Opioid receptor "biased" ligand, preparation method thereof and medical application thereof

Abstract

The present invention relates to an opioid receptor "biased" ligand, a preparation method thereof and its use in medicine. Specifically, the compound of the present invention has a structure shown in formula (I), wherein the definitions of each group and substituent are as described in the specification. The present invention also discloses a preparation method of the compound and its use in preventing and / or treating pain or pain-related diseases.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to an opioid receptor "biased" ligand, a preparation method thereof and its application in medicine, and more particularly to a small molecule ligand of a μ-type opioid receptor (MOR), a preparation method thereof and its application in medicine. Background Art

[0002] Opioid receptor drugs are effective in treating moderate to severe pain and have an irreplaceable position in the treatment of acute / chronic moderate to severe pain. However, existing opioid receptor drugs (such as morphine and its derivatives, oxycodone, fentanyl and its derivatives, etc.) all show similar serious side effects: addiction, respiratory depression, drug tolerance, constipation, sedation, nausea, etc., which greatly limit their clinical use, and addiction also brings serious social problems. In the past decade, the number of deaths caused by the abuse of such prescriptions and illegal narcotics has increased dramatically (Clin J Pain.2010 26:S10-15). According to the data from the Centers for Disease Control and Prevention of the United States, a record 72,000 people died from opioid overdose in the United States in 2017, an increase of nearly 10% over 2016. The main cause of death was severe respiratory depression caused by overdose of potent opioid receptor drugs [Science.2017 358(6365):847-848; Science.2018 361(6405):831-832].

[0003] In recent years, studies have found that when morphine binds to the μ-opioid receptor (MOR), it can not only activate the G protein signaling pathway and produce analgesic physiological activity, but also activate the β-arrestin pathway. The binding of β-arrestin to the activated MOR can lead to desensitization of the G protein signaling pathway, promote receptor endocytosis, and open other signal transduction pathways (Nature. 2016 537(7619):185-190). Studies have shown that the analgesic effect of morphine comes from the activation of the G protein signaling pathway, while various side effects such as constipation, respiratory depression and drug resistance are closely related to the activation of the β-arrestin pathway. After the β-arrestin 2 gene was knocked out in mice and then administered morphine, side effects such as constipation, respiratory depression and drug resistance were significantly reduced [Science. 1999 286(5449):2495-2498; J Pharmacol Exp Ther. 314(3):1195-1201]. Therefore, selectively activating the G protein signaling pathway and avoiding the activation of the MOR "biased" ligand of the β-Arrestin 2 signaling pathway can significantly reduce various side effects such as constipation, respiratory depression and drug resistance while exerting analgesic effects.

[0004] In 2017, Cullen L. Schmid's study [Cell. 2017 171(5):1165-1175] showed that the "bias factor" is an important indicator for evaluating the "biased activation ability" of MOR ligands. The authors synthesized several compounds with different "bias factors" and tested the ED of these compounds for analgesic effects in animals. 50 Values ​​and ED for respiratory depression 50 The value was calculated, and the "Therapeutic Window" for evaluating drug safety was calculated. The results showed that the "Bias Factor" had a good negative correlation with respiratory depression; the higher the Bias Factor, the weaker the respiratory depression; the larger the corresponding "Therapeutic Window", the higher the safety of the compound.

[0005] Currently, representative MOR "biased" ligands include TRV130 [J Med Chem. 2013 56 (20): 8019-8031; WO2012129495], PZM21 [Nature. 2016 537 (7619): 185-190; WO2017007695, WO2018129393] and SR17018 [Cell. 2017 171 (5): 1165-1175; WO2017161017]. TRV130 is the first "biased" ligand of the μ-type opioid receptor, and has clinically shown analgesic efficacy equivalent to that of morphine. However, due to its low "bias factor" [approximately 3, J Med Chem. 2013 56(20):8019-8031; Cell. 2017 171(5):1165-1175], side effects such as respiratory depression still exist, and the therapeutic window cannot meet clinical needs. Animal experiments on the compound PZM21 showed that its respiratory depression, constipation, and addiction tendency were significantly weaker than morphine, but its "bias factor" was also low; in addition, PZM21 also has poor metabolic properties (T 1 / 2 <1h, high clearance, low exposure) and potential cardiotoxicity issues (IC 50 2 to 4 μM), and poor drug properties.

[0006]

[0007] In view of this, the present invention provides a new type of MOR "biased" agonist ligand with high "Bias Factor", which retains excellent G protein pathway agonist activity, while activating the β-Arrestin 2 signaling pathway with very low ability, or even does not activate the β-Arrestin 2 signaling pathway, and the "Bias Factor" is greatly improved compared with the currently available "biased" agonists. In addition, the metabolic properties of the compounds of the present invention are significantly improved, the hERG inhibitory activity is low, and the drugability and analgesic activity in animals are also greatly improved compared with the currently reported compound PZM21.

[0008] The MOR small molecule ligand disclosed in the present invention has the characteristic of "biased" activation of the G protein signaling pathway and can be used to treat and / or prevent pain or pain-related diseases. Summary of the invention

[0009] The object of the present invention is to provide a compound of formula (I) having a high "Bias Factor", excellent metabolic properties and drugability, a preparation method thereof, and use thereof in the treatment and / or prevention of pain or pain-related diseases.

[0010] In a first aspect of the present invention, there is provided a compound represented by formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0011]

[0012] Wherein, Ring A is selected from the following group: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 4-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; the substitution refers to substitution by one or more substituents selected from the following group: hydrogen, hydroxyl, halogen, -B(OH) 2 , C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy, -OC(O)R 5 and

[0013] G is selected from the following group: CR 7 R 8 and NR 2 ;

[0014] R 2 Selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy and cyano;

[0015] R 3 and R4 Each is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, or R 3 and R 4 The carbon atoms to which they are attached are closed to form a 3-6 membered cycloalkyl group;

[0016] R 5 Selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy;

[0017] Each R 6 are the same or different and are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy and halogen;

[0018] R 7 and R 8 The same or different, and each independently selected from the following group: H, NO 2 , C1-C6 alkyl, halogenated C1-C6 alkyl;

[0019] n is 0, 1, 2 or 3;

[0020] q is 0, 1, 2, 3, or 4;

[0021] Z is selected from the following group: NR 11 , O, S and CR 9 R 10 ;

[0022] R 9 , R 10 , R 11 Each is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy and cyano;

[0023] t is 0, 1, 2, or 3.

[0024] In another preferred embodiment, Ring A is selected from the following group:

[0025] G is selected from the following group: CHNO 2 and NR 2 ;

[0026] Each R 1 are the same or different and are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, -B(OH) 2 , C1-C6 alkyl, -CF 3 、-OC(O)R5 and

[0027] R 2 Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy and cyano;

[0028] R 3 and R 4 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R 3 and R 4 The carbon atoms to which they are attached are closed to form a 3-6 membered cycloalkyl group;

[0029] R 5 is hydrogen or C1-C6 alkyl;

[0030] Each R 6 are the same or different and are each independently selected from the group consisting of hydrogen, C1-C6 alkyl and halogen;

[0031] m is 0, 1, 2, 3, 4 or 5;

[0032] n is 0 or 1;

[0033] q is 0, 1, 2, 3, or 4;

[0034] Z is selected from the group consisting of O and CH 2 ;

[0035] t is 0, 1, or 2.

[0036] In another preferred embodiment, Ring A is a substituted C6-C10 aryl group, wherein the substitution refers to substitution by m substituents selected from the group consisting of hydrogen, hydroxyl, halogen, -B(OH) 2 , C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy, -OC(O)R 5 and m is 0, 1, 2, 3, 4 or 5;

[0037] G is selected from the following group: CR 7 R 8 and NR 2 ;

[0038] R 2 Selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy and cyano;

[0039] R 3 and R 4 Each is independently selected from the following group: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, or R3 and R 4 The carbon atoms to which they are attached are closed to form a 3-6 membered cycloalkyl group;

[0040] R 5 Selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy;

[0041] Each R 6 are the same or different and are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy and halogen;

[0042] R 7 and R 8 The same or different, and each independently selected from the following group: H, NO 2 , C1-C6 alkyl, halogenated C1-C6 alkyl;

[0043] n is 0, 1, 2 or 3;

[0044] q is 0, 1, 2, 3, or 4;

[0045] Z is selected from the following group: NR 11 , O, S and CR 9 R 10 ;

[0046] R 9 , R 10 , R 11 Each is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy and cyano;

[0047] t is 0, 1, 2, or 3.

[0048] In another preferred embodiment, Ring A is a substituted or unsubstituted 4-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; the substitution refers to substitution by one or more substituents selected from the following group: hydrogen, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy;

[0049] G is selected from the following group: CR 7 R 8 and NR 2 ;

[0050] R 2Selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy and cyano;

[0051] R 3 and R 4 Each is independently selected from the following group: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, or R 3 and R 4 The carbon atoms to which they are attached are closed to form a 3-6 membered cycloalkyl group;

[0052] Each R 6 are the same or different and are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy and halogen;

[0053] R 7 and R 8 The same or different, and each independently selected from the following group: H, NO 2 , C1-C6 alkyl, halogenated C1-C6 alkyl;

[0054] n is 0, 1, 2 or 3;

[0055] q is 0, 1, 2, 3, or 4;

[0056] Z is selected from the following group: NR 11 , O, S and CR 9 R 10 ;

[0057] R 9 , R 10 , R 11 Each is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy and cyano;

[0058] t is 0, 1, 2, or 3.

[0059] In another preferred embodiment, Ring A is selected from the following group:

[0060] In another preferred embodiment, the compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof is selected from the following group:

[0061]

[0062] The second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more compounds of formula (I) described in the first aspect of the present invention or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0063] The third aspect of the present invention provides a method for preparing the compound represented by formula (I) according to the first aspect of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the method is selected from the group consisting of:

[0064] Method 1: including the steps:

[0065]

[0066] (i-1) the compound represented by formula A or its salt, the compound represented by formula B or its salt, and Reaction to obtain a compound of formula I-1, wherein the reaction order of the compound of formula A or its salt and the compound of formula B or its salt can be interchanged;

[0067] Among them, Ring A, G, R 3 , R 4 , R 6 , Z, t, q, n are as described in the first aspect of the present invention;

[0068] M is selected from the group consisting of -S-(C1-C6 alkyl), -O-(C6-C10 aryl);

[0069] Method 2: including the following steps:

[0070]

[0071] (ii-1) reacting the compound represented by formula A or a salt thereof with the compound represented by formula C or a salt thereof to obtain the compound represented by formula I-2;

[0072] Among them, Ring A, R 2 , R 3 , R 4 , R 6 , Z, t, q, n are as described in the first aspect of the present invention;

[0073] M is selected from the group consisting of -S-(C1-C6 alkyl), -O-(C6-C10 aryl);

[0074] Method 3: including the following steps:

[0075]

[0076] (iii-1) reacting the compound represented by formula D or a salt thereof with the compound represented by formula E or a salt thereof to obtain a compound represented by formula I-3;

[0077] Among them, Ring A, R 3 , R 4 , R 6 , Z, t, q, n are as described in the first aspect of the present invention;

[0078] M is -S-(C1-C6 alkyl);

[0079] Q is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy.

[0080] In another preferred embodiment, the method further comprises the following steps:

[0081] The obtained product is further reacted with the first substance to obtain a compound represented by formula (I);

[0082] The first substance is selected from the following group: NaOH, p-toluenesulfonic acid.

[0083] The fourth aspect of the present invention provides a use of a compound represented by formula (I) according to the first aspect of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for preparing a medicament for preventing and / or treating pain or pain-related diseases.

[0084] In another preferred embodiment, the pain or pain-related disease is a pain disease associated with MOR receptors.

[0085] In another preferred embodiment, the pain or pain-related disease is a pain-related disease in a mammal.

[0086] In another preferred embodiment, the pain is selected from the group consisting of postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain and pain caused by inflammation.

[0087] In another preferred embodiment, the cancer is selected from the group consisting of solid tumors and non-solid tumors.

[0088] In another preferred embodiment, the cancer is selected from the group consisting of lung cancer, bone cancer, gastric cancer, pancreatic cancer, liver cancer, colon cancer, breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, lymphoma, esophageal cancer, oral cancer and leukemia.

[0089] The fifth aspect of the present invention provides a method for preventing and / or treating pain or pain-related diseases, comprising the steps of: administering a therapeutically effective amount of the compound represented by formula (I) according to the first aspect of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof to a patient in need.

