Serotonin 5-HT2A receptor agonist as well as preparation method and application thereof

Abstract

The invention discloses a serotonin 5-HT2A receptor agonist as well as a preparation method and application thereof. The invention provides a compound as shown in a formula I or pharmaceutically acceptable salt thereof. The serotonin 5-HT2A receptor agonist provided by the invention can be used for treating and / or preventing 5-HT2A receptor related diseases, such as depression. # imgabs0 #

Description

[0001] This application claims priority to Chinese patent application No. 202410177623X filed on February 8, 2024. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a serotonin 5-HT 2A Receptor agonist, preparation method and use thereof. Background Art

[0003] Depression is a common mental illness with a high incidence and widespread impact. Depending on the severity of the patient's clinical symptoms, it is categorized as mild, moderate, or severe. The pathogenesis of depression is complex, and a definitive conclusion remains to be drawn.

[0004] Currently known antidepressants mainly include selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors, and other major categories. SSRIs are widely used in clinical practice and include sertraline, citalopram, escitalopram, fluoxetine, paroxetine, vilazodone, and vortioxetine. SSRIs are believed to work by inhibiting the reabsorption of the central neurotransmitter serotonin and increasing the concentration of serotonin in the synaptic cleft. Although SSRIs have the advantages of better tolerability and higher safety than traditional tricyclic antidepressants, this type of drug still has several obvious disadvantages: (1) slow onset of action, taking several weeks to months to take effect; (2) low response rate, with more than one-third of patients having no response; (3) adverse reactions are still relatively common, such as nausea, weight gain, and sexual dysfunction. Therefore, there is an urgent need to develop new antidepressant drugs.

[0005] Studies have shown that psychedelics have great potential in treating depression, anxiety, drug addiction, post-traumatic stress disorder and other diseases (Nutt et al., Cell, 2020, 181(1): 24-28). In terms of pharmacological mechanism, psychedelics are serotonin 5-HT 2A agonists of 5-HT receptors by activating 2A Classic hallucinogens include psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT). Psilocybin, among others, has demonstrated rapid onset and long-lasting relief of depression in multiple Phase II clinical studies, demonstrating significant development potential.

[0006] Reported 5-HT 2A The main structural types of receptor agonists are: (1) tryptamines, such as psilocybin and N,N-dimethyltryptamine; (2) phenylethylamines, such as mescaline and 25-CN-NBOH; (3) ergot alkaloids, such as lysergic acid diethylamide (LSD). The 5-HT2 receptor family has 5-HT 2A , 5-HT 2B and 5-HT 2C There are three receptor subtypes. Among them, 5-HT 2A Receptors and 5-HT 2B The binding pockets of the receptors are very similar, so most of the 5-HT 2A Both 5-HT receptor agonists activate 2B receptors (Hatzipantelis and Olson, Annu Rev Physiol., 2024, 86:27-47). 2B The 5-HT receptor has been shown to cause the risk of valvular heart disease (Roth, N Engl J Med., 2007, 356, 6-9; Dumotier and Urban, J Pharmacol Toxicol Methods, 2024, 128: 107542.). Therefore, the development of selective 5-HT 2A receptor agonists to avoid activating 5-HT 2B Receptors are very important.

[0007] In summary, due to the currently known 5-HT 2A There are relatively few chemical structures of receptor agonists, and most known compounds activate 5-HT 2B receptors, so it is urgent to develop new selective 5-HT 2A Receptor agonists. Summary of the Invention

[0008] The problem to be solved by the present invention is that 5-HT 2A The receptor agonist has the disadvantages of less chemical structure types and poor selectivity. 2A Receptor agonist, its preparation method and application. The serotonin 5-HT 2A 5-HT receptor agonists 2A It has a selective activating effect on 5-HT receptors and can be used to treat and / or prevent 2A Receptor-related diseases, such as depression.

[0009] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof:

[0010]

[0011] Where A, B and T are independently CR a or N;

[0012] is a double bond or a single bond; When it is a double bond, D is a carbon atom; When it is a single bond, D is CH or N;

[0013] X and Y are independently O or CH2;

[0014] m is 1 or 2;

[0015] n is 1, 2, or 3;

[0016] R a are independently hydrogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0017] R b is hydrogen or C 1-6 alkyl;

[0018] R d is hydrogen or C 1-6 alkyl;

[0019] Z is a single bond, C 1-4 Straight chain alkylene, C 2-4 Straight chain alkenylene, separated by one or more R c Substituted C 1-4 A straight chain alkylene or one or more R c Substituted C 2-4 straight-chain alkenylene;

[0020] Each R c are independently halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0021] The compound shown in formula I satisfies the following conditions (1), (2) or (3):

[0022] Case (1): D is a carbon atom or CH;

[0023] Scenario (2): for 、 or ;

[0024] Scenario (3): for or ; Z is a single bond, C 3-4 Straight chain alkylene, C 2-4 Straight chain alkenylene, separated by one or more R c Substituted C 3-4 A straight chain alkylene or one or more R c Substituted C 2-4 Straight chain alkenylene.

[0025] In a preferred embodiment, in the compound of Formula I or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as described below, and the definitions of other groups may be as described in any of the above embodiments (hereinafter referred to as "in a preferred embodiment").

[0026] In a preferred embodiment, R a In the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0027] In a preferred embodiment, R a In the C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy.

[0028] In a preferred embodiment, R b In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0029] In a preferred embodiment, R d In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0030] In a preferred embodiment, in Z, the C 1-4 The straight chain alkylene is 、 、 or .

[0031] In a preferred embodiment, in Z, the C 2-4 The number of olefinic bonds in the straight-chain alkenylene group is 1 or 2, for example, 1.

[0032] In a preferred embodiment, in Z, the C 2-4 Straight chain alkenylene is 、 、 or ,For example . (Note: C2-4 The specific structure of the straight-chain alkenylene group is not limited to being in the trans configuration.)

[0033] In a preferred embodiment, R c wherein the halogen is independently fluorine, chlorine, bromine or iodine.

[0034] In a preferred embodiment, R c In the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0035] In a preferred embodiment, R c In the C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0036] In a preferred embodiment, each “plurality” is independently 2, 3, 4 or 5, for example 2 or 3.

[0037] In a preferred embodiment, A is CH or N.

[0038] In a preferred embodiment, B is CH or N.

[0039] In a preferred embodiment, T is CR a .

[0040] In a preferred embodiment, D is a carbon atom or CH.

[0041] In a preferred embodiment, D is N.

[0042] In a preferred embodiment, n is 1 or 2.

[0043] In a preferred embodiment, R a is hydrogen or C 1-6 Alkoxy, such as hydrogen.

[0044] In a preferred embodiment, R b For hydrogen.

[0045] In a preferred embodiment, R d For hydrogen.

[0046] In a preferred embodiment, X and Y are CH2.

[0047] In a preferred embodiment, For a single bond.

[0048] In a preferred embodiment, Z is a single bond, C 1-4 Straight chain alkylene or C 2-4 Straight chain alkenylene.

[0049] In a preferred embodiment, Z is a single bond, C 3-4 Straight chain alkylene or C 2-4 Straight chain alkenylene.

[0050] In a preferred embodiment, Z is C 3-4 Straight chain alkylene.

[0051] In a preferred embodiment, for 、 、 、 、 、 、 、 or .

[0052] In a preferred embodiment, R b C 1-6 alkyl; for ;For example or , for example or , the carbon atom marked with "*" is a chiral carbon atom, and its configuration is R configuration or S configuration; for example or , the carbon atom marked with “*” is a chiral carbon atom, and its configuration is R configuration or S configuration.

[0053] In a preferred embodiment, for 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

[0054] In a preferred embodiment, for 、 、 、 、 、 or .

[0055] In a preferred embodiment, for ,For example , for example .

[0056] In a preferred embodiment, for 、 、 、 、 、 or .

[0057] In a preferred embodiment, for 、 、 、 、 、 、 、 、 、 、 、 、 or .

[0058] In a preferred embodiment, in the compound shown in formula I,

[0059] A and B are independently CH or N, and T is CR a or N;

[0060] is a double bond or a single bond; D is a carbon atom or CH;

[0061] X and Y are O or CH2;

[0062] m is 1 or 2;

[0063] n is 1, 2, or 3;

[0064] R a are independently hydrogen or C 1-6 alkoxy;

[0065] R b is hydrogen or C 1-6 alkyl;

[0066] R d is hydrogen or C 1-6 alkyl;

[0067] Z is a single bond, C 1-4 Straight chain alkylene or C 2-4 straight-chain alkenylene;

[0068] Preferably, for ;

[0069] X and Y are CH2;

[0070] m is 1 or 2;

[0071] n is 1, 2, or 3;

[0072] R b is hydrogen;

[0073] R d is hydrogen;

[0074] Z is C 3-4 Straight chain alkylene.

[0075] In a preferred embodiment, in the compound shown in formula I,

[0076] for or ;

[0077] is a double bond or a single bond; When it is a double bond, D is a carbon atom; When it is a single bond, D is CH or N;

[0078] X and Y are independently O or CH2;

[0079] m is 1 or 2;

[0080] n is 1, 2, or 3;

[0081] R b is hydrogen or C 1-6 alkyl;

[0082] R d is hydrogen or C 1-6 alkyl;

[0083] Z is a single bond, C 1-4 Straight chain alkylene or C 2-4 straight-chain alkenylene;

[0084] Preferably, is a single bond, D is N;

[0085] R d is hydrogen;

[0086] Z is C 3-4 Straight chain alkylene.

[0087] In a preferred embodiment, in the compound shown in formula I,

[0088] for ;

[0089] is a double bond or a single bond; When it is a double bond, D is a carbon atom; When it is a single bond, D is CH or N;

[0090] X and Y are independently O or CH2;

[0091] m is 1 or 2;

[0092] n is 1, 2, or 3;

[0093] R b is hydrogen or C 1-6 alkyl;

[0094] R d is hydrogen or C 1-6 alkyl;

[0095] Z is a single bond, C 1-4 Straight chain alkylene or C 2-4 straight-chain alkenylene;

[0096] Preferably, is a single bond, D is N, R d For hydrogen.

[0097] In a preferred embodiment, in the compound shown in formula I,

[0098] for ;

[0099] When it is a single bond, D is N;

[0100] m is 1 or 2;

[0101] n is 1, 2, or 3;

[0102] R b is hydrogen or C 1-6 alkyl;

[0103] R d is hydrogen;

[0104] Z is C 3-4 Straight chain alkylene or C 2-4 Straight chain alkenylene.

[0105] In a preferred embodiment, in the compound shown in formula I,

[0106] for or ;

[0107] is a double bond or a single bond; When it is a double bond, D is a carbon atom; When it is a single bond, D is CH or N;

[0108] X and Y are independently O or CH2;

[0109] m is 1 or 2;

[0110] n is 1, 2, or 3;

[0111] R a is hydrogen or C 1-6 alkyl;

[0112] R b is hydrogen or C 1-6 alkyl;

[0113] R d is hydrogen or C 1-6 alkyl;

[0114] Z is a single bond, C 3-4 Straight chain alkylene or C 2-4 straight-chain alkenylene;

[0115] Preferably, X and Y are CH2; R d is hydrogen; Z is C 3-4 Straight chain alkylene.

[0116] In a preferred embodiment, in the compound shown in formula I,

[0117] for or ;

[0118] is a single bond; D is N;

[0119] X and Y are independently O or CH2;

[0120] m is 1 or 2;

[0121] n is 1, 2, or 3;

[0122] R a is hydrogen or C 1-6 alkyl;

[0123] R b is hydrogen;

[0124] R d is hydrogen or C 1-6 alkyl;

[0125] Z is C 3-4 Straight chain alkylene or C 2-4 Straight chain alkenylene.

[0126] In a preferred embodiment, in the compound shown in formula I,

[0127] for or ;

[0128] X and Y are CH2;

[0129] R a is hydrogen or C 1-6 alkyl;

[0130] for or , the carbon atom marked with "*" is a chiral carbon atom, and its configuration is R configuration or S configuration;

[0131] R b C 1-6 alkyl;

[0132] Z is C 3-4 straight-chain alkylene;

[0133] Preferably, the carbon atom marked with "*" is a chiral carbon atom, and its configuration is R configuration.

[0134] The present invention provides a cyclic compound or a pharmaceutically acceptable salt thereof, wherein the cyclic compound is any one of the following compounds:

[0135] 、 、 .

[0136] In a preferred embodiment, the annular compound is any one of the following compounds:

[0137] .

[0138] In a preferred embodiment, the annular compound is any one of the following compounds:

[0139] .

[0140] The present invention provides a pharmaceutical composition comprising:

[0141] (1) (Therapeutically effective amount) of substance A, wherein substance A is a compound of formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, or a cyclic compound as described above or a pharmaceutically acceptable salt thereof;

[0142] (2) Pharmaceutical excipients.

[0143] The present invention provides a substance A, the above-mentioned pharmaceutical composition, compound F or a pharmaceutically acceptable salt thereof in the preparation of 5-HT 2A The application of the present invention in the field of receptor agonists, wherein the substance A is a compound as shown in formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, a cyclic compound as described above, or a pharmaceutically acceptable salt thereof; and the compound F is selected from any one of the following compounds:

[0144] 、 、 、 、 、 、 or .

[0145] The present invention provides a substance A, the above-mentioned pharmaceutical composition, the above-mentioned compound F or a pharmaceutically acceptable salt thereof for preparing a method for treating and / or preventing 5-HT 2A The invention relates to a drug for a disease related to a 5-HT receptor, wherein the substance A is a compound as shown in formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, a cyclic compound as described above, or a pharmaceutically acceptable salt thereof; ... 2A The receptor-associated disease may be a central nervous system disease, such as depression.

[0146] The present invention provides a use of a substance A, the above-mentioned pharmaceutical composition, the above-mentioned compound F or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a central nervous system disease, wherein the substance A is a compound as shown in Formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, the aforementioned cyclic compound or a pharmaceutically acceptable salt thereof; and the central nervous system disease may be depression.

[0147] The present invention provides a substance A, the above-mentioned pharmaceutical composition, the above-mentioned compound F or a pharmaceutically acceptable salt thereof in the preparation of 5-HT 2A Receptor agonists and / or 5-HT 2B The substance A is a compound as shown in formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, or a cyclic compound as described above or a pharmaceutically acceptable salt thereof.

[0148] The present invention provides a substance A for use as a medicine, the above-mentioned pharmaceutical composition, the above-mentioned compound F or a pharmaceutically acceptable salt thereof, wherein the substance A is a compound as shown in Formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, or a cyclic compound as described above or a pharmaceutically acceptable salt thereof.

[0149] The present invention provides a substance A for use as a treatment or medicine, the pharmaceutical composition, the compound F, or a pharmaceutically acceptable salt thereof, wherein the substance A is a compound as shown in Formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, or a cyclic compound as described above, or a pharmaceutically acceptable salt thereof.

[0150] The present invention provides a substance A, the above-mentioned pharmaceutical composition, the above-mentioned compound F or a pharmaceutically acceptable salt thereof for treating and / or preventing a central nervous system disease, wherein the substance A is a compound as shown in Formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof or the aforementioned cyclic compound, a pharmaceutically acceptable salt thereof, and the central nervous system disease may be depression.

[0151] The present invention provides a method for treating and / or preventing a central nervous system disease, comprising administering to a subject a therapeutically effective amount of substance A, the above-mentioned pharmaceutical composition, the above-mentioned compound F, or a pharmaceutically acceptable salt thereof, wherein the substance A is a compound as shown in Formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, the aforementioned cyclic compound, or a pharmaceutically acceptable salt thereof, and the central nervous system disease may be depression.

[0152] The present invention provides a method for preparing a compound as shown in Formula I according to any embodiment of the present invention, wherein the preparation method is the following method 1 or method 2:

[0153] The method 1 comprises the following steps: in an organic solvent, in the presence of a deprotection agent, subjecting the compound represented by formula II to a deprotection reaction as shown in the following formula to obtain a compound represented by formula I:

[0154]

[0155] in, ,A,B,T,D,X,Y,Z,n,m and R b The definition of R is as described in any embodiment of the present invention; h is an amino protecting group; R d For H.

[0156] The method 2 comprises the following steps: in an organic solvent, in the presence of a base and a catalyst, reacting a compound represented by formula III-1 with a compound represented by formula III-2 to obtain a compound represented by formula I.

[0157]

[0158] Among them, A, B, T, X, Y, Z, n, m, R a and R b The definition of R is as described in any embodiment of the present invention; e is halogen, R d C 1-6 Alkyl; D is N.

[0159] In a preferred embodiment, in the method 1, the organic solvent is 1,4-dioxane or dichloromethane.

[0160] In a preferred embodiment, in the method 1, the deprotection reagent is hydrochloric acid or trifluoroacetic acid.

[0161] In a preferred embodiment, in the method 1, the amino protecting group is .

[0162] In a preferred embodiment, in the method 2, the organic solvent is 1,4-dioxane.

[0163] In a preferred embodiment, in the method 2, the catalyst is Pd2(dba)3.

[0164] In a preferred embodiment, in the method 2, the base is potassium tert-butoxide.

[0165] In a preferred embodiment, in the method 2, the R e Chlorine or bromine.

[0166] The present invention provides a compound as shown in formula II,

[0167]

[0168] Among them, A, B, T, D, X, Y, Z, n, m and R b The definition of R is as described in any embodiment of the present invention; h It is an amino protecting group.

[0169] In a preferred embodiment, the compound shown in Formula II is any one of the following compounds:

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178] .

[0179] The present invention provides a method for preparing the compound shown in Formula II, which is the following method I or method II:

[0180] The method I comprises the following steps: in a solvent, in the presence of a base and a catalyst, reacting a compound represented by formula IV-1 with a compound represented by formula IV-2 to obtain a compound represented by formula II.

[0181]

[0182] Among them, A, B, T, X, Y, Z, n, m, R b 、R e and R h The definition of is as described in any embodiment of the present invention; is a double bond or a single bond; D is C or H;

[0183] The method II comprises the following steps: in a solvent, in the presence of a base and a catalyst, reacting a compound represented by formula IV-1 with a compound represented by formula IV-3 to obtain a compound represented by formula II.

[0184]

[0185] Among them, A, B, T, X, Y, Z, n, m, R b 、R e and R h The definition of is as described in any embodiment of the present invention; is a single bond; D is N.

[0186] In a preferred embodiment, in the method I, the solvent is 1,4-dioxane and water.

[0187] In a preferred embodiment, in the method I, the catalyst is tetrakis(triphenylphosphine)palladium.

[0188] In a preferred embodiment, in the method I, the base is sodium carbonate.

[0189] In a preferred embodiment, when the compound of formula IV-2 is a double bond, and the compound shown in formula II When it is a single bond, the method I further comprises the following post-treatment step after the reaction is completed: hydrogenating the product obtained in the method 1 in a solvent in the presence of a catalyst (e.g., 10% palladium carbon) and a hydrogen source (e.g., hydrogen gas).

[0190] In a preferred embodiment, in the method II, the solvent is 1,4-dioxane.

[0191] In a preferred embodiment, in the method II, the catalyst is Pd2(dba)3.

[0192] In a preferred embodiment, in the method II, the base is potassium tert-butoxide.

[0193] Unless otherwise specified, the terms used in this invention have the following meanings:

[0194] Those skilled in the art will understand that, according to the conventions used in the art, the “ " means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0195] In the claims of this application, the term "multiple" in the phrase "satisfies one or more of the following conditions" refers to 2, 3, 4, or more conditions. The maximum value of "more" is the maximum number of conditions recited in each claim. For example, if a claim recites 8 conditions, the term "one or more" in the phrase "satisfies one or more of the following conditions" in that claim can be any integer from 1 to 8, such as 1, 2, 3, 4, 5, 6, 7, or 8.

[0196] The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.

[0197] When any variable (such as R c ) appears multiple times in the definition of a compound, the definition of each position of the variable is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is replaced by 1, 2 or 3 R c group substituted, that is, the group may be replaced by up to 3 R c Replace, the position R c Definition and other positions R c In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0198] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0199] The term "alkyl" refers to a straight or branched chain alkyl group having the specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0200] The term "alkylene" refers to a substituent formed by removing two hydrogen atoms from a saturated straight-chain or branched alkane. The two hydrogen atoms removed can be on the same carbon atom or on different carbon atoms (e.g., on two carbon atoms at opposite ends). Thus, C1 alkylene (i.e., methylene) refers to -CH2-, and C2 alkylene (i.e., ethylene) refers to -CH2-CH2- or -CH(CH3)-.

[0201] The term "alkoxy" refers to the group -OR X , where R X is an alkyl group as defined above.

