mu.L to 384 well-cell plates, and incubated at 37℃with 5% CO ₂ Culturing for 24 hours.

4) The cell culture plates were removed from the CO2 incubator and equilibrated for 10 minutes at room temperature.

5) 1000 XFluo-8 AM was removed and diluted to 1 XFluo-8 AM, 2. Mu.M, with assay buffer 1 equilibrated to room temperature.

6) The medium of the cell culture plate was removed, 20. Mu.L of 1 XFluo-8 AM was added to each well, and after centrifugation at 300rpm at room temperature for 60 seconds, the cells were incubated at room temperature for 1 hour in the absence of light.

7) Positive control compound and test compound working solution (3X) are prepared:

(1) the compounds were diluted 11 concentration spots on 384 well-Echo compound plates (LABCYTE: LP-0200) with the apparatus Bravo;

(2) then 90nL of compound per well (compound storage concentration, e.g.10 mM at peak concentration) was transferred to 384 well-compound plates (PE: 6008590) using the apparatus ECHO;

(3) 30. Mu.L of assay buffer 2 to 384 well-plates (PE: 6008590) were added with Multidrop Combi, and the positive control compound and test compound were diluted to 30. Mu.M (3X) and left at room temperature for use.

8) mu.L of diluted 3X compound was added to the experimental wells of the corresponding 384-well cell plate using FLIPR Tetra, while the collected data were read.

4. The experimental data processing method comprises the following steps:

FLIPR Tetra reads and collects fluorescence signal value (RFU), takes the maximum RFU value, calculates the data of percent activation {% activation = (RFUsample-RFUlow control)/(RFUhigh control-RFUlow control) ×100} according to the read values of the Low control (DMSO control) and the High control (100 nM positive compound) experimental group, calculates the EC of the compound by using the XLfit percentage activation and 11 point concentration data to parameter nonlinear logic formula, wherein the concentration of the compound to be tested is 10 mu M to 0.17nM after 3 times dilution of the reaction system ₅₀ Values.

5. Experimental results:

EC of Table 14 Compounds on HEK293-MT1/HEK293-MT2 cells ₅₀ Value of

Note that: "NA" means undetected.

6. Conclusion of experiment:

the compounds of the examples shown in the present invention show good agonistic activity in experiments of the effect of cells stably expressing MT1 and MT2 receptors on calcium flux.

Test example 2 Compounds of the invention are stably expressing 5-HT _2C Determination of the influence of recipient cells on calcium flux

1. The purpose of the experiment is as follows:

detection of compound pair HEK293-5HT _2C Antagonism of cellular activity.

2. Laboratory instruments and reagents:

2.1 instrument:

384 well-assay plate (Corning: 3764);

384 well-Echo compound plate (Labcyte: LP-0200);

384 well-compound plates (PE: 6008590);

Bravo Tip(Agilent：10734-202)；

FLIPR Tip(Molecular Device：9000-0764)；

plate reader FLIPR Tetra (Molecular Device);

pipetting stations Bravo (Agilent) and ECHO 550 (labcytoe);

liquid applicator Multidrop Combi (ThermoFisher).

2.2 reagents:

DMEM,high glucose(Gibco：12100)；

fetal bovine serum (Biosera: FB-1058/500);

P/S(Biosera：XC-A4122)；

5X Matrigel(Corning：354230)；

HBSS(Sigma：H1387)；

HEPES(Invitrogen：15630080)；

Fluo-8 AM(AAT Bioquest：21080)；

Probenecid(Sigma：P8761)；

Pluronic F-127(Sigma：P2443-250G)

complete medium: dmem+10% fbs+1X P/S;

cell inoculation medium: dmem+10% fbs+1xps;

liquid-changing culture medium: dmem+1X P/S;

experiment buffer 1:1X HBSS+20mM HEPES+1mM Probenecid+0.025%Pluronic F-127;

cell lines: HDB HEK293-5HT _2C 。

3. The experimental method comprises the following steps:

1)HEK293-5HT _2C the cell strain is cultured in complete culture medium at 37 ℃ and 5% CO ₂ To 70 to 90 percent of fusion degree.

2) 384 well-cell plates were coated with 1X Matrigel, 5. Mu.L per well, and room temperature for 10-30 min.

4) The cells were observed under a microscope to have attached. The inoculation medium was removed and 20. Mu.L of serum-free medium pre-warmed to 37℃was added to each well, at 37℃with 5% CO ₂ Incubation was carried out overnight (18 hours).

5) Cell culture plate was removed from CO ₂ The incubator was removed and equilibrated at room temperature for 10 minutes.

6) 1000 XFluo-8 AM was removed and diluted to 1 XFluo-8 AM, 2. Mu.M, with assay buffer 1 equilibrated to room temperature.

7) The medium of the cell culture plate was removed, 20. Mu.L of 1 XFluo-8 AM was added to each well, and after centrifugation at 300rpm at room temperature for 60 seconds, the cells were incubated at room temperature for 1 hour in the absence of light.

8) Positive control compound and test compound working solution (3X) are prepared:

9) mu.L of diluted 3X compound was added to the experimental wells of the corresponding 384-well cell plate using FLIPR Tetra, while the collected data were read.

4. The experimental data processing method comprises the following steps:

FLIPR Tetra reads and collects fluorescence signal value (RFU), takes the maximum RFU value, calculates the data of percent activation {% activation = (RFUsample-RFUlow control)/(RFUhigh control-RFUlow control) ×100} according to the read values of the Low control (DMSO control) and the High control (100 nM positive compound) experimental group, calculates the IC of the compound by using the XLfit percentage activation and 11 point concentration data to parameter nonlinear logic formula, wherein the concentration of the compound to be tested is 10 mu M to 0.17nM after 3 times dilution of the reaction system ₅₀ Values.

5. Experimental results:

table 15 Compound pair HEK293-5HT _2C IC of cell ₅₀ Value of

6. Conclusion of experiment:

the compounds of the examples of the present invention are shown to be stable in the expression of 5HT _2C The receptor cells show a certain antagonism in the experiments of the influence of the receptor cells on the calcium flux.

Test example 3, rat pharmacokinetic assay

3.1. Study purposes:

the pharmacokinetic behavior of the compounds of the invention in vivo (plasma) in rats by intravenous and oral administration was studied using SD rats as test animals.

3.2. Test protocol

3.2.1 test drug:

the compound of the embodiment of the invention is self-made.