[0090] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] Figure 1 This is the result obtained in Test Example 5. DETAILED DESCRIPTION

[0092] After long-term and in-depth research, the inventor unexpectedly prepared a novel compound represented by formula (I) with high "bias factor", excellent metabolic properties and drugability. On this basis, the inventor completed the present invention.

[0093] the term

[0094] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0095] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0096] In the present invention, "C1-C6 alkyl" refers to a straight or branched alkyl group comprising 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.

[0097] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-C4 alkoxy group.

[0098] In the present invention, the term "C3-C6 cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0099] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, preferably "C6-C10 aryl group". The term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.

[0100] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 carbon atoms. Non-limiting examples include: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0101] In the present invention, Indicates a single bond.

[0102] In the present invention, the term "halo" means substituted with halogen.

[0103] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those stable or chemically feasible combinations. The substituents include, for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic radical, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, etc.

[0104] In the present invention, the term multiple refers to 1-6.

[0105] In the present invention, the term 1-6 means 1, 2, 3, 4, 5 or 6. Other similar terms have similar meanings.

[0106] Compound

[0107] The present invention provides a compound represented by formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0108]

[0109] The groups are as defined above.

[0110] In another preferred embodiment, in the compound, Ring A, G, R 3 , R 4 , R 6 Any one of Z, t, q, and n is a corresponding group in the specific compounds described in the embodiments.

[0111] In another preferred embodiment, the compound is preferably the compound prepared in the examples.

[0112] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0113] Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0114] Preparation method

[0115] The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combination can be easily carried out by a technician in the field to which the present invention belongs.

[0116] Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0117] The general formula (Ia) is a guanidine structure compound of the general formula (I), and its preparation method comprises the following steps:

[0118]

[0119] The amino group of the amine compound of general formula (Ia-1) reacts with CS 2and acetyl chloride to obtain an isothiocyanate compound of the general formula (Ia-2); the compound of the general formula (Ia-2) reacts with the amino group of an amine compound of the general formula (Ia-3) to obtain a thiourea compound of the general formula (Ia-4); the compound of the general formula (Ia-4) is substituted with iodomethane to obtain a methylthio compound of the general formula (Ia-5); the methylthio group of the compound of the general formula (Ia-5) is substituted with the amino group of an amine compound of the general formula (Ia-6) under alkaline conditions to obtain a guanidine structure compound of the general formula (Ia). Wherein, Ring A, R 2 , R 3 , R 4 , R 6 , Z, t, q, and n are as defined in the general formula (I).

[0120] In another preferred embodiment, the compound of general formula (Ib) is a cyanoguanidine structure compound of general formula (I) prepared by the following method

[0121]

[0122] The amine compounds of the general formula (Ia-1) and the amine compounds of the general formula (Ia-6) are reacted in turn with N-cyanocarbonyl diester reagents in a solvent to obtain compounds of the general formula (Ib). The order of reaction of the amine compounds of the general formula (Ia-1) and the compounds of the general formula (Ia-6) with N-cyanocarbonyl diester reagents can be interchanged. The N-cyanocarbonyl diester reagents used include but are not limited to N-cyanocarbonyl diphenyl ester (CAS: 79463-77-7), N-cyanocarbonyl dimethyl ester (CAS: 24771-25-3), N-cyanocarbonyl diethyl ester and N-cyanocarbonyl dimethyl thioester (CAS: 10191-60-3). The reaction temperature is 0°C to 100°C. The reaction can be carried out under neutral or alkaline conditions. Wherein, Ring A, R 3 , R 4 , R 6 , Z, t, q, and n are as defined in the general formula (I).

[0123] In another preferred embodiment, the compound of formula (Ic) is prepared as follows

[0124]

[0125] The amine compound of the general formula (Ia-1) and the amine compound of the general formula (Ia-6) are reacted with 1,1-(bismethylthio)-2-nitroethylene in a solvent in sequence to obtain the compound of the general formula (Ic). The order of the reaction of the amine compound of the general formula (Ia-1) and the amine compound of the general formula (Ia-6) with 1,1-(bismethylthio)-2-nitroethylene can be interchanged. The reaction temperature is 20°C to 160°C. The reaction can be carried out under neutral or alkaline conditions. Wherein, Ring A, R3 , R 4 , R 6 , Z, t, q, and n are as defined in the general formula (I).

[0126] The solvents used in the preparation method of the present invention include but are not limited to methanol, ethanol, isopropanol, water, toluene, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, 1,4-dioxane, DMF, acetonitrile, DMSO and NMP. The reagents providing alkaline conditions include commonly used inorganic bases and organic bases, and the inorganic bases include but are not limited to sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate; the organic bases include but are not limited to triethylamine, N, N-diisopropylethylamine, imidazole, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, LDA, butyllithium.

[0127] To ensure that each synthesis step proceeds smoothly, those skilled in the art may use common protecting groups such as TBS, TMS, TBDPS, Bn, THP, Tf, etc. to protect and deprotect the hydroxyl groups in the compounds involved in the reaction, and use common protecting groups such as Boc, Cbz, Bn, Ts, THP, etc. to protect the NH or NH 2 Perform protection and deprotection operations.

[0128] The general formula (I) of the present invention indicates that the compound contains one or more chiral centers, and there are enantiomers and diastereomers. For enantiomers, two enantiomers can be obtained by general chiral separation methods or asymmetric synthesis methods. For diastereomers, they can be separated by methods such as fractional recrystallization or chromatographic separation.

[0129] Pharmaceutical compositions and methods of administration

[0130] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0131] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0132] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0133] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0134] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0135] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0136] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0137] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0138] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0139] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0140] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0141] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0142] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0143] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0144] Compared with the prior art, the present invention has the following main advantages:

[0145] (1) The compounds of the present invention have excellent G protein pathway agonist activity and low β-Arrestin 2 signaling pathway agonist activity, with significant bias;

[0146] (2) The compounds of the present invention have excellent pharmacokinetic properties, such as high plasma exposure (AUC), low clearance (CL), and significantly prolonged half-life (T 1 / 2 );

[0147] (3) The compounds of the present invention have excellent in vivo activity and drugability, and are safer for preventing and / or treating pain-related diseases.

[0148] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0149] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0150] In the present invention, the structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NNMR is determined using a Bruker AVANCE-400 nuclear magnetic spectrometer. LCMS is determined using a Waters 2695 liquid chromatography-mass spectrometer (MS model: Micromass ZQ).

[0151] HPLC determination was performed using an Agilent 1100 high pressure liquid chromatograph (ZORBAX SP-C18 250x4.6mm chromatographic column, Eclipse Plus-C18 250x4.6mm chromatographic column).

[0152] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from Acros Organics, Aldrich Chemical Company, J&Chem, Shaoyuan Chemical Technology, Darui Chemicals, Anaiji Chemicals and other companies.

[0153] Unless otherwise specified in the examples, all reactions were carried out under an argon or nitrogen atmosphere.

[0154] The microwave reaction was carried out using a CEM Discover-SP 909155 microwave reactor.

[0155] Unless otherwise specified in the examples, the reaction temperature is room temperature (20°C to 35°C).

[0156] The silica gel plate used in the thin layer chromatography (TLC) in the embodiment has a specification of 0.2mm±0.03mm. The thin layer chromatography separation and purification (prep-TLC) used for purifying compounds has a specification of 0.4mm~0.5mm; the column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier; the fully automatic medium pressure rapid purification instrument (Combi Flash Rf+UV-VIS) is used, and the separation column models are: Silica Flash Column 4g, 12g, 25g. The eluent system of the column chromatography and the development system of the thin layer chromatography include: A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as ammonia water or acetic acid can also be added for adjustment.

[0157] The final sample compound was purified using a high pressure preparative liquid chromatograph (manufacturer: Shimadzu, model: LC-20AP), Ultimate XB-C18 chromatographic column (150x30mm, 5μm). The mobile phase systems were: A: acetonitrile and water (containing 0.1% trifluoroacetic acid) system; B: acetonitrile and water (containing 0.1% acetic acid) system.

[0158] Example 1

[0159] 2-Cyano-1-(1-(1-(dimethylamino)-2-(1H-indazol-5-yl)ethyl)cyclopropyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 1

[0160]

[0161] Step 1: Preparation of (1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)methanol 1a

[0162] Indazole-5-carboxylic acid methyl ester (5 g, 28.4 mmol) was dissolved in THF (50 mL), and 3,4-dihydro-2H-pyran (4.77 g, 56.8 mmol) and methanesulfonic acid (820 mg, 8.5 mmol) were added under stirring at room temperature, and then the temperature was raised to 60°C and stirred for 2 h. After the reaction was completed, the mixture was cooled to 0-5°C and LiAlH was slowly added. 4After the addition of the THF solution (28.4 mL, 28.4 mmol), stirring was continued for 20 min. After TLC detection, the reaction was completed, and EA and MeOH were used to quench the reaction, diatomaceous earth was spread for filtration, the filter cake was washed with EA, the filtrate was concentrated, and column chromatography (EA:PE=1:2) was performed to obtain 6.12 g of a light yellow oil, with a yield of 92.4%.

[0163] 1 H NMR (400 MHz, CDCl 3 )δ:7.93(s,1H),7.61(s,1H),7.53(d,J=8.6Hz,1H),7.36(dd,J=8.6,1.3Hz,1H),5.69-5.66(m,1H),4.7 1(s,2H),3.99-3.97(m,1H),3.74-3.68(m,1H),2.57-2.49(m,2H),2.14-2.04(m,2H),1.81-1.67(m,2H).

[0164] MS(M+H) + :233

[0165] Step 2: Preparation of 5-(bromomethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 1b

[0166] (1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)methanol (5 g, 21.5 mmol) was dissolved in DCM (100 mL) and N 2 After protection, Ph 3 P (6.21 g, 23.7 mmol) and NBS (5.35 g, 23.7 mmol) were stirred at room temperature for 15 min. After the reaction was completed, the solvent was dried by spin drying and column chromatography (EA:PE=1:10) was performed to obtain 5.1 g of light yellow solid with a yield of 80.3%.

[0167] MS(M+H) + :295

[0168] Step 3: Preparation of 2-((benzhydryl)amino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propionitrile 1c

[0169] Dissolve dibenzylideneaminoacetonitrile (1.12 g, 5.1 mmol) in THF (5 mL) and add N 2After protection, the mixture was stirred at -70°C, and LDA (2.5 mL, 5 mmol, 2 M THF solution) was slowly added dropwise, followed by a THF (5 mL) solution of 5-(bromomethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.0 g, 3.4 mmol). The mixture was naturally heated to 0°C and stirred for 30 min. After the reaction was completed, a saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with EA (20 mL x 2). The organic phases were combined, washed with brine, dried (anhydrous sodium sulfate), filtered, concentrated, and column chromatographed (EA: PE = 1: 5) to obtain 1.04 g of a white solid with a yield of 70.6%.

[0170] 1 H NMR (400 MHz, CDCl 3 )δ:7.93(s,1H),7.61-7.59(m,2H),7.48-7.32(m,8H),7.11(t,J=8.1Hz,1H),6.81(dd,J=25.5,7.0Hz,2H),5.68(dd,J=9.3,2.5Hz,1H),4 .45-4.41(m,1H),4.01(d,J=11.4Hz,1H),3.76-3.70(m,1H),3.39-3.24(m,2H),2.56-2.53(m,1H),2.15-2.04(m,2H),1.78-1.65(m,3H).

[0171] MS(M+H) + :435

[0172] Step 4: Preparation of tert-butyl (1-(1-((diphenylmethylene)amino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)cyclopropyl)carbamate 1e

[0173] Take 2-((benzhydryl)amino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propionitrile (4 g, 9.21 mmol) and dissolve it in dry THF (50 mL). 2 Protect, place at -70℃ and stir, add Ti(O i Pr) 4 (7.85 g, 27.6 mmol), then ethylmagnesium bromide (27.6 mL, 27.6 mmol) was added dropwise to the above reaction solution at -70 °C. After the addition, the mixture was returned to room temperature and reacted for 1 h. Then BF 3 E 2O solution (3.9 g, 27.6 mmol), stirred at room temperature for 1 h. LCMS showed that the starting material disappeared and the product was generated. Saturated sodium bicarbonate was added to quench the reaction (150 mL), extracted with EA (200 mL x 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound 1d. The crude product of the above compound 1d was dissolved in EA solution (50 mL), and di-tert-butyl dicarbonate (1.52 g, 6.97 mmol) was added and stirred at room temperature for 4 h. LCMS and TLC showed that the starting material disappeared and the reaction was complete. The reaction solution was mixed with silica gel and column chromatography (EA: PE = 1: 5) was performed to obtain 1.2 g of a white solid, with a two-step yield of 23%.