[0202] The term "alkenylene" refers to a substituent formed by removing two hydrogen atoms from a linear or branched alkene having a specific number of carbon atoms, containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds. The carbon-carbon double bond can be located at any position within the alkenylene group, and the two hydrogen atoms removed can be on the same carbon atom or on different carbon atoms (for example, the two hydrogen atoms removed are on carbon atoms at the two ends). Thus, C2 alkenylene (i.e., vinylene) includes but is not limited to -CH=CH-, C3 alkenylene includes but is not limited to -CH2-CH=CH-, and -C(CH3)=CH-, C4 alkenylene includes but is not limited to -CH2-CH=CH-CH2-, , -CH2=CH-CH2-CH2- and -CH2-CH-CH2=CH2-.

[0203] The term "pharmaceutical excipients" refers to excipients and additives used in the production of medicines and the preparation of prescriptions. It is all substances contained in pharmaceutical preparations in addition to the active ingredients.

[0204] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0205] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0206] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0207] The term "subject" refers to any animal, preferably a mammal, and most preferably a human, that is about to receive or has received a compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0208] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0209] The reagents and raw materials used in the present invention are commercially available.

[0210] The positive effect of the present invention is that the compounds of the present invention can be used to treat and / or prevent 5-HT 2A Receptor-related diseases, such as depression. DETAILED DESCRIPTION

[0211] The present invention is further illustrated by the following examples, but the invention is not limited to the scope of these examples. Experimental methods in the following examples, where specific conditions are not specified, were performed according to conventional methods and conditions, or according to the product specifications. All parameters in the examples and other descriptions, unless otherwise stated, are expressed in grams.

[0212] Example 1: Preparation of 2-(2,5-dihydro-1H-pyrrol-3-yl)-5,6,7,8,9,9,10-hexahydrocyclooctane[b]pyridine (Compound I-1)

[0213] Step 1: Preparation of tert-butyl 3-(5,6,7,8,9,10-hexahydrocyclooctyl[b]pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (Intermediate ZJF-07-115)

[0214]

[0215] The starting material, compound A1, was synthesized according to patent (WO2008083353). Compound A1 (75 mg, 0.383 mmol), 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (170 mg, 0.575 mmol), tetrakistriphenylphosphine palladium (22 mg, 0.019 mmol), and Na₂CO₃ (64 mg, 0.602 mmol) were dissolved in 1,4-dioxane (15 mL) / H₂O (3.4 mL). The mixture was refluxed and stirred overnight. The reaction mixture was diluted with water and extracted three times with dichloromethane. The organic phases were combined and dried once over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure, and the remaining solid was isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1-10%) to obtain the white solid intermediate ZJF-07-115 (99 mg, 79% yield). 1 H NMR (800 MHz, CDCl3) δ7.34 (d, J = 7.0 Hz, 1H), 7.06 (dd, J = 74.0, 7.8 Hz, 1H), 6.48, 6.45 (2s,1H), 4.60 – 4.50 (m, 2H), 4.38 – 4.28 (m, HRMS(ESI) C 20 H 29 N2O2 + [M+H] + Calculated value: 329.2224, measured value: 329.2219.

[0216] Step 2: Preparation of 2-(2,5-dihydro-1H-pyrrol-3-yl)-5,6,7,8,9,9,10-hexahydrocyclooctane[b]pyridine (Compound I-1)

[0217]

[0218] A 2 M HCl solution in 1,4-dioxane (2 mL) was added to the intermediate ZJF-07-115 (70 mg, 0.215 mmol) and stirred at room temperature for 45 minutes. After the reaction, the solvent was evaporated and methanol was added. The reaction solution was neutralized with an aqueous solution of NaHCO₃ to pH 7.4. The solvent was evaporated under reduced pressure, and the remaining solid was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 0-6%, methanol containing 0.5% triethylamine) to obtain a light yellow solid (I-1) (35 mg, 72% yield). 1 H NMR (600 MHz, MeOH-d4) δ 7.47(d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 6.56 – 6.53 (m, 1H), 4.23 –4.20 (m, 2H), 4.01 – 3.98 (m, 2H), 2.97 – 2.94 (m, 2H), 2.82 – 2.78 (m, 2H), 1.79 – 1.74 (m, 2H), 1.73 – 1.68 (m, 2H), 1.41 – 1.36 (m, 4H). 13 C NMR (201MHz, MeOH-d4) δ 161.87, 151.17, 141.84, 138.54, 137.06, 125.90, 120.10,55.09, 54.08, 34.94, 33.26, 32.51, 31.76, 27.01, 26.99. HRMS(ESI) C 15 H 20 N2 + [M+H] + Calculated value: 229.1699, measured value: 229.1706. Purity: 98.5% (t R = 8.542 min; 254 nm).

[0219] Example 2: Preparation of 2-(pyrrolidin-3-yl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine (Compound I-2)

[0220] Step 1: Preparation of tert-butyl 3-(5,6,7,8,9,10-hexahydrocyclooctane[b]pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (Intermediate ZJF-07-115) by the same procedure as Step 1 in Example 1.

[0221] Step 2: Preparation of tert-butyl 3-(5,6,7,8,9,10-hexahydrocyclooctyl[b]pyridin-2-yl)pyrrolidine-1-carboxylate (Intermediate ZJF-07-118)

[0222]

[0223] Intermediate ZJF-07-115 (93 mg, 0.283 mmol) was dissolved in methanol (15 mL), and 10% palladium on carbon (23 mg, 0.019 mmol) was added. The mixture was stirred at room temperature overnight under a hydrogen atmosphere. After monitoring the reaction, the filtrate was filtered and the solvent was evaporated under reduced pressure to obtain the intermediate (ZJF-07-118) as a colorless oil (65 mg, 69% yield). 1 H NMR (800 MHz, CDCl3) δ 7.33(d, J = 7.0 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 3.83 – 3.74 (m, 1H), 3.64 –3.35 (m, 4H), 3.00 – 2.91 (m, 2H), 2.74 (t, J = 6.2 Hz, 2H), 2.29 – 2.20 (m,1H), 2.18 – 2.10 (m, 1H), 1.77 (s, 2H), 1.70 – 1.65 (m, 2H), 1.47, 1.46 (2s,9H), 1.39 – 1.34 (m, 4H). HRMS(ESI) C 20 H 31 N2O2 + [M+H] + Calculated value: 331.2380, measured value: 331.2390.

[0224] Step 3: Preparation of 2-(pyrrolidin-3-yl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine (Compound I-2)

[0225]

[0226] Intermediate ZJF-07-118 (65 mg, 0.188 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 45 minutes. After the reaction, the solvent was evaporated and methanol was added. The reaction mixture was neutralized with an aqueous solution of NaHCO₃ to a pH of 7.4. The solvent was evaporated under reduced pressure, and the remaining solid was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 0-10%, methanol containing 0.5% triethylamine) to obtain a light yellow oil (I-2) (40 mg, 96% yield). 1H NMR (800 MHz, MeOH-d4) δ 7.45 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 3.47 – 3.42 (m,1H), 3.34 – 3.31 (m, 1H), 3.23 – 3.19 (m, 1H), 3.09 – 3.03 (m, 2H), 2.96 –2.93 (m, 2H), 2.81 – 2.76 (m, 2H), 2.31 – 2.26 (m, 1H), 1.99 – 1.94 (m, 1H),1.77 – 1.74 (m, 2H), 1.70 – 1.67 (m, 2H), 1.40 – 1.34 (m, 4H). 13 C NMR (201MHz, MeOH-d4) δ 161.60, 160.93, 139.10, 135.97, 120.72, 53.64, 47.59, 47.24,34.77, 34.27, 33.29, 32.35, 31.79, 27.00, 26.97. HRMS(ESI) C 15 H 23 N2 + [M+H] + Calculated value: 231.1856, measured value: 231.1874. Purity: 99.3% (t R = 6.873 min; 254 nm).

[0227] Example 3: Preparation of 2-(piperidin-3-yl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine (Compound I-3)

[0228] Step 1: Preparation of tert-butyl 5-(5,6,7,8,9,10-hexahydrocyclooctane[b]pyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate ZJF-07-125)

[0229]

[0230] The 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester in step 1 of Example 1 was replaced with 1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 1 to obtain a colorless oily intermediate (ZJF-07-125) (186 mg, yield 82%). 1H NMR (800 MHz, CDCl3) δ 7.33 (d, J = 4.5 Hz, 1H), 7.16 – 7.07 (m, 1H), 6.71 (s, 1H), 4.46 –4.35 (m, 2H), 3.60 – 3.51 (m, 2H), 3.03 – HRMS(ESI) C 21 H 31 N2O2 + Calculated value: [M+H] + 343.2380, measured value; 343.2393.

[0231] Step 2: Preparation of tert-butyl 3-(5,6,7,8,9,10-hexahydrocyclooctyl[b]pyridin-2-yl)piperidine-1-carboxylate (Intermediate ZJF-07-126)

[0232]

[0233] The intermediate ZJF-07-115 in step 2 of Example 2 was replaced with intermediate ZJF-07-125. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 2 to obtain a colorless oily intermediate (ZJF-07-126) (142 mg, yield 78%). 1 HNMR (800 MHz, CDCl3) δ 7.30 (d, J = 4.5 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 4.38 – 3.97 (m, 2H), 3.08 – 2.62 (m, 8H), 2.09 – 2.00 (m, 1H), 1.79 – 1.65(m, 6H), 1.46 (s, 9H), 1.38 – 1.32 (m, 4H). HRMS(ESI) C 21 H 33 N2O2 + [M+H] + Calculated value: 345.2537, measured value: 345.2546.

[0234] Step 3: Preparation of 2-(piperidin-3-yl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine (Compound I-3)

[0235]

[0236] The intermediate ZJF-07-118 in step 3 of Example 2 was replaced with intermediate ZJF-07-126. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 2 to obtain a colorless oil (I-3) (90 mg, yield 92%). 1 H NMR (800MHz, MeOH-d4) δ 7.46 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 3.18 – 3.14 (m, 1H), 3.07 – 3.05 (m, 1H), 2.96 – 2.93 (m, 2H), 2.90 – 2.85 (m, 1H), 2.82 – 2.76 (m, 3H), 2.71 – 2.66 (m, 1H), 2.04 – 2.00 (m, 1H), 1.77 – 1.62(m, 7H), 1.40 – 1.33 (m, 4H). 13 C NMR (201 MHz, MeOH-d4) δ 161.65, 161.30,139.19, 135.99, 120.27, 52.09, 46.63, 45.38, 34.54, 33.30, 32.37, 31.77,31.74, 27.03, 26.94, 26.64. HRMS(ESI) C 16 H 25 N2 + [M+H] + Calculated value: 245.2012, found: 245.2032. Purity: 98.2% (t R = 7.983 min; 254 nm).

[0237] Example 4: Preparation of 2-(piperidin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine (Compound I-4)

[0238] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctyl[c]pyridin-2-yl)-3,6-dihydropyridine-1-(2H)-carboxylate (Intermediate ZJF-07-116)

[0239]

[0240] The 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester in step 1 of Example 1 was replaced with N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The remaining raw materials, reagents and preparation method were the same as those required in step 1 of Example 1 to obtain a colorless oily intermediate (ZJF-07-116) (112 mg, yield 60%). 1 H NMR (800 MHz, CDCl3) δ 7.36 (d, J = 43.1 Hz, 1H), 7.12 (d, J = 17.4 Hz, 1H), 6.61 (s, 1H), 4.16 – 4.09 (m, 2H), 3.69 – 3.60 (m, 2H), 2.99 – 2.92 (m, 2H), 2.78 – 2.73(m, 2H), 2.65 – 2.60 (m, 2H), 1.82 – 1.75 (m, 2H), 1.71 – 1.66 (m, 2H), 1.48(s, 9H), 1.39 – 1.37 (m, 4H). HRMS(ESI) C 21 H 31 N2O2 + [M+H] + Calculated value: 343.2380, measured value: 343.2379.

[0241] Step 2: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctyl[b]pyridin-2-yl)piperidine-1-(2H)-carboxylate (Intermediate ZJF-07-120)

[0242]

[0243] The intermediate ZJF-07-115 in step 2 of Example 2 was replaced by intermediate ZJF-07-116. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 2 to obtain a colorless oily intermediate (ZJF-07-120) (68 mg, yield 61%). 1H NMR (800 MHz, CDCl3) δ 7.38 – 7.28 (m, 2H), 6.96 – 6.82 (m, 2H), 4.23 (d, J= 58.4 Hz, 2H), 3.02 – 2.78 (m, 5H), 1.96 – 1.89 (m, 2H), 1.82 – 1.75 (m,2H), 1.70 – 1.59 (m, 4H), 1.47 (s, 9H), 1.38 – 1.34 (m, 4H). HRMS(ESI)C 21 H 33 N2O2 + [M+H] + Calculated value: 345.2537, measured value: 345.2557.

[0244] Step 3: Preparation of 2-(piperidin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine (Compound I-4)

[0245]

[0246] The intermediate ZJF-07-118 in step 3 of Example 2 was replaced with intermediate ZJF-07-120. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 2 to obtain a yellow solid (I-4) (20 mg, yield 43%). 1 H NMR (800MHz, MeOH-d4) δ 7.47 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 3.24 – 3.20 (m, 2H), 2.96 – 2.93 (m, 2H), 2.86 – 2.76 (m, 5H), 1.95 – 1.90 (m, 2H), 1.78 – 1.67 (m, 6H), 1.41 – 1.33 (m, 4H). 13 C NMR (201 MHz, MeOH-d4) δ 163.05,161.19, 139.30, 135.91, 119.64, 46.84(2C), 44.55, 34.51, 33.30, 32.79(2C),32.37, 31.77, 27.03, 26.94. HRMS(ESI) C 16 H 25 N2 + [M+H] +Calculated value: 245.2012, measured value: 245.2016. Purity: 99.5% (t R = 7.575 min; 254 nm).

[0247] Example 5: Preparation of 2-(1,2,3,6-tetrahydropyridin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine (Compound I-5)

[0248] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctane[c]pyridin-2-yl)-3,6-dihydropyridine-1-(2H)-carboxylate (Intermediate ZJF-07-116) by the same procedure as Step 1 in Example 4.

[0249] Step 2: Preparation of 2-(1,2,3,6-tetrahydropyridin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine (Compound I-5)

[0250]

[0251] The intermediate ZJF-07-118 in step 3 of Example 2 was replaced by intermediate ZJF-07-116. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 2 to obtain a yellow oil (I-5) (112 mg, yield 79%). 1 H NMR (800MHz, MeOH-d4) δ 7.45 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.52 – 6.50 (m, 1H), 3.54 – 3.52 (m, 2H), 3.08 (t, J = 5.8 Hz, 2H), 2.97 – 2.94 (m,2H), 2.81 – 2.78 (m, 2H), 2.60 – 2.57 (m, 2H), 1.78 – 1.74 (m, 2H), 1.72 –1.68 (m, 2H), 1.41 – 1.35 (m, 4H). 13 C NMR (201 MHz, MeOH-d4) δ 161.27,156.78, 138.68, 136.78, 136.36, 125.66, 118.65, 45.47, 43.56, 34.95, 33.30,32.43, 31.78, 27.03, 27.01, 26.76. HRMS(ESI) C 16 H 23 N2 +[M+H] + Calculated value: 243.1856, measured value: 243.1853. Purity: 98.9% (t R = 8.048 min; 280 nm).

[0252] Example 6: Preparation of 2-(1,2,5,6-tetrahydropyridin-3-yl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine (Compound I-6)

[0253] Step 1: Preparation of tert-butyl 5-(5,6,7,8,9,10-hexahydrocyclooctane[b]pyridin-2-yl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate ZJF-07-125) by the same procedure as Step 1 in Example 3.

[0254] Step 2: Preparation of 2-(1,2,5,6-tetrahydropyridin-3-yl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine (Compound I-6)

[0255]

[0256] The intermediate ZJF-07-118 in step 3 of Example 2 was replaced with intermediate ZJF-07-125. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 2 to obtain a light yellow solid (I-6) (99 mg, yield 74%). 1 H NMR (800MHz, MeOH-d4) δ 7.42 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.57 –6.54 (m, 1H), 3.80 – 3.77 (m, 2H), 2.98 (t, J = 5.9 Hz, 2H), 2.95 – 2.92 (m,2H), 2.79 – 2.75 (m, 2H), 2.34 – 2.30 (m, 2H), 1.77 – 1.72 (m, 2H), 1.71 –1.66 (m, 2H), 1.41 – 1.33 (m, 4H). 13 C NMR (201 MHz, MeOH-d4) δ 161.17,155.92, 138.54, 137.15, 136.18, 126.18, 118.36, 46.01, 42.92, 35.03, 33.29,32.43, 31.76, 27.02 (2C), 26.16. HRMS(ESI) C 16 H23 N2 + [M+H] + Calculated value: 243.1856, measured value: 243.1852. Purity: 99.5% (t R = 8.212 min; 280 nm).

[0257] Example 7: Preparation of 2-(1,4-diazacycloheptane-1-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyridine (Compound I-7)

[0258] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctan-2-yl)-1,4-diazacyclo-1-carboxylate (Intermediate ZJF-07-130)

[0259]

[0260] Compound A1 (100 mg, 0.511 mmol), Pd2(dba)3 (47 mg, 0.051 mmol), xantphos (59 mg, 0.102 mmol), tert-butyl 1,4-diazepane-1-carboxylate (154 mg, 0.767 mmol), and t-BuOK (86 mg, 0.767 mmol) were dissolved in 1,4-dioxane (30 mL). The mixture was stirred under reflux overnight. The reaction mixture was diluted with water and extracted three times with dichloromethane. The organic phases were combined and dried once over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the remaining solid was isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-4%) to obtain the white solid intermediate ZJF-07-130 (36 mg, 20% yield). 1HNMR (600 MHz, CDCl3) δ 7.13 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 8.4 Hz, 1H), 3.81 – 3.75 (m, 2H), 3.67 – 3.58 (m, 2H), 3.57 – 3.52 (m, 2H), 3.30 (t, J =6.0 Hz, 1H), 3.18 (t, J = 6.1 Hz, 1H), 2.77 (t, J = 6.3 Hz, 2H), 2.61 (t, J =6.2 Hz, 2H), 1.99 – 1.93 (m, 2H), 1.75 – 1.69 (m, 2H), 1.64 – 1.60 (m, 2H),1.44, 1.40 (2s, 9H), 1.38 – 1.33 (m, 4H). HRMS(ESI) C 21 H 34 N3O2 + [M+H] + Calculated value: 360.2646, measured value: 360.2646.

[0261] Step 2: Preparation of 2-(1,4-diazepan-1-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyridine (Compound I-7)

[0262]

[0263] The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with intermediate ZJF-07-130. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a white solid (I-7) (24 mg, yield 93%). 1 H NMR (600MHz, MeOH-d4) δ 7.22 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 3.89 –3.86 (m, 2H), 3.70 (t, J = 6.2 Hz, 2H), 3.18 – 3.15 (m, 2H), 3.02 – 2.99 (m, 2H), 2.81 – 2.77 (m, 2H), 2.67 – 2.63 (m, 2H), 2.06 – 2.01 (m, 2H), 1.74 –1.68 (m, 2H), 1.65 – 1.60 (m, 2H), 1.42 – 1.34 (m, 4H). 13C NMR (201 MHz, MeOH-d4) δ 159.62, 157.61, 139.90, 125.22, 104.68, 47.71, 47.46, 47.08,35.29, 33.56, 31.84, 31.64, 28.63, 28.61, 27.15, 27.08. HRMS(ESI) C 16 H 26 N3 + [M+H] + Calculated value: 260.2121, measured value: 260.2121. Purity: 97.6% (t R = 8.864 min; 254 nm).

[0264] Example 8: Preparation of 2-(4-methylpiperazin-1-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyridine (Compound I-8)

[0265]

[0266] Compound A1 (150 mg, 0.767 mmol), Pd2(dba)3 (70 mg, 0.077 mmol), xantphos (89 mg, 0.154 mmol), N-methylpiperazine (115 mg, 1.150 mmol), and t-BuOK (129 mg, 1.150 mmol) were dissolved in 1,4-dioxane (40 mL). The mixture was stirred under reflux overnight. The reaction mixture was diluted with water and extracted three times with dichloromethane. The organic phases were combined and dried once over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the remaining solid was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 0-4%) to obtain a red oil (I-8) (108 mg, 54% yield). 1 H NMR (800 MHz, MeOH-d4) δ 7.27 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 3.47 (s, 4H), 2.82– 2.79 (m, 2H), 2.68 – 2.65 (m, 2H), 2.60 – 2.55 (m, 4H), 2.35 (s, 3H), 1.74 – 1.69 (m, 2H), 1.65 – 1.61 (m, 2H), 1.40 – 1.34 (m, 4H). 13C NMR (201 MHz, MeOH-d4) δ 159.73, 159.67, 140.01, 127.43, 106.74, 55.82 (2C), 46.74, 46.10(2C), 35.13, 33.45, 31.84, 31.58, 27.11, 27.05. HRMS(ESI) C 16 H 26 N3 + [M+H] + Calculated value: 260.2121, measured value: 260.2132. Purity: 97.8% (t R = 8.864 min; 280 nm).