3.2.2 test animals:

SD rats were 3 in each group, male. Shanghai JieJie laboratory animal Co., ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

3.2.3 preparation of drug:

intravenous drug formulation: (5%DMSO+10%Solutol HS15+85%PBS preparation method)

Weighing the compound of the embodiment, firstly adding 5% DMSO, carrying out vortex and ultrasonic treatment for 2min to completely dissolve the compound, then adding 10% Solutol HS15, carrying out vortex and ultrasonic treatment for 2min to completely dissolve the compound, finally adding 85% PBS, and carrying out vortex and ultrasonic treatment for 5min to obtain colorless transparent clear solution with the concentration of 0.2mg/mL.

The preparation of orally administered medicine comprises the following steps: (0.5% CMC-Na (1% Tween 80))

5g of sodium carboxymethylcellulose (CMC-Na, viscosity: 800-1200 Cps) was weighed, dissolved in 1000mL of purified water, and 10g of Tween80 was added. Mixing and stirring uniformly to obtain a clear solution.

The compound of the example was weighed and dissolved in the solution, shaken well and sonicated for 15 minutes to give a colorless clear solution at a concentration of 0.5mg/mL.

3.2.4 dosing:

intravenous administration:

SD rats were dosed at 1mg/kg in 3 groups, IV each after one night of fasting, and 5mL/kg of dosing volume.

Oral administration:

SD rats were 3 animals per group, and had a PO dose of 5mg/kg and a dosing volume of 10mL/kg after one night of fasting.

3.2.5 sample collection:

intravenous administration:

blood is collected for 0.2mL at 0h,0.083h,0.25h,0.5h,1.0h,2.0h and 4.0h jugular vein before and after administration, and is placed in an EDTA-2K test tube, centrifuged at 6000rpm at 4 ℃ for 6min to separate blood plasma, and the blood plasma is stored at-80 ℃; the feed was fed 4h after administration.

Oral administration:

blood is collected for 0.2mL at the jugular vein for 0.25h,0.5h,1.0h,2.0h and 4.0h before and after administration, and the obtained mixture is placed in an EDTA-2K test tube, centrifuged at 6000rpm for 6min at 4 ℃ to separate blood plasma, and the blood plasma is preserved at-80 ℃; the feed was fed 4h after administration.

3.3 experimental results:

the final measurement results were obtained by LCMS/MS method, see tables 16 and 17

Table 16: rat intravenous administration pharmacokinetic parameters of the Compounds of the invention

Table 17: oral administration pharmacokinetic parameters of the Compounds of the invention in rats

3.4 experimental conclusion:

the data show that the compounds of the examples of the present invention have good exposure and bioavailability in rat plasma at an oral dose of 5 mg/kg.

Test example 4 CYP enzyme phenotype identification test

4.1 purpose of experiment

And (3) adopting a CYPs recombinase incubation system, and primarily judging the main metabolic enzymes of the compound in the metabolic process of the human body according to the metabolic conditions of different subtype CYPs recombinases on the compound.

4.2 Experimental procedure

4.2.1 preparation of solution:

10.0mM NADPH, 16.7mg NADPH (reduced nicotinamide adenine dinucleotide phosphate) was weighed to 2mL in 100mM phosphate buffer. Each CYPs recombinase was diluted to 12.5pmol/L with 100mM phosphate buffer, and mixed well.

Preparing a reaction solution of a compound to be tested:

the compound of the test example was weighed, diluted to 10mM with DMSO and then diluted to 10. Mu.M with 100mM phosphate buffer.

4.2.2 experimental procedure:

1. in a 96-well plate, 400. Mu.L of recombinase and 50. Mu.L of test compound are added and pre-incubated for 10min.

2. NADPH 50. Mu.L was added.

3. At 0,5,10,15,20 and 30min, 50. Mu.L of each of these was removed and 200. Mu.L of acetonitrile stop solution containing an internal standard was added.

4. And (5) centrifuging and sampling.

4.3 experimental results:

table 18: example Compound CYP enzyme phenotype identification results

4.4 experimental conclusion:

the above data shows that compounds of the present examples have reduced metabolic dependence on CYP1A2 and that the increased metabolic proportion of other CYP enzyme subtypes to the compounds of the present examples can reduce compound variability.

Test example 5 CYP enzyme single-point inhibition test

5.1 purpose of experiment

And the inhibition condition of the compound on the CYP450 enzyme subtype is rapidly predicted by a single-point method by adopting a human liver microsome incubation system.

5.2 Experimental procedure

5.2.1 preparation of solution:

2.5mM NADPH, 4.165mg NADPH (reduced nicotinamide adenine dinucleotide phosphate) was weighed to 2mL in 100mM phosphate buffer. 0.25mg/mL microsomes, 50. Mu.L of 20mg/mL microsomes, and 4mL of 100mM phosphate buffer were added and mixed well.

Preparing a reaction solution of a compound to be tested:

the compound of the test example was weighed, diluted to 10mM with DMSO and then diluted to 100. Mu.M with 100mM phosphate buffer.

5.2.2 experimental procedure:

1. in a 96-well plate, 40. Mu.L of liver microsomes, 10. Mu.L of substrate, 10. Mu.L of test compound were added and pre-incubated for 3min.

2. NADPH 40. Mu.L was added.

3. 300. Mu.L of acetonitrile stop solution containing an internal standard was added at 20 min.

4. And (5) centrifuging and sampling.

5.3 experimental results:

table 19: example Compound CYP enzyme Single Point inhibition results

Note that:

strong inhibition: IC (integrated circuit) ₅₀ <1. Mu.M; moderate inhibition: 1 mu M<IC ₅₀ <10. Mu.M; weak inhibition: IC (integrated circuit) ₅₀ >Conclusion of 10 μΜ 5.4 experiment:

the data show that the compounds of the examples of the present invention have strong inhibition to CYP1A2, no strong inhibition to other CYP enzyme subtypes, and little risk of DDI (drug interactions).

Test example 6, plasma protein binding Rate experiment

6.1 experimental purposes:

the purpose of this experimental procedure was to detect plasma protein binding of the compounds of the examples in plasma.

6.2 laboratory instruments and materials:

liquid phase mass spectrometer, centrifuge, vortex, pipette, continuous liquid feeder, 96-well plate, tissue homogenizer (used in tissue sample analysis), 50% methanol water solution, and acetonitrile solution of internal standard and blank matrix (plasma, urine or tissue homogenate, etc.) are added.

6.3 experimental procedure:

6.3.1 preparation of stock solution of analyte A

The compound of the example was formulated with DMSO as a 1mM solution A.

6.3.2 preparation of plasma solution B

Solution A was added to the plasma solution to prepare 5uM solution B.

6.3.3 Process flow

1) 200uL of solution B was added to the membrane.

2) 350uLPBS was added to the membrane.

3) Incubate in a 37℃water bath for 6h.

4) The samples were diluted and mass detected.