[0174] MS(M+H) + :565

[0175] Step 5: Preparation of tert-butyl (1-(1-(dimethylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)cyclopropyl)carbamate 1 g

[0176] Take tert-butyl (1-(1-((diphenylmethylene)amino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)cyclopropyl)carbamate (994mg, 1.76mmol), dissolve it in methanol (20mL), add potassium acetate (225mg, 2.3mmol), stir to dissolve, then add hydroxylamine hydrochloride (135mg, 1.94mmol), and stir at room temperature for 20min. After the reaction, add sodium bicarbonate solution (10mL) to quench the reaction, extract with EA (20mLx3), combine the organic phases, wash the organic phases with brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product of compound 1f. The crude product of the above compound 1f was dissolved in a mixed solvent of acetonitrile (15mL) and water (7mL), and then N 2 After protection, the mixture was placed in an ice bath and 37% HCHO (1.05 g, 8.8 mmol) and NaBH(OAc) were added in sequence. 3 (1.1 g, 5.28 mmol), stirred at room temperature for 30 min. LCMS showed that the starting material disappeared and the product was generated, saturated sodium bicarbonate solution (50 mL) was added to quench the reaction, extracted with DCM (40 mL x 3), the combined organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (DCM: MeOH = 10: 1) was performed to obtain 550 mg of light yellow oil, two-step yield: 73.1%.

[0177] 1 H NMR (400 MHz, CDCl 3)δ:7.96(s,1H),7.62(s,1H),7.51(d,J=8.5Hz,1H),7.34(d,J=8.5Hz,1H),5.69(dd,J=9.5,2.5Hz,1H),5.15(s,1H),4.05-4.02(m,1H),3. 77-3.72(m,1H),3.10-3.07(m,2H),2.53(s,6H),2.16-2.14(m,1H),2 .09-2.01(m,2H),1.78-1.65(m,4H),1.44(s,9H),0.96-0.80(m,4H).

[0178] MS(M+H) + :429

[0179] Step 6: Preparation of 1-(1-(dimethylamino)-2-(1H-indazol-5-yl)ethyl)cyclopropylamine hydrochloride 1h

[0180] Tert-butyl (1-(1-(dimethylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)cyclopropyl)carbamate (200 mg, 0.47 mmol) was dissolved in DCM (2 mL), and then HCl / dioxane (4N, 1.2 mL) was added, and the mixture was stirred at room temperature for 1 h. LCMS showed that the starting material disappeared and the product was generated. After the reaction was completed, the mixture was directly concentrated and dried to obtain 1-(1-(dimethylamino)-2-(1H-indazol-5-yl)ethyl)cyclopropylamine.

[0181] Step 7: Preparation of 2-cyano-1-(1-(1-(dimethylamino)-2-(1H-indazol-5-yl)ethyl)cyclopropyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 1

[0182] Take N-cyanocarbonyl diphenyl ester (1.62g, 6.8mmol) and dissolve it in acetonitrile (20mL), then add 1,2,3,4-tetrahydronaphthalene-2-amine (1g, 6.8mmol) and triethylamine (1.42mL, 10.2mmol). After addition, stir at room temperature for 1h. LCMS shows that the raw material disappears and the product is generated. Dilute with water (40mL), extract with EA (30mLx3), wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate, add a small amount of PE / EA (2 / 1, 10mL) to pulp, filter with suction, and obtain 1.57g of phenyl N'-cyano-N-(1,2,3,4-tetrahydronaphthalene-2-yl)carbamide ester, yield: 79.6%, for the next step.

[0183] 1-(1-(dimethylamino)-2-(1H-indazol-5-yl)ethyl)cyclopropylamine (88 mg, 0.36 mmol) and phenyl N'-cyano-N-(1,2,3,4-tetrahydronaphthalen-2-yl)carbamide ester (94 mg, 0.32 mmol) were dissolved in acetonitrile (3 mL), triethylamine (73 mg, 0.72 mmol) was added, and the temperature was raised to 80°C for overnight reaction. LCMS showed that the product was generated. Water (20 mL) was added, EA was extracted (15 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and column chromatography (DCM: MeOH = 90: 10) was performed to obtain 38 mg of a white solid, which was prepared by HPLC and freeze-dried to obtain a product of 14.3 mg of a white solid, i.e., compound 1. Yield: 9.0%.

[0184] 1 H NMR (400 MHz, DMSO-d 6 )δ:12.91(s,1H),8.77(s,2H),7.96(d,J=4.4Hz,1H),7.68(d,J=6.4Hz,1 H),7.43-7.28(m,3H),7.12-7.05(m,4H),4.03-3.93(m,1H),3.09-2.92(m ,3H),2.89-2.80(m,3H),2.72-2.61(m,1H),2.14(s,3H),2.02-1.96(m,1 H),1.91(s,3H),1.83-1.73(m,1H),0.70-0.53(m,2H),0.50-0.36(m,2H).

[0185] MS(M+H) + :442

[0186] Example 2

[0187] 2-Cyano-1-(1-(1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidine

[0188]

[0189] Step 1: Preparation of (S)-4-(3-amino-2-((tert-butyloxycarbonyl)amino)-3-oxopropyl)phenyl trifluoromethanesulfonate 2a

[0190] (S)-2-amino-3-(4-hydroxyphenyl)propionamide (15 g, 83.2 mmol) was dissolved in DMF (150 mL), and then (Boc) was added under ice-cooling. 2O (19.5 g, 91.6 mmol), warm to room temperature, and stir to react for 1 h. TLC (DCM: MeOH = 10: 1) showed that the starting material disappeared, and K 2 CO 3 (17.3 g, 125 mmol) and PhNTf 2 (32.7 g, 91.6 mmol), stirred at room temperature for 1 h. LCMS showed product formation. After the reaction was completed, water (1 L) was added to quench the reaction, EA (400 mL x 3) was extracted, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was dissolved in DCM (100 mL), PE (500 mL) was added, slurrying and suction filtration were performed to obtain 31 g of white solid, yield: 90.3%.

[0191] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.43-7.37(m,5H),7.05(brs,1H),6.89(d,J=8.9Hz,1H),4.11-4.08(m,1H),3.02-2.97(m,1H),2.79-2.67(m,1H),1.25(s,9H).

[0192] MS(M+Na) + :413

[0193] Step 2: Preparation of (S)-4-(2,3-diamino-3-oxopropyl)phenyl trifluoromethanesulfonate hydrochloride 2b

[0194] (S)-4-(3-amino-2-(tert-butyloxycarbonyl)amino)-3-oxopropyl)phenyl trifluoromethanesulfonate (10 g, 24.25 mmol) was dissolved in THF (150 mL), and HCl / dioxane (4N, 100 mL) was added under stirring, and stirred at room temperature for 30 min. After the reaction was completed, the mixture was directly concentrated and dried to obtain a crude white solid of 11 g, with a yield of 100%, which was directly used in the next step.

[0195] MS(M+H) + :313

[0196] Step 3: Preparation of (S)-4-(3-amino-2-(dimethylamino)-3-oxopropyl)phenyl trifluoromethanesulfonate 2c

[0197] (S)-4-(2,3-diamino-3-oxopropyl)phenyl trifluoromethanesulfonate hydrochloride (10 g, 32 mmol) was dissolved in a mixed solvent of acetonitrile (150 mL) and water (10 mL). 2After protection, the mixture was placed in an ice bath and 37% HCHO (23.25 mL, 320 mmol) and NaBH(OAc) were added in sequence under stirring. 3 (18.25 g, 96 mmol), stirred at room temperature overnight. LCMS showed that the starting material disappeared and the product was generated. Saturated sodium bicarbonate solution (100 mL) was added to quench the reaction, extracted with DCM (40 mL x 3), and the combined organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM: MeOH = 90: 10) to obtain 4 g of light yellow oil, yield: 36.7%.

[0198] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.39-7.36(m,4H),7.32-7.29(m,1H),7.06-6.97(m,1H),4.13-4.05(m,1H),2.97-2.84(m,2H),2.37(s,6H).

[0199] MS(M+H) + :341

[0200] Step 4: Preparation of (S)-4-(2-cyano-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate 2d

[0201] (S)-4-(3-amino-2-(dimethylamino)-3-oxopropyl)phenyl trifluoromethanesulfonate (500 mg, 1.47 mmol) was dissolved in THF (10 mL), and pyridine (0.59 mL, 7.35 mmol) was added. 2 After protection, the mixture was placed in an ice bath, and TFAA (0.41 mL, 2.94 mmol) was added dropwise under stirring, and the mixture was stirred under ice bath for 1 h. LCMS showed that the starting material disappeared, and a saturated sodium bicarbonate solution (15 mL) was added to quench the reaction, and the mixture was extracted with EA (20 mL x 2), and the combined organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (PE:EA=80:20) to obtain 320 mg of a light yellow oil, with a yield of 67.5%.

[0202] 1 H NMR (400 MHz, CDCl 3 )δ:7.36(d,J=8.6Hz,2H),7.25(d,J=8.3Hz,2H),3.67(t,J=7.8Hz,1H),3.04(d,J=7.8Hz,2H),2.37(s,6H).

[0203] MS(M+H) + :323

[0204] Step 5: Preparation of 4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate 2e

[0205] (S)-4-(2-cyano-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (400 mg, 1.24 mmol) was dissolved in dry THF (10 mL) and Ti(O i Pr) 4 (400 mg, 1.39 mmol), then stirred at -70 °C, ethylmagnesium bromide (2.7 mL, 2.7 mmol) was added dropwise to the above reaction solution at -70 °C. After the addition, the mixture was returned to room temperature and reacted for 1 h. Then BF 3 Et 2 O solution (0.67mL, 2.48mmol), stirred at room temperature for 1h. LCMS showed that the starting material disappeared and the product was generated. Saturated sodium bicarbonate was added to quench the reaction (15mL), water (15mL) was added to dilute, EA (20mLx3) was extracted, and the combined organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (DCM:MeOH=91:9) was performed to obtain 92mg of light yellow oil, yield: 21.1%.

[0206] 1 H NMR (400 MHz, CDCl 3 )δ:7.34(d,J=8.6Hz,2H),7.21(d,J=8.6Hz,2H),3.21-3.08(m,2H),2.66(s,6H ),2.29-2.25(m,1H),0.92-0.77(m,2H),0.69-0.64(m,1H),0.41-0.36(m,1H).

[0207] MS(M+H) + :353

[0208] Step 6: Preparation of 4-(2-(1-(2-cyano-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate 2f

[0209] 4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (150 mg, 0.42 mmol) and active ester phenyl N'-cyano-N-(1,2,3,4-tetrahydronaphthalen-2-yl)carbamide ester (123 mg, 0.42 mmol) were dissolved in DMSO (2 mL), triethylamine (42 mg, 0.42 mmol) was added, and the temperature was raised to 80°C for 2 h. LCMS showed that the product was generated. Water (20 mL) was added, EA was extracted (15 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and column chromatography (EA: PE = 1: 1) was performed to obtain 150 mg of yellow oil. Yield: 60.9%.

[0210] MS(M+H) + :550

[0211] Step 7: Preparation of 2-cyano-1-(1-(1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 2

[0212] 4-(2-(1-(2-cyano-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (30 mg, 0.055 mmol) was dissolved in THF / MeOH (2 mL, 1 / 1) and water (1 drop), and then NaOH (22 mg, 0.55 mmol) was added. The reaction was stirred at room temperature for 2 h. LCMS showed that the product was generated. After the reaction was completed, NH 4 The reaction was quenched with a saturated aqueous solution of Cl (5 mL), extracted with EA (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and prepared by HPLC and freeze-dried to obtain 5 mg of the product as a white solid, namely compound 2. Yield: 21.8%.

[0213] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.75(s,2H),7.25(d,J=10.5Hz,1H),7.10-7.06(m,5H),6.63(dd,J=8.3,6.2Hz,2H),4.06-4.03(m,1H),3.07-2.97(m,1H ),2.89-2.60(m,5H),2.30-2.21(m,1H),2.11(s,4H),2.03-1.94(m,1H),1.89(s,2H),1.79-1.74(m,1H),0.76-0.39(m,4H).