[0267] According to the method provided in Example 7, the compounds listed in Examples 9-13 can be prepared by changing the corresponding starting materials using the same method, as shown in Table 1 for details.

[0268] Table 1

[0269]

[0270]

[0271] Example 14: Preparation of 2-(piperazin-1-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyrazine (Compound I-14)

[0272] Step 1: Preparation of 2-chloro-5,6,7,8,9,10-hexahydrocyclooctylpyrazine (Compound A2)

[0273]

[0274] Intermediate ZJF-07-156 was synthesized according to the literature (Rüedi, Oberli et al., Synlett., 2004, 13, 2315-2318). Aq 1.5 N NaOH (3.11 g, 77.77 mmol) was added to a suspension of glycineamide hydrochloride (3.40 g, 30.74 mmol) in MeOH (40 mL) at -30°C and stirred for 10 minutes. A solution of ZJF-07-156 (5.13 g, 36.6 mmol) in MeOH (20 mL) was then added dropwise to the mixture. The mixture was maintained at -30°C for another half hour and then stirred at room temperature for 3 hours. Insoluble salts were removed by filtration, and the filtrate was dried once over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure, and the remaining solid was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain the yellow solid intermediate ZJF-07-157 (564 mg, 9% yield). A colorless oil (Compound A2) (305 mg, 49% yield) was synthesized from ZJF-07-157 according to patent (WO2008083353). 1 HNMR (600 MHz, CDCl3) δ 8.32 (s, 1H), 2.99 – 2.93 (m, 4H), 1.83 – 1.77 (m,4H), 1.41 – 1.36 (m, 4H). 13 C NMR (151 MHz, CDCl3) δ 156.72, 154.68, 146.05,141.12, 33.98, 33.41, 30.47, 30.43, 25.82, 25.81. HRMS(ESI) C 10 H 14 N2Cl + [M+H] + Calculated value: 197.0840, measured value: 197.0863.

[0275] Step 2: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctazin-2-yl)piperazine-1-carboxylate (Intermediate ZJF-08-015)

[0276]

[0277] In step 1 of Example 7, tert-butyl 1,4-diazepane-1-carboxylate was replaced with tert-butyl piperazine-1-carboxylate, and Compound A1 was replaced with Compound A2. The remaining raw materials, reagents and preparation methods were the same as those required in step 1 of Example 7 to obtain a yellow oily intermediate (ZJF-08-015) (95 mg, yield 52%). 1H NMR (800 MHz, CDCl3) δ 7.85 (s, 1H), 3.59 – 3.51 (m, 8H), 2.96 – 2.92 (m, 2H), 2.87 – 2.84 (m, 2H), 1.81 – 1.75(m, 4H), 1.49 (s, 9H), 1.42 – 1.37 (m, 4H). HRMS(ESI) C 19 H 31 N2O2 + Calculated value: [M+H] + 347.2442, measured value; 347.2444.

[0278] Step 3: Preparation of 2-(piperazin-1-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyrazine (Compound I-14)

[0279]

[0280] The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with the intermediate ZJF-08-015. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a colorless oil (I-14) (48 mg, yield 73%). 1 H NMR (800MHz, DMSO-d6) δ 8.61 (s, 1H), 8.11 (s, 1H), 3.70 – 3.67 (m, 4H), 3.20 – 3.18(m, 4H), 2.83 – 2.80 (m, 2H), 2.80 – 2.77 (m, 2H), 1.69 – 1.61 (m, 4H), 1.35– 1.30 (m, 4H). 13 C NMR (201 MHz, DMSO-d6) δ 152.46, 151.79, 144.15, 128.05,42.53 (2C), 41.62 (2C), 33.45, 32.39, 30.47, 30.10, 25.54, 25.47. HRMS(ESI)C 14 H 23 N4 + [M+H] + Calculated value: 247.1917, measured value: 247.1922. Purity: 98.0% (t R = 10.631 min; 254 nm).

[0281] Example 15: Preparation of 2-(1,4-diazacycloheptane-1-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyrazine (Compound I-15)

[0282] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctazin-2-yl)-1,4-diazepane-1-carboxylate (Intermediate ZJF-08-020)

[0283]

[0284] The piperazine-1-carboxylic acid tert-butyl ester in step 2 of Example 14 was replaced with tert-butyl 1,4-diazepane-1-carboxylate. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 14 to obtain a yellow oily intermediate (ZJF-08-020) (60 mg, yield 31%). 1 H NMR (800 MHz, CDCl3) δ 7.75 (s, 1H), 3.79 (t, J = 5.3 Hz, 1H), 3.75 (t, J = 5.5 Hz, 1H), 3.65 (t, J = 6.2 Hz, 2H), 3.57 – 3.54 (m, 2H), 3.33(t, J = 6.1 Hz, 1H), 3.22 (t, J = 6.2 Hz, 1H), 2.86 (t, J = 6.6 Hz, 2H), 2.80(t, J = 6.4 Hz, 2H), 1.96 (p, J = 6.2 Hz, 2H), 1.77 – 1.71 (m, 4H), 1.44 –1.38 (m, 9H), 1.39 – 1.35 (m, 4H). HRMS(ESI) C 20 H 33 N4O2 + Calculated value: [M+H] + 361.2598, measured value; 361.2594.

[0285] Step 2: Preparation of 2-(1,4-diazepan-1-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyrazine (Compound I-15)

[0286]

[0287] The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with intermediate ZJF-08-020. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a yellow-white solid (I-15) (35 mg, yield 81%). 1H NMR (800MHz, DMSO-d6) δ 7.88 (s, 1H), 3.76 (t, J = 5.3 Hz, 2H), 3.67 (t, J = 6.1 Hz, 2H), 3.06 – 3.03 (m, 2H), 2.91 – 2.88 (m, 2H), 2.79 – 2.76 (m, 2H), 2.75 –2.72 (m, 2H), 1.92 (p, J = 6.1 Hz, 2H), 1.68 – 1.60 (m, 4H), 1.35 – 1.29 (m,4H). 13 C NMR (201 MHz, DMSO-d6) δ 151.90, 151.51, 141.33, 126.31, 46.57,46.06, 45.79, 45.11, 33.49, 32.35, 30.58, 30.12, 26.60, 25.60, 25.48. HRMS(ESI) C 15 H 25 N4 + [M+H] + Calculated value: 261.2074, measured value: 261.2081. Purity: 99.5% (t R = 10.710 min; 254 nm).

[0288] Example 16: Preparation of 2-(piperidin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyrazine (Compound I-16)

[0289] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate ZJF-08-025)

[0290]

[0291] The compound A1 in step 1 of Example 4 was replaced by compound A2. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 4 to obtain a colorless oily intermediate (ZJF-08-025) (399 mg, yield 75%). 1H NMR (800 MHz, CDCl3) δ 8.39 (s, 1H), 6.88 – 6.66 (m, 1H), 4.21 – 4.13 (m, 2H), 3.71 – 3.63 (m, 2H), 3.19 – 3.03 (m, 4H), 2.68 – 2.58 (m, 2H), 1.93 – 1.81 (m, 4H), 1.49(s, 9H), 1.43 – 1.40 (m, 4H). HRMS(ESI) C 21 H 30 N3O2 + Calculated value: [M+H] + 344.2333, measured value; 344.2361.

[0292] Step 2: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctyl[b]pyrazin-2-yl)piperidine-1-carboxylate (Intermediate ZJF-08-026)

[0293]

[0294] The intermediate ZJF-07-116 in step 2 of Example 4 was replaced with the intermediate ZJF-08-025. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 4 to obtain a colorless oily intermediate (ZJF-08-026) (252 mg, yield 63%). 1 H NMR (800 MHz, CDCl3) δ 8.20 (s, 1H), 4.41 – 4.10 (m, 2H), 2.99 – 2.95 (m, 4H), 2.86 – 2.82 (m, 2H), 1.93 – 1.88 (m, 2H), 1.82 – 1.78 (m, 4H), 1.76– 1.70 (m, 2H), 1.49 (s, 1H), 1.47 (s, 9H), 1.40 – 1.37 (m, 4H). HRMS(ESI)C 20 H 32 N3O2 + [M+H] + Calculated value: 346.2489, measured value: 346.2503.

[0295] Step 3: Preparation of 2-(piperidin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyrazine (Compound I-16)

[0296]

[0297] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-026. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow-white oil (I-16) (80 mg, yield 45%). 1 H NMR(800 MHz, DMSO-d6) δ 8.25 (s, 1H), 3.06 – 3.01 (m, 2H), 2.92 – 2.89 (m, 4H), 2.78 – 2.72 (m, 1H), 2.62 – 2.58 (m, 2H), 1.76 – 1.71 (m, 2H), 1.70 – 1.66 (m, 4H), 1.64 – 1.58 (m, 2H), 1.33 – 1.28 (m, 4H). 13 C NMR (201 MHz, DMSO) δ156.91, 154.45, 153.06, 139.62, 45.91, 41.19 (2C), 33.50, 33.16, 31.90 (2C), 30.31, 30.29, 25.49, 25.42. HRMS(ESI) C 15 H 24 N3 + [M+H] + Calculated value: 246.1965, measured value: 246.1953. Purity: 99.3% (t R = 10.384 min; 254 nm).

[0298] Example 17: Preparation of 2-(piperidin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyrazine (Compound I-17)

[0299] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctan-2-yl)-3,6-dihydropyrimidine-1(2H)-carboxylate (Intermediate ZJF-08-101)

[0300] \

[0301] Intermediate ZJF-08-086 was synthesized according to the literature (Ali, Hosni et al., Arch Pharm (Weinheim), 2012, 345, 231-239). Starting material Compound A3 was synthesized from ZJF-08-086 according to patent (PCT2008083353). Substituting Compound A1 in Step 1 of Example 4 with Compound A3, the remaining starting materials, reagents, and preparation method were the same as those in Step 1 of Example 4 to obtain the intermediate (ZJF-08-101) as a yellow oil (307 mg, 98% yield). 1 H NMR (800 MHz, CDCl3) δ8.34 (s, 1H), 5.30 (s, 1H), 4.20 – 4.13 (m, 2H), 3.68 – 3.58 (m, 2H), 2.90(t, J = 6.4 Hz, 2H), 2.76 – 2.71 (m, HRMS(ESI)C 20 H 30 N3O2 + [M+H] + Calculated value: 344.2333, measured value: 344.2330.

[0302] Step 2: Preparation of 2-(1,2,3,6-tetrahydropyridin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctane[d]pyrimidine (Compound I-17)

[0303]

[0304] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-101. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a white solid (I-17) (25 mg, yield 34%). 1H NMR (800MHz, CDCl3) δ 8.32 (s, 1H), 7.19 – 7.16 (m, 1H), 3.67 – 3.63 (m, 2H), 3.15(t, J = 5.8 Hz, 2H), 2.90 – 2.87 (m, 2H), 2.75 – 2.71 (m, 2H), 2.71 – 2.67(m, 2H), 1.82 – 1.78 (m, 2H), 1.71 – 1.67 (m, 2H), 1.43 – 1.39 (m, 2H), 1.39– 1.34 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 168.96, 162.95, 155.94, 135.22,131.11, 129.55, 45.13, 42.90, 34.14, 31.92, 30.02, 28.74, 25.77, 25.67,25.50. HRMS(ESI) C 15 H 22 N3 + [M+H] + Calculated value: 244.1808, measured value: 244.1803. Purity: 99.7% (t R = 11.270 min; 254 nm).

[0305] Example 18: Preparation of 2-(piperidin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyrimidine (Compound I-18)

[0306] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctan-2-yl)-3,6-dihydropyrimidine-1(2H)-carboxylate (Intermediate ZJF-08-101) was carried out in the same manner as in Step 1 of Example 17.

[0307] Step 2: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctane[d]pyrimidin-2-yl)piperidine-1-carboxylate (Intermediate ZJF-08-104)

[0308]

[0309] The intermediate ZJF-07-116 in step 2 of Example 4 was replaced with the intermediate ZJF-08-101. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 4 to obtain a colorless oily intermediate (ZJF-08-104) (166 mg, yield 83%). 1H NMR (800 MHz, CDCl3) δ 8.32 (s, 1H), 7.19 – 7.16 (m, 1H), 3.67 – 3.63(m, 2H), 3.15 (t, J = 5.8 Hz, 2H), 2.90 – 2.87 (m, 2H), 2.75 – 2.71 (m, 2H), 2.71 – 2.67 (m, 2H), 1.82 – 1.78 (m, 2H), 1.71 – 1.67 (m, 2H), 1.43 – 1.39 (m, 2H), 1.39 – 1.34 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 168.96, 162.95,155.94, 135.22, 131.11, 129.55, 45.13, 42.90, 34.14, 31.92, 30.02, 28.74,25.77, 25.67, 25.50. HRMS(ESI) C 20 H 32 N3O2 + [M+H] + Calculated value: 346.2489, measured value: 346.2486.

[0310] Step 3: Preparation of 2-(piperidin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyrimidine (Compound I-18)

[0311]

[0312] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-104. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a white solid (I-18) (63 mg, yield 53%). 1 H NMR (800MHz, CDCl3) δ 8.31 (s, 1H), 3.24 – 3.19 (m, 2H), 2.99 – 2.94 (m, 1H), 2.89 –2.85 (m, 2H), 2.82 – 2.76 (m, 2H), 2.73 – 2.69 (m, 2H), 2.63 (brs, 1H), 2.01– 1.97 (m, 2H), 1.86 – 1.77 (m, 4H), 1.71 – 1.66 (m, 2H), 1.42 – 1.38 (m,2H), 1.37 – 1.33 (m, 2H).13 C NMR (201 MHz, CDCl3) δ 170.81, 169.29, 156.30,130.76, 46.24 (2C), 44.92, 33.98, 31.84, 31.79 (2C), 30.00, 28.65, 25.80,25.62. HRMS(ESI) C 15 H 24 N3 + [M+H] + Calculated value: 246.1965, measured value: 246.1956. Purity: 99.8% (t R = 10.808 min; 254 nm).

[0313] Example 19: Preparation of 2-(piperazin-1-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyrimidine (Compound I-19)

[0314] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctane[d]pyrimidin-2-yl)piperazine-1-carboxylate (Intermediate ZJF-08-107)

[0315]

[0316] The compound A1 in step 1 of Example 7 was replaced by compound A3, and tert-butyl 1,4-diazepane-1-carboxylate was replaced by tert-butyl piperazine-1-carboxylate. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 7 to obtain a colorless oily intermediate (ZJF-08-107) (38 mg, yield 11%). 1 H NMR (800 MHz, CDCl3) δ 7.99 (s, 1H), 3.80 – 3.73 (m, 4H), 3.51 – 3.45 (m, 4H), 2.74 – 2.71 (m, 2H), 2.60 – 2.57(m, 2H), 1.76 – 1.73 (m, 2H), 1.64 – 1.60 (m, 2H), 1.48 (s, 9H), 1.43 – 1.40(m, 2H), 1.39 – 1.37 (m, 2H). HRMS(ESI) C 19 H 31 N4O2 + [M+H] + Calculated value: 347.2442, measured value: 347.2442.

[0317] Step 2: Preparation of 2-(piperazin-1-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyrimidine (Compound I-19)

[0318]

[0319] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-107. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a white solid (I-19) (15 mg, yield 56%). 1 H NMR (800MHz, CDCl3) δ 7.98 (s, 1H), 3.99 (t, J = 5.0 Hz, 4H), 3.13 (t, J = 5.3 Hz, 4H), 2.73 – 2.70 (m, 2H), 2.60 – 2.57 (m, 2H), 1.76 – 1.71 (m, 2H), 1.64 –1.59 (m, 2H), 1.42 – 1.39 (m, 2H), 1.38 – 1.34 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 170.10, 160.64, 156.85, 122.89, 44.22 (2C), 42.55 (2C), 34.11,32.20, 29.84, 28.13, 25.84, 25.67. HRMS(ESI) C 14 H 23 N4 + [M+H] + Calculated value: 247.1917, measured value: 247.1908. Purity: 99.6% (t R = 11.703 min; 254 nm).

[0320] Example 20: Preparation of 2-(1,4-diazepan-1-yl)-5,6,7,8,9,10-hexahydrocyclooctane pyrimidine (Compound I-20)

[0321] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctan-2-ylpyrimidinyl)-1,4-diazacyclopentane-1-carboxylate (Intermediate ZJF-08-109)

[0322]

[0323] The compound A1 in step 1 of Example 7 was replaced by compound A3. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 7 to obtain a yellow oily intermediate (ZJF-08-109) (28 mg, yield 8%). 1 H NMR (800 MHz, CDCl3) δ 7.94 (s, 1H), 3.88 – 3.81 (m, 2H), 3.76 – 3.71 (m, 2H), 3.54 – 3.50(m, 2H), 3.33 (t, J = 6.1 Hz, 1H), 3.22 (t, J = 6.2 Hz, 1H), 2.72 – 2.68 (m,2H), 2.58 – 2.54 (m, 2H), 1.96 – 1.92 (m, 2H), 1.75 – 1.71 (m, 2H), 1.62 –1.57 (m, 2H), 1.43, 1.40 (2s, 9H), 1.42 – 1.40 (m, 2H), 1.37 – 1.34 (m, 2H).HRMS(ESI) C 20 H 33 N4O2 + [M+H] + Calculated value: 361.2598, measured value: 361.2604.

[0324] Step 2: Preparation of 2-(1,4-diazepan-1-yl)-5,6,7,8,9,10-hexahydrocyclooctane pyrimidine (Compound I-20)

[0325]

[0326] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-109. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-20) (6 mg, yield 30%). 1H NMR (800MHz, CDCl3) δ 7.97 (s, 1H), 4.11 – 4.08 (m, 2H), 3.94 (t, J = 6.7 Hz, 2H), 3.31 – 3.28 (m, 2H), 3.16 – 3.12 (m, 2H), 2.74 – 2.70 (m, 2H), 2.61 – 2.57(m, 2H), 2.32 – 2.28 (m, 2H), 1.76 – 1.72 (m, 2H), 1.65 – 1.60 (m, 2H), 1.44– 1.41 (m, 2H), 1.39 – 1.36 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 170.21,160.23, 157.04, 122.34, 47.03, 45.61, 44.41, 44.21, 34.14, 32.29, 29.92,28.19, 25.93, 25.71, 25.45. HRMS(ESI) C 15 H 25 N4 + [M+H] + Calculated value: 261.2074, measured value: 261.2069. Purity: 94.1% (t R = 11.235 min; 254 nm).

[0327] Example 21: Preparation of 3-(piperazin-1-yl)-5,6,7,8,9,10-hexahydrocycloxanthridine (Compound I-21)

[0328] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclopyridazin-3-yl)pyridazine-1-carboxylate (Intermediate ZJF-08-123)

[0329]

[0330] The starting material, compound A4, was synthesized according to patent (WO2008083353). In step 1 of Example 7, compound A1 was replaced with compound A4, and tert-butyl 1,4-diazepane-1-carboxylate was replaced with tert-butyl piperazine-1-carboxylate. The remaining raw materials, reagents, and preparation method were the same as those in step 1 of Example 7 to obtain a yellow solid intermediate (ZJF-08-123) (180 mg, 51% yield). 1H NMR (600 MHz, CDCl3) δ 6.67 (s, 1H), 3.60 – 3.54 (m, 4H), 3.26 – 3.22(m, 1H), 3.04 (t, J = 6.3 Hz, 2H), 2.90 – 2.86 (m, 1H), 2.70 – 2.65 (m, 2H),1.84 – 1.78 (m, 2H), 1.75 – 1.68 (m, 2H), 1.48 (s, 9H), 1.44 – 1.35 (m, 6H).HRMS(ESI) C 19 H 31 N4O2 + [M+H] + Calculated value: 347.2442, measured value: 347.2437.

[0331] Step 2: Preparation of 3-(piperazin-1-yl)-5,6,7,8,9,10-hexahydrocycloxanthine (Compound I-21)

[0332]

[0333] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-123. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-21) (64 mg, yield 53%). 1 H NMR (600MHz, CDCl3) δ 6.63 (s, 1H), 3.67 – 3.62 (m, 4H), 3.10 – 3.03 (m, 4H), 3.01 –2.96 (m, 2H), 2.67 – 2.63 (m, 2H), 1.80 – 1.74 (m, 2H), 1.72 – 1.66 (m, 2H), 1.41 – 1.32 (m, 4H). 13 HRMS(ESI) C 14 H 23 N4 + [M+H] + Calculated value: 247.1917, measured value: 247.1922. Purity: 97.9% (t R= 4.821 min; 254 nm).