6.4 chromatographic conditions:

instrument: shimadzu LC-20AD;

chromatographic column: phenomenexC18 (50 x 4.6mm,5 μm particle size);

mobile phase: a: acetonitrile, 0.1% formic acid solution, 0-0.5 min:5% of A to 90% of A, and 2.0 to 2.1min:90% A to 5% A; flow rate: 0.8mL/min; run time: 5.0min; sample injection volume: 5. Mu.L. 6.5 Mass Spectrometry conditions:

An instrument, namely an API4000 type liquid chromatography-mass spectrometer, AB company in the United states;

the ion source is an electrospray ionization source (ESI);

drying gas (N) ₂ ) The temperature is 500 ℃;

the electrospray voltage is 5500V;

the detection mode is positive ion detection;

the scanning mode is a selective reaction monitoring (MRM) mode; the scan time was 0.1s.

6.6 experimental results:

table 20: example Compounds plasma protein binding Rate (%)

Numbering device	Human body	Rat (rat)	A mouse	Dogs
					Example 1A	93.6	89.6	93.5	98.6
Example 5	99.9	99.4	/	/
					Example 6	100.0	99.7	/	/
Example 9	97.6	97.1	94.8	99.2

6.7 experimental conclusion:

the compounds of the examples of the present invention show high plasma protein binding rates with small species differences.

Test example 7 evaluation of efficacy in rat acquisition helplessness and sugar water preference model

7.1 Experimental purposes:

the objective of this experiment was to evaluate the antidepressant effect of the test compounds in the SD rat acquisition helplessness (LH model) and the syrup preference model.

7.2 experimental animals:

SD rats, male, 7-8 weeks old, 136.

7.3 laboratory apparatus:

TABLE 21 Main experiment instrument

7.4 experimental procedure:

7.4.1. adaptation to

After 136 SD male rats reached the experimental facility, the experiment was started after one week of adaptation in the facility, and was adapted in the experimental room for 2 days before starting training.

7.4.2. Training

The animals were placed in the shuttle box and the animals were confined to one side of the shuttle box and the sole received 60 current levels of 0.8mA for 15 seconds with 2 seconds of acoustic stimulation before each shock was initiated, with a 20 second interval between the two.

7.4.3. Screening

After the animals were placed in the shuttle box, the shuttle door was opened and the animals were allowed to freely shuttle within the box, the sole received 30 shots of current of 0.6mA for a duration of 10 seconds (if the animals escaped to the other side during the current duration, the shock stopped), 2 seconds of sound and light stimulation were provided before each shock started, the interval between the two shots was 20 seconds, and recordings were made:

number of active evasions: actively evade to the non-electric shock side under the stimulation of sound and light

Passive escape times: after the sound and illumination stimulation is finished, the escape failure times from the electric shock continuous process to the non-electric shock side are counted: still not evade after electric shock is finished

Animals with failure times of escape over 20 are considered to be unoccupied and can be used for drug screening 7.4.4. Group

Immediately grouping the animals after finishing the learning unassisted screening, and randomly grouping the screened learning unassisted animals according to the escape failure times for compound screening test.

7.4.5. Administration of drugs

The first administration was performed after the control group and the compound group were completely divided, and the administration was continued for seven days, with a volume of 10mL/kg. The positive compounds (imipramine group) were administered four consecutive days before the start of the first learning unassisted test, with a dosing volume of 2mL/kg.

7.4.6. Testing

7.4.6.1 learning helplessness test (LH model)

The study performance unassisted tests were performed on days 2 and 5 of compound dosing (days 1 and 4 of positive compound dosing), 0.5 hours after positive compound dosing, and the number of shock evasion tests, rat evasion failures and shuttles to rats was recorded for analysis after 0.25 or 0.5 hours of test compound dosing.

Experimental results:

table 22: example Compound LH experimental rats were tested for number of evasion failures and shuttling times

Numbering device	Number of escape failures	Shuttle times
			Vehicle	24.2	5.8
Prominozine (64 mg/kg)	10.7	19.9
			Example 1A (20 mg/kg)	19.9	10.5
Example 1A (50 mg/kg)	20.0	10.2
			Example 9 (20 mg/kg)	24.8	5.2
Example 9 (50 mg/kg)	26.5	3.6

Conclusion of experiment:

in the LH model, the compounds of the examples have a tendency to reduce the rate of escape failure in rats.

7.4.6.2 sugar water preference test

After day 4 of compound dosing, animals were given two bottles of plain water acclimation;

on the 5 th day of compound administration, after the end of the acquisition helplessness test, one bottle of ordinary water is replaced by 1% syrup, and the position is replaced for 6 times within 24 hours;

after the end of the administration of the compound on day 6, the compound is fasted and water is forbidden;

1 hour after the end of the day 7 dosing of the compounds, one bottle of sugar water and one bottle of plain water were added and tested for water consumption for 1, 12 and 24 hours.

Sugar water preference rate = sugar water intake/(normal water intake + sugar water intake) ×100%

Data collection and analysis:

data were collected using Excel software. Data analysis was performed using Prism (GraphPad software, inc.) software, and Fisher's LSD multiplex comparison test data was attached using One-way ANOVA. p <0.05 was considered to be a significant difference.

Experimental results:

table 23: example compound sucrose preference experiments 12h and 24h rat sugar water preference

Note that: * p <0.05; * P <0.01

Conclusion of experiment:

in the syrup preference experiment, compared with the veccle group, the compound to be tested can obviously increase the syrup preference rate of rats for 12h and 24h, and no obvious side effect is found in the experiment.

Crystal form study of Compounds

As is well known to those of ordinary skill in the art, the compounds of the above examples demonstrate good agonistic activity at MT1 and MT2 receptors, and the crystal forms, co-crystals and co-crystals tend to have the same pharmacological and pharmacodynamic activity. Based on this, the inventors further studied the physicochemical properties of the corresponding compound crystal forms, eutectic crystals and eutectic crystal forms, but the preparation and characterization of the specific crystal forms, eutectic crystals and eutectic crystal forms do not represent limitations on the scope of the present invention, and those skilled in the art can obtain more crystals of the compound of the present invention by conventional crystallization means based on the present invention, and these crystals are all the schemes protected by the present invention. The method comprises the following steps:

1. Experimental instrument

1.1 some parameters of the physicochemical detection Instrument

1.2 liquid phase analytical instrument

Preparation of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide form A

3.5g of N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide is weighed, 15mL of ethanol is added, the mixture is heated to 50 ℃ to be dissolved until the mixture is clear, 16mL of water is added dropwise into the mixture, the mixture is naturally cooled to 25 ℃, the mixture is stirred for 16 hours and then filtered, 10mL of water is used for leaching, 3.2g of light yellow solid is obtained after vacuum drying, and the XRPD of the solid is measured, thus obtaining N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide crystal form A. A detected analysis, having an XRPD pattern as shown in figure 1 and a DSC pattern as shown in figure 2.