[0214] MS(M+H) + :418

[0215] Example 3

[0216] (4-(2-(1-(2-cyano-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl)boronic acid 3

[0217]

[0218] Step 1: Preparation of 2-cyano-1-(1-(1-(dimethylamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)cyclopropyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 3a

[0219] 4-(2-(1-(2-cyano-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (150 mg, 0.27 mmol) was dissolved in dioxane (5 mL), and then pinacol diboron (105 mg, 0.41 mmol), Pd(dppf)Cl 2 (45 mg, 0.061 mmol) and potassium acetate (89 mg, 0.91 mmol) were placed in a microwave reactor (80 degrees, 80w, 1 h). After the reaction, the mixture was concentrated and subjected to column chromatography (EA:PE=1:1) to obtain 80 mg of a light brown solid, with a yield of 56.2%.

[0220] MS(M+H) + :528

[0221] Step 2: Preparation of (4-(2-(1-(2-cyano-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl)boronic acid 3

[0222] Take 2-cyano-1-(1-(1-(dimethylamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)cyclopropyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidine (80 mg, 0.15 mmol) and dissolve it in THF (2 mL), then add dilute HCl (1N, 1 mL), and stir the reaction at room temperature for 3 h. LCMS shows that most of the raw materials disappear and products are generated. After the reaction is completed, it is directly concentrated and dried, and 39 mg of white solid is obtained after HPLC preparation and freeze drying, namely compound 3. Yield: 58.4%.

[0223] 1 H NMR (400 MHz, DMSO-d 6)δ:8.72(s,1H),8.07(s,2H),7.70-7.60(m,2H),7.38-7.23(m,3H),7.09-7.06(m,4H),4.05-4.02(m,1H),3.07-2.96(m,1H ),2.92-2.59(m,5H),2.38-2.30(m,1H),2.10(s,3H),2.01-1.95(m,1H),1.88(s,3H),1.82-1.73(m,1H),0.84-0.44(m,4H).

[0224] MS(M+H) + :446

[0225] Example 4

[0226] 2-Cyano-1-(1-(1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 4

[0227]

[0228] Step 1: Preparation of 6-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride 4a

[0229] Dissolve 6-fluoro-3,4-dihydronaphthalen-2(1H)-one (492 mg, 3 mmol) in methanol (30 mL), then add ammonium acetate (2.4 g, 30 mmol) and stir at room temperature for 30 min. 3 CN (372 mg, 6 mmol) was added in batches, and the temperature was raised to 60°C for 4 h. LCMS showed that the raw material disappeared and the product was generated. Water (40 mL) was added to quench the reaction, methanol was removed by vortexing, and the pH was adjusted to 8-9 with sodium bicarbonate aqueous solution. EA (30 mL x 5) was used for extraction, and the product was dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography (DCM: MeOH = 10: 1) to obtain the free product. EA (5 mL) and HCl (2 mL) were added to precipitate the solid, which was filtered by suction. The filter cake was washed with EA to obtain 360 mg of a white powder solid, with a yield of 59.7%.

[0230] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.34(s,2H),7.20-7.09(m,1H),6.97-6.93(m,2H),3.46-3.38(m,1H),3.07( dd,J=16.0,4.9Hz,1H),2.92-2.73(m,3H),2.13-2.11(m,1H),1.80-1.70(m,1H).

[0231] MS(M+H) + :166

[0232] Step 2: Preparation of phenyl 4-((2S)-2-(1-(2-cyano-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)trifluoromethanesulfonate 4c

[0233] Take N-cyanocarbonyl diphenyl ester (247mg, 1.04mmol) and dissolve it in acetonitrile (5mL), then add 6-fluoro-1,2,3,4-tetrahydronaphthalene-2-amine hydrochloride (210mg, 1.04mmol) and triethylamine (0.29mL, 2.08mmol). After addition, stir at room temperature for 1h. LCMS shows that the raw material disappears and the product is generated. Add water (15mL) to dilute, EA extraction (30mLx3), wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate, add a small amount of PE / EA (1 / 1, 10mL) to pulp, filter with suction, and obtain 156mg of phenyl N'-cyano-N-(6-fluoro-1,2,3,4-tetrahydronaphthalene-2-yl)carbamide, i.e., compound 4b, with a yield of 69.7%, which is used in the next step.

[0234] 4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (248 mg, 0.68 mmol) and phenyl N'-cyano-N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)carbamide (187 mg, 0.61 mmol) were dissolved in DMSO (6 mL), triethylamine (75 mg, 0.7 mmol) was added, and the temperature was raised to 80°C for 5 h. LCMS showed that the product was generated. Water (20 mL) was added, EA was extracted (15 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and column chromatography (EA:PE = 3:1) was performed to obtain 180 mg of a yellow oil. Yield: 52.1%.

[0235] MS(M+H) + :568

[0236] Step 3: Preparation of 2-cyano-1-(1-(-1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 4

[0237] 4-(2-(1-(2-cyano-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (65 mg, 0.11 mmol) was dissolved in THF / MeOH (4 mL, 1 / 1) and water (2 drops), and then NaOH (50 mg, 1.2 mmol) was added. The reaction was stirred at room temperature for 2 h. LCMS showed that the product was generated. After the reaction was completed, NH 4 The reaction was quenched with a saturated aqueous solution of Cl (5 mL), extracted with EA (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and prepared by HPLC and freeze-dried to obtain 27 mg of the product as a white solid, namely compound 4. Yield: 56.4%.

[0238] 1 H NMR (400 MHz, DMSO-d 6 )δ:9.11(s,1H),8.73(s,1H),7.30(d,J=8.4Hz,1H),7.12-7.06(m,3H), 6.94-6.89(m,2H),6.64-6.60(m,2H),3.97-3.93(m,1H),3.05-2.91(m,1 H),2.87-2.70(m,3H),2.69-2.56(m,2H),2.29-2.25(m,1H),2.11(s,4H ),1.98-1.95(m,1H),1.91(s,2H),1.80-1.69(m,1H),0.84-0.32(m,4H).

[0239] MS(M+H) + :436

[0240] Example 5

[0241] (4-(2-(1-(2-cyano-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl)boronic acid 5

[0242]

[0243] Step 1: Preparation of 2-cyano-1-(1-(1-(dimethylamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)cyclopropyl)-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 5a

[0244] 4-(2-(1-(2-cyano-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (114 mg, 0.2 mmol) was dissolved in dioxane (3 mL), and then pinacol diboron (77 mg, 0.3 mmol), Pd(dppf)Cl 2 (29 mg, 0.04 mmol) and potassium acetate (60 mg, 0.6 mmol), N 2 The product was protected and placed in a microwave reactor (80 degrees, 80w, 1h). After the reaction, the product was concentrated and subjected to column chromatography (EA:PE=4:1) to obtain 60 mg of a light brown solid, with a yield of 54.9%.

[0245] MS(M+H) + :546

[0246] Step 2: Preparation of (4-(2-(1-(2-cyano-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl)boronic acid 5

[0247] Take 2-cyano-1-(1-(1-(dimethylamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)cyclopropyl)-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine (60 mg, 0.11 mmol) and dissolve it in THF (2 mL), then add dilute HCl (1N, 1 mL), and stir the reaction at room temperature for 3 h. LCMS shows that most of the raw materials disappear and products are generated. After the reaction is completed, it is directly concentrated and dried. After HPLC preparation and freeze-drying, the product is 24 mg of white solid, that is, compound 5. Yield: 47.1%.

[0248] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.69(s,1H),7.91-7.81(m,2H),7.68-7.54(m,2H),7.38-7.20(m,3H),7.14-7.09(m,1H),6.94-6.90(m,2H),4.08-3.96(m,1H),3.03 -2.75(m,5H),2.66-2.58(m,1H),2.39-2.31(m,1H),2.12(s,3H),1.99-1.94(m,1H),1.92(s,3H),1.79-1.74(m,1H),0.83-0.40(m,4H).

[0249] MS(M+H) +:464

[0250] Example 6

[0251] 1-(Chromane-3-yl)-2-cyano-3-(1-(1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)guanidine 6

[0252]

[0253] Step 1: Preparation of 4-(2-(1-(3-(chroman-3-yl)-2-cyanoguanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate 6b

[0254] Take N-cyanocarbonyl diphenyl ester (277 mg, 1.16 mmol) and dissolve it in acetonitrile (6 mL), then add chroman-3-amine hydrochloride (220 mg, 1.16 mmol) and triethylamine (0.34 mL, 2.44 mmol). After the addition, stir at room temperature for 1 h. LCMS shows that the raw material disappears. Add water (15 mL) to dilute, extract with EA (30 mL x 3), wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate, add a small amount of PE / EA (1 / 1, 10 mL) to pulp, filter with suction, and obtain phenyl N-chroman-3-yl-N'-cyanocarbamide ester 260 mg (yield: 76.5%), which is used in the next step.

[0255] (S)-4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (93 mg, 0.26 mmol) and phenyl N-chroman-3-yl-N'-cyanocarbamide (79 mg, 0.27 mmol) were dissolved in DMSO (3 mL), triethylamine (34 mg, 0.3 mmol) was added, and the temperature was raised to 80°C for 5 h. LCMS showed that the product was generated. Water (20 mL) was added, EA was extracted (15 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and column chromatography (EA: PE = 3: 1) was performed to obtain 68 mg of light brown solid. Yield: 46.8%.

[0256] MS(M+H) + :552

[0257] Step 2: Preparation of 1-(chroman-3-yl)-2-cyano-3-(1-(1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)guanidine 6

[0258] 4-(2-(1-(3-(chroman-3-yl)-2-cyanoguanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (68 mg, 0.12 mmol) was dissolved in THF / MeOH (4 mL, 1 / 1) and water (2 drops), and then NaOH (50 mg, 1.2 mmol) was added. The reaction was stirred at room temperature for 2 h. LCMS showed that the product was generated. After the reaction was completed, NH 4 The reaction was quenched with a saturated aqueous solution of Cl (5 mL), extracted with EA (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and prepared by HPLC and freeze-dried to obtain 19 mg of the product as a white solid, namely compound 6. Yield: 37.7%.

[0259] 1 H NMR (400 MHz, DMSO-d 6 )δ:9.33-8.89(m,2H),7.41(d,J=20.2Hz,1H),7.09-7.03(m,4H),6.87-6.74(m,2H),6.61-6.58(m,2H),4.15-4. 04(m,3H),3.13-3.06(m,1H),2.76-2.56(m,3H),2.20-2.06(m,1H),1.96(s,4H),1.76(s,2H),0.63-0.24(m,4H).

[0260] MS(M+H) + :420

[0261] Example 7

[0262] 2-Cyano-1-(2-(dimethylamino)-2-(thien-3-yl)ethyl)-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 7

[0263]

[0264] Step 1: Preparation of 2-(dimethylamino)-2-(thiophen-3-yl)acetonitrile 7a

[0265] Dissolve NaCN (14.9 g, 304 mmol) in water (150 mL), add dimethylamine hydrochloride (45 g, 560 mmol) and 3-thiophenecarboxaldehyde (25 g, 223 mmol) in acetonitrile (150 mL) in turn under stirring, and react overnight at room temperature. TLC (PE: EA = 10: 1) shows that the raw material disappears and new spots are generated. After the reaction is completed, add sodium carbonate aqueous solution to adjust the pH to alkaline, extract with EA (300 mL x 2), wash the combined organic phase with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate, and column chromatography (PE: EA = 10: 1) to obtain 33 g of the product as a light yellow oil, with a yield of 89.1%.

[0266] 1 H NMR (400 MHz, CDCl 3 )δ:7.44-7.43(m,1H),7.35(dd,J=5.0,3.0Hz,1H),7.13(dd,J=5.0,1.1Hz,1H),4.81(s,1H),2.31(s,6H).

[0267] MS(M+H) + :167

[0268] Step 2: Preparation of N,N-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine dihydrochloride 7b

[0269] Take 2-(dimethylamino)-2-(thiophen-3-yl)acetonitrile (23 g, 138 mmol) and dissolve it in THF (200 mL). 2 After protection, place in an ice bath and slowly add 10N BH 3 After adding dimethyl sulfide solution (140 mL, 1.4 mol), the temperature was raised to 60°C and the reaction was allowed to proceed overnight. LCMS showed that the raw material disappeared and the product was generated. After the reaction was completed, methanol (150 mL) was slowly added dropwise to quench the reaction, and concentrated hydrochloric acid (100 mL) was added and stirred at 60°C for 2 h. The mixture was directly concentrated and spin-dried, and a small amount of PE / EA (1 / 1, 30 mL) was added for pulping and suction filtration was performed to obtain 21 g of a white solid with a yield of 63.6%.

[0270] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.47(s,2H),7.98(s,1H),7.75(dd,J=4.8,2.9Hz,1H),7.42(d,J=4.7Hz,1H),4. 83-4.80(m,1H),3.80(dd,J=13.1,5.1Hz,1H),3.63-3.50(m,1H),2.59-2.57(m,6H).