[0334] Example 22: Preparation of 3-(1,4-diazepan-1-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyridazine (Compound I-22)

[0335] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclopyridazin-3-yl)-1,4-diazacyclopyrazine-1-carboxylate (Intermediate ZJF-08-124)

[0336]

[0337] The compound A1 in step 1 of Example 7 was replaced by compound A4. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 7 to obtain a yellow oily intermediate (ZJF-08-124) (90 mg, yield 12%). 1 H NMR (600 MHz, CDCl3) δ 6.55 (d, J = 10.4 Hz, 1H), 3.88 (t, J = 5.5 Hz, 1H), 3.80 – 3.74 (m,2H), 3.66 – 3.58 (m, 3H), 3.33 (t, J = 6.2 Hz, 1H), 3.25 (t, J = 6.2 Hz, 1H), 3.05 – 3.00 (m, 2H), 2.67 (t, J = 6.4 Hz, 2H), 2.00 – 1.94 (m, 2H), 1.83 –1.78 (m, 2H), 1.73 – 1.68 (m, 2H), 1.42 (s, 9H), 1.39 – 1.36 (m, 4H). HRMS(ESI) C 20 H 33 N4O2 + [M+H] + Calculated value: 361.2598, measured value: 361.2589.

[0338] Step 2: Preparation of 3-(1,4-diazepan-1-yl)-5,6,7,8,9,10-hexahydrocycloxanthine (Compound I-22)

[0339]

[0340] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-124. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow-white solid (I-22) (19 mg, yield 29%). 1 H NMR (800MHz, CDCl3) δ 6.49 (s, 1H), 3.87 (t, J = 5.3 Hz, 2H), 3.74 (t, J = 6.3 Hz, 2H), 3.14 – 3.10 (m, 2H), 2.97 – 2.94 (m, 2H), 2.93 – 2.91 (m, 2H), 2.65 –2.61 (m, 2H), 2.03 – 1.99 (m, 2H), 1.78 – 1.73 (m, 2H), 1.70 – 1.66 (m, 2H), 1.40 – 1.33 (m, 4H). 13 C NMR (201 MHz, CDCl3) δ 158.21, 154.38, 142.09,110.55, 48.49, 48.17, 47.44, 46.23, 31.63, 31.60, 31.58, 30.76, 28.38, 25.86,25.43. HRMS(ESI) C 15 H 25 N4 + [M+H] + Calculated value: 261.2074, measured value: 261.2076. Purity: 90.5% (t R = 6.186 min; 254 nm).

[0341] Example 23: Preparation of 3-(1,2,3,6-tetrahydropyridin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyridazine (Compound I-23)

[0342] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclopyridazin-3-yl)-3,6-dihydropyridine-1(2H)carboxylate (Intermediate ZJF-08-101)

[0343]

[0344] The compound A1 in step 1 of Example 4 was replaced by compound A4. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 4 to obtain a yellow-white oily intermediate (ZJF-08-129) (116 mg, yield 17%). 1H NMR (800MHz, CDCl3) δ 6.63 (d, J = 40.4 Hz, 1H), 5.32 (s, 1H), 4.21 – 4.16 (m, 2H), 3.73 – 3.64 (m, 2H), 3.20 (t, J = 6.3 Hz, 2H), 2.86 – 2.74 (m, 4H), 1.90 (dd,J = 8.0, 4.5 Hz, 2H), 1.79 – 1.74 (m, 2H), 1.51 (s, 9H), 1.45 – 1.38 (m, 4H).HRMS(ESI) C 20 H 30 N3O2 + [M+H] + Calculated value: 344.2333, measured value: 344.2327.

[0345] Step 2: Preparation of 3-(1,2,3,6-tetrahydropyridin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyridazine (Compound I-23)

[0346]

[0347] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-129. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a white solid (I-23) (61 mg, yield 74%). 1 H NMR (800MHz, CDCl3) δ 7.22 (s, 1H), 6.63 – 6.60 (m, 1H), 3.60 – 3.57 (m, 2H), 3.13 –3.08 (m, 4H), 2.85 (brs, 1H), 2.72 – 2.67 (m, 4H), 1.83 – 1.78 (m, 2H), 1.71 – 1.67 (m, 2H), 1.38 – 1.30 (m, 4H). 13 C NMR (201 MHz, CDCl3) δ 162.49,157.87, 140.82, 133.78, 127.53, 122.10, 45.42, 43.04, 32.25, 31.57, 31.38,30.72, 25.85 (2C), 25.56. HRMS(ESI) C 15 H 22 N3 + [M+H] +Calculated value: 244.1808, measured value: 244.1829. Purity: 96.2% (t R = 8.288 min; 254 nm).

[0348] Example 24: Preparation of R-3-(2-methylpiperazin-1-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyridazine (Compound I-24)

[0349] Step 1: Preparation of tert-butyl R-4-(5,6,7,8,9,10-hexahydrocyclooctylpyridazin-3-yl)-3-methylpyridazine-1-carboxylate (Intermediate ZJF-09-081)

[0350]

[0351] The piperazine-1-carboxylic acid tert-butyl ester in step 1 of Example 21 was replaced with (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 21 to obtain a yellow solid intermediate (ZJF-09-081) (68 mg, yield 11%). 1 H NMR (800 MHz, CDCl3) δ 6.56 (s, 1H), 3.22 – 3.18 (m, 2H), 3.18 – 3.15 (m, 1H), 2.99 – 2.95 (m, 2H), 2.86 – 2.83 (m, 2H), 2.64 – 2.61 HRMS(ESI) C 20 H 33 N4O2 + [M+H] + Calculated value: 361.2598, measured value: 361.2597.

[0352] Step 2: Preparation of R-3-(2-methylpiperazin-1-yl)-5,6,7,8,9,10-hexahydrocycloxanthine (Compound I-24)

[0353]

[0354] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-081. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-24) (27 mg, yield 55%).1 H NMR (800MHz, CDCl3) δ 6.57 (s, 1H), 4.43 – 4.39 (m, 1H), 4.05 – 4.00 (m, 1H), 3.15 –3.08 (m, 3H), 3.00 – 2.97 (m, 2H), 2.95 – 2.92 (m, 1H), 2.89 – 2.84 (m, 1H), 2.66 – 2.63 (m, 2H), 1.80 – 1.75 (m, 2H), 1.71 – 1.66 (m, 2H), 1.42 – 1.33(m, 4H), 1.22 (d, J = 6.7 Hz, 3H). 13 C NMR (201 MHz, CDCl3) δ 159.29, 155.37,142.13, 112.05, 50.72, 47.22, 46.06, 40.10, 31.80, 31.78 (2C), 30.91, 26.04,25.61, 12.89. [α]20 D = -73.0 (c = 0.2, MeOH). HRMS(ESI) C 15 H 25 N4 + [M+H] + Calculated value: 261.2074, measured value: 261.2083. Purity: 98.5% (t R = 5.427 min; 254 nm).

[0355] Example 25: Preparation of 3-methoxy-2-piperazin-1-yl-5,6,7,8,9,10-hexahydrocyclooctylpyridine (Compound I-25)

[0356] Step 1: Preparation of 3-nitro-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridin-2-ol (Intermediate ZJF-08-001)

[0357]

[0358] The starting material ZJF-07-170 was synthesized according to patent (WO2016176460), and the starting material ZJF-07-171 was synthesized according to literature (Miura, Kiyota et al., Org Lett., 2005, 7, 1445-1447). To a solution of NaOH (0.44 g, 10.89 mmol) in H₂O (30 mL) was added ZJF-07-171 (1.6 g, 10.38 mmol). To the clear yellow solution was added an aqueous solution of piperidineacetic acid (3 mL, synthesized by mixing glacial acetic acid (1.04 mL), piperidine (1.8 mL), and H₂O (2.5 mL)). The resulting solution was stirred at 100°C for 5 minutes, after which ZJF-07-170 (1.08 g, 10.38 mmol) was added portionwise over 20 minutes. The reaction mixture was then stirred at 100°C for 3 hours and then cooled to room temperature. The reaction mixture was diluted with water and extracted three times with dichloromethane. The organic phases were combined and dried once over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure, and the remaining solid was purified by silica gel column chromatography (methanol / dichloromethane = 0-10% HCl). 2%, methanol containing 0.5% triethylamine) to obtain a yellow solid intermediate ZJF-08-001 (821 mg, yield 36%). 1 H NMR (800 MHz, CDCl3) δ 13.28 (s, 1H), 8.30 (s, 1H), 2.92 – 2.88 (m, 2H), 2.66 – 2.61 (m, 2H), 1.89 – 1.85 (m, 2H), 1.72 – 1.68 (m, 2H),1.48 – 1.43 (m, 4H). 13 C NMR (201 MHz, CDCl3) δ 157.66, 156.99, 141.84,134.90, 118.60, 31.33, 30.31, 29.69, 29.55, 25.72, 25.42. HRMS(ESI) C 11 H 15 N2O3 + [M+H] + Calculated value: 223.1077, measured value: 223.1063.

[0359] Step 2: Preparation of 2-chloro-3-nitro-5,6,7,8,9,10-hexahydrocyclooctylpyridine (Intermediate ZJF-08-011)

[0360]

[0361] ZJF-08-001 (931 mg, 4.19 mmol) was added to POCl₃ (15 mL) and stirred at 100°C under a N₂ atmosphere for 2 hours. The solvent (including the bulk POCl₃) was evaporated under reduced pressure, and the residue was poured into ice water (30 mL) and stirred for 15 minutes. The mixture was adjusted to pH 7 with aqueous NaHCO₃ and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with H₂O (60 mL), the combined organic layers were washed with brine, and dried once over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure, and the remaining solid was isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-2%) to obtain the yellow-white solid intermediate ZJF-08-011 (787 mg, 78% yield). 1 H NMR (800 MHz, CDCl3) δ 7.97 (s, 1H), 3.03 – 3.00 (m, 2H), 2.85 – 2.83 (m, 2H), 1.86 – 1.82 (m, 2H), 1.78 – 1.74 (m, 2H), 1.44 – 1.39 (m, 4H).HRMS(ESI) C 11 H 14 ClN2O2 + [M+H] + Calculated value: 241.0738, measured value: 241.0749.

[0362] Step 3: Preparation of 2-chloro-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridin-3-amine (Intermediate ZJF-08-017)

[0363]

[0364] To a stirred solution of ZJF-08-011 (787 mg, 3.27 mmol) in ethanol (25 mL) was added glacial acetic acid (15 mL), followed by iron powder (1.28 g, 22.89 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was treated with ethyl acetate (30 mL) and aqueous NaHCO₃ (30 mL). The mixture was stirred for 30 minutes and then filtered. The mixture was washed with ethyl acetate (100 mL), and the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated to yield a crude residue. The residue was purified by flash chromatography (ethyl acetate / petroleum ether = 0-12%) to afford the intermediate ZJF-08-011 as an off-white solid (519 mg, 75% yield). 1H NMR (800 MHz, DMSO-d6) δ 6.87(s, 1H), 5.21 (s, 2H), 2.69 – 2.66 (m, 2H), 2.61 – 2.58 (m, 2H), 1.61 – 1.56(m, 4H), 1.33 – 1.27 (m, 4H). HRMS(ESI) C 11 H 16 ClN2 + [M+H] + Calculated value: 211.0997, measured value: 211.0984.

[0365] Step 4: Preparation of 2-chloro-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridin-3-ol (Intermediate ZJF-08-028)

[0366]

[0367] To a stirred solution of ZJF-08-017 (670 mg, 3.18 mmol) in trifluoroacetic acid (10 mL) at 0°C was added dropwise a pre-formed solution of sodium nitrite (439 mg, 6.36 mmol) in H₂O (4 mL), and the mixture was stirred for 1 hour. The ice bath was removed, and the mixture was stirred at room temperature for 30 minutes. The mixture was then heated in a preheated oil bath at 70°C for 40 minutes. The mixture was refluxed overnight and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated to yield a crude residue. The residue was purified by flash chromatography (ethyl acetate / petroleum ether = 0-20%) to afford the intermediate ZJF-08-028 (420 mg, 62% yield) as an off-white solid. 1 H NMR (800 MHz, DMSO-d6) δ 10.23 (s,1H), 7.05 (s, 1H), 2.75 – 2.72 (m, 2H), 2.66 – 2.63 (m, 2H), 1.63 – 1.58 (m,4H), 1.33 – 1.27 (m, 4H). HRMS(ESI) C 11 H 15 ClNO + [M+H] + Calculated value: 212.0837, measured value: 212.0841.

[0368] Step 5: Preparation of 2-chloro-3-methoxy-5,6,7,8,9,10-hexahydrocyclooctylpyridine (Intermediate Compound A5)

[0369]

[0370] To a stirred solution of ZJF-08-028 (420 mg, 1.98 mmol) in DMF (15 mL) were added iodomethane (422 mg, 2.98 mmol) and KCO (686 mg, 4.96 mmol), and the mixture was stirred at room temperature for 4 hours. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, and the residue was purified by flash chromatography (ethyl acetate / petroleum ether = 0-8%) to afford intermediate compound A5 as an off-white solid (265 mg, 59% yield). 1 H NMR (800 MHz, CDCl3) δ6.95 (s, 1H), 3.89 (s, 3H), 2.90 – 2.86 (m, 2H), 2.76 – 2.72 (m, 2H), 1.78 –1.73 (m, 2H), 1.72 – 1.68 (m, 2H), 1.40 – 1.35 (m, 4H). 13 HRMS(ESI) C 12 H 17 ClNO + [M+H] + Calculated value: 226.0993, measured value: 226.0987.

[0371] Step 6: Preparation of tert-butyl 4-(3-methoxy-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridin-2-yl)piperazine-1-carboxylate (Intermediate ZJF-08-015)

[0372]

[0373] In step 1 of Example 7, tert-butyl 1,4-diazepane-1-carboxylate was replaced with tert-butyl piperazine-1-carboxylate, and Compound A1 was replaced with Compound A5. The remaining raw materials, reagents and preparation methods were the same as those required in step 1 of Example 7 to obtain a yellow oily intermediate (ZJF-08-015) (65 mg, yield 48%). 1H NMR (800 MHz, DMSO-d6) δ 7.01 (s, 1H), 3.76 (s, 3H), 3.44 – 3.39 (m, 4H), 3.17 (t, J = 5.1 Hz, 4H), 2.71 – 2.68 (m,2H), 2.66 – 2.63 (m, 2H), 1.62 – 1.58 (m, 4H), 1.41 (s, 9H), 1.31 – 1.28 (m,4H). HRMS(ESI) C 21 H 34 N3O3 + Calculated value: [M+H] + 376.2595, measured value; 376.2590.

[0374] Step 7: Preparation of 3-methoxy-2-piperazin-1-yl-5,6,7,8,9,10-hexahydrocyclooctylpyridine (Compound I-25)

[0375]

[0376] The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with intermediate ZJF-08-038. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a colorless oil (I-25) (45 mg, yield 94%). 1 H NMR (800MHz, DMSO-d6) δ 7.09 (s, 1H), 3.78 (s, 3H), 3.44 – 3.42 (m, 4H), 3.21 – 3.18(m, 4H), 2.73 – 2.71 (m, 2H), 2.67 – 2.65 (m, 2H), 1.63 – 1.59 (m, 4H), 1.31 – 1.28 (m, 4H), 1.23 (s, 1H). 13 C NMR (201 MHz, DMSO-d6) δ 158.14, 155.74,147.37, 144.64, 129.35, 55.53, 44.87(2C), 42.80(2C), 32.99, 31.58, 30.38,30.25, 25.59, 25.41. HRMS(ESI) C 16 H 26 N3O + [M+H] + Calculated value: 276.2070, measured value: 276.2073. Purity: 95.2% (tR = 10.060 min; 254 nm).

[0377] Example 26: Preparation of 2-(1,4-diazepan-1-yl)-3-methoxy-5,6,7,8,9,10-hexahydrocyclooctylpyridine (Compound I-26)

[0378] Step 1: Preparation of 3-nitro-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridin-2-ol (Intermediate ZJF-08-001)

[0379]

[0380] The compound A1 in step 1 of Example 7 was replaced by compound A5. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 7 to obtain a colorless oily intermediate (ZJF-08-040) (50 mg, yield 29%). 1 H NMR (800 MHz, MeOH-d4) δ 6.88 (d, J = 6.9 Hz, 1H), 3.78 (s, 3H), 3.60 – 3.54 (m, 4H), 2.86– 2.83 (m, 2H), 2.81 – 2.79 (m, 2H), 2.75 – HRMS(ESI) C 22 H 36 N3O3 + Calculated value: [M+H] + 390.2751, measured value; 390.2754.

[0381] Step 2: Preparation of 2-(1,4-diazepan-1-yl)-3-methoxy-5,6,7,8,9,10-hexahydrocyclooctylpyridine (Compound I-26)

[0382]

[0383] The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with intermediate ZJF-08-040. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a colorless oil (I-26) (11 mg, yield 30%). 1H NMR (800MHz, MeOH-d4) δ 6.89 (s, 1H), 3.78 (s, 3H), 3.64 – 3.61 (m, 4H), 3.03 (t, J =5.5 Hz, 2H), 2.90 – 2.87 (m, 2H), 2.75 – 2.73 (m, 2H), 2.68 – 2.65 (m, 2H), 1.91 – 1.87 (m, 2H), 1.69 – 1.63 (m, 4H), 1.38 – 1.33 (m, 4H). 13 C NMR (201MHz, MeOH-d4) δ 150.62, 149.99, 145.63, 128.26, 121.00, 56.06, 53.19, 50.80,50.38, 48.13, 34.39, 33.30, 32.12, 31.78, 31.37, 27.16, 27.09. HRMS(ESI)C 17 H 28 N3O + [M+H] + Calculated value: 290.2227, measured value: 290.2216. Purity: 99.8% (t R = 8.941 min; 254 nm).

[0384] Example 27: Preparation of 3-methoxy-2-(piperidin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyridine (Compound I-27)

[0385] Step 1: Preparation of tert-butyl 4-(3-methoxy-5,6,7,8,9,10-hexahydrocyclooctan-2-yl)-3,6-dihydropyridine-1(2H)carboxylate (Intermediate ZJF-08-042)

[0386]

[0387] The compound A1 in step 1 of Example 4 was replaced by compound A5. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 4 to obtain a colorless oily intermediate (ZJF-08-042) (166 mg, yield 83%). 1H NMR (800MHz, MeOH-d4) δ 7.17 (s, 1H), 6.12 – 5.99 (m, 1H), 3.81 (s, 3H), 3.66 – 3.64(m, 2H), 2.89 – 2.87 (m, 2H), 2.81 – 2.78 (m, HRMS(ESI) C 22 H 33 N2O3 + [M+H] + Calculated value: 373.2486, measured value: 373.2477.

[0388] Step 2: Preparation of tert-butyl 4-(3-methoxy-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridin-2-yl)piperidine-1-carboxylate (Intermediate ZJF-08-042)

[0389]

[0390] The intermediate ZJF-07-116 in step 2 of Example 4 was replaced with the intermediate ZJF-08-042. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 4 to obtain a colorless oily intermediate (ZJF-08-043) (34 mg, yield 34%). 1 H NMR (800 MHz, MeOH-d4) δ 7.07 (s, 1H), 4.17 (d, J = 12.4 Hz, 2H), 3.82(s, 3H), 2.88 (t, J = 6.4 Hz, 2H), 2.85 – 2.80 (m, 1H), 2.76 (t, J = 6.3 Hz,2H), 1.90 – 1.84 (m, 2H), 1.72 – 1.69 (m, 4H), 1.67 – 1.63 (m, 2H), 1.47 (s,9H), 1.38 – 1.34 (m, 4H), 1.30 – 1.27 (m, 2H). HRMS(ESI) C 22 H 35 N2O3 + [M+H] + Calculated value: 375.2642, measured value: 375.2640.

[0391] Step 3: Preparation of 3-methoxy-2-(piperidin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyridine (Compound I-27)

[0392]

[0393] The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with intermediate ZJF-08-043. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a colorless oil (I-27) (15 mg, yield 64%). 1 H NMR (800MHz, MeOH-d4) δ 7.08 (s, 1H), 3.82 (s, 3H), 3.37 – 3.33 (m, 2H), 3.30 – 3.28(m, 1H), 2.98 – 2.94 (m, 2H), 2.88 – 2.85 (m, 2H), 2.77 – 2.75 (m, 2H), 2.10 – 2.04 (m, 2H), 1.87 – 1.84 (m, 2H), 1.72 – 1.67 (m, 4H), 1.38 – 1.33 (m, 4H). 13 C NMR (201 MHz, MeOH-d4) δ 153.10, 152.37, 150.41, 136.34, 119.98,55.96, 46.15(2C), 37.46, 34.25, 33.20, 32.68, 31.92, 29.41(2C), 27.10, 26.94.HRMS(ESI) C 17 H 27 N2O + [M+H] + Calculated value: 275.2118, measured value: 275.2121. Purity: 98.9% (t R =8.509 min; 280 nm).