3. Stable crystal form confirmation experiment

3.1 Experimental purposes:

the compound N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide is found to be a relatively stable crystal form through a crystal form beating experiment and a stability investigation experiment.

3.2 experimental protocol:

organic solvent with certain solubility and water are selected, different crystal forms are suspended in a solvent system, stirred and pulped at 50 ℃ for 1 week, centrifugated, supernatant liquid is removed, and solid is dried in vacuum (-0.1 Mpa) at 50 ℃ overnight, and then XRPD, DSC and TGA of the solid are measured and compared.

3.3 experimental results:

About 20mg of N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide form A was weighed out, 100. Mu.L of solvent was added thereto, and the mixture was stirred and beaten at 50 ℃. The specific results are shown in table 24 below.

Table 24 results of experiments for confirming the stable crystal form of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide

Sequence number	Solvent(s)	Product XRPD
			1	Isopropyl alcohol	Crystal form A
2	Acetic acid isopropyl ester	Crystal form A
			3	Acetic acid ethyl ester	Crystal form A
4	Methyl tert-butyl ether	Crystal form A
			5	Toluene (toluene)	Crystal form A
6	Formic acid ethyl ester	Crystal form A
			7	Water and its preparation method	Crystal form A
8	Cyclohexane	Crystal form A
			9	N-pentane	Crystal form A
10	N-heptane	Crystal form A

Conclusion of experiment: from the above experiments, form a was stable and DSC/TGA showed that it was anhydrous.

4. Solid stability test

4.1 experimental purposes:

the physicochemical stability of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide crystal form A is examined under the conditions of 5000lx illumination, high temperature 60 ℃, high humidity 92.5% RH and high temperature and high humidity 50 ℃ 75% RH, and a basis is provided for compound storage.

4.2 experimental protocol:

taking about 2mg of N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide crystal form A, inspecting for 20 days and 30 days under the conditions of 5000lx illumination, high temperature 60 ℃, high humidity 92.5% RH and high temperature high humidity 50 ℃ 75% RH, measuring the content by using HPLC and an external standard method, and calculating the change of related substances by using a chromatographic peak area normalization method.

4.3 chromatographic parameters

4.4 experimental results:

the solid stability test results for crystalline form a of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide are shown in table 25 below:

table 25 results of solid stability experiments for N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide form A

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Conclusion of experiment: the above data indicate that form a of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide is substantially stable under conditions other than light.

5. Moisture permeability test

5.1 purpose of experiment

The hygroscopicity of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide crystal form A under different relative humidity conditions is examined, and a basis is provided for the storage of the compound crystal form.

5.2 experimental protocol:

n- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide crystal form A is placed in saturated water vapor with different relative humidity, so that the compound and the water vapor reach dynamic balance, and the percentage of moisture absorption and weight gain of the compound after the balance is calculated.

5.3 experimental results:

n- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide crystal form A has a moisture absorption and weight gain of about 0.1985% under the condition of RH80%, and has a slight moisture absorption property. The XRPD pattern of compound form a was unchanged by 2 cycles of moisture absorption and desorption at 0-95% relative humidity, i.e. form no conversion.

6. Solubility experiments in different Medium

6.1 purpose of experiment

The solubility of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide crystal form A in the mediums of pH 1-pH 8USP buffer solution, artificial simulated gastric fluid (FaSSGF), fasted artificial simulated intestinal fluid (FaSSIF), non-fasted artificial simulated intestinal fluid (FeSSIF), pure water and the like is compared, so that a basis is provided for the evaluation of the patentability.

6.2 experimental protocol:

about 1mg of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide form A was suspended in various media for 4 hours and the thermodynamic solubility of the compound was determined by HPLC, external standard method at 37 ℃.

6.3 experimental results:

the results of solubility experiments in different media are shown in table 26 below:

table 26 results of solubility experiments in different media for crystal form A of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide

solubility/Medium	Solubility of Crystal form A (mg/mL)
		pH1	0.061
pH2	0.059
		pH3	0.085
pH4	0.070
		pH5	0.072
pH6	0.058
		pH7	0.051
pH8	0.046
		H ₂ O	0.062
FaSSIF	0.068
		FeSSIF	0.115
FaSSGF	0.174

Conclusion of experiment: the data above show that crystalline form a of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide has better solubility in fasted artificial simulated intestinal fluid (FaSSIF) and non-fasted artificial simulated intestinal fluid (FeSSIF).

7. Co-crystal screening of compounds

7.1 Experimental purposes:

different ligands are selected and by appropriate crystallization methods, which ligands can form a co-crystal is detected.

7.2 experimental procedure:

7.2.1 instruments and apparatus

Name of the name	Model number	Source
			Analytical balance	XA105	METTLER TOLEDO
Ultrasonic cleaning instrument	SK5200LHC	Shanghai department ultrasonic guide instrument
			Pipetting gun	Eppendorf(20μL,100μL)	Eppendorf

7.2.2 operating procedure

200. Mu.L of a 50mg/mL sample solution of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide was prepared and placed in a 2mL sample bottle according to API: ligand = 1:1.2 molar ratio of the corresponding ligand was added and the resulting clear solution was left open to evaporation of the solvent at room temperature.

7.3 experimental results

The experimental results are shown in the following table:

table 27 compound co-crystal screening results

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Conclusion of experiment: screening to obtain N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphate eutectic A, N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphate eutectic B, N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide benzenesulfonic acid eutectic, N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide fumaric acid eutectic, N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide oxalic acid eutectic A, N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide oxalic acid eutectic B, N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide 1, 5-naphthalene disulfonic acid eutectic, N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide p-aminobenzoic acid eutectic, N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide L-proline A, N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide L-proline co-crystal B, N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide urea co-crystal A and N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide urea co-crystal B.

8 compound eutectic process preparation

8.1 experimental purposes:

and selecting a proper crystallization method according to the eutectic screening result to prepare the eutectic.

8.2 experimental procedure:

8.2.1 instruments and apparatus

Name of the name	Model number	Source
			Analytical balance	XA105	METTLER TOLEDO
Ultrasonic cleaning instrument	SK5200LHC	Shanghai department ultrasonic guide instrument
			Pipetting gun	Eppendorf(50μL,100μL，1mL)	Eppendorf

8.2.2 operating procedure

(1) Preparation of N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphoric acid cocrystal B

50mg of N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide is weighed, 300 mu L of ethyl acetate is added for dissolution and clarification, and the mixture is prepared according to the following formula 1 at room temperature: 1.2 adding 85% concentrated phosphoric acid to the mixture in a molar ratio, precipitating a white solid, stirring for 6 hours, filtering, vacuum drying the obtained solid at 50 ℃ overnight, and measuring XRPD of the solid to obtain N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphoric acid eutectic B. It has an XRPD pattern as shown in figure 4, as analyzed by detection.