[0271] MS(M+H) + :171

[0272] Step 3: Preparation of phenyl N'-cyano-N-(2-(dimethylamino)-2-(thien-3-yl)ethyl)carbamide 7c

[0273] Take N-cyanocarbonyl imide diphenyl ester (454mg, 1.9mmol) and dissolve it in acetonitrile (10mL), then add N,N-dimethyl-1-(thiophene-3-yl)ethane-1,2-diamine hydrochloride (462mg, 1.9mmol) and triethylamine (0.93mL, 6.68mmol). After the addition, stir at room temperature for 1h. LCMS shows that the raw material disappears and the product is generated. Dilute with water (15mL), extract with EA (30mLx3), wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate, add a small amount of PE / EA (1 / 1, 10mL) to pulp, filter with suction, and obtain 427mg of the title compound, yield: 71.6%.

[0274] MS(M+H) + :315

[0275] Step 4: 2-Cyano-1-(2-(dimethylamino)-2-(thien-3-yl)ethyl)-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 7

[0276] The product was synthesized from phenyl N'-cyano-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)carbamide (135 mg, 0.43 mmol) and 6-fluoro-1,2,3,4-tetrahydronaphthalene-2-amine hydrochloride (86 mg, 0.43 mmol) according to the above example, and the product was 87 mg of white solid, namely compound 7. Yield: 52.5%.

[0277] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.52(dd,J=4.8,2.9Hz,1H),7.35(d,J=2.1Hz,1H),7.14-7.07(m,1H),7.04 (d,J=4.9Hz,1H),6.97-6.88(m,2H),6.68(s,1H),3.99-3.80(m,2H),3.67-3.5 6(m,1H),3.46-3.35(m,1H),2.94(dd,J=16.2,4.6Hz,1H),2.83-2.79(m,2H),2 .62(dd,J=16.1,9.4Hz,1H),2.03(s,6H),1.94-1.88(m,1H),1.74-1.64(m,1H).

[0278] MS(M+H) + :386

[0279] Example 8

[0280] 2-Cyano-1-(2-(dimethylamino)-2-(thien-3-yl)ethyl)-3-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 8

[0281]

[0282] Step 1: Preparation of 6-bromo-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride 8a

[0283] Dissolve 6-bromo-3,4-dihydronaphthalen-2(1H)-one (505 mg, 2.25 mmol) in methanol (30 mL), then add ammonium acetate (1.8 g, 22.5 mmol) and stir at room temperature for 30 min. 3 CN (300 mg, 4.5 mmol) was added in batches, and the temperature was raised to 60 °C for 4 h. LCMS showed that the raw material disappeared and the product was generated. Water (40 mL) was added to quench the reaction, and the methanol was removed by vortexing. The pH was adjusted to 8-9 with sodium bicarbonate aqueous solution, and extracted with EA (30 mL x 5), dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography (DCM: MeOH = 10: 1) to obtain the product. EA (5 mL) and HCl / dioxane (4N, 1 mL) were added to precipitate the solid, which was filtered by suction and the filter cake was washed with EA to obtain 260 mg of light brown solid, with a yield of 44.2%.

[0284] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.43(s,2H),7.32(s,1H),7.30(d,J=8.1Hz,1H),7.09(d,J=8.1Hz,1H),3.47-3.38(m,1 H),3.05(dd,J=16.4,4.8Hz,1H),2.92-2.72(m,3H),2.14-2.11(m,1H),1.83-1.68(m,1H).

[0285] MS(M+H) + :226

[0286] Step 2: Preparation of 2-cyano-1-(2-(dimethylamino)-2-(thien-3-yl)ethyl)-3-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 8

[0287] The product was synthesized from phenyl N'-cyano-N-(2-(dimethylamino)-2-(thien-3-yl)ethyl)carbamide (140 mg, 0.44 mmol) and 6-bromo-1,2,3,4-tetrahydronaphthalene-2-amine hydrochloride (116 mg, 0.44 mmol) according to the above example, and the product was 92 mg of white solid, namely compound 8. Yield: 47.0%.

[0288] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.52(dd,J=4.8,2.9Hz,1H),7.34(d,J=2.0Hz,1H),7.30(s,1H),7.27(d,J= 8.4Hz,1H),7.05-7.03(m,2H),6.97-6.88(m,2H),6.67(s,1H),3.90-3.82(m,2H ),3.64-3.58(m,1H),3.44-3.40(m,1H),2.93(dd,J=16.2,4.6Hz,1H),2.81-2.7 7(m,2H),2.64-2.55(m,1H),2.03(s,6H),1.94-1.89(m,1H),1.73-1.65(m,1H).

[0289] MS(M+H) + :446

[0290] Example 9

[0291] (R)-N 1 , N 1 Dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine9

[0292]

[0293] Step 1: Preparation of (R)-2-(((R)-1-(4-methoxyphenyl)ethyl)amino)-2-(thiophen-3-yl)acetonitrile 9a

[0294] (R)-1-(4-methoxyphenyl)ethylamine hydrochloride (20g, 107mmol) was dissolved in a mixed solvent of methanol (50mL) and water (50mL), 3-thiophenecarboxaldehyde (10g, 89.3mmol) was added, and the mixture was stirred at room temperature for 15min. Then, a solution of NaCN (4.87g, 99.4mmol) in water (10mL) was added, and the reaction was stirred overnight at room temperature. TLC (PE:EA=10:1) showed that most of the raw materials disappeared and new spots were generated. After the reaction was completed, water (170mL) was added, stirred for 15min, filtered, and the filter cake was rinsed with clean water three times. The filter cake was dissolved in DCM (100mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was slurried with PE / EA (10 / 1, 200mL), filtered, and the product 21.1g of light yellow solid was obtained, with a yield of 86.8%.

[0295] 1 H NMR (400 MHz, CDCl 3 )δ:7.45-7.42(m,1H),7.37(d,J=8.6Hz,2H),7.34(dd,J=5.0,3.0Hz,1H),7.13(dd,J=5.0,0.9Hz,1H),6.91(d ,J=8.6Hz,2H),4.40(d,J=5.1Hz,1H),4.17(q,J=6.4Hz,1H),3.82(s,3H),1.81(s,1H),1.41(d,J=6.5Hz,3H).

[0296] MS(M+H) + :273

[0297] Step 2: Preparation of (R)-2-(((R)-1-(4-methoxyphenyl)ethyl)amino)-2-(thiophen-3-yl)acetamide hydrochloride 9b

[0298] (R)-2-(((R)-1-(4-methoxyphenyl)ethyl)amino)-2-(thiophen-3-yl)acetonitrile (8 g, 29.4 mmol) and potassium carbonate (8.1 g, 58.7 mmol) were dissolved in DMSO (80 mL), the internal temperature was kept below 20°C in an ice bath, and then H 2 O 2(33g), after addition, remove the ice bath and continue stirring at room temperature for 10min. LCMS shows that the raw material disappears and the product is generated. Add water (500mL) to dilute, extract with DCM (100mLx3), wash the combined organic phase with sodium bisulfite aqueous solution and saturated sodium chloride solution in turn, dry with anhydrous sodium sulfate, filter, concentrate about half of the solvent, add HCl / dioxane (4N) to adjust the pH value to 1, precipitate solid, filter by suction, and obtain 9.2g of white solid. The product is dissolved in ethanol (80mL), heated to 60℃ and stirred for 5min, cooled to room temperature, filtered by suction, and the filter cake is washed with a small amount of ethanol to obtain 5.7g of white solid. Yield: 66.8%.

[0299] 1 H NMR (400 MHz, DMSO-d 6 )δ:9.77(d,J=41.3Hz,2H),7.87(s,1H),7.66-7.59(m,3H),7.43(d,J=8.5Hz,2H),7.22(d,J=4.8Hz ,1H),7.02(d,J=8.6Hz,2H),4.54(d,J=7.3Hz,1H),4.25(s,1H),3.78(s,3H),1.60(d,J=6.6Hz,3H).

[0300] MS(M+H) + :291

[0301] Step 3: Preparation of (R)-2-(dimethylamino)-2-(thiophen-3-yl)acetamide 9d

[0302] Take (R)-2-(((R)-1-(4-methoxyphenyl)ethyl)amino)-2-(thiophen-3-yl)acetamide hydrochloride (3g, 9.2mmol) and TFA (15mL), stir evenly, heat to 65℃ and stir for 3h. Concentrate the reaction solution, dilute with water (35mL), extract with EA (30mLx2), and use the obtained aqueous phase directly in the next step. Take the above aqueous phase, add acetonitrile (30mL), add 37% HCHO (3g, 37mmol) under stirring at room temperature, stir at room temperature for 2min, and add NaBH(OAc) in batches. 3(6.1g, 27.6mmol), continue stirring at room temperature for 30min. LCMS shows that the starting material disappears and the product is generated. EA (40mLx3) is added for extraction, the combined organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (DCM: MeOH = 10:1) to obtain 1.14g of colorless gel, two-step yield: 67.8%. Chiral HPLC analysis: retention time 11.395min, chiral purity: >99% (chromatographic column: Chiralpak IC, IC00CE-UE048, 250mmLx4.6mm; mobile phase: n-hexane: isopropanol = 7:3 (containing 0.1% triethylamine)).

[0303] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.47-7.43(m,2H),7.38(dd,J=2.8,1.2Hz,1H),7.13(dd,J=5.0,1.0Hz,1H),7.03(s,1H),3.73(s,1H),2.09(s,6H).

[0304] MS(M+H) + :185

[0305] Step 4: (R)-N 1 , N 1 Preparation of dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine 9

[0306] (R)-2-(dimethylamino)-2-(thiophen-3-yl)acetamide (720 mg, 3.9 mmol) was dissolved in THF (10 mL). 2 After protection, place in an ice bath and slowly add 10N BH 3 / THF (4mL, 40mmol), after addition, heat to 65℃ and react overnight. LCMS shows that the raw material disappears and the product is generated. After the reaction is completed, methanol (15mL) is added to quench the reaction, and concentrated hydrochloric acid (1.5mL) is added. Stir at 60℃ for 2h, and then directly concentrate and dry. The crude product is dissolved in THF (7mL), saturated sodium bicarbonate aqueous solution (10mL) is added, the pH is adjusted to 8, and then (Boc) is added 2O (853 mg, 3.9 mmol), stirred at room temperature for 30 min. Diluted with water (10 mL), extracted with EA (30 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, column chromatography (DCM: MeOH = 20: 1), 618 mg waxy solid was obtained, two-step yield: 58.5%. Chiral HPLC analysis: retention time 4.488 min, chiral purity: 98.8% (chromatographic column: Chiralpak IC, IC00CE-UE048, 250 mmL x 4.6 mm; mobile phase: n-hexane: isopropanol = 7: 3 (containing 0.1% triethylamine)).

[0307] The above product (618 mg, 2.29 mmol) was dissolved in DCM (5 mL), and HCl / dioxane (3 mL, 12 mmol) was added and stirred at room temperature for 1 h. After the reaction was completed, the solvent was dried by spin drying. The product was obtained as 550 mg of light yellow solid, which was used directly in the next step.

[0308] MS(M+H) + :171

[0309] Example 10

[0310] (S)-N 1 , N 1 Dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine 10

[0311]

[0312] Step 1: Preparation of (S)-2-(((S)-1-(4-methoxyphenyl)ethyl)amino)-2-(thiophen-3-yl)acetonitrile 10a

[0313] The product was synthesized by using (S)-1-(4-methoxyphenyl)ethylamine hydrochloride (9.37 g, 50 mmol) according to the above example to obtain 7.9 g of off-white solid product with a yield of 56.2%.

[0314] 1 H NMR (400 MHz, CDCl 3 )δ:7.45-7.40(m,1H),7.37(d,J=8.6Hz,2H),7.33(dd,J=5.0,3.0Hz,1H),7.12(dd,J=5.0,1.0Hz,1H),6.91(d ,J=8.6Hz,2H),4.40(d,J=6.9Hz,1H),4.16(q,J=6.4Hz,1H),3.81(s,3H),1.81(s,1H),1.40(d,J=6.5Hz,3H).

[0315] MS(M+H) + :273

[0316] Step 2: Preparation of (S)-2-(((S)-1-(4-methoxyphenyl)ethyl)amino)-2-(thiophen-3-yl)acetamide hydrochloride 10b

[0317] The product was synthesized by using (S)-2-(((S)-1-(4-methoxyphenyl)ethyl)amino)-2-(thiophen-3-yl)acetonitrile (960 mg, 3.53 mmol) according to the above example. The product was obtained as 840 mg of a white solid. Yield: 65.7%.