[0394] Example 28: Preparation of 4-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxolan-8-yl)piperidine (Compound I-28)

[0395] Step 1: Preparation of tert-butyl Z-4-(2,5-dihydrobenzo[b][1,4]dioxol-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate ZJF-08-073)

[0396]

[0397] The starting material, compound A6, was synthesized according to patent (CN112574183). A solution of compound A6 (654 mg, 2.71 mmol) in DMF (24 mL) was treated with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (300 mg, 0.969 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (91 mg, 0.126 mmol), followed by the addition of an aqueous solution of K2CO3 (670 mg, 4.84 mmol) in H2O (4 mL). The mixture was stirred at 90°C for 2 hours. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined and dried once over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-10%) to obtain the intermediate ZJF-08-073 (173 mg, yield 52%) as a colorless oil. 1 H NMR (800 MHz, MeOH-d4) δ 6.92 – 6.85 (m, 2H), 6.81 – 6.75 (m, 1H), 5.97 – 5.88 (m, 2H), 5.50 – 5.45 (m, 1H), 5.35 – 5.30 (m, 1H), 4.61 – 4.56 (m, 1H), 4.26 – 4.21 (m, 1H), 4.03 – 3.95 (m, 2H), 3.86 – 3.81 (m, 1H), 3.61 – 3.52 (m, 2H), 2.46 – 2.39 (m, 2H), 1.47 (s, 9H).

[0398] Step 2: Preparation of tert-butyl 4-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxol-8-yl)piperidine-1-carboxylate (Intermediate ZJF-08-077)

[0399]

[0400] The intermediate ZJF-07-116 in step 2 of Example 4 was replaced with the intermediate ZJF-08-073. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 4 to obtain a colorless oily intermediate (ZJF-08-077) (72 mg, yield 71%). 1H NMR (800 MHz, MeOH-d4) δ 6.74 – 6.71 (m, 1H), 6.68 – 6.66 (m, 1H), 6.66 – 6.64 (m, 1H), 4.24 – 4.20 (m, 1H), 4.16 (d, J = 13.2 Hz, 2H), 3.99 – 3.95 (m, 1H), 3.83 – 3.78 (m, 1H), 2.91 – 2.72 (m, 2H), 2.61 – 2.55 (m, 1H), 1.76 (d, J = 13.2 Hz, 2H), 1.70 – 1.60 (m, 2H), 1.53 – 1.48 (m, 2H), 1.46 (s,9H), 1.08 – 1.04 (m, 3H).

[0401] Step 3: Preparation of 4-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxolan-8-yl)piperidine (Compound I-28)

[0402]

[0403] The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with intermediate ZJF-08-077. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a colorless oil (I-28) (22 mg, yield 44%). 1 H NMR (800MHz, MeOH-d4) δ 6.74 – 6.72 (m, 1H), 6.70 – 6.69 (m, 1H), 6.68 – 6.65 (m,1H), 4.23 – 4.19 (m, 1H), 3.98 – 3.94 (m, 1H), 3.82 – 3.77 (m, 1H), 3.20 –3.16 (m, 2H), 2.81 – 2.75 (m, 2H), 2.61 – 2.54 (m, 1H), 1.83 – 1.79 (m, 2H), 1.68 – 1.59 (m, 4H), 1.07 – 1.04 (m, 3H). 13 C NMR (201 MHz, MeOH-d4) δ 144.67,143.12, 140.51, 120.29, 117.71, 116.25, 75.74, 68.85, 46.95 (2C), 42.44,34.08 (2C), 25.09, 9.73. HRMS(ESI) C15 H 22 NO2 + [M+H] + Calculated value: 248.1645, measured value: 248.1654. Purity: 96.1% (t R = 11.328 min; 280 nm).

[0404] Example 29: Preparation of (Z)-1-(2,5-dihydrobenzo[b][1,4]dioxo-8-yl)piperazine (Compound I-29)

[0405] Step 1: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclopyridazin-3-yl)pyridazine-1-carboxylate (Intermediate ZJF-09-012)

[0406]

[0407] A solution of palladium acetate (30 mg, 0.135 mmol) and R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (84 mg, 0.135 mmol) in toluene (20 mL) was stirred at room temperature for 5 minutes. Compound A6 (325 mg, 1.35 mmol), tert-butyl piperazine-1-carboxylate (251 mg, 1.35 mmol), and sodium tert-butoxide (194 mg, 2.02 mmol) were then added and refluxed overnight. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined and dried once over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the remaining solid was isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-10%) to obtain intermediate ZJF-09-012 (26 mg, 6% yield) as a colorless oil. 1 H NMR (800 MHz, CDCl3) δ 6.89 (d, J = 8.7 Hz, 1H), 6.57– 6.50 (m, 1H), 6.47 (s, 1H), 5.90 – 5.84 (m, 2H), 4.98 (d, J = 6.4 Hz, 2H), 4.77 (d, J = 3.6 Hz, 2H), 3.58 – 3.51 (m, 4H), 3.07 – 2.99 (m, 4H), 1.47 (s,9H). HRMS(ESI) C 19 H 27 N2O4 + [M+H] + Calculated value: 347.1965, measured value: 347.1960.

[0408] Step 2: Preparation of (Z)-1-(2,5-dihydrobenzo[b][1,4]dioxol-8-yl)piperazine (Compound I-29)

[0409]

[0410] The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with intermediate ZJF-09-012. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a white solid (I-29) (10 mg, yield 54%). 1 H NMR (800MHz, CDCl3) δ 6.89 (d, J = 8.8 Hz, 1H), 6.52 (dd, J = 8.8, 2.9 Hz, 1H), 6.46 (d, J = 2.9 Hz, 1H), 5.91 – 5.84 (m, 2H), 4.97 (d, J = 6.5 Hz, 2H), 4.77 (d,J = 3.3 Hz, 2H), 3.14 – 3.11 (m, 4H), 3.09 – 3.06 (m, 4H). 13 C NMR (201 MHz, CDCl3) δ 148.97, 148.82, 141.08, 132.16, 126.95, 123.92, 111.52, 108.95,72.93, 67.35, 50.13 (2C), 45.63 (2C). HRMS(ESI) C 14 H 19 N2O2 + [M+H] + Calculated value: 247.1441, measured value: 247.1439. Purity: 95.6% (t R = 10.033 min; 254 nm).

[0411] Example 30: Preparation of (R,Z)-1-(2,5-dihydrobenzo[b][1,4]dioxo-8-yl)-2-methylpiperazine (Compound I-30)

[0412] Step 1: Preparation of tert-butyl (R,Z)-4-(2,5-dihydrobenzo[b][1,4]dioxol-8-yl)-3-methylpiperazine-1-carboxylate (Intermediate ZJF-09-090)

[0413]

[0414] In step 1 of Example 29, tert-butyl 1,4-diazepane-1-carboxylate was replaced with tert-butyl (R)-3-methylpiperazine-1-carboxylate. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 29 to obtain a yellow oily intermediate (ZJF-09-090) (203 mg, yield 17%). 1 H NMR (800 MHz, CDCl3) δ 6.81 (dd, J = 31.1, 8.6 Hz,1H), 6.53 (s, 1H), 6.50 – 6.46 (m, 1H), 5.92 – 5.86 (m, 1H), 5.53 – 5.49 (m,1H), 5.39 – 5.36 (m, 1H), 4.64 – 4.60 (m, 1H), 4.24 – 4.20 (m, 1H), 3.89 –3.85 (m, 1H), 3.83 – 3.64 (m, 1H), 3.53 – 3.24 (m, 4H), 3.02 – 2.89 (m, 2H),1.48 (s, 9H), 0.93 (d, J = 6.3 Hz, 3H). HRMS(ESI) C 20 H 29 N2O4 + [M+H] + Calculated value: 361.2122, measured value: 361.2124.

[0415] Step 2: Preparation of (R,Z)-1-(2,5-dihydrobenzo[b][1,4]dioxol-8-yl)-2-methylpiperazine (Compound I-30)

[0416]

[0417] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-090. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-30) (30 mg, yield 52%). 1H NMR (800MHz, CDCl3) δ 6.78 (d, J = 8.7 Hz, 1H), 6.58 – 6.56 (m, 1H), 6.53 – 6.50 (m,1H), 5.92 – 5.86 (m, 1H), 5.52 – 5.48 (m, 1H), 5.38 – 5.35 (m, 1H), 4.63 –4.59 (m, 1H), 4.22 – 4.19 (m, 1H), 3.88 – 3.84 (m, 1H), 3.41 – 3.36 (m, 1H), 3.12 – 3.02 (m, 2H), 2.99 – 2.90 (m, 3H), 2.78 – 2.73 (m, 1H), 0.95 (d, J =6.5 Hz, 3H). 13 C NMR (201 MHz, CDCl3) δ 145.92, 143.32, 137.89, 132.61,119.30, 117.13, 113.76, 108.95, 74.04, 67.67, 53.29, 52.32, 49.21, 46.50,13.89. [α]20 D = +8.0 (c = 0.1, MeOH). HRMS(ESI) C 15 H 21 N2O2 + [M+H] + Calculated value: 261.1598, measured value: 261.1597. Purity: 98.0% (t R = 10.753 min; 280 nm).

[0418] Example 31: Preparation of (R)-2-methyl-1-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxazo-8-yl)piperazine (Compound I-31)

[0419] Step 1: Preparation of (R)-tert-butyl 3-methyl-4-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxol-8-yl)piperazine-1-carboxylate (Intermediate ZJF-09-093)

[0420]

[0421] The ZJF-07-115 in step 2 of Example 2 was replaced by ZJF-09-090. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 2 to obtain a colorless oily intermediate (ZJF-09-093) (110 mg, yield 73%).1 H NMR (800MHz, CDCl3) δ 6.80 – 6.74 (m, 1H), 6.53 – 6.42 (m, 2H), 4.23 – 4.16 (m, 1H), 4.05 – 3.97 (m, 1H), 3.88 – 3.81 (m, 1H), 3.55 – 3.26 (m, 5H), 3.04 – 2.86(m, 2H), 1.75 – 1.69 (m, 1H), 1.66 – 1.61 (m, 1H), 1.48 (s, 9H), 1.08 – 1.05(m, 3H), 0.93 – 0.90 (m, 3H). HRMS(ESI) C 20 H 31 N2O4 + [M+H] + Calculated value: 363.2278, measured value: 363.2281.

[0422] Step 2: Preparation of (R)-2-methyl-1-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxol-8-yl)piperazine (Compound I-31)

[0423]

[0424] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-093. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-31) (36 mg, yield 49%). 1 H NMR(800 MHz, CDCl3) δ 6.76 (d, J = 8.5 Hz, 1H), 6.54 – 6.52 (m, 1H), 6.51 – 6.48(m, 1H), 4.21 – 4.18 (m, 1H), 4.05 – 4.00 (m, 1H), 3.86 – 3.82 (m, 1H), 3.41 – 3.35 (m, 1H), 3.13 – 3.09 (m, 1H), 3.08 – 3.03 (m, 1H), 3.00 – 2.95 (m,2H), 2.95 – 2.90 (m, 1H), 2.78 – 2.74 (m, 1H), 1.76 – 1.69 (m, 1H), 1.65 –1.59 (m, 1H), 1.07 – 1.04 (m, 3H), 0.95 (d, J = 6.5 Hz, 3H).13 C NMR (201 MHz, CDCl3) δ 145.73, 143.71, 138.33, 117.00, 113.68, 109.10, 74.66, 67.91, 53.31,52.30, 49.41, 46.47, 24.31, 14.03, 9.57. [α]20 D = -10.0 (c = 0.1, MeOH).HRMS(ESI) C 15 H 23 N2O2 + [M+H] + Calculated value: 263.1754, measured value: 263.1756. Purity: 98.7% (t R =11.034 min; 280 nm).

[0425] Example 32: Preparation of 1-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxo-8-yl)piperazine (Compound I-32)

[0426] Step 1: Preparation of tert-butyl 4-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxol-8-yl)piperazine-1-carboxylate (Intermediate ZJF-09-096)

[0427]

[0428] The ZJF-07-115 in step 2 of Example 2 was replaced by ZJF-09-012. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 2 to obtain a colorless oily intermediate (ZJF-09-096) (190 mg, yield 54%). 1 H NMR (600MHz, CDCl3) δ 6.80 – 6.76 (m, 1H), 6.51 – 6.43 (m, 2H), 4.22 – 4.16 (m, 1H), 4.05 – 3.96 (m, 1H), 3.88 – 3.81 (m, 1H), 3.60 – HRMS(ESI) C 19 H 29 N2O4 + [M+H] +Calculated value: 349.2122, measured value: 349.2129.

[0429] Step 2: Preparation of 1-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxol-8-yl)piperazine (Compound I-32)

[0430]

[0431] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-096. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-32) (66 mg, yield 50%). 1 H NMR (600MHz, CDCl3) δ 6.79 – 6.75 (m, 1H), 6.49 – 6.44 (m, 2H), 4.22 – 4.16 (m, 1H), 4.05 – 3.95 (m, 1H), 3.88 – 3.80 (m, 1H), 3.04 – 3.00 (m, 8H), 1.75 – 1.68 (m, 1H), 1.66 – 1.58 (m, 1H), 1.08 – 1.03 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ147.09, 143.71, 137.31, 117.13, 110.39, 105.86, 74.69, 67.82, 51.59 (2C), 46.25 (2C), 24.28, 9.57. HRMS(ESI) C 14 H 21 N2O2 + [M+H] + Calculated value: 249.1598, Found: 249.1598. Purity: 97.0% (t R = 10.453 min; 254 nm).

[0432] Example 33: Preparation of 1-(5,6,7,8,9,10-hexahydrobenzo[8]cyclo-2-yl)piperazine (Compound I-33)

[0433] Step 1: Preparation of 2-chloro-5,6,7,8,9,10-hexahydrobenzo[8]cycloolefin (Compound A7)

[0434]

[0435] The starting material, ZJF-08-097, was synthesized according to the literature (Zhang, Burgess et al., J. Med. Chem., 2008, 51, 3526–3539). ZJF-08-097 (558 mg, 2.65 mmol) was dissolved in a solution of TFA (4.53 g, 39.72 mmol) and triethylsilane (462 mg, 3.97 mmol). The mixture was stirred at 60°C overnight. The solvent was removed under vacuum. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined and dried once over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the remaining solid was isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-10%) to obtain intermediate Z compound A7 (203 mg, 39% yield) as a colorless oil. 1 H NMR (800 MHz, CDCl3) δ 7.11 – 7.08 (m, 2H), 7.02 (d, J= 7.8 Hz, 1H), 2.73 – 2.70 (m, 4H), 1.70 – 1.63 (m, 4H), 1.38 – 1.33 (m, 4H). 13 C NMR (201 MHz, CDCl3) δ 143.15, 139.75, 131.35, 130.29, 128.77, 126.11,32.14, 32.12, 32.03, 31.67, 25.78, 25.74.

[0436] Step 2: Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrobenzo[8]cyclopent-2-yl)piperazine-1-carboxylate (Intermediate ZJF-09-007)

[0437]

[0438] Compound A6 (100 mg, 0.513 mmol), t-BuONa (74 mg, 0.77 mmol), and tert-butylpiperazine-1-carboxylate (478 mg, 2.57 mmol) were added to a degassed toluene solution (6.6 mL) in a sealed tube. A solution of freshly prepared palladium acetate (58 mg, 0.257 mmol) and 2-(di-tert-butylphosphino)biphenyl (75 mg, 0.257 mmol) in degassed toluene (1.4 mL) was added and stirred for 30 minutes. The tube was sealed and the reaction was stirred at 100°C overnight. The reaction solution was extracted with dichloromethane. The organic phases were combined and dried once over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the remaining solid was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-10%) to obtain intermediate ZJF-09-007 (40 mg, 23% yield) as a colorless oil. 1 H NMR (800 MHz, CDCl3) δ 7.38 – 7.30 (m, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.72 (s, 1H), 3.67 –3.52 (m, 4H), 3.15 – 3.01 (m, 4H), 2.71 (t, J = HRMS(ESI) C 21 H 33 N2O2 + [M+H] + Calculated value: 345.2537, measured value: 345.2560.

[0439] Step 3: Preparation of 1-(5,6,7,8,9,10-hexahydrobenzo[8]cyclo-2-yl)piperazine (Compound I-33)

[0440]

[0441] The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with intermediate ZJF-09-007. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a yellow-white solid (I-33) (5 mg, yield 18%). 1H NMR (800MHz, CDCl3) δ 7.01 (d, J = 8.2 Hz, 1H), 6.71 (dd, J = 8.3, 2.6 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 3.46 – 3.43 (m, 4H), 3.40 – 3.37 (m, 4H), 2.72 – 2.66 (m, 4H), 1.67 – 1.60 (m, 4H), 1.36 – 1.31 (m, 4H). 13 C NMR (201 MHz, CDCl3) δ148.55, 142.46, 135.16, 130.02, 118.22, 115.46, 47.61 (2C), 43.84 (2C),32.69, 32.51, 32.34, 31.71, 26.10, 25.92. HRMS(ESI) C 16 H 25 N2 + [M+H] + Calculated value: 245.2012, measured value: 245.2011. Purity: 98.3% (t R = 12.396 min; 254 nm).

[0442] Example 34: Preparation of 2-piperazin-1-yl-6,7,8,9-tetrahydro-5H-cycloheptylpyridine (Compound I-34)

[0443] Step 1: Preparation of tert-butyl 4-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)piperazine-1-carboxylate (Intermediate ZJF-08-142)

[0444]

[0445] Compound A8 was synthesized by replacing the starting material cyclooctanone with cycloheptanone according to patent (WO2008083353). In step 1 of Example 7, Compound A1 was replaced with Compound A8, and tert-butyl 1,4-diazepane-1-carboxylate was replaced with tert-butyl piperazine-1-carboxylate. The remaining raw materials, reagents, and preparation methods were the same as those in step 1 of Example 7 to obtain the intermediate (ZJF-08-142) as a yellow oil (101 mg, 62% yield). 1H NMR (800 MHz, CDCl3) δ 7.22 (d, J = 6.1 Hz, 1H), 6.36 (d, J = 5.5 Hz, 1H), 3.59 – 3.51 (m, 4H), 3.48 – 3.41 (m, 4H), 2.93 –2.84 (m, 2H), 2.65 (t, J = 5.7 Hz, 2H), 1.86 – 1.80 (m, 2H), 1.70 – 1.64 (m,2H), 1.62 – 1.57 (m, 2H), 1.48 (s, 9H). HRMS(ESI) C 19 H 30 N3O2 + [M+H] + Calculated value: 332.2333, measured value: 332.2330.

[0446] Step 2: Preparation of 2-piperazin-1-yl-6,7,8,9-tetrahydro-5H-cycloheptylpyridine (Compound I-34)

[0447]

[0448] The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with intermediate ZJF-08-142. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a yellow oil (I-34) (55 mg, yield 81%). 1 H NMR (800MHz, CDCl3) δ 7.24 (d, J = 8.2 Hz, 1H), 6.37 (d, J = 8.2 Hz, 1H), 3.67 (t, J= 5.2 Hz, 4H), 3.19 (t, J = 5.2 Hz, 4H), 2.90 – 2.86 (m, 2H), 2.67 – 2.64 (m,2H), 1.86 – 1.81 (m, 2H), 1.69 – 1.64 (m, 2H), 1.63 – 1.58 (m, 2H). 13 C NMR(201 MHz, CDCl3) δ 161.75, 156.61, 138.90, 128.86, 104.15, 44.39 (2C), 44.10(2C), 39.74, 34.42, 32.77, 28.50, 26.71. HRMS(ESI) C 14 H 22 N3 + [M+H]+ Calculated value: 232.1808, measured value: 232.1842. Purity: 99.7% (t R = 7.416 min; 254 nm).

[0449] Example 35: Preparation of R-2-(2-methylpiperazin-1-yl)-6,7,8,9-tetrahydro-5H-cycloheptylpyridine (Compound I-35)

[0450] Step 1: Preparation of tert-butyl R-3-methyl-4-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)piperazine-1-carboxylate (Intermediate ZJF-09-083)

[0451]

[0452] The piperazine-1-carboxylic acid tert-butyl ester in step 1 of Example 34 was replaced with (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 34 to obtain a yellow solid intermediate (ZJF-09-083) (74 mg, yield 19%). 1 H NMR (800 MHz, CDCl3) δ 7.19 (d, J = 8.3 Hz, 1H), 6.29 (d, J =6.1 Hz, 1H), 4.45 (s, 1H), 4.00 – 3.87 (m, 2H), 3.21 – 3.03 (m, 2H), 2.89 –2.85 (m, 2H), 2.67 – 2.60 (m, 2H), 1.86 – 1.79 (m, 2H), 1.68 – 1.59 (m, 6H),1.48 (s, 9H), 1.08 (s, 3H). HRMS(ESI) C 20 H 32 N3O2 + [M+H] + Calculated value: 346.2489, measured value: 346.2481.