(2) Preparation of N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide benzenesulfonic acid eutectic

50mg of N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide is weighed, 300 mu L of ethyl acetate is added for dissolution and clarification, and the mixture is prepared according to the following formula 1 at room temperature: 1.2 molar ratio of benzenesulfonic acid solid was added thereto, the solution was clarified first and then the solid was gradually increased, stirred for 6 hours and then filtered, and the resulting solid was dried overnight under vacuum at 50 c, and the XRPD of the solid was determined to give N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide benzenesulfonic acid co-crystal B. It has an XRPD pattern as shown in figure 5, as analyzed by detection.

(3) Preparation of N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide oxalic acid eutectic B

50mg of N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide is weighed, 300 mu L of ethyl acetate is added for dissolution and clarification, and the mixture is prepared according to the following formula 1 at room temperature: 1.2 adding oxalic acid solid in a molar ratio, stirring for 6 hours, filtering, vacuum drying at 50deg.C overnight, and measuring XRPD to obtain N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide oxalic acid eutectic B. It has an XRPD pattern as shown in figure 8, as analyzed by detection.

Claims

1. A crystalline form of a compound of formula (I), the compound having the structure:

wherein:

R ₁ or R is ₂ Independently selected from deuterium, halogen, cyano or C _1-3 An alkyl group; deuterium, fluorine, chlorine, bromine or methyl are preferred.

2. The crystalline form of a compound of claim 1, having a structure according to formula (II):

wherein:

r is selected from C _1-3 Alkyl, C _1-3 Deuterated alkyl or C _3-6 Cycloalkyl;

methyl, deuterated methyl or cyclopropyl are preferred.

3. A crystalline form of a compound according to claim 1 or 2, which is:

n- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide;

N- (2- (7-cyclopropoxy-4-fluoronaphthalen-1-yl) ethyl) acetamide;

n- (2- (7-isopropoxy-naphthalen-1-yl-3-d) ethyl) acetamide;

n- (2- (7-cyclopropoxy-naphthalen-1-yl-3-d) ethyl) acetamide;

n- (2- (7-cyclopropoxy-3-fluoronaphthalen-1-yl) ethyl) acetamide;

n- (2- (7-cyclopropoxy-3-chloronaphthalen-1-yl) ethyl) acetamide;

n- (2- (7-cyclopropoxy-3-bromonaphthalen-1-yl) ethyl) acetamide;

n- (2- (7-cyclopropoxy-3-methylnaphthalen-1-yl) ethyl) acetamide;

n- [2- [ 3-bromo-7- (cyanomethoxy) -1-naphthyl ] ethyl ] acetamide;

n- (2- (3-chloro-7- (cyanomethoxy) naphthalen-1-yl) ethyl) acetamide;

n- (2- (7- (cyanomethoxy) -3-methyl-1-naphthyl) ethyl) acetamide.

4. A crystalline form of a compound according to any one of claims 1 to 3, characterized in that the crystalline form is N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide crystalline form a;

5. A crystalline form of a compound according to claim 4,

the X-ray powder diffraction pattern of the crystal form A at least comprises one or more diffraction peaks positioned in the angles of 11.7+/-0.2 DEG, 12.8+/-0.2 DEG and 15.3+/-0.2 DEG, preferably comprises two of the diffraction peaks, more preferably comprises three of the diffraction peaks; optionally, it may further comprise at least one of 18.0±0.2°, 21.2±0.2°, 25.6±0.2°, 26.4±0.2°, 27.0±0.2°, preferably 2, 3, 4 or 5 thereof.

6. A crystalline form of a compound according to claim 5,

the X-ray powder diffraction pattern of form a optionally further comprises one or more diffraction peaks at 17.4±0.2°, 22.1±0.2°, 30.8±0.2°, 8.4±0.2°, 20.0±0.2°, 21.6±0.2° or 23.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included.

7. A crystalline form of a compound according to claim 6,

the X-ray powder diffraction pattern of form a optionally comprises one or more diffraction peaks at 11.7±0.2°, 12.8±0.2°, 15.3±0.2°, 18.0±0.2°, 21.2±0.2°, 25.6±0.2°, 26.4±0.2°, 27.0±0.2°, 17.4±0.2°, 22.1±0.2°, 30.8±0.2°, 8.4±0.2°, 20.0±0.2°, 21.6±0.2° or 23.7±0.2°,

Preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally; for example, the X-ray powder diffraction pattern of a has diffraction peaks at 2θ: 11.7+ -0.2 °, 12.8+ -0.2 °, 15.3+ -0.2 °, 18.0+ -0.2 °, 21.2+ -0.2 °, 25.6+ -0.2 °, 26.4+ -0.2 °, 17.4+ -0.2 °;

11.7±0.2°、12.8±0.2°、15.3±0.2°、18.0±0.2°、21.2±0.2°、25.6±0.2°、26.4±0.2°、22.1±0.2°。

8. a crystalline form of a compound according to any one of claims 4 to 7,

form a has an X-ray powder diffraction pattern as shown in fig. 1, or has a DSC pattern as shown in fig. 2.

9. A co-crystal of a compound according to any one of claims 1 to 3, wherein the co-crystal of the compound is selected from the group consisting of sulfuric acid co-crystal, nitric acid co-crystal, phosphoric acid co-crystal, formic acid co-crystal, benzenesulfonic acid co-crystal, benzoic acid co-crystal, gentisic acid co-crystal, camphoric acid co-crystal, tartaric acid co-crystal, malonic acid co-crystal, succinic acid co-crystal, dodecylsulfuric acid co-crystal, 1, 5-naphthalenedisulfonic acid co-crystal, ethanesulfonic acid co-crystal, fumaric acid co-crystal, hydroxyethylsulfonic acid co-crystal, pamoic acid co-crystal, maleic acid co-crystal, oxalic acid co-crystal, p-toluenesulfonic acid co-crystal, p-aminobenzoic acid co-crystal, glycine co-crystal, lysine co-crystal, sarcosine co-crystal, citric acid co-crystal, L-proline co-crystal, L-malic acid co-crystal, isonicotinamide co-crystal or urea co-crystal; preferably phosphoric acid co-crystal, benzenesulfonic acid co-crystal, fumaric acid co-crystal, oxalic acid co-crystal, 1, 5-naphthalene disulfonic acid co-crystal, p-aminobenzoic acid co-crystal, L-proline co-crystal or urea co-crystal.

10. The co-crystal of a compound according to claim 9, wherein the number of ligands in the co-crystal is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3; further preferably 1.