[0318] 1 H NMR (400 MHz, DMSO-d 6 )δ:9.81(d,J=33.2Hz,2H),7.89(s,1H),7.67-7.58(m,3H),7.44(d,J=8.6Hz,2H),7.24(d,J=5.0Hz ,1H),7.01(d,J=8.6Hz,2H),4.56(d,J=6.8Hz,1H),4.25(s,1H),3.78(s,3H),1.60(d,J=6.7Hz,3H).

[0319] MS(M+H) + :291

[0320] Step 3: Preparation of (S)-2-(dimethylamino)-2-(thiophen-3-yl)acetamide 10d

[0321] (S)-2-(((S)-1-(4-methoxyphenyl)ethyl)amino)-2-(thiophen-3-yl)acetamide hydrochloride (2.63 g, 7.2 mmol) was used to synthesize the above example. 1.18 g of white solid was obtained, and the two-step yield was 80.1%. Chiral HPLC analysis: retention time 18.618 min, chiral purity: >99% (chromatographic column: Chiralpak IC, IC00CE-UE048, 250 mmLx4.6 mm; mobile phase: n-hexane:isopropanol=7:3 (containing 0.1% triethylamine)).

[0322] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.48-7.43(m,2H),7.39(d,J=2.8Hz,1H),7.13(dd,J=4.9,1.0Hz,1H),7.03(s,1H),3.73(s,1H),2.10(s,6H).

[0323] MS(M+H) + :185

[0324] Step 4: (S)-N 1 , N 1 Preparation of dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine 10

[0325] (S)-2-(dimethylamino)-2-(thiophen-3-yl)acetamide (500 mg, 2.72 mmol) was used to synthesize the above example. 470 mg of waxy solid was obtained, and the two-step yield was 58.5%. Chiral HPLC analysis: retention time 4.202 min, chiral purity: 97.5% (chromatographic column: Chiralpak IC, IC00CE-UE048, 250 mmLx4.6 mm; mobile phase: n-hexane: isopropanol = 7:3 (containing 0.1% triethylamine)).

[0326] The above product (470 mg, 1.74 mmol) was dissolved in DCM (4 mL), and HCl / dioxane (2.5 mL, 10 mmol) was added and stirred at room temperature for 1 h. After the reaction was completed, the solvent was dried by spin drying. The product was obtained as 380 mg of light yellow solid, which was used directly in the next step.

[0327] MS(M+H) + :171

[0328] Embodiment 11, 12

[0329] Resolution of 1,2,3,4-Tetrahydronaphthalene-2-amine

[0330]

[0331] Dissolve S-mandelic acid (3.64 g, 24 mmol) in ethanol (65 mL), then add 1,2,3,4-tetrahydronaphthalene-2-amine (3.52 g, 24 mmol), heat to 90°C and reflux, recrystallize twice to obtain the product (S)-1,2,3,4-tetrahydronaphthalene-2-amine S-mandelate salt as 2.21 g white solid, yield: 30.9%. [a] D 22 =-90.3(c 0.2,CHCl 3 )(Literature value is [a] D 22 =-84.5(c 0.54, CHCl 3)). Chiral HPLC analysis: retention time 10.005 min, chiral purity: >99% (chromatographic column: Chiralpak AD-H, ADH0CE-UI049, 250 mmL x 4.6 mm; mobile phase system, n-hexane: ethanol = 8:2 (containing 0.1% triethylamine)).

[0332] The above two batches of mother liquor were combined, most of the solvent was spun off, water (20 mL) and EA (50 mL) were added to dissolve, the pH was adjusted to 8-9 with aqueous potassium carbonate solution, EA (40 mL x 2) was extracted, the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.74 g of brown oil.

[0333] R-mandelic acid (2.83 g, 18.6 mmol) was dissolved in ethanol (30 mL), and then 1,2,3,4-tetrahydronaphthalene-2-amine (2.74 g, 18.6 mmol) was added, the temperature was raised to 90°C and refluxed, and water (1 mL) was added until it was completely dissolved. The product was crystallized once to obtain 2.9 g of white solid R-mandelate salt of (R)-1,2,3,4-tetrahydronaphthalene-2-amine, with a yield of 52%. Chiral HPLC analysis: retention time 10.323 min, chiral purity: >99% (chromatographic column: Chiralpak AD-H, ADH0CE-UI049, 250 mmLx4.6 mm; mobile phase system, n-hexane: ethanol = 8:2 (containing 0.1% triethylamine)).

[0334] Embodiment 13

[0335] 1-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-2-methyl-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 13

[0336]

[0337] Step 1: Preparation of 2-isothiocyanato-1,2,3,4-tetrahydronaphthalene 13a

[0338] Take 1,2,3,4-tetrahydronaphthalen-2-amine (260 mg, 1.77 mmol) and dissolve it in dry THF (5 mL), then add triethylamine (0.9 mL, 6.3 mmol). 2 After protection, place in an ice bath at 0°C. Add CS dropwise 2(0.13mL, 2.1mmol) in THF (5mL) solution, return to room temperature and react for 1h. TLC shows that the starting material disappears, the reaction solution is placed in an ice bath at 0℃ again, and acetyl chloride (0.15mL, 2.1mmol) is added dropwise, and the reaction solution is returned to room temperature and stirred for 1h. LCMS shows that the product is generated. After the reaction is completed, DCM (40mL) and water (20mL) are added, the organic phase is separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 330mg of yellow oil, yield: 99%.

[0339] MS(M+H) + :190

[0340] Step 2: Preparation of 1-methyl-3-(1,2,3,4-tetrahydronaphthalen-2-yl)thiourea 13b

[0341] 2-isothiocyanato-1,2,3,4-tetrahydronaphthalene (500 mg, 2.64 mmol) and methylamine hydrochloride (350 mg, 5.3 mmol) were dissolved in dry THF (15 mL), triethylamine (1.5 mL, 10.6 mmol) was added, and the temperature was raised to 60°C for 4 h. The mixture was cooled to room temperature, diluted with water (25 mL), extracted with DCM (30 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and column chromatography (EA:PE=1:1) was performed to obtain 460 mg of a yellow oil, with a yield of 78.9%.

[0342] MS(M+H) + :221

[0343] Step 3: Preparation of methyl-N-methyl-N'-(1,2,3,4-tetrahydronaphthalen-2-yl)imide carboxylic acid thioester 13c

[0344] 1-Methyl-3-(1,2,3,4-tetrahydronaphthalen-2-yl)thiourea (460 mg, 2.1 mmol) was dissolved in methanol (30 mL) and then N 2 After protection, CH 3 I (300 mg, 2.1 mmol), heated to 30 °C and reacted for 1 h. CH 3 I (300 mg, 2.1 mmol), reacted at 30 ° C for 6 h. LCMS showed that the starting material disappeared and the product was generated. After the reaction was completed, it was concentrated and dried. The crude product was dissolved in DCM (20 mL), and a saturated sodium bicarbonate aqueous solution was added to adjust the pH value to 9-10. The organic phase was separated, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and column chromatography (DCM: MeOH = 10: 1) to obtain 270 mg of a colorless oil, with a yield of 55.3%.

[0345] MS(M+H)+ :234

[0346] Step 4: Preparation of 1-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-2-methyl-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 13

[0347] Take methyl-N-methyl-N'-(1,2,3,4-tetrahydronaphthalen-2-yl)imide carboxylic acid thioester (124 mg, 0.53 mmol) and N 1 , N 1 Dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine (96 mg, 0.56 mmol) was dissolved in DMF (5 mL), and then triethylamine (0.16 mL, 1.12 mmol) was added. 2 After protection, the temperature was raised to 80°C and the reaction was continued for 5 hours. LCMS showed that a product was generated. After the reaction was completed, a saturated ammonium chloride solution (15 mL) was added to quench the reaction, and EA (30 mL x 2) was used for extraction. The mixture was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (MeOH: DCM = 1:5) to obtain 50 mg of a crude product. The product was prepared by HPLC and freeze-dried to obtain 9.2 mg of a white solid, namely compound 13. Yield: 5.2%.

[0348] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.55-7.52(m,1H),7.36(d,J=2.1Hz,1H),7.12-7.06(m,4H),7.04(d,J=5.0Hz,1H),3.89-3.66(m,4H),3.42(dd,J=14.1,5.0H z,1H),3.04-2.90(m,1H),2.87-2.79(m,2H),2.74(d,J=1.1Hz,3H),2.03(d,J=2.0Hz,6H),1.97-1.89(m,1H),1.78-1.70(m,1H).

[0349] MS(M+H) + :357

[0350] Embodiment 14

[0351] 1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-2-methoxy-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 14

[0352]

[0353] Step 1: Preparation of 1-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)thiourea 14a

[0354] 2-isothiocyanato-1,2,3,4-tetralin (117 mg, 0.59 mmol) and N 1 , N 1 Dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine hydrochloride (170 mg, 0.71 mmol) was dissolved in dry THF (6 mL), triethylamine (0.3 mL, 2.13 mmol) was added, and the mixture was stirred at room temperature for 2 h. Water (25 mL) was added for dilution, and DCM (30 mL x 3) was used for extraction. The combined organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (DCM: MeOH = 10: 1) to obtain 182 mg of a light yellow solid, with a yield of 71.4%.

[0355] 1 H NMR (400 MHz, CDCl 3 )δ:7.32(dd,J=4.6,3.0Hz,1H),7.14-7.07(m,5H),6.93(s,1H),6.46(s,1H),3.77-3.71(m,3H),3.25-3.21( m,1H),2.90(t,J=6.3Hz,2H),2.76-2.69(m,1H),2.16-2.12(m,1H),2.07(d,J=9.6Hz,6H),1.98-1.87(m,2H).

[0356] MS(M+H) + :360

[0357] Step 2: Preparation of 1-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-2-methoxy-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 14

[0358] 1-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)thiourea (182 mg, 0.51 mmol) was dissolved in methanol (6 mL) and then N 2 After protection, CH 3 A solution of I (72 mg, 0.51 mmol) in methanol (1 mL) was heated to 30 °C and reacted for 1 h. CH 3I (94 mg, 0.66 mmol), reacted at 30 ° C for 6 h. LCMS showed that the starting material disappeared and the product was generated. After the reaction was completed, the mixture was concentrated and dried. Prep-TLC chromatography (DCM: MeOH = 10: 1) gave methyl-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-N'-(1,2,3,4-tetrahydronaphthalen-2-yl)imide carboxylic acid thioester, i.e., the crude product of compound 14b, which was directly used in the next step.

[0359] The crude product of methyl-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-N'-(1,2,3,4-tetrahydronaphthalen-2-yl)imide carboxylic acid thioester (14b) and methoxyamine hydrochloride (220 mg, 2.7 mmol) were dissolved in acetonitrile (6 mL), and then triethylamine (0.55 mL, 4 mmol) was added. 2 After protection, the temperature was raised to 80°C and the reaction was continued for 5 hours. LCMS showed that a product was generated. After the reaction was completed, the product was concentrated and subjected to column chromatography (MeOH:DCM=1:6) to obtain 90 mg of a crude product, which was prepared by HPLC and freeze-dried to obtain 7.3 mg of a white solid, namely compound 14. Two-step yield: 3.8%.

[0360] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.49-7.46(m,1H),7.31-7.27(m,1H),7.07-6.98(m,5H),5.39-5. 31(m,1H),5.26-4.97(m,1H),4.76-3.80(m,1H),3.63-3.55(m,1H),3. 44(d,J=6.3Hz,3H),3.22-3.13(m,1H),3.07-3.01(m,1H),2.77-2.70(m,2H),2.61-2.52(m,1H),1.99(d,J=10.8Hz,6H),1.71-1.51(m,2H).

[0361] MS(M+H) + :373

[0362] Embodiment 15

[0363] 2-Cyano-1-((S)-2-(dimethylamino)-2-(thien-3-yl)ethyl)-3-(6-fluorochroman-3-yl)guanidine 15

[0364]

[0365] Step 1: Preparation of tert-butyl 6-fluoro-2H-chromene-3-carboxylate 15a

[0366] 5-Fluorosalicylaldehyde (5 g, 35.71 mmol) was added to N-methylpyrrolidone (25 mL) and stirred to dissolve. Anhydrous K 2 CO 3 (7.4g, 53.57mmol), tert-butyl acrylate (6.9g, 53.57mmol). Heat to 150℃ and stir for 3h. Monitor by TLC (EA:PE=1:10), the reaction is complete. Cool to room temperature, add water (150mL), extract twice with EA (150mL). Wash the organic layer once with saturated brine and dry with anhydrous sodium sulfate. Then separate by column (EA:PE=1:20) to obtain 3.66g waxy solid. Yield: 38.2%.