[0453] Step 2: Preparation of R-2-(2-methylpiperazin-1-yl)-6,7,8,9-tetrahydro-5H-cycloheptylpyridine (Compound I-35)

[0454]

[0455] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-083. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-35) (37 mg, yield 72%). 1 H NMR (800MHz, CDCl3) δ 7.18 (d, J = 8.3 Hz, 1H), 6.29 (d, J = 8.3 Hz, 1H), 4.45 – 4.40(m, 1H), 3.96 – 3.91 (m, 1H), 3.17 – 3.13 (m, 1H), 3.13 – 3.09 (m, 1H), 3.06 – 3.02 (m, 1H), 2.97 – 2.94 (m, 1H), 2.90 – 2.85 (m, 3H), 2.65 – 2.61 (m,2H), 1.85 – 1.80 (m, 2H), 1.68 – 1.63 (m, 2H), 1.62 – 1.57 (m, 2H), 1.18 (d,J = 6.8 Hz, 3H). 13 C NMR (201 MHz, CDCl3) δ 161.51, 156.71, 138.64, 127.04,103.71, 50.52, 47.10, 45.90, 40.03, 39.88, 34.40, 32.83, 28.65, 26.80, 12.41.[α]20 D = -62.5 (c = 0.2, MeOH). HRMS(ESI) C 15 H 24 N3 + [M+H] + Calculated value: 246.1965, measured value: 246.1956. Purity: 98.1% (t R = 8.055 min; 254 nm).

[0456] According to the method provided in Example 35, by changing the corresponding starting materials, the compounds listed in Examples 36-38 can be prepared using the same method, as shown in Table 2 for details.

[0457] Table 2

[0458]

[0459] Example 39: Preparation of 2-(1,4-diazepan-1-yl)-6,7,8,9-tetrahydro-5H-cycloheptapyridine (Compound I-39)

[0460] Step 1: Preparation of tert-butyl 4-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)-1,4-diazepine-1-carboxylate (Intermediate ZJF-08-145)

[0461]

[0462] The compound A1 in step 1 of Example 7 was replaced by compound A8. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 7 to obtain a yellow oily intermediate (ZJF-08-145) (60 mg, yield 32%). 1 H NMR (800 MHz, CDCl3) δ 7.07 (dd, J = 8.9, 2.9 Hz, 1H), 6.14 (d, J = 8.3 Hz, 1H), 3.72 –3.69 (m, 2H), 3.56 (t, J = 6.2 Hz, 1H), 3.53 (t, J = 6.1 Hz, 1H), 3.49 – 3.45(m, 2H), 3.25 (t, J = 6.0 Hz, 1H), 3.15 (t, J = 6.5 Hz, 1H), 2.79 – 2.76 (m,2H), 2.56 – 2.53 (m, 2H), 1.89 – 1.86 (m, 2H), 1.76 – 1.74 (m, 2H), 1.59 –1.56 (m, 2H), 1.54 – 1.51 (m, 2H), 1.32 (s, 9H). HRMS(ESI) C 20 H 32 N3O2 + [M+H] + Calculated value: 346.2489, measured value: 346.2479.

[0463] Step 2: Preparation of 2-(1,4-diazepan-1-yl)-6,7,8,9-tetrahydro-5H-cycloheptapyridine (Compound I-39)

[0464]

[0465] The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with intermediate ZJF-08-145. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a white solid (I-39) (40 mg, yield 94%). 1H NMR (800MHz, CDCl3) δ 7.19 (d, J = 8.2 Hz, 1H), 6.22 (d, J = 8.2 Hz, 1H), 4.04 – 4.00(m, 2H), 3.66 (t, J = 6.6 Hz, 2H), 3.30 – 3.26 (m, 2H), 3.15 – 3.12 (m, 2H), 2.87 – 2.83 (m, 2H), 2.65 – 2.61 (m, 2H), 2.26 – 2.22 (m, 2H), 1.85 – 1.81(m, 2H), 1.67 – 1.63 (m, 2H), 1.62 – 1.58 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ161.68, 155.08, 138.93, 126.76, 102.08, 47.66, 45.83, 45.61, 44.11, 39.85,34.33, 32.81, 28.64, 26.73, 25.39. HRMS(ESI) C 15 H 24 N2 + [M+H] + Calculated value: 246.1965, measured value: 246.1983. Purity: 99.0% (t R = 7.360 min; 254 nm).

[0466] Example 40: Preparation of 2-(1,2,3,6-tetrahydropyridin-4-yl)-6,7,8,9-tetrahydro-5H-cycloheptapyridine (Compound I-40)

[0467] Step 1: Preparation of tert-butyl 4-(6,7,8,9-tetrahydro-5H-cycloheptane-2-yl)-3,6-dihydropyridine-1(2H)carboxylate (Intermediate ZJF-08-147)

[0468]

[0469] The compound A1 in step 1 of Example 4 was replaced by compound A8. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 4 to obtain a white solid intermediate (ZJF-08-147) (357 mg, yield 99%). 1H NMR (800 MHz, CDCl3) δ 7.33 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.63 – 6.56 (m,1H), 4.15 – 4.09 (m, 2H), 3.67 – 3.60 (m, 2H), 3.06 – 2.99 (m, 2H), 2.79 –2.72 (m, 2H), 2.63 – 2.58 (m, 2H), 1.89 – 1.84 (m, 2H), 1.72 – 1.68 (m, 2H),1.67 – 1.63 (m, 2H), 1.48 (s, 9H). HRMS(ESI) C 20 H 29 N2O2 + [M+H] + Calculated value: 329.2224, measured value: 329.2221.

[0470] Step 2: Preparation of 2-(1,2,3,6-tetrahydropyridin-4-yl)-6,7,8,9-tetrahydro-5H-cycloheptapyridine (Compound I-40)

[0471]

[0472] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-147. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-40) (38 mg, yield 48%). 1 H NMR (800MHz, CDCl3) δ 7.32 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.70 – 6.67(m, 1H), 3.59 – 3.56 (m, 2H), 3.11 (t, J = 5.7 Hz, 2H), 3.05 – 3.02 (m, 2H), 2.76 – 2.73 (m, 2H), 2.55 – 2.51 (m, 2H), 2.01 (brs, 1H), 1.88 – 1.83 (m,2H), 1.72 – 1.67 (m, 2H), 1.67 – 1.63 (m, 2H). 13C NMR (201 MHz, CDCl3) δ162.57, 154.49, 137.00, 136.41, 135.30, 125.91, 116.29, 45.65, 43.35, 39.92,35.18, 32.71, 28.28, 26.83, 26.65. HRMS(ESI) C 15 H 21 N2 + [M+H] + Calculated value: 229.1699, measured value: 229.1708. Purity: 97.4% (t R = 5.558 min; 254 nm).

[0473] Example 41: Preparation of 2-(4-piperidinyl)-6,7,8,9-tetrahydro-5H-cycloheptylpyridine (Compound I-41)

[0474] Step 1: Preparation of tert-butyl 4-(6,7,8,9-tetrahydro-5H-cycloheptane-2-yl)-3,6-dihydropyridine-1(2H)carboxylate (Intermediate ZJF-08-147) by the same method as in Step 1 of Example 37.

[0475] Step 2: Preparation of tert-butyl 4-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)piperidine-1-carboxylate (Intermediate ZJF-08-149)

[0476]

[0477] The intermediate ZJF-07-116 in step 2 of Example 4 was replaced with the intermediate ZJF-08-147. The remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 4 to obtain the intermediate (ZJF-08-149) as a colorless oil (150 mg, yield 72%). HRMS (ESI) C 20 H 31 N2O2 + [M+H] + Calculated value: 331.2380, measured value: 331.2373.

[0478] Step 3: Preparation of 2-(4-piperidinyl)-6,7,8,9-tetrahydro-5H-cycloheptapyridine (Compound I-41)

[0479]

[0480] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-149. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow solid (I-41) (18 mg, yield 17%). 1 H NMR (800MHz, CDCl3) δ 7.27 (d, J = 7.7 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 3.20 – 3.16(m, 2H), 3.02 (brs, 1H), 2.98 – 2.95 (m, 2H), 2.77 – 2.72 (m, 3H), 2.71 –2.67 (m, 2H), 1.93 – 1.88 (m, 2H), 1.84 – 1.79 (m, 2H), 1.69 – 1.63 (m, 4H), 1.62 – 1.58 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 162.47, 161.46, 137.09,135.54, 117.54, 46.70 (2C), 44.45, 39.50, 34.96, 32.95 (2C), 32.60, 28.05,26.61. HRMS(ESI) C 15 H 23 N2 + [M+H] + Calculated value: 231.1856, measured value: 231.1887. Purity: 99.6% (t R = 4.819 min; 254 nm).

[0481] Example 42: Preparation of 3-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine (Compound I-42)

[0482] Step 1: Preparation of tert-butyl 4-(6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-3-yl)piperazine-1-carboxylate (Intermediate LHQ-08-145)

[0483]

[0484] The compound A1 in step 1 of Example 7 was replaced by compound A9, and tert-butyl 1,4-diazepane-1-carboxylate was replaced by tert-butyl piperazine-1-carboxylate. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 7 to obtain a yellow solid intermediate (LHQ-04-113) (187 mg, yield 51%). 1H NMR (800 MHz, CD3OD) δ 7.78 (s, 1H),6.63 (s, 1H), 3.54 – 3.50 (m, 4H), 3.42 – 3.40 (m, 4H), 2.75 – 2.73 (m, 2H),2.69 – 2.67 (m, 2H), 1.86 – 1.81 (m, 2H), 1.65 – 1.58 (m, 4H), 1.47 (s, 9H).HRMS(ESI) C 19 H 30 N3O2 + [M+H] + Calculated value: 332.2333, measured value: 332.2333.

[0485] Step 2: Preparation of 2-(4-piperidinyl)-6,7,8,9-tetrahydro-5H-cycloheptapyridine (Compound I-42)

[0486]

[0487] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with the intermediate LHQ-04-113. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a white solid (I-42) (85 mg, yield 81%). 1 H NMR (800MHz, CD3OD) δ 7.81 (s, 1H), 6.66 (s, 1H), 3.56 (t, J = 5.2 Hz, 4H), 3.12 (t,J = 5.3 Hz, 4H), 2.76 – 2.73 (m, 2H), 2.70 – 2.67 (m, 2H), 1.86 – 1.81 (m, 2H), 1.61 (d, J = 3.8 Hz, 4H). 13 C NMR (201 MHz, CD3OD) δ 159.78, 156.19,147.21, 131.25, 109.40, 45.86 (2C), 45.32 (2C), 37.64, 33.61, 33.26, 30.03,29.21. HRMS(ESI) C 14 H 22 N3 + [M+H] + Calculated value: 232.1808, measured value: 232.1809. Purity: 99.5% (t R = 7.716 min; 254 nm).

[0488] According to the method provided in Example 42, by changing the corresponding starting materials, the compounds listed in Examples 43 and 44 can be prepared using the same method, as shown in Table 3 for details.

[0489] Table 3

[0490]

[0491] Example 45: Preparation of 2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinoline (Compound I-45)

[0492] Step 1: Preparation of tert-butyl 4-(5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate (Intermediate ZJF-08-137)

[0493]

[0494] The starting material, compound A10, is commercially available. A stirred solution of compound A10 (108 mg, 0.509 mmol) in toluene (20 mL) at room temperature was purged with nitrogen for 30 minutes. BINAP (63 mg, 0.102 mmol), Pd(dba) (0.019 g, 0.020 mmol), and sodium tert-butoxide (98 mg, 1.02 mmol) were added to the reaction mixture, and the nitrogen purge was continued for an additional 20 minutes. Finally, tert-butyl piperazine-1-carboxylate (95 mg, 0.509 mmol) was added, and the mixture was stirred at 100°C under a nitrogen atmosphere overnight. The reaction mixture was extracted with ethyl acetate. The combined organic phases were dried once over anhydrous NaSO, and the solvent was evaporated under reduced pressure. The remaining solid was isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain intermediate ZJF-08-137 (93 mg, 58% yield) as a colorless oil. 1 H NMR (800 MHz, CDCl3) δ 7.19 (d, J = 8.4 Hz, 1H), 6.44 (d, J= 8.4 Hz, 1H), 3.56 – 3.50 (m, 4H), 3.44 (t, J = 5.3 Hz, 4H), 2.74 (t, J =6.5 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 1.85 – 1.81 (m, 2H), 1.77 – 1.74 (m,2H), 1.48 (s, 9H). HRMS(ESI) C 18 H 28 N3O2 + [M+H] +Calculated value: 318.2176, measured value: 318.2178.

[0495] Step 2: Preparation of 2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinoline (Compound I-45)

[0496]

[0497] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-137. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a white solid (I-45) (41 mg, yield 69%). 1 H NMR (800MHz, CDCl3) δ 7.17 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 8.5 Hz, 1H), 3.46 – 3.44(m, 4H), 3.01 – 2.98 (m, 4H), 2.73 (t, J = 6.5 Hz, 2H), 2.65 (brs, 1H), 2.61(t, J = 6.4 Hz, 2H), 1.84 – 1.80 (m, 2H), 1.76 – 1.72 (m, 2H). 13 HRMS(ESI) C 13 H 20 N3 + [M+H] + Calculated value: 218.1652, measured value: 218.1648. Purity: 98.1% (t R = 4.819 min; 254 nm).

[0498] According to the method provided in Example 45, by changing the corresponding starting materials, the compounds listed in Examples 46-49 can be prepared using the same method, as shown in Table 4 for details.

[0499] Table 4

[0500]

[0501] Example 50: Preparation of 3-(piperazin-1-yl)-5,6,7,8-tetrahydroisoquinoline (Compound I-50)

[0502] Step 1: Preparation of tert-butyl 4-(5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (Intermediate ZJF-09-042)

[0503]

[0504] The starting material, compound A11, is commercially available. Replace compound A1 in step 1 of Example 7 with compound A10 and tert-butyl 1,4-diazepane-1-carboxylate with tert-butyl piperazine-1-carboxylate. The remaining raw materials, reagents, and preparation methods are the same as those in step 1 of Example 7 to obtain a yellow solid intermediate (ZJF-09-042) (55 mg, 29% yield). 1 H NMR (800MHz, CDCl3) δ 7.92 (s, 1H), 6.37 (s, 1H), 3.55 – 3.50 (m, 4H), 3.44 – 3.40(m, 4H), 2.70 – 2.67 (m, 2H), 2.65 – 2.62 (m, 2H), 1.78 – 1.74 (m, 4H), 1.48(s, 9H). HRMS(ESI) C 18 H 28 N3O2 + [M+H] + Calculated value: 318.2176, measured value: 318.2172.

[0505] Step 2: Preparation of 3-(piperazin-1-yl)-5,6,7,8-tetrahydroisoquinoline (Compound 50)

[0506]

[0507] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-042. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a white solid (I-50) (27 mg, yield 73%). 1 H NMR (600MHz, CDCl3) δ 7.91 (s, 1H), 6.35 (s, 1H), 3.55 – 3.50 (m, 4H), 3.10 – 3.06(m, 4H), 2.68 – 2.65 (m, 2H), 2.64 – 2.60 (m, 2H), 1.78 – 1.72 (m, 4H). 13CNMR (151 MHz, CDCl3) δ 157.97, 148.09, 147.98, 123.83, 107.05, 45.90 (2C), 45.09 (2C), 29.45, 25.58, 23.21, 22.79. HRMS(ESI) C 13 H 20 N3 + [M+H] + Calculated value: 218.1652, measured value: 218.1652. Purity: 99.5% (t R = 5.029 min; 254 nm).

[0508] Example 51: Preparation of (S)-3-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydroisoquinoline (Compound I-51)

[0509] Step 1: Preparation of (S)-tert-butyl 2-methyl-4-(5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (Intermediate ZJF-09-048)

[0510]

[0511] The piperazine-1-carboxylic acid tert-butyl ester in step 1 of Example 50 was replaced with (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 50 to obtain a yellow solid intermediate (ZJF-09-048) (90 mg, yield 46%). 1 H NMR (800 MHz, CDCl3) δ 7.91 (s, 1H), 6.35 (s, 1H), 4.36 – 4.28 (m, 1H), 4.06 – 3.98 (m, 1H), 3.95 – 3.86 (m, 2H), 3.24 (t, J = 12.8 Hz, 1H),3.13 – 3.04 (m, 1H), 2.93 – 2.80 (m, 1H), 2.71 – 2.67 (m, 2H), 2.65 – 2.61(m, 2H), 1.77 – 1.74 (m, 4H), 1.48 (s, 9H), 1.23 – 1.21 (m, 3H). HRMS(ESI)C 19 H 30 N3O2 + [M+H] + Calculated value: 332.2333, measured value: 332.2336.

[0512] Step 2: Preparation of (S)-3-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydroisoquinoline (Compound I-51)

[0513]

[0514] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-048. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-51) (27 mg, yield 73%). 1 H NMR (800MHz, CDCl3) δ 7.90 (s, 1H), 6.35 (s, 1H), 4.05 (d, J = 12.5 Hz, 1H), 3.97 (d,J = 12.4 Hz, 1H), 3.13 – 3.09 (m, 1H), 2.98 – 2.91 (m, 2H), 2.82 – 2.77 (m,1H), 2.67 – 2.64 (m, 2H), 2.62 – 2.60 (m, 2H), 2.44 (t, J = 11.4 Hz, 1H), 1.76 – 1.71 (m, 4H), 1.16 (d, J = 6.1 Hz, 3H). 13 C NMR (201 MHz, CDCl3) δ158.23, 148.00, 147.86, 123.35, 106.95, 53.12, 50.65, 45.95, 45.63, 29.44,25.57, 23.24, 22.82, 19.58. [α]20 D = +22.5 (c = 0.2, MeOH). HRMS(ESI) C 14 H 22 N3 + [M+H] + Calculated value: 232.1808, measured value: 232.1803. Purity: 98.2% (t R = 4.883 min; 254 nm).

[0515] Example 52: Preparation of 3-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydroisoquinoline (Compound I-52)

[0516] Step 1: Preparation of (R)-tert-butyl 2-methyl-4-(5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (Intermediate ZJF-09-050)

[0517]

[0518] The piperazine-1-carboxylic acid tert-butyl ester in step 1 of Example 50 was replaced with (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 47 to obtain a yellow solid intermediate (ZJF-09-050) (46 mg, yield 23%). 1 H NMR (800 MHz, CDCl3) δ 7.91 (s, 1H), 6.34 (s, 1H), 4.38 – 4.27 (m, 1H), 4.02 (d, J = 11.8 Hz, 1H), 3.95 – 3.84 (m, 2H), 3.24 (t, J = 12.8Hz, 1H), 3.12 – 3.03 (m, 1H), 2.89 – 2.81 (m, 1H), 2.70 – 2.67 (m, 2H), 2.65 – 2.62 (m, 2H), 1.78 – 1.75 (m, 4H), 1.48 (s, 9H), 1.23 – 1.21 (m, 3H). HRMS(ESI) C 19 H 30 N3O2 + [M+H] + Calculated value: 332.2333, measured value: 332.2335.

[0519] Step 2: Preparation of 3-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydroisoquinoline (Compound I-52)

[0520]

[0521] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-050. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-52) (17 mg, yield 54%). 1H NMR (800MHz, CDCl3) δ 7.90 (s, 1H), 6.35 (s, 1H), 4.05 (d, J = 12.4 Hz, 1H), 3.97 (d,J = 12.3 Hz, 1H), 3.12 – 3.09 (m, 1H), 2.97 – 2.90 (m, 2H), 2.78 (t, J = 12.0Hz, 1H), 2.67 – 2.65 (m, 2H), 2.63 – 2.60 (m, 2H), 2.43 – 2.40 (m, 1H), 2.38(brs, 1H), 1.76 – 1.72 (m, 4H), 1.14 (d, J = 4.0 Hz, 3H). 13 C NMR (201 MHz, CDCl3) δ 158.30, 148.01, 147.85, 123.32, 106.95, 53.24, 50.64, 46.07, 45.73, 29.45, 25.57, 23.26, 22.83, 19.70. [α]20 D = -20.0 (c = 0.2, MeOH). HRMS(ESI)C 14 H 22 N3 + [M+H] + Calculated value: 232.1808, measured value: 232.1804. Purity: 95.2% (t R = 5.951 min; 254 nm).

[0522] Example 53: Preparation of R-3-(2-methylpiperazin-1-yl)-5,6,7,8-tetrahydroisoquinoline (Compound I-53)

[0523] Step 1: Preparation of (R)-tert-butyl 3-methyl-4-(5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (Intermediate ZJF-09-086)

[0524]

[0525] The piperazine-1-carboxylic acid tert-butyl ester in step 1 of Example 50 was replaced with (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 47 to obtain a yellow solid intermediate (ZJF-09-086) (63 mg, yield 22%). 1H NMR (800 MHz, CDCl3) δ 7.91 (s, 1H), 6.29 (s, 1H), 4.41 (d, J =59.4 Hz, 1H), 4.23 – 3.68 (m, 3H), 3.22 – 2.88 (m, 3H), 2.69 – 2.64 (m, 2H),2.63 – 2.60 (m, 2H), 1.77 – 1.73 (m, 4H), 1.47 (s, 9H), 1.08 (d, J = 6.2 Hz,3H). HRMS(ESI) C 19 H 30 N3O2 + [M+H] + Calculated value: 332.2333, measured value: 332.2334.