11. The co-crystal of a compound according to claim 9 or 10, characterized in that the co-crystal of the compound is a crystalline form, preferably a co-crystal form of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide, which is:

n- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphoric acid eutectic A, wherein an X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphoric acid eutectic A has diffraction peaks at the position of 10.9+/-0.2 DEG of 2 theta; or a diffraction peak at 13.0±0.2°; or a diffraction peak at 16.9±0.2°; or a diffraction peak at 19.5±0.2°; or a diffraction peak at 20.4±0.2°; or a diffraction peak at 21.2±0.2°; or a diffraction peak at 21.7±0.2°; or a diffraction peak at 26.5±0.2°; or a diffraction peak at 8.4±0.2°; or a diffraction peak at 17.9±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

Preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal a comprises at least one or more diffraction peaks located in the 2θ of 10.9±0.2°, 13.0±0.2°, 16.9±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 19.5±0.2°, 20.4±0.2°, 21.2±0.2°, 21.7±0.2°, 26.5±0.2°, preferably 2, 3, 4 or 5 thereof;

more preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal a optionally further comprises one or more diffraction peaks at 2θ of 8.4±0.2°, 17.9±0.2°, 19.8±0.2°, 22.7±0.2°, 25.0±0.2°, 27.3±0.2° or 27.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

further preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal a optionally comprises one or more diffraction peaks at 2θ of 10.9±0.2°, 13.0±0.2°, 16.9±0.2°, 19.5±0.2°, 20.4±0.2°, 21.2±0.2°, 21.7±0.2°, 26.5±0.2°, 8.4±0.2°, 17.9±0.2°, 19.8±0.2°, 22.7±0.2°, 25.0±0.2°, 27.3±0.2° or 27.7±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal a has diffraction peaks at 2θ:

Still more preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal a is shown in fig. 3;

or N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphoric acid eutectic B, wherein an X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide phosphoric acid eutectic B has diffraction peaks at the position of 11.5+/-0.2 DEG; or a diffraction peak at 12.8±0.2°; or a diffraction peak at 17.9±0.2°; or a diffraction peak at 19.7±0.2°; or a diffraction peak at 21.3±0.2°; or a diffraction peak at 22.4 + -0.2 deg.; or a diffraction peak at 23.2±0.2°; or a diffraction peak at 28.6±0.2°; or a diffraction peak at 9.0±0.2°; or a diffraction peak at 10.6 + -0.2 deg.; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal B comprises at least one or more diffraction peaks located in 2θ of 11.5±0.2°, 12.8±0.2°, 17.9±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 19.7±0.2°, 21.3±0.2°, 22.4±0.2°, 23.2±0.2°, 28.6±0.2°, preferably 2, 3, 4 or 5 thereof;

More preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal B optionally further comprises one or more diffraction peaks at 9.0±0.2°, 10.6±0.2°, 20.3±0.2°, 21.5±0.2°, 25.6±0.2°, 26.2±0.2° or 27.8±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

further preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal B optionally comprises one or more diffraction peaks at 11.5±0.2°, 12.8±0.2°, 17.9±0.2°, 19.7±0.2°, 21.3±0.2°, 22.4±0.2°, 23.2±0.2°, 28.6±0.2°, 9.0±0.2°, 10.6±0.2°, 20.3±0.2°, 21.5±0.2°, 25.6±0.2°, 26.2±0.2° or 27.8±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of them; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal B has diffraction peaks at 2θ:

still more preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide phosphoric acid co-crystal B is shown in fig. 4;

preferably, the X-ray powder diffraction pattern of the co-crystal of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide benzenesulfonic acid comprises at least one or more diffraction peaks in the range of 12.1±0.2°, 12.7±0.2°, 14.0±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 18.7±0.2°, 21.1±0.2°, 22.1±0.2°, 24.5±0.2°, 25.0±0.2°, preferably 2, 3, 4 or 5 thereof;

More preferably, the X-ray powder diffraction pattern of the co-crystal of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide benzenesulfonic acid optionally further comprises one or more diffraction peaks at 16.0±0.2°, 16.9±0.2°, 17.3±0.2°, 21.4±0.2°, 27.1±0.2°, 28.0±0.2° or 29.8±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

further preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide benzenesulfonic acid co-crystal optionally comprises one or more diffraction peaks at 2θ of 12.1±0.2°, 12.7±0.2°, 14.0±0.2°, 18.7±0.2°, 21.1±0.2°, 22.1±0.2°, 24.5±0.2°, 25.0±0.2°, 16.0±0.2°, 16.9±0.2°, 17.3±0.2°, 21.4±0.2°, 27.1±0.2°, 28.0±0.2° or 29.8±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of them; for example, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide benzenesulfonic acid co-crystal has diffraction peaks at the following positions in 2θ:

Still more preferably, the X-ray powder diffraction pattern of the co-crystal of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide benzenesulfonic acid is shown in fig. 5;

preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide fumarate co-crystal comprises at least one or more diffraction peaks at 2θ of 8.1±0.2°, 13.1±0.2°, 16.3±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 19.3±0.2°, 20.5±0.2°, 22.0±0.2°, 24.9±0.2°, 25.6±0.2°, preferably 2, 3, 4 or 5 thereof;

More preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide fumarate co-crystal optionally further comprises one or more diffraction peaks at 9.2±0.2°, 12.4±0.2°, 14.9±0.2°, 17.4±0.2°, 18.8±0.2°, 24.4±0.2° or 26.5±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

further preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide fumarate co-crystal optionally comprises one or more diffraction peaks at 2θ of 8.1±0.2°, 13.1±0.2°, 16.3±0.2°, 19.3±0.2°, 20.5±0.2°, 22.0±0.2°, 24.9±0.2°, 25.6±0.2°, 9.2±0.2°, 12.4±0.2°, 14.9±0.2°, 17.4±0.2°, 18.8±0.2°, 24.4±0.2° or 26.5±0.2°, preferably comprises one or more diffraction peaks at optional 4, 5, 6, 8 or 10; for example, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide fumarate co-crystal has diffraction peaks at the following positions of 2θ:

Still more preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide fumarate co-crystal is shown in fig. 6;

preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal a comprises at least one or more diffraction peaks located in 5.6±0.2°, 11.1±0.2°, 11.7±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 12.7±0.2°, 16.9±0.2°, 19.6±0.2°, 21.1±0.2°, 22.6±0.2°, preferably 2, 3, 4 or 5 thereof;

More preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide of oxalic acid co-crystal a optionally further comprises one or more diffraction peaks at 2θ of 12.1±0.2°, 14.9±0.2°, 15.3±0.2°, 16.3±0.2°, 17.9±0.2°, 20.8±0.2° or 25.6±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

further preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal a optionally comprises one or more diffraction peaks at 2θ of 5.6±0.2°, 11.1±0.2°, 11.7±0.2°, 12.7±0.2°, 16.9±0.2°, 19.6±0.2°, 21.1±0.2°, 22.6±0.2°, 12.1±0.2°, 14.9±0.2°, 15.3±0.2°, 16.3±0.2°, 17.9±0.2°, 20.8±0.2° or 25.6±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of the optional diffraction peaks; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal a has diffraction peaks at 2θ:

still more preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal a is shown in fig. 7;

preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal B optionally further comprises one or more diffraction peaks at 9.3±0.2°, 14.2±0.2°, 16.4±0.2°, 19.5±0.2°, 22.0±0.2°, 23.1±0.2° or 24.9±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

More preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal B optionally further comprises one or more diffraction peaks at 9.3±0.2°, 14.2±0.2°, 16.4±0.2°, 19.5±0.2°, 22.0±0.2°, 23.1±0.2° or 24.9±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

further preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal B optionally comprises one or more diffraction peaks at 2θ of 13.0±0.2°, 14.9±0.2°, 16.9±0.2°, 19.9±0.2°, 24.1±0.2°, 26.9±0.2°, 27.9±0.2°, 29.0±0.2°, 9.3±0.2°, 14.2±0.2°, 16.4±0.2°, 19.5±0.2°, 22.0±0.2°, 23.1±0.2° or 24.9±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of the foregoing; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal B has diffraction peaks at 2θ:

still more preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamido oxalic acid co-crystal B is shown in fig. 8;

Or N- (2- (4-fluoro-7-methoxynaphthalene-1-yl) ethyl) acetamide 1, 5-naphthalene disulfonic acid eutectic, wherein the X-ray powder diffraction pattern of the eutectic has diffraction peaks at the 2 theta of 12.7+/-0.2 degrees; or a diffraction peak at 15.5±0.2°; or a diffraction peak at 22.1±0.2°; or a diffraction peak at 23.3±0.2°; or a diffraction peak at 24.0±0.2°; or a diffraction peak at 25.7±0.2°; or a diffraction peak at 29.3±0.2°; or a diffraction peak at 39.3±0.2°; or a diffraction peak at 12.1±0.2°; or a diffraction peak at 16.1±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide 1, 5-naphthalene disulfonic acid co-crystal comprises at least one or more diffraction peaks located in 2θ of 12.7±0.2°, 15.5±0.2°, 22.1±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 23.3±0.2°, 24.0±0.2°, 25.7±0.2°, 29.3±0.2°, 39.3±0.2°, preferably 2, 3, 4 or 5 thereof;

More preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide 1, 5-naphthalenedisulfonic acid co-crystal optionally further comprises one or more diffraction peaks at 2θ of 12.1±0.2°, 16.1±0.2°, 17.1±0.2°, 21.5±0.2°, 22.5±0.2°, 25.3±0.2° or 33.5±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

further preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide 1, 5-naphthalene disulfonic acid co-crystal optionally comprises one or more diffraction peaks at 2θ of 12.7±0.2°, 15.5±0.2°, 22.1±0.2°, 23.3±0.2°, 24.0±0.2°, 25.7±0.2 °, 29.3±0.2°, 39.3±0.2°, 12.1±0.2°, 16.1±0.2 °, 17.1±0.2°, 21.5±0.2°, 22.5±0.2°, 25.3±0.2° or 33.5±0.2°, preferably comprises one or more diffraction peaks at optional 4, 5, 6, 8 or 10; for example, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide 1, 5-naphthalene disulfonic acid co-crystal has diffraction peaks at the following positions in 2θ:

Still more preferably, the X-ray powder diffraction pattern of the co-crystal of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide 1, 5-naphthalene disulfonic acid is shown in fig. 9;

preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide to aminobenzoic acid co-crystal comprises at least one or more diffraction peaks located in 9.5±0.2°, 11.0±0.2°, 13.9±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 15.4±0.2°, 16.9±0.2°, 19.2±0.2°, 19.6±0.2°, 21.9±0.2°, preferably 2, 3, 4 or 5 thereof;

More preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide to aminobenzoic acid co-crystal optionally further comprises one or more diffraction peaks at 5.6±0.2°, 14.8±0.2°, 20.7±0.2°, 22.5±0.2°, 25.5±0.2°, 31.0±0.2° or 35.9±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

further preferably, the X-ray powder diffraction pattern of the co-crystal of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide para-aminobenzoic acid optionally comprises one or more diffraction peaks at 9.5±0.2°, 11.0±0.2°, 13.9±0.2°, 15.4±0.2°, 16.9±0.2°, 19.2±0.2°, 19.6±0.2°, 21.9±0.2°, 5.6±0.2°, 14.8±0.2°, 20.7±0.2°, 22.5±0.2°, 25.5±0.2°, 31.0±0.2° or 35.9±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10 of the optional positions; for example, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide para-aminobenzoic acid co-crystal has diffraction peaks at 2θ:

Still more preferably, the X-ray powder diffraction pattern of the co-crystal of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide to aminobenzoic acid is shown in fig. 10;

preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal a comprises at least one or more diffraction peaks located in 5.6±0.2°, 8.6±0.2°, 11.1±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 16.9±0.2°, 17.3±0.2°, 19.2±0.2°, 19.6±0.2°, 26.1±0.2°, preferably 2, 3, 4 or 5 thereof;

More preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal a optionally further comprises one or more diffraction peaks at 9.6±0.2°, 14.7±0.2°, 14.9±0.2°, 20.8±0.2°, 22.9±0.2°, 33.7±0.2° or 35.1±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

further preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal a optionally comprises one or more diffraction peaks at 2θ of 5.6±0.2°, 8.6±0.2°, 11.1±0.2°, 16.9±0.2°, 17.3±0.2°, 19.2±0.2°, 19.6±0.2°, 26.1±0.2°, 9.6±0.2°, 14.7±0.2°, 14.9±0.2°, 20.8±0.2°, 22.9±0.2°, 33.7±0.2° or 35.1±0.2°, preferably wherein there are diffraction peaks at optional 4, 5, 6, 8 or 10; for example, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal has diffraction peaks at 2θ:

Still more preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal a is shown in fig. 11.

preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal B comprises at least one or more diffraction peaks located in 15.2±0.2°, 18.1±0.2°, 19.6±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 22.7±0.2°, 24.8±0.2°, 30.6±0.2°, 32.2±0.2°, 36.6±0.2°, preferably 2, 3, 4 or 5 thereof;

More preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal B optionally further comprises one or more diffraction peaks at 18.5±0.2°, 21.1±0.2°, 26.0±0.2°, 27.1±0.2°, 30.3±0.2°, 34.0±0.2° or 34.8±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

further preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal B optionally comprises one or more diffraction peaks at 15.2±0.2°, 18.1±0.2°, 19.6±0.2°, 22.7±0.2°, 24.8±0.2°, 30.6±0.2°, 32.2±0.2°, 36.6±0.2°, 18.5±0.2°, 21.1±0.2°, 26.0±0.2°, 27.1±0.2°, 30.3±0.2°, 34.0±0.2° or 34.8±0.2°, preferably wherein there are diffraction peaks at optional 4, 5, 6, 8 or 10; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal B has diffraction peaks at 2θ:

Still more preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide L-proline co-crystal B is shown in fig. 12;

preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal a comprises at least one or more diffraction peaks located in 5.7±0.2°, 11.0±0.2°, 16.9±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 19.2±0.2°, 19.6±0.2°, 20.7±0.2°, 22.3±0.2°, 35.5±0.2°, preferably 2, 3, 4 or 5 thereof;

More preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal a optionally further comprises one or more diffraction peaks at 11.2±0.2°, 14.9±0.2°, 24.2±0.2°, 25.5±0.2°, 28.0±0.2°, 29.4±0.2° or 31.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

further preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal a optionally comprises one or more diffraction peaks at 2θ of 5.7±0.2°, 11.0±0.2°, 16.9±0.2°, 19.2±0.2°, 19.6±0.2°, 20.7±0.2°, 22.3±0.2°, 35.5±0.2°, 11.2±0.2°, 14.9±0.2°, 24.2±0.2°, 25.5±0.2°, 28.0±0.2°, 29.4±0.2° or 31.7±0.2°, preferably comprises one or more diffraction peaks at 4, 5, 6, 8 or 10; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal a has diffraction peaks at 2θ:

still more preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal a is shown in fig. 13;

preferably, the X-ray powder diffraction pattern of the N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal B comprises at least one or more diffraction peaks located in 2θ of 4.6±0.2°, 9.3±0.2°, 12.3±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 13.9±0.2°, 14.9±0.2°, 18.0±0.2°, 19.2±0.2°, 23.2±0.2°, preferably 2, 3, 4 or 5 thereof;

More preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal B optionally further comprises one or more diffraction peaks at 2θ of 12.9±0.2°, 18.6±0.2°, 25.5±0.2°, 27.1±0.2°, 27.7±0.2°, 28.0±0.2° or 37.6±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

further preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal B optionally comprises one or more diffraction peaks at 2θ of 4.6±0.2°, 9.3±0.2°, 12.3±0.2°, 13.9±0.2°, 14.9±0.2°, 18.0±0.2°, 19.2±0.2°, 23.2±0.2°, 12.9±0.2°, 18.6±0.2°, 25.5±0.2°, 27.1±0.2°, 27.7±0.2°, 28.0±0.2° or 37.6±0.2°, preferably comprises one or more diffraction peaks at optional 4, 5, 6, 8 or 10; for example, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal B has diffraction peaks at 2θ:

4.6±0.2°、9.3±0.2°、12.3±0.2°、13.9±0.2°、14.9±0.2°、18.0±0.2°、19.2±0.2°、23.2±0.2°、12.9±0.2°、18.6±0.2°；

still more preferably, the X-ray powder diffraction pattern of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide urea co-crystal B is shown in fig. 14.

12. A crystalline form of a compound according to any one of claims 4 to 8, or a co-crystal of a compound according to claims 9 to 11,

the 2 theta error of the diffraction peak at the position of the diffraction peak with the relative peak intensity of the first ten intensities in the X-ray powder diffraction pattern and the diffraction peak at the position of the X-ray powder diffraction attached drawing corresponding to the position of the diffraction peak is +/-0.2 degrees to +/-0.5 degrees, preferably +/-0.2 degrees to +/-0.3 degrees, and more preferably +/-0.2 degrees.

13. A crystalline form of a compound as claimed in any one of claims 4 to 8 or a co-crystal of a compound as claimed in any one of claims 9 to 11,

the crystal form is anhydrous or hydrate, and when the crystal form is hydrate, the number of water is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3;

preferably, the crystalline form is an anhydrate.

14. A process for preparing a crystalline form of a compound according to any one of claims 1 to 8, comprising in particular the steps of:

2) Adding a poor solvent, and naturally cooling to room temperature;

3) Stirring to separate out, filtering and drying the obtained solid;

15. A method for preparing a co-crystal of a compound according to any one of claims 9 to 11, comprising in particular the steps of:

3) Stirring to separate out, filtering and drying the obtained solid;

the benign solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, acetonitrile, isopropanol, isopropyl acetate, butanone, tetrahydrofuran or 2-methyl-tetrahydrofuran; ethyl acetate is preferred;

16. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form or co-crystal of a compound of any one of claims 1-13, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

17. The crystalline form or co-crystal of a compound of any one of claims 1-13, or the pharmaceutical composition of claim 16, comprising a therapeutically effective amount of a crystalline form, a pharmaceutically acceptable salt, or a crystalline form thereof, selected from 0.0001-99%, 0.0001-95%, 0.0001-90%, 0.0001-85%, 0.0001-80%, 0.0001-75%, 0.0001-70%, 0.001-60%, 0.001-55%, 0.01-50%, 0.01-40%, 0.01-30%, 0.01-20%, 0.01-10%, or 0.01-5%.

18. Use of a crystalline form or co-crystal of a compound according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 16 in the manufacture of a melatonin receptor agonist medicament.

19. A crystalline form or co-crystal of a compound of any one of claims 1 to 13 or a pharmaceutical composition of claim 16 in the preparation of MT1 and MT2 receptor agonists and 5-HT _2C Use in receptor antagonist medicaments.

20. Use of a crystalline form or co-crystal of a compound according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 16 for the manufacture of a medicament for the treatment or prophylaxis of cardiovascular diseases, digestive diseases, central nervous system diseases and/or psychotic diseases; preferably, the central nervous system and/or psychiatric disorder is selected from melatonin system disorders, stress, anxiety disorders, seasonal affective disorders, schizophrenia, phobia, depression, major depressive disorder, sleep disorders, insomnia or fatigue caused by jet lag, weight disorders, mood disorders, schizophrenic lineage disorders, spasticity disorders, memory disorders and/or cognitive disorders, movement disorders, personality disorders, autism lineage disorders, pain, traumatic brain injury, substance abuse disorders and/or withdrawal syndromes, tinnitus, autism, alzheimer's disease, epileptic seizures, neuralgia or drug addiction withdrawal symptoms major depressive disorder or manic disorder.