[0367] 1 H NMR (400 MHz, CDCl 3 )δ7.26(s,1H),6.90(td,J=8.5,3.0Hz,1H),6.84(dd,J=8.2,2.9Hz,1H),6.78(dd,J=8.8,4.5Hz,1H),4.92(d,J=1.0Hz,2H),1.52(s,9H).

[0368] Step 2: Preparation of tert-butyl 6-fluorochroman-3-carboxylate 15b

[0369] Add tert-butyl 6-fluoro-2H-chromene-3-carboxylate (3.66 g, 14.64 mmol) to methanol (40 mL) and stir to dissolve, then add water (1.5 mL) and 10% palladium carbon (732 mg, 50% water content). Add hydrogen at normal pressure and stir at room temperature overnight for about 16 h. Monitor by TLC (EA:PE=1:10), the reaction is complete. Filter and recover palladium carbon, concentrate the filtrate, then add DCM, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, add PE (30 mL) and stir for 30 min, filter, and dry to obtain 3.66 g of white solid. Yield: 99.2%.

[0370] Step 3: Preparation of 6-fluorochroman-3-carboxylic acid 15c

[0371] 6-Fluorochroman-3-carboxylic acid tert-butyl ester (3.66g, 14.52mmol), dichloromethane (30mL) was added, stirred to dissolve, and trifluoroacetic acid (10mL) was added. Stir at room temperature for 2 hours. TLC monitored the disappearance of the raw material (petroleum ether: ethyl acetate 10:1). The reaction solution was poured into (100mL) water and extracted three times with dichloromethane (30mL). The organic layer was washed once with saturated brine. Dry over anhydrous sodium sulfate. After concentration, petroleum ether (20mL) was added and stirred for 30 minutes. Filter and drain. 2.53g of white solid was obtained. Yield: 88.8%.

[0372] MS(M+H) + :197.

[0373] Step 4: Preparation of tert-butyl (6-fluorochroman)-3-carbamate 15d

[0374] Add tert-butyl alcohol (30 mL) to 6-fluorochroman-3-carboxylic acid (2 g, 10.20 mmol) and stir at room temperature to dissolve. Add DPPA (3.37 g, 12.24 mmol) and then add triethylamine (2.2 mL, 15.30 mmol). Heat to 85 °C and stir under reflux overnight for about 20 h. Monitor by TLC and LC-MS, the reaction is complete. After concentration, separate by column (EA: PE = 1: 20). Obtain 1.15 g of white solid, yield: 42%.

[0375] 1 H NMR (400 MHz, CDCl 3 )δ6.87-6.80(m,1H),6.80-6.76(m,1H),6.76-6.70(m,1H),4.97-4.75(m,1H),4.22-4.12(m ,1H),4.12-4.03(m,2H),3.08(dd,J=16.8,5.1Hz,1H),2.72(d,J=16.8Hz,1H),1.44(s,9H).

[0376] MS(M+H) + :268.

[0377] Step 5: Preparation of 6-fluorochroman-3-amine hydrochloride 15e

[0378] Add DCM (10 mL) to tert-butyl (6-fluorochroman)-3-carbamate (1.246 g, 4.7 mmol) and stir to dissolve. Add 4N HCl ethanol solution (5 mL). Stir at room temperature for 1-2 h. Monitor by TLC and LC-MS. The reaction is complete. After concentration, 954 mg of off-white solid is obtained. The yield is 100%.

[0379] MS(M+H) + :168.

[0380] Step 6: Preparation of phenyl N'-cyano-N-(6-fluorochroman-3-yl)carbamide ester 15f

[0381] 6-Fluorobenzodihydropyran-3-amine hydrochloride (300mg, 1.47mmol), acetonitrile (6mL) was added and stirred at room temperature, N-cyanocarbonyl imide diphenyl ester (357mg, 1.47mmol), triethylamine (0.65mL, 4.5mmol) were added, and stirred at room temperature for 1.5h. TLC and LC-MS monitoring showed that the reaction was complete. Water (20mL) was added and extracted with EA (20mL) three times. The organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. PE (10mL) was added and stirred for 30min. Filtered and dried to obtain 407mg of a white solid. Yield: 89%.

[0382] MS(M+H) + :312.

[0383] Step 7: Preparation of 2-cyano-1-((S)-2-(dimethylamino)-2-(thien-3-yl)ethyl)-3-(6-fluorochroman-3-yl)guanidine 15

[0384] (S)-N 1 , N 1 Dimethyl-1-(thiophene-3-yl)ethane-1,2-diamine dihydrochloride (120 mg, 0.494 mmol) was added to N,N-dimethylformamide (3 mL) and stirred at room temperature, and then phenyl N'-cyano-N-(7-fluorochroman-3-yl)carbamide (154 mg, 0.494 mmol) and triethylamine (0.35 mL, 2.47 mmol) were added. Stirred for 3 h at 80 ° C in an oil bath. After the reaction was completed, the temperature was cooled to room temperature, and water (20 mL) was added, and EA (10 mL) was extracted three times. The organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column (MeOH: DCM = 1: 20). 167 mg of light yellow viscous liquid was obtained. 70 mg of white solid, i.e., compound 15, was obtained by HPLC preparation and freeze drying, with a yield of 36.6%.

[0385] 1 H NMR (400 MHz, DMSO-d 6 )δ8.07(brs,1H),7.54-7.47(m,1H),7.34-7.25(m,1H),7.04-6.87(m,4H),6.84-6.76(m,1H),4.18-4.03(m,2H),4.00-3.88(m,1H),3.76 (td,J=8.3,4.4Hz,1H),3.67-3.54(m,1H),3.02(dd,J=16.8,5.2Hz,1H),2.83-2.69(m,1H),1.94(d,J=7.0Hz,6H),1.86(d,J=7.8Hz,1H).

[0386] MS(M+H) + :388.

[0387] Example 16

[0388] 4-(2-(dimethylamino)-2-(1-((2-nitro-1-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)vinyl)amino)cyclopropyl)ethyl)phenol 16

[0389]

[0390] Step 1: Preparation of 4-(2-(dimethylamino)-2-(1-((1-(methylthio)-2-nitrovinyl)amino)cyclopropyl)ethyl)phenyl trifluoromethanesulfonic acid 16a

[0391] 1,1-(Bismethylthio)-2-nitroethylene (240 mg, 1.46 mmol) and 4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (342 mg, 0.97 mmol) were dissolved in ethanol (10 mL), heated to 80°C and reacted for 16 h. The mixture was cooled to room temperature, concentrated, and column chromatographed (DCM / MeOH=15 / 1) to obtain 90 mg of a light yellow oily product with a yield of 20%.

[0392] MS(M+H)+:470

[0393] Step 2: Preparation of 4-(2-(dimethylamino)-2-(1-((2-nitro-1-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)vinyl)amino)cyclopropyl)ethyl)phenyl trifluoromethanesulfonate 16b

[0394] 4-(2-(dimethylamino)-2-(1-((1-(methylthio)-2-nitrovinyl)amino)cyclopropyl)ethyl)phenyl trifluoromethanesulfonate (90 mg, 0.19 mmol) and 1,2,3,4-tetrahydronaphthalen-2-amine (56 mg, 0.38 mmol) were dissolved in ethanol (10 mL), triethylamine (77 mg, 0.76 mmol) was added, and then the temperature was raised to 80° C. for 48 h. The mixture was cooled to room temperature, concentrated, and separated by preparative TLC (DCM / MeOH=15 / 1) to obtain 26 mg of the product as a light yellow oil, with a yield of 24%.

[0395] MS(M+H)+:569

[0396] Step 3: Preparation of 4-(2-(dimethylamino)-2-(1-((2-nitro-1-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)vinyl)amino)cyclopropyl)ethyl)phenol 16

[0397] 4-(2-(Dimethylamino)-2-(1-((2-nitro-1-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)vinyl)amino)cyclopropyl)ethyl)phenyl trifluoromethanesulfonate (30 mg, 0.053 mmol) was dissolved in THF / MeOH (4 mL, 1 / 1) and water (2 drops), and then NaOH (21 mg, 0.53 mmol) was added. The reaction was stirred at room temperature for 2 h. LCMS showed that the product was generated. After the reaction was completed, NH 4 The reaction was quenched with a saturated aqueous solution of Cl (10 mL), extracted with EA (15 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and prepared by HPLC and freeze-dried to obtain 7.8 mg of the product as a white solid, namely compound 16. Yield: 34%.

[0398] 1H NMR (400MHz, DMSO-d6) δ: 9.96 (d, J = 14.0Hz, 1H), 9.22 (s, 1H), 7.10 (s, 4H), 7. 01(t,J=7.7Hz,2H),6.69-6.61(m,3H),3.94-3.87(m,1H),3.12-3.01(m,2H),2 .91-2.82(m,3H),2.72-2.59(m,2H),2.25-2.23(m,1H),2.15(s,3H),2.08-2. 01(m,1H),1.80(s,3H),0.89-0.74(m,2H),0.48-43(m,1H),0.30-0.25(m,1H).

[0399] MS(M+H)+:437

[0400] Embodiment 17

[0401] 2-Cyano-1-((S)-2-(dimethylamino)-2-(thien-3-yl)ethyl)-3-(6-fluoro-1,2,3,4-tetrahydronaphthyridin-2-yl)guanidine single configuration 17

[0402]

[0403] Step 1: Chiral resolution of 6-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine

[0404] S-mandelic acid (925 mg, 6.08 mmol) was dissolved in ethanol (3 mL), and then 6-fluoro-1,2,3,4-tetrahydronaphthalene-2-amine (1 g, 6.08 mmol) was added, and the temperature was gradually raised to 85°C for reflux, and ethanol (2 mL) was added until it was completely dissolved, and the product was recrystallized six times to obtain 330 mg. Yield: 10%.

[0405] Chiral HPLC analysis: retention time 27.397 min, chiral purity: >99% (chromatographic column: Chiralpak AD-H, ADH0CE-UI049, 250 mmLx4.6 mm; mobile phase system, n-hexane:isopropanol=92:8 (containing 0.1% TFA).

[0406] Step 2: Preparation of phenyl N'-cyano-N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)carbamide (JH-82-16-S) 17b

[0407] Take 6-fluoro1,2,3,4-tetrahydronaphthalene-2-amine (S-mandelic acid resolution) (228 mg, 0.72 mmol) and add aqueous potassium carbonate solution (15 mL, 25%) and NaOH (2N, 1 mL), extract with DCM (20 mLx2), dry over anhydrous sodium sulfate, filter and concentrate to obtain 126 mg of colorless oil.

[0408] The above colorless oil (126 mg, 0.72 mmol) was dissolved in acetonitrile (5 mL), and N-cyanocarbonyl imide diphenyl ester (180 mg, 0.75 mmol) and triethylamine (0.21 mL, 1.5 mmol) were added. After addition, the mixture was stirred for 2 h at room temperature. LCMS showed that the raw material disappeared and the product was generated. Water (20 mL) was added for dilution, EA was extracted (20 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and separated by Flash column (PE / EA = 2 / 1) to obtain 160 mg of active ester (yield: 70%), which was used for the next step.

[0409] MS(M+H)+:310

[0410] Step 3: Preparation of 2-cyano-1-((S)-2-(dimethylamino)-2-(thien-3-yl)ethyl)-3-(6-fluoro-1,2,3,4-tetrahydronaphthyridin-2-yl)guanidine 17

[0411] (S)-N 1 , N 1Dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine hydrochloride (63 mg, 0.26 mmol) and (S)-phenyl N'-cyano-N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)carbamide (65 mg, 0.21 mmol) were dissolved in DMF (2 mL), triethylamine (104 mg, 1.03 mmol) was added, and the temperature was raised to 80 ° C for 3 h. LCMS showed that the raw material disappeared and the product was generated. Ammonium chloride aqueous solution (10 mL) and water (10 mL) were added, EA was extracted (15 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, prepared by HPLC, and freeze-dried to obtain a product of 30 mg of milky white solid, i.e., compound 17. Yield: 30%.