[0526] Step 2: Preparation of R-3-(2-methylpiperazin-1-yl)-5,6,7,8-tetrahydroisoquinoline (Compound I-53)

[0527]

[0528] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-086. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-53) (30 mg, yield 49%). 1 H NMR (800MHz, CDCl3) δ 7.90 (s, 1H), 6.28 (s, 1H), 4.37 – 4.32 (m, 1H), 3.77 – 3.72(m, 1H), 3.10 – 3.04 (m, 2H), 3.01 – 2.96 (m, 1H), 2.90 – 2.87 (m, 1H), 2.85 – 2.81 (m, 1H), 2.65 (t, J = 5.8 Hz, 2H), 2.61 (t, J = 5.9 Hz, 2H), 2.08(brs, 1H), 1.76 – 1.72 (m, 4H), 1.14 (d, J = 6.8 Hz, 3H). 13C NMR (201 MHz, CDCl3) δ 157.57, 148.06, 147.65, 122.50, 106.58, 50.97, 47.46, 46.28, 40.68,29.48, 25.55, 23.32, 22.88, 12.34. [α]20 D = -66.5 (c = 0.2, MeOH). HRMS(ESI)C 14 H 22 N3 + [M+H] + Calculated value: 232.1808, measured value: 232.1807. Purity: 98.1% (t R = 5.291 min; 254 nm).

[0529] Example 54: Preparation of (S)-3-(2-methylpiperazin-1-yl)-5,6,7,8-tetrahydroisoquinoline (Compound I-54)

[0530] Step 1: Preparation of (S)-tert-butyl 3-methyl-4-(5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (Intermediate ZJF-09-126)

[0531]

[0532] The piperazine-1-carboxylic acid tert-butyl ester in step 1 of Example 50 was replaced with (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester. The remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 47 to obtain a yellow oily intermediate (ZJF-09-126) (155 mg, yield 30%). 1 H NMR (800 MHz, CDCl3) δ 7.94 (s, 1H), 6.32 (s, 1H), 4.37 – 4.17 (m, 1H), 4.04 – 3.87 (m, 1H), 3.26 – 2.95 (m, 3H), 2.86 – 2.78 (m, HRMS(ESI) C 19 H 30 N3O2 + [M+H] + Calculated value: 332.2333, measured value: 332.2345.

[0533] Step 2: Preparation of (S)-3-(2-methylpiperazin-1-yl)-5,6,7,8-tetrahydroisoquinoline (Compound 54)

[0534]

[0535] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-126. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-54) (48 mg, yield 46%). 1 H NMR(800 MHz, CDCl3) δ 7.92 (s, 1H), 6.30 (s, 1H), 4.43 – 4.38 (m, 1H), 3.83 –3.78 (m, 1H), 3.16 – 3.13 (m, 1H), 3.11 – 3.09 (m, 1H), 3.07 – 3.02 (m, 1H), 2.96 – 2.93 (m, 1H), 2.90 – 2.85 (m, 1H), 2.67 (t, J = 6.0 Hz, 2H), 2.63 (t,J = 6.0 Hz, 2H), 1.78 – 1.75 (m, 4H), 1.19 (d, J = 6.7 Hz, 3H). 13 C NMR (151MHz, CDCl3) δ 157.45, 147.98, 147.55, 122.44, 106.48, 50.80, 47.33, 46.12,40.51, 29.38, 25.45, 23.22, 22.78, 12.28. [α]20 D = +67.5 (c = 0.2, MeOH).HRMS(ESI) C 14 H 22 N3 + [M+H] + Calculated value: 232.1808, measured value: 232.1822. Purity: 98.1% (t R =6.824 min; 254 nm).

[0536] Example 55: Preparation of 2-piperazin-1-yl-6,7-dihydro-5H-cyclopentylpyridine (Compound I-55)

[0537] Step 1: Preparation of tert-butyl 4-(6,7-dihydro-5H-cyclopentylpyridin-2-yl)piperazine-1-carboxylate (Intermediate ZJF-08-114)

[0538]

[0539] The starting material, compound A11, is commercially available. Substitute compound A12 for compound A11 in step 1 of Example 7, and replace tert-butyl 1,4-diazepane-1-carboxylate with tert-butyl piperazine-1-carboxylate. The remaining raw materials, reagents, and preparation methods are the same as those in step 1 of Example 7 to obtain the intermediate (ZJF-08-114) as a yellow oil (98 mg, 50% yield). 1 H NMR (800MHz, CDCl3) δ 7.35 (d, J = 10.7 Hz, 1H), 6.41 (d, J = 8.1 Hz, 1H), 3.59 – 3.52 (m, 4H), 3.49 – 3.42 (m, 4H), 2.92 – 2.84 (m, 2H), 2.81 (t, J = 7.4 Hz,2H), 2.11 – 2.04 (m, 2H), 1.48 (s, 9H). HRMS(ESI) C 17 H 26 N3O2 + [M+H] + Calculated value: 304.2020, measured value: 304.2018.

[0540] Step 2: Preparation of 2-piperazin-1-yl-6,7-dihydro-5H-cyclopentylpyridine (Compound I-55)

[0541]

[0542] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-114. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-55) (39 mg, yield 59%). 1 H NMR (800MHz, CDCl3) δ 7.30 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 3.47 (t, J= 5.1 Hz, 4H), 3.01 (t, J = 5.0 Hz, 4H), 2.85 (t, J = 7.7 Hz, 2H), 2.78 (t, J= 7.4 Hz, 2H), 2.06 – 2.02 (m, 2H). 13C NMR (201 MHz, CDCl3) δ 163.70, 159.48,133.57, 126.21, 104.39, 46.59 (2C), 45.50 (2C), 34.41, 29.78, 23.21. HRMS(ESI) C 12 H 18 N3 + [M+H] + Calculated value: 204.1495, measured value: 204.1486. Purity: 99.0% (t R = 3.544 min; 254 nm).

[0543] According to the method provided in Example 55, by changing the corresponding starting materials, the compounds listed in Examples 56-59 can be prepared using the same method, as shown in Table 5 for details.

[0544] Table 5

[0545]

[0546]

[0547] Example 60: Preparation of 3-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound I-60)

[0548] Step 1: Preparation of tert-butyl 4-(6,7-dihydro-5H-cyclopentyl[c]pyridin-3-yl)piperazine-1-carboxylate (Intermediate ZJF-09-141)

[0549]

[0550] The starting material, compound A13, is commercially available. Replace compound A1 in step 1 of Example 7 with compound A13, and replace tert-butyl 1,4-diazepane-1-carboxylate with tert-butyl piperazine-1-carboxylate. The remaining raw materials, reagents, and preparation methods are the same as those in step 1 of Example 7 to obtain a yellow solid intermediate (ZJF-09-141) (102 mg, 52% yield). 1 H NMR (600MHz, CDCl3) δ 8.04 (s, 1H), 6.61 (s, 1H), 3.57 – 3.53 (m, 4H), 3.52 – 3.46(m, 4H), 2.83 (s, 4H), 2.10 – 2.04 (m, 2H), 1.48 (s, 9H). HRMS(ESI) C 17 H 26 N3O2 +[M+H] + Calculated value: 304.2020, measured value: 304.2025.

[0551] Step 2: Preparation of 3-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound I-60)

[0552]

[0553] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-141. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a white solid (I-60) (37 mg, yield 54%). 1 H NMR (600MHz, CDCl3) δ 8.04 (s, 1H), 6.58 (s, 1H), 3.46 – 3.43 (m, 4H), 3.01 – 2.98(m, 4H), 2.83 – 2.78 (m, 4H), 2.18 (brs, 1H), 2.07 – 2.01 (m, 2H). 13 HRMS(ESI) C 12 H 18 N3 + [M+H] + Calculated value: 204.1495, measured value: 204.1498. Purity: 99.7% (t R = 2.993 min; 254 nm).

[0554] Example 61: Preparation of (R)-3-(2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound I-61)

[0555]

[0556] According to the method listed in Example 60, by replacing the corresponding starting materials, a yellow oil (I-61) (33 mg, yield 57%) was obtained using the same method. 1H NMR (800 MHz, CDCl3) δ 8.03 (s, 1H), 6.52 (s,1H), 4.39 (t, J = 5.9 Hz, 1H), 3.83 (d, J = 12.8 Hz, 1H), 3.13 – 3.08 (m,2H), 3.06 – 3.02 (m, 1H), 2.92 (d, J = 12.2 Hz, 1H), 2.89 – 2.84 (m, 1H), 2.82 – 2.78 (m, 4H), 2.08 (brs, 1H), 2.06 – 2.02 (m, 2H), 1.17 (d, J = 6.3Hz, 3H). 13 C NMR (201 MHz, CDCl3) δ 158.31, 155.89, 143.04, 129.65, 103.21,50.91, 47.75, 46.24, 40.84, 33.06, 29.36, 25.67, 12.49. [α]20 D = -60.0 (c =0.2, MeOH). HRMS(ESI) C 13 H 19 N3 + [M+H] + Calculated value: 218.1652, measured value: 218.1658. Purity: 99.5% (t R = 4.083 min; 254 nm).

[0557] Example 62: Preparation of 1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)piperazine (Compound I-62)

[0558] Step 1: Preparation of tert-butyl 4-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)piperazine-1-carboxylate (Intermediate ZJF-08-135)

[0559]

[0560] The starting material, compound A14, is commercially available. Replace compound A9 in step 1 of Example 42 with compound A14, and replace tert-butyl 1,4-diazepane-1-carboxylate with tert-butyl piperazine-1-carboxylate. The remaining raw materials, reagents, and preparation methods are the same as those in step 1 of Example 42 to obtain the intermediate (ZJF-08-135) as a yellow oil (194 mg, 62% yield). 1H NMR(800 MHz, CDCl3) δ 6.96 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.71(s, 1H), 3.60 – 3.56 (m, 4H), 3.12 – 3.10 (m, 4H), 3.07 – 3.02 (m, 4H), 1.48(s, 9H). HRMS(ESI) C 17 H 25 N2O2 + [M+H] + Calculated value: 289.1911, measured value: 289.1919.

[0561] Step 2: Preparation of 1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)piperazine (Compound I-62)

[0562]

[0563] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-135. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-62) (38 mg, yield 37%). 1 H NMR (800MHz, CDCl3) δ 6.95 (d, J = 8.0 Hz, 1H), 6.82 – 6.79 (m, 1H), 6.72 (d, J = 2.2Hz, 1H), 3.12 – 3.09 (m, 4H), 3.09 – 3.06 (m, 4H), 3.05 – 3.03 (m, 4H), 2.21 (brs, 1H). 13 C NMR (201 MHz, CDCl3) δ 152.10, 146.38, 137.58, 123.16, 116.47,112.18, 51.93 (2C), 46.32 (2C), 29.23, 28.97. HRMS(ESI) 12 H 17 N2 + [M+H] + Calculated value: 189.1386, measured value: 189.1391. Purity: 98.2% (t R = 10.661 min; 254 nm).

[0564] Example 63: Preparation of (S)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-3-methylpiperazine (Compound I-63)

[0565] Step 1: Preparation of (S)-tert-butyl 4-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-2-methylpiperazine-1-carboxylate (Intermediate ZJF-09-034)

[0566]

[0567] In step 1 of Example 45, compound A10 was replaced by compound A14, and tert-butyl 1,4-diazepane-1-carboxylate was replaced by (S)-1-N-Boc-2-methylpiperazine. The remaining raw materials, reagents and preparation methods were the same as those required in step 1 of Example 45 to obtain a yellow oily intermediate (ZJF-09-034) (55 mg, yield 17%). 1 H NMR (800 MHz, CDCl3) δ 6.95(d, J = 7.9 Hz, 1H), 6.91 – 6.85 (m, 1H), 6.73 (d, J = 63.3 Hz, 1H), 4.37 –4.28 (m, 1H), 3.93 (d, J = 12.9 Hz, 1H), 3.40 – 3.35 (m, 1H), 3.28 – 3.21 (m,2H), 3.15 – 3.06 (m, 4H), 2.95 – 2.83 (m, 1H), 2.78 – 2.66 (m, 1H), 1.48 (2s,9H), 1.30 (d, J = 6.8 Hz, 3H). HRMS(ESI) C 18 H 27 N2O2 + [M+H] + Calculated value: 303.2067, measured value: 303.2058.

[0568] Step 2: Preparation of (S)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-3-methylpiperazine (Compound I-63)

[0569]

[0570] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-034. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-63) (8 mg, yield 22%). 1H NMR (600MHz, CDCl3) δ 6.94 (d, J = 8.0 Hz, 1H), 6.80 (dd, J = 8.1, 2.1 Hz, 1H), 6.72(d, J = 2.1 Hz, 1H), 3.43 – 3.39 (m, 2H), 3.12 – 3.08 (m, 5H), 3.08 – 2.97(m, 2H), 2.71 – 2.65 (m, 1H), 2.35 – 2.30 (m, 1H), 1.80 (brs, 1H), 1.12 (d, J= 6.4 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 151.94, 146.43, 137.50, 123.19,116.53, 112.26, 58.75, 51.16, 50.87, 46.21, 29.26, 29.00, 19.97. [α] 20 D = +7.5 (c = 0.2, MeOH). HRMS(ESI) C 13 H 19 N2 + [M+H] + Calculated value: 203.1543, measured value: 203.1544. Purity: 98.4% (t R = 10.826 min; 254 nm).

[0571] Example 64: Preparation of (R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-3-methylpiperazine (Compound I-64)

[0572] Step 1: Preparation of (R)-tert-butyl 4-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-2-methylpiperazine-1-carboxylate (Intermediate ZJF-09-036)

[0573]

[0574] In step 1 of Example 45, compound A10 was replaced by compound A14, and tert-butyl 1,4-diazepane-1-carboxylate was replaced by (R)-1-N-Boc-2-methylpiperazine. The remaining raw materials, reagents and preparation methods were the same as those required in step 1 of Example 45 to obtain a yellow oily intermediate (ZJF-09-036) (281 mg, yield 43%). 1H NMR (800 MHz, CDCl3) δ 6.95(d, J = 8.0 Hz, 1H), 6.92 – 6.86 (m, 1H), 6.73 (d, J = 63.2 Hz, 1H), 4.37 –4.29 (m, 1H), 3.96 – 3.90 (m, 1H), 3.40 – 3.35 (m, 1H), 3.27 – 3.21 (m, 2H), 3.13 – 3.09 (m, 4H), 2.95 – 2.85 (m, 1H), 2.77 – 2.66 (m, 1H), 1.49 (2s, 9H), 1.31 (d, J = 6.8 Hz, 3H). HRMS(ESI) C 18 H 27 N2O2 + [M+H] + Calculated value: 303.2067, measured value: 303.2057.

[0575] Step 2: Preparation of (R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-3-methylpiperazine (Compound I-64)

[0576]

[0577] The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-036. The remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-64) (57 mg, yield 31%). 1 H NMR (600MHz, CDCl3) δ 6.94 (d, J = 8.0 Hz, 1H), 6.80 (dd, J = 8.0, 2.1 Hz, 1H), 6.72(d, J = 2.1 Hz, 1H), 3.42 – 3.37 (m, 2H), 3.12 – 3.09 (m, 4H), 3.09 – 2.95 (m, 3H), 2.70 – 2.64 (m, 1H), 2.34 – 2.29 (m, 1H), 1.84 (brs, 1H), 1.11 (d, J= 6.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 151.87, 146.31, 137.36, 123.10,116.43, 112.15, 58.69, 51.09, 50.76, 46.15, 29.18, 28.92, 19.92. [α] 20 D = -8.5 (c = 0.2, MeOH). HRMS(ESI) C 13 H 19 N2 + [M+H] + Calculated value: 203.1543, measured value: 203.1544. Purity: 99.8% (t R = 10.519 min; 254 nm).

[0578] Biological test example 1: Test on the binding ability of the compounds of the present invention to 5-hydroxytryptamine receptors.

[0579] Method: The compounds of the present invention are effective for 5-HT 2A Receptors and 5-HT 2B The receptor affinity was determined by radioligand competition assay.

[0580] The first step is to prepare a specific 5-HT 2A 5-HT receptors 2B 10 cm culture dishes filled with HEK-293T cells (ATCC, CRL-11268) were incubated with 5-HT 2A 5-HT receptors 2B The receptor plasmid (10 ng) and PEI (40 μL) were transfected. After 48 hours, the 10 cm culture dish was taken out, in which the cultured cells had expressed 5-HT. 2A 5-HT receptors 2B Receptor. Use a vacuum pump to suck away the culture medium, add 3 mL of lysis solution to each well, place the cells in a 4°C cold storage, and let them stand for 10 minutes. After the cells fall off, transfer them to a 15 mL centrifuge tube, centrifuge at 1500 rpm at 4°C for 5 minutes, and discard the supernatant. Transfer the cell pellet to a tissue homogenizer, add 3 mL of lysis solution to it, and grind it thoroughly until the cells are broken. Then, divide the cell suspension equally into EP tubes, centrifuge at 12000 rpm at 4°C for 5 minutes, and discard the supernatant. The precipitate contains 5-HT 2A 5-HT receptors 2B Cell membrane component of the receptor.

[0581] The second step is to transiently express 5-HT 2A 5-HT receptors 2BThe ligand-receptor binding experiment was performed on the 293T membrane fraction containing 5-HT. 2A 5-HT receptors 2B The cell membrane fraction of the receptor was added to the standard binding buffer and the cell membrane was broken and resuspended using an electric tissue homogenizer. 30 μL of membrane protein suspension was added to each well of the 96-well plate. Then, 30 μL of different drugs were added from left to right in the 96-well plate to ensure that the final drug concentration was 10 from bottom to top. -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 0 M, and two replicates for each treatment. Then, 30 μL [ 3 H]-LSD. Incubate at room temperature in the dark for 2 hours. Detection. Machine reading reaction membrane binding [ 3 H]-LSD, and further data processing revealed the effects of different compounds on 5-HT 2A 5-HT receptors 2B Receptor affinity K i value.

[0582] Results: The compounds of the present invention have an effect on 5-HT 2A Receptors and 5-HT 2B Receptor affinity K i The values are shown in Table 6 (“NT”, not tested).

[0583] Table 6

[0584]

[0585] As can be seen from Table 6, the compounds of the present invention have an effect on 5-HT 2A The receptor has a moderate affinity for 5-HT 2B The receptor has high affinity.

[0586] Biological Test Example 2: Testing of the functional activity of the compounds of the present invention on 5-hydroxytryptamine receptors.

[0587] Methods: (1) BRET method was used to determine the functional activity of compounds on 5-HT receptors: 2A On the first day, 6 cm culture dishes filled with HEK-293T cells (ATCC, CRL-11268) were incubated with 1 μg 5-HT 2A The receptor plasmid, 1 μg of Gαq containing C-terminal algal luciferase (Gαq-Rluc), 1 μg of Gβ3, 1 μg of Gγ9 containing C-terminal green fluorescent protein (Gγ9-GFP) and 16 μL of PEI were transfected.2A 5-HT receptors 2B On the first day, 6 cm culture dishes filled with HEK-293T cells (ATCC, CRL-11268) were inoculated with 500 μg of 5-HT containing C-terminal algae luciferase. 2A 5-HT receptors 2B Receptor plasmid (5-HT 2A -Rluc or 5-HT 2B -Rluc), 500 μg G protein coupled receptor kinase 2 (GRK2), 2500 μg β-arrestin2 containing N-terminal green fluorescent protein (GFP2-ARRB2) and 14 μL PEI were transfected. On the second day, the confluent cells were digested and the amount of cells in a 6 cm culture dish full of cells was plated on a 96-well plate, with 100 μL of culture medium per well. On the third day, drug addition test was performed. The 96-well plate was taken out of the cell room and the culture medium was removed. 40 μL of substrate coelenterazine 400a (final concentration 5 μM) was added to each well, followed by 20 μL of drugs of different concentrations from left to right to ensure that the final concentration of the drug decreased gradually from bottom to top, with two replicates for each treatment. Finally, the test was performed on the machine. The machine reading reflects the situation on the membrane of intracellular β-arrestin2 and the dissociation of G protein trimers. The former characterizes 5-HT 2A 5-HT receptors 2B The degree of activation of the β-arrestin2 signaling pathway downstream of the receptor represents the degree of activation of the 5-HT 2A The degree of activation of the G protein signaling pathway downstream of the receptor, thus, the effects of various compounds on 5-HT 2A 5-HT receptors 2B Agonism of the receptor can be characterized.

[0588] (2) FLIPR method was used to determine the activity of compounds on the G protein signaling pathway downstream of 5-HT receptors: (including 5-HT 2A Receptors and 5-HT 2B receptors)

[0589] On the first day, cells cultured in a 6 cm culture dish were used to induce stable expression of 5-HT. 2A 5-HT receptors 2B 293 cells were spread on a 384-well black-bottomed corning plate treated with 50 μg / μL poly-(l-lysine) (Sigma) at 37°C for 2 h, and 30 μL of culture medium (DMEM (Gibco) + 2% dFBS (Ausbian WS500TZ)) was added to each well. 1 / 10,000 tetracycline (Sangon) was added to the culture medium to induce 5-HT. 2AThe next day, the culture medium was removed from the 384-well plate and 15 μL of the dye Fluo-4 (4 μM, Invitrogen) was added. The plates were incubated for 1 hour at 37°C in a 5% CO2 incubator. Drugs were prepared using a drug buffer containing 2.5 mM probenecid (Sigma) to ensure that the final concentration of the drug added to the 384-well plate was 10 μM from bottom to top. -4.5 M, 10 -5 M, 10 -5.5 M, 10 -6 M, 10 -6.5 M, 10 -7 M, 10 -7.5 M, 10 -8 M, 10 -8.5 M, 10 -9 M, 10 -9.5 M, 10 -10 M, 10 -10.5 M, 10 -11 M, 10 -11.5 Each treatment was repeated three times. Drugs (7.5 μL per well) were added and the plate was read using a FLIPR Penta high-throughput real-time fluorescence detector. Fluorescence readings at 520 nm reflect the amount of intracellular calcium signaling released after Gq protein activation; an increase in readings indicates receptor activation. Data were processed using the Graphpad Prism "log (agonist) vs. response --Variable slope (four parameters)" formula to determine the effects of different compounds on 5-HT. 2A EC activated by Gq receptor protein 50 After the machine detection is completed, for compounds that do not show agonist activity, 7.5 μL of serotonin (Sigma) is added to the machine immediately to make all concentration-treated wells of the compound contain a final concentration of 10 -9 M of serotonin, and read the plate. The data were processed using the Graphpad Prism "log (inhibitor vs. response -- Variable slope (four parameters)" formula to obtain the effect of different compounds on 5-HT 2A Receptors and 5-HT 2B IC of Gq receptor protein inhibition 50 value.

[0590] Results: The compounds of the present invention have an effect on 5-HT 2A Receptors and 5-HT 2B The functional activities of the receptors are shown in Table 7 ("NT", not tested; "NA", no activity; Emax value is set to 100%).

[0591] Table 7. Effects of the compounds of the present invention on 5-HT 2A Receptors and 5-HT 2B Functional activity of the receptor. (agonist activity EC 50 or antagonistic activity IC 50 (nM), and the agonist E max value(%)))

[0592]

[0593]

[0594]

[0595]

[0596] As can be seen from Table 7, the compounds of the present invention are all 5-HT 2A Receptor agonists with moderate to strong agonist activity. Most of the compounds of the present invention have 5-HT 2B Receptors exhibit antagonistic activity.

[0597] Biological test example 3: Pharmacokinetic property test of some compounds of the present invention in mice.

[0598] Methods: (1) After male mice were orally gavaged with 10 mg / kg or intravenously injected with 2 mg / kg of compound I-9, 0.03 mL of blood was collected from the eye sockets at different time points (15, 30 min, 1, 2, 4, 6, 8, 24 h) and placed in EDTAK2 centrifuge tubes on an ice bath. The tubes were centrifuged at 5000 rpm and 4 °C for 10 min to collect plasma. LC-MS / MS was used to determine the concentration of the compound in mouse plasma and calculate the relevant pharmacokinetic parameters to investigate the exposure of the compound in mice. The observed indicators included half-life and maximum blood drug concentration. The data acquisition and control system software was Analyst1.5.1 software (Applied Biosystem). The chromatographic sample peak integration method was automatic integration; the ratio of the sample peak area to the internal standard peak area was used as an indicator and regressed with the sample concentration. t 1 / 2 is the half-life, C max The area under the plasma concentration-time curve AUC is the maximum measured plasma concentration. 0→t Calculated by the trapezoidal method, F is the bioavailability.

[0599] (2) Nine male C57 mice of random weight were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration. The drug was administered by intraperitoneal injection at a concentration of 10 mg / mL in a solvent of 5% DMSO + 20% PEG400 + 75% saline. Before and after administration, 0.1 mL of blood was collected from the eye socket under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube on ice. The tube was centrifuged at 5000 rpm for 4 h. o C centrifugation for 10 minutes, plasma was collected. IP blood and brain tissue collection time points: 30min, 2h, 6h. All plasma samples were stored at -80 o C. After the mice were bled and euthanized, the brain tissue was cleaned and weighed accurately, then homogenized with 50% methanol and water at a ratio of 1:4. The homogenate samples were stored at -80 o C is to be analyzed. Plasma and brain tissue drug concentrations were measured using LC-MS (API4000QTRAP triple quadrupole tandem mass spectrometer, electrospray ionization (ESI)). The data acquisition and control system software was Analyst1.5.1 software (Applied Biosystem). The chromatographic sample peak integration method was automatic integration; the ratio of the sample peak area to the internal standard peak area was used as an indicator and regressed with the sample concentration. Regression method: linear regression with a weighting coefficient of 1 / X2. Pharmacokinetic parameters were analyzed using WinNonlin Professional v6.3 (Pharsight, USA) using a non-compartmental model. t 1 / 2 is the half-life, C max is the maximum measured blood drug concentration, and the area under the blood drug concentration-time curve AUC(0→t) was calculated by the trapezoidal method.

[0600] Experimental results: The pharmacokinetic parameters of compound I-9 are shown in Table 8.

[0601] Table 8. Pharmacokinetic properties of compound I-9 in mice

[0602]

[0603] As shown in Table 8, compound I-9 has good pharmacokinetic properties, good oral bioavailability (94.6%) and excellent brain penetration.

[0604] Biological test example 4: Pharmacokinetic property test of some compounds of the present invention in mice.

[0605] Methods: Male C57 mice were randomly divided into groups according to body weight, with 9 mice in each group. The mice were fasted but not watered for 12-14 h before administration and fed 4 h after administration. The mice were intraperitoneally injected at a concentration of 3 mg / mL in a vehicle consisting of 5% DMSO + 20% PEG400 + 75% saline. Before and after administration, 0.1 mL of blood was collected from the eye sockets under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube on ice. The tubes were centrifuged at 5000 rpm for 4 h. o The cells were centrifuged at 400 °C for 10 minutes and plasma was collected. Time points for IP blood, brain tissue, and cerebrospinal fluid collection were: 30 min, 2 h, and 6 h. All plasma samples were stored at -80 °C before analysis. o C. After the mice were bled and euthanized, the brain tissue was cleaned and weighed accurately, then homogenized with 50% methanol and water at a ratio of 1:4. The homogenate samples were stored at -80 o C is pending analysis. Plasma and brain tissue drug concentrations were measured using LC-MS (API4000QTRAP triple quadrupole tandem mass spectrometer, electrospray ionization (ESI)). The data acquisition and control system software was Analyst 1.5.1 software (Applied Biosystem). Chromatographic sample peak integration was automatic; the ratio of the sample peak area to the internal standard peak area was used as an indicator for regression with the sample concentration. Regression method: linear regression with a weighting coefficient of 1 / X2. Pharmacokinetic parameters were analyzed using WinNonlin Professional v6.3 (Pharsight, USA) using a non-compartmental model. T 1 / 2 is the half-life, C max is the maximum measured blood drug concentration, and the area under the blood drug concentration-time curve AUC(0→t) was calculated by the trapezoidal method.

[0606] Experimental results: The pharmacokinetic parameters of some of the inventive compounds are shown in Table 9.

[0607] Table 9

[0608]

[0609] As can be seen from Table 9, the compounds of the present invention are well absorbed and have excellent brain penetration.

[0610] Biological Test Example 5: Testing of the Antidepressant Effect of Compounds in Vivo.

[0611] Method (1): For male C57BL / 6 mice (8 weeks old, purchased from Shanghai Lingchang Biotechnology Co., Ltd.), corticosterone was dissolved in the drinking water of mice at a concentration of 25 μg / mL. The corticosterone solution was administered to the mice using a drinking water bottle for 21 days. The mice were maintained in a 12-hour light cycle. Fresh drinking water containing corticosterone was replaced every other day for the first two weeks, and then gradually replaced with normal drinking water without corticosterone every two days in the last week. After 21 days of corticosterone exposure, the mice were injected with a single dose of 10 mg / kg of the example compound at 30 minutes and 4 days to test the antidepressant activity of the compound by tail suspension test. Tail suspension test: The mice in the control group and the treatment group were suspended by tape on their tails for 6 minutes, and the time was recorded by a camera. The final 4 minutes of immobility were manually timed and evaluated by an uninformed observer.

[0612] Method (2): For male C57BL / 6 mice (8 weeks old, purchased from Shanghai Lingchang Biotechnology Co., Ltd.), corticosterone was dissolved in the drinking water of mice at a concentration of 25 μg / mL. The corticosterone solution was administered to the mice using a drinking water bottle for 21 days. The mice were maintained in a 12-hour light cycle. Fresh drinking water containing corticosterone was replaced every other day for the first two weeks, and then gradually replaced with normal drinking water without corticosterone every two days in the last week. After 21 days of corticosterone exposure, the mice were injected with 1 mg / kg of the compound every day for one week. The antidepressant activity of the compound was tested by tail suspension test at two time periods, 7 days and 14 days later. Tail suspension test: The mice in the control group and the drug group were suspended by tape on their tails for 6 minutes, and the time was recorded by a camera. The final 4 minutes of immobility were manually timed and evaluated by an uninformed observer.

[0613] The compounds of the present invention have antidepressant effects.

Claims

1. A compound as shown in Formula I or a pharmaceutically acceptable salt thereof: ， in, A, B and T are independently CR a or N; is a double bond or a single bond; When it is a double bond, D is a carbon atom; When it is a single bond, D is CH or N; X and Y are independently O or CH2; m is 1 or 2; n is 1, 2, or 3; R a are independently hydrogen, C 1-6 Alkyl or C 1-6 alkoxy; R b is hydrogen or C 1-6 alkyl; R d is hydrogen or C 1-6 alkyl; Z is a single bond, C 1-4 Straight chain alkylene, C 2-4 Straight chain alkenylene, separated by one or more R c Substituted C 1-4 A straight chain alkylene or one or more R c Substituted C 2-4 straight-chain alkenylene; Each R c are independently halogen, C 1-6 Alkyl or C 1-6 alkoxy; The compound shown in formula I satisfies the following conditions (1), (2) or (3): Case (1): D is a carbon atom or CH; Scenario (2): for 、 or ; Scenario (3): for or ; Z is a single bond, C 3-4 Straight chain alkylene, C 2-4 Straight chain alkenylene, separated by one or more R c Substituted C 3-4 A straight chain alkylene or one or more R c Substituted C 2-4 Straight chain alkenylene.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound shown in formula I satisfies one or more of the following conditions: (1) R a In the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (2) R a In the C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy; (3) R b In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (4) R d In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (5) In Z, the C 1-4 The straight chain alkylene is 、 、 or ; (6) Z, the C 2-4 The number of olefinic bonds in the straight-chain alkenylene group is 1 or 2, for example, 1; for example, the C 2-4 Straight chain alkenylene is 、 、 or , for example ; (7) R c wherein the halogen is independently fluorine, chlorine, bromine or iodine; (8) R c In the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (9) R c In the C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; and (10) Each of the “plurality” mentioned above is independently 2, 3, 4 or 5.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound shown in formula I satisfies one or more of the following conditions: (1) A is CH or N; (2) B is CH or N; (3) T is CR a ; (4) D is a carbon atom or CH; or D is N; (5) n is 1 or 2; (6) R a is hydrogen or C 1-6 alkoxy groups, such as hydrogen; (7) R b is hydrogen; (8) R d is hydrogen; (9) X and Y are CH2; (10) is a single bond; and (11) Z is a single bond, C 1-4 Straight chain alkylene or C 2-4 Straight chain alkenylene; or Z is a single bond, C 3-4 Straight chain alkylene or C 2-4 Straight chain alkenylene, for example, Z is C 3-4 Straight chain alkylene.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound shown in formula I satisfies one or both of the following conditions: (1) R b C 1-6 alkyl; for ;For example or , for example or , the carbon atom marked with "*" is a chiral carbon atom, and its configuration is R configuration or S configuration; for example or ; and (2) for ,For example ; Preferably, the compound as shown in Formula I satisfies one or more of the following conditions: (1) for 、 、 、 、 、 、 、 or ; preferably, for 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or ; (2) for 、 、 、 、 or ; and (3) for 、 、 、 、 、 or ; Preferably, for 、 、 、 、 、 、 、 、 、 、 、 、 or .

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound shown in Formula I is the following Scheme 1, Scheme 2, Scheme 3, Scheme 4, Scheme 5, Scheme 6 or Scheme 7: Scheme 1: A and B are independently CH or N, and T is CR a or N; is a double bond or a single bond; D is a carbon atom or CH; X and Y are O or CH2; m is 1 or 2; n is 1, 2, or 3; R a are independently hydrogen or C 1-6 alkoxy; R b is hydrogen or C 1-6 alkyl; R d is hydrogen or C 1-6 alkyl; Z is a single bond, C 1-4 Straight chain alkylene or C 2-4 straight-chain alkenylene; Preferably, for ; X and Y are CH2; m is 1 or 2; n is 1, 2, or 3; R b is hydrogen; R d is hydrogen; Z is C 3-4 straight-chain alkylene; Option 2: for or ; is a double bond or a single bond; When it is a double bond, D is a carbon atom; When it is a single bond, D is CH or N; X and Y are independently O or CH2; m is 1 or 2; n is 1, 2, or 3; R b is hydrogen or C 1-6 alkyl; R d is hydrogen or C 1-6 alkyl; Z is a single bond, C 1-4 Straight chain alkylene or C 2-4 straight-chain alkenylene; Preferably, is a single bond, D is N; R d is hydrogen; Z is C 3-4 straight-chain alkylene; Option 3: for ; is a double bond or a single bond; When it is a double bond, D is a carbon atom; When it is a single bond, D is CH or N; X and Y are independently O or CH2; m is 1 or 2; n is 1, 2, or 3; R b is hydrogen or C 1-6 alkyl; R d is hydrogen or C 1-6 alkyl; Z is a single bond, C 1-4 Straight chain alkylene or C 2-4 straight-chain alkenylene; Preferably, is a single bond, D is N, R d is hydrogen; Option 4: for or ; is a double bond or a single bond; When it is a double bond, D is a carbon atom; When it is a single bond, D is CH or N; X and Y are independently O or CH2; m is 1 or 2; n is 1, 2, or 3; R a is hydrogen or C 1-6 alkyl; R b is hydrogen or C 1-6 alkyl; R d is hydrogen or C 1-6 alkyl; Z is a single bond, C 3-4 Straight chain alkylene or C 2-4 straight-chain alkenylene; Preferably, X and Y are CH2; R d is hydrogen; Z is C 3-4 straight-chain alkylene; Scheme 5: In the compound shown in formula I, for ; When it is a single bond, D is N; m is 1 or 2; n is 1, 2, or 3; R b is hydrogen or C 1-6 alkyl; R d is hydrogen; Z is C 3-4 Straight chain alkylene or C 2-4 straight-chain alkenylene; Scheme 6: In the compound shown in Formula I, for or ; is a single bond; D is N; X and Y are independently O or CH2; m is 1 or 2; n is 1, 2, or 3; R a is hydrogen or C 1-6 alkyl; R b is hydrogen; R d is hydrogen or C 1-6 alkyl; Z is C 3-4 Straight chain alkylene or C 2-4 straight-chain alkenylene; Scheme 7: In the compound shown in Formula I, for or ; X and Y are CH2; R a is hydrogen or C 1-6 alkyl; for or , the carbon atom marked with "*" is a chiral carbon atom, and its configuration is R configuration or S configuration; R b C 1-6 alkyl; Z is C 3-4 straight-chain alkylene; Preferably, the carbon atom marked with "*" is a chiral carbon atom, and its configuration is R configuration.

6. A cyclic compound or a pharmaceutically acceptable salt thereof, characterized in that: The annular compound is any of the following compounds: 、 、 。 7. A pharmaceutical composition comprising: (1) Substance A, wherein Substance A is a compound of formula I as described in any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a cyclic compound as described in claim 6 or a pharmaceutically acceptable salt thereof; and (2) Pharmaceutical excipients.

8. A substance A, a pharmaceutical composition according to claim 7, a compound F or a pharmaceutically acceptable salt thereof in the preparation of 5-HT 2A The use of the compound as a receptor agonist, wherein the substance A is a compound as shown in formula I according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a cyclic compound according to claim 6 or a pharmaceutically acceptable salt thereof, and the compound F is selected from any one of the following compounds: 、 、 、 、 、 、 or .

9. A substance A, a pharmaceutical composition as claimed in claim 7, a compound F as claimed in claim 8 or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition for treating and / or preventing 5-HT 2A The use of a drug for a disease related to a 5-HT receptor, wherein the substance A is a compound as shown in formula I according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a cyclic compound according to claim 6 or a pharmaceutically acceptable salt thereof; the substance A is a compound as shown in formula I according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof; 2A The receptor-associated disease may be a central nervous system disease, such as depression.

10. Use of a substance A, a pharmaceutical composition according to claim 7, or a compound F according to claim 8, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating and / or preventing a central nervous system disease, wherein the substance A is a compound of formula I according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a paracyclic compound according to claim 6, or a pharmaceutically acceptable salt thereof; and the central nervous system disease may be depression.

11. A substance A, a pharmaceutical composition as claimed in claim 7, a compound F as claimed in claim 8 or a pharmaceutically acceptable salt thereof in the preparation of 5-HT 2A Receptor agonists and / or 5-HT 2B The use of the substance A in a receptor antagonist, wherein the substance A is a compound as shown in formula I according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a cyclic compound according to claim 6 or a pharmaceutically acceptable salt thereof.

12. A method for preparing the compound of formula I, wherein the method is the following method 1 or method 2: The method 1 comprises the following steps: In an organic solvent, in the presence of a deprotection agent, the compound represented by Formula II is subjected to a deprotection reaction as shown in the following formula to obtain a compound represented by Formula I: ， in, ,A,B,T,D,X,Y,Z,n,m and R b The definition as described in any one of claims 1 to 5; R h is an amino protecting group; R d is H; The method 2 comprises the following steps: in an organic solvent, in the presence of a base and a catalyst, reacting a compound represented by formula III-1 with a compound represented by formula III-2 to obtain a compound represented by formula I. ， Among them, A, B, T, X, Y, Z, n, m, R a and R b The definition as described in any one of claims 1 to 5; R e is halogen, R d C 1-6 Alkyl; D is N; Preferably, the method 1 satisfies one or more of the following conditions: (1) The organic solvent is 1,4-dioxane or dichloromethane; (2) the deprotection reagent is hydrochloric acid or trifluoroacetic acid; and (3) The amino protecting group is ; Preferably, the method 2 satisfies one or more of the following conditions: (1) The organic solvent is 1,4-dioxane; (2) The catalyst is Pd2(dba)3; (3) the base is potassium tert-butoxide; and (4) R e Chlorine or bromine.

13. A compound as shown in formula II, ， in, A, B, T, D, X, Y, Z, n, m and R b The definition as described in any one of claims 1 to 5; R h is an amino protecting group; Preferably, the compound represented by Formula II is any one of the following compounds: 。 14. A method for preparing a compound of formula II, which is the following method I or method II: Described method 1 comprises the following steps: In a solvent, in the presence of a base and a catalyst, the compound represented by formula IV-1 and the compound represented by formula IV-2 are reacted as shown in the following formula to obtain the compound represented by formula II. ， Among them, A, B, T, X, Y, Z, n, m and R b The definition as described in any one of claims 1 to 5; R e and R h The definition of is as stated in claim 12; is a double bond or a single bond; D is C or H; The method II comprises the following steps: in a solvent, in the presence of a base and a catalyst, reacting a compound represented by formula IV-1 with a compound represented by formula IV-3 to obtain a compound represented by formula II. ， Among them, A, B, T, X, Y, Z, n, m and R b The definition as described in any one of claims 1 to 5; R e and R h The definition of is as stated in claim 12; is a single bond; D is N; Preferably, the method I satisfies one or more of the following conditions: (1) The solvent is 1,4-dioxane and water; (2) The catalyst is tetrakis(triphenylphosphine)palladium; (3) the base is sodium carbonate; and (4) When the compound of formula IV-2 is a double bond, and the compound shown in formula II When it is a single bond, the reaction of method I further includes the following post-treatment step after completion: in a solvent, in the presence of a catalyst (e.g., 10% palladium carbon) and a hydrogen source (e.g., hydrogen gas), the product obtained in method 1 is subjected to a hydrogenation reaction; Preferably, the method II satisfies one or more of the following conditions: (1) The solvent is 1,4-dioxane; (2) the catalyst is Pd2(dba)3; and (3) The base is potassium tert-butoxide.

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