[0412] 1H NMR (400MHz, DMSO-d6) δ: 7.51 (dd, J=4.8, 2.9Hz, 1H), 7.33 (d, J=2.0Hz, 1H), 7.09 (dd, J=8.9 ,6.2Hz,1H),7.03(d,J=4.6Hz,1H),6.93-6.89(m,2H),6.70(s,1H),3.90(s,1H),3.82(dd,J= 8.8,5.2Hz,1H),3.63-3.56(m,1H),3.41-3.35(m,2H),2.93(dd,J=16.1,4.1Hz,1H),2.83-2 .77(m,2H),2.60(dd,J=16.0,9.5Hz,1H),2.01(s,6H),1.91-1.85(m,1H),1.72-1.62(m,1H).

[0413] MS(M+H)+:386

[0414] Embodiment 18

[0415] 2-Cyano-1-(1-((S)-1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 18

[0416]

[0417] Step 1: Resolution of 4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate

[0418] 5.6g of 4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate was dissolved in methanol and separated by chiral column. Separation conditions: Instrument: SHIMADZU LC-20; Chromatographic column: S-Chiral C, 7μm, 20*250mm; Mobile phase: n-hexane / ethanol / triethylamine 90 / 10 / 0.1; Flow rate: 25mL / min; Column temperature: 20℃; Detection wavelength: 220nm. 2.4g of (S)-4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (retention time 5.1min, ee%>95%) and 1.0g of (R)-4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (retention time 7.8min, ee%>95%) were obtained.

[0419] Step 2: Preparation of 4-((S)-2-(1-(2-cyano-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate 18b

[0420] (S)-4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (200 mg, 0.57 mmol) was added to 2.5 mL and stirred to dissolve, and single-configuration phenyl (R)-N'-cyano-N-(1,2,3,4-tetrahydronaphthalen-2-yl)carbamide ester (164 mg, 0.57 mmol) was added, and TEA (230 mg, 2.28 mmol) was added, and the mixture was stirred at 80°C for 3 h. The reaction was monitored by TLC and LC-MS, and the reaction was completed. Water (20 mL) was added, and DCM was extracted three times, washed twice with saturated brine, and anhydrous Na 2 SO 4 The product was dried and purified by silica gel column. EA:PE 30%. 228 mg of light yellow solid was obtained. Yield: 72.9%.

[0421] MS(M+H + ):550.

[0422] Step 3: Synthesis of 2-cyano-1-(1-((S)-1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 18

[0423] 4-((S)-2-(1-(2-cyano-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (114 mg, 0.21 mmol) was added to THF (2.5 mL) and stirred to dissolve. NaOH (83 mg, 2.1 mmol), water (0.4 mL) and methanol (2.5 mL) were added and stirred at room temperature for 2 h. The reaction was monitored by TLC and LC-MS. Saturated NH 4 Cl solution 50mL, EA extraction three times, saturated brine washing once, anhydrous Na 2 SO 4 The product was dried and concentrated. After preparation by HPLC and freeze-drying, 47 mg of the product was obtained as a white solid, namely compound 18. HPLC: 98.00%.

[0424] 1 H NMR (400 MHz, DMSO-d 6 )δ8.81(s,1H),7.30(s,1H),7.11-6.97(m,6H),6.63(d,J=8.3Hz,2H),4.11(s,1H),3.05(dd,J=16.5,4.7Hz,1H),2.86(dd,J=15.3,8.7Hz,2H),2 .79-2.59(m,4H),2.25-2.13(m,1H),1.89(s,6H),1.82-1.75(m,1H),0.8 4-0.76(m,1H),0.70-0.62(m,1H),0.61-0.53(m,1H),0.49-0.40(m,1H).

[0425] MS(M+H + ):418.

[0426] Embodiment 19

[0427] 2-Cyano-1-(1-((S)-1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 19

[0428]

[0429] The compound was synthesized from (S)-4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate and phenyl (S)-N'-cyano-N-(1,2,3,4-tetrahydronaphthalen-2-yl)carbamide according to the method of the above example.

[0430] 1 H NMR (400 MHz, DMSO-d6 )δ8.76(s,1H),7.27(s,1H),7.14-7.05(m,6H),6.64(d,J=8.4Hz,2H),3.98(s,1H),3.02(dd,J=16.3,4.7Hz,1H),2.87-2.75(m ,3H),2.71-2.61(m,2H),2.28(s,1H),2.11(s,6H),2.04-1.96(m,1H),1.83-1.72(m,1H),0.76-0.60(m,2H),0.53-0.39(m,2H).

[0431] MS(M+H + ):418.

[0432] Embodiment 20

[0433] (4-((S)-2-(1-(2-cyano-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl)boronic acid 20

[0434]

[0435] The product was synthesized from (S)-4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate and phenyl (S)-N'-cyano-N-(1,2,3,4-tetrahydronaphthalen-2-yl)carbamide according to the method of the previous example.

[0436] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.97(s,1H),7.66(d,J=7.8Hz,2H),7.33(s,1H),7.28(d,J=7.9Hz,2H ),7.08-7.06(m,5H),3.96(s,1H),3.00(dd,J=16.2,4.6Hz,1H),2.93-2.7 2(m,4H),2.64(dd,J=16.3,7.5Hz,1H),2.40-2.35(m,1H),2.10(s,6H),2. 01-1.95(m,1H),1.79-1.73(m,1H),0.77-0.58(m,2H),0.48-0.40(m,2H).

[0437] MS(M+H) + :446

[0438] Embodiment 21

[0439] (4-((S)-2-(1-(3-((R)-chroman-3-yl)-2-cyanoguanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl)boronic acid 21

[0440]

[0441] Step 1: Preparation of 21a of 4-((S)-2-(1-(3-((R)-chroman-3-yl)-2-cyanoguanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate

[0442] (S)-4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (100 mg, 0.28 mmol) and (R)-phenyl N-chroman-3-yl-N'-cyanocarbamide ester (105 mg, 0.36 mmol) ((R)-chroman-3-amine was prepared according to Example 6) were dissolved in DMSO (2.5 mL), triethylamine (59 mg, 0.59 mmol) was added, and then the temperature was raised to 80°C for 4 h. After cooling to room temperature, aqueous ammonium chloride solution (15 mL) was added, and EA was extracted (15 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and column chromatography (EA:PE=2:1) ​​was performed to obtain 110 mg of a colorless gel. Yield: 70%.

[0443] MS(M+H) + :552

[0444] Step 2: Preparation of 1-((R)-chroman-3-yl)-2-cyano-3-(1-((S)-1-(dimethylamino)-2-(4-(4,4,5,5-tetramethyl-5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)cyclopropyl)guanidine 21b

[0445] 4-((S)-2-(1-(3-((R)-chroman-3-yl)-2-cyanoguanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (110 mg, 0.20 mmol) was dissolved in dioxane (3 mL), and then pinacol diboron (76 mg, 0.30 mmol), Pd(dppf)Cl 2 (30 mg, 0.04 mmol) and potassium acetate (60 mg, 0.6 mmol) were placed in a microwave reactor (80 degrees, 100w, 1 h). After the reaction, the mixture was concentrated and subjected to column chromatography (EA:PE=2:1) ​​to obtain 90 mg of off-white solid, with a yield of 85%.

[0446] MS(M+H) + :530

[0447] Step 3: Preparation of (4-((S)-2-(1-(3-((R)-chroman-3-yl)-2-cyanoguanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl)boronic acid 21

[0448] 1-((R)-chroman-3-yl)-2-cyano-3-(1-((S)-1-(dimethylamino)-2-(4-(4,4,5,5-tetramethyl-5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)cyclopropyl)guanidine (90 mg, 0.17 mmol) was dissolved in THF (2 mL), and then diluted HCl (2N, 1 mL) was added, and the reaction was stirred at room temperature for 3 h. LCMS showed that most of the raw materials disappeared and products were generated. After the reaction was completed, it was directly concentrated and dried, and the product was prepared by HPLC and freeze-dried to obtain 43 mg of a white solid, namely compound 21. Yield: 56%.

[0449] 1 H NMR (400 MHz, DMSO-d 6 )δ:9.21(s,1H),8.04(s,2H),7.66(d,J=7.8Hz,2H),7.48(s,1H),7.27(d,J=7.8Hz,2H),7.0 9(t,J=7.7Hz,2H),6.85(t,J=7.4Hz,1H),6.79(d,J=8.0Hz,1H),4.18-4.12(m,J=11.7Hz,3H ),3.11(dd,J=16.5,4.2Hz,1H),2.87(dd,J=14.4,7.2Hz,1H),2.79-2.64(m,2H),2.28(s,1H ),1.98(s,6H),0.62-0.57(m,1H),0.53-0.49(m,1H),0.41-0.36(m,1H),0.34-0.29(m,1H).

[0450] MS(M+H) + :448

[0451] Embodiment 22

[0452] (4-((S)-2-(1-(3-((S)-chroman-3-yl)-2-cyanoguanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl)boronic acid 22

[0453]

[0454] Prepared according to the above example using (S)-phenyl N-chroman-3-yl-N'-cyanocarbamide ester as the starting material.

[0455] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.93(s,1H),8.11(s,1H),7.61(d,J=8.2Hz,1H),7.51(s,1H),7.24(d,J=8. 2Hz,1H),7.16(d,J=7.6Hz,1H),7.09-7.04(m,2H),6.83(t,J=7.4Hz,1H),6.78( d,J=8.0Hz,1H),4.22-4.01(m,3H),3.10(dd,J=16.7,4.6Hz,1H),2.86-2.63(m ,3H),2.22(s,1H),1.78(d,J=7.1Hz,6H),0.75-0.53(m,3H),0.43-0.33(m,1H).

[0456] MS(M+H) + :448

[0457] Embodiment 23

[0458] 2-Cyano-1-(1-((S)-1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)-3-(5-fluorochroman-3-yl)guanidine 23

[0459]

[0460] Step 1: Preparation of phenyl N'-cyano-N-(5-fluorochroman-3-yl)carbamide 23d

[0461] Synthesized using 2-fluoro-6-hydroxybenzaldehyde as the starting material according to the method of Example 15e

[0462] MS(M+H) + :312

[0463] Step 2: Preparation of 4-((2S)-2-(1-(2-cyano-3-(5-fluorochroman-3-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate 23e

[0464] (S)-4-(2-(1-aminocyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (103 mg, 0.29 mmol) and phenyl N'-cyano-N-(5-fluorochroman-3-yl)carbamide (100 mg, 0.37 mmol) were dissolved in DMSO (2 mL), triethylamine (65 mg, 0.64 mmol) was added, and then the temperature was raised to 80°C for 3 h. After cooling to room temperature, aqueous ammonium chloride solution (15 mL) was added, and EA was extracted (15 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and column chromatography (EA:PE=2:1) ​​was performed to obtain 90 mg of a yellow oil. Yield: 54%.

[0465] MS(M+H) + :570

[0466] Step 3: Preparation of 2-cyano-1-(1-((S)-1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)-3-(5-fluorochroman-3-yl)guanidine 23

[0467] 4-((2S)-2-(1-((E)-2-cyano-3-(5-fluorochroman-3-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl trifluoromethanesulfonate (90 mg, 0.16 mmol) was dissolved in THF / MeOH (4 mL, 1 / 1) and water (2 drops), and then NaOH (64 mg, 1.6 mmol) was added. The reaction was stirred at room temperature for 2 h. After the reaction was completed, NH 4 The reaction was quenched with a saturated aqueous solution of Cl (5 mL), extracted with EA (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and prepared by HPLC and freeze-dried to obtain 47 mg of the product as a white solid. Yield: 68.1%.

[0468] 1 H NMR (400 MHz, DMSO-d 6)δ:9.34(s,1H),8.99(s,1H),7.49(d,J=20.9Hz,1H),7.14(dd,J=15.4,7.9Hz,1H),7.08 -7.05(m,2H),6.76-6.72(m,1H),6.71-6.66(m,1H),6.64-6.60(m,2H),4.125-4.15(m,2H ),4.11(t,J=11.4Hz,1H),2.99(dt,J=16.6,4.5Hz,1H),2.80-2.68(m,2H),2.66-2.59(m ,1H),2.22-2.12(m,1H),2.00(s,3H),1.80(s,3H),0.71-0.58(m,2H),0.55-0.28(m,2H).

[0469] MS(M+H) + :438

[0470] Embodiment 24

[0471] 2-Cyano-1-(1-((S)-1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)-3-(8-fluorochroman-3-yl)guanidine 24

[0472]

[0473] The synthesis was carried out according to the above Example 23 using 3-fluoro-2-hydroxybenzaldehyde as the starting material.

[0474] 1 H NMR (400 MHz, DMSO-d 6 )δ9.40-8.93(m,2H),7.48(d,J=23.8Hz,1H),7.10-7.05(m,,2H),7.05-7.0 0(m,1H),6.96-6.92(m,1H),6.87-6.80(m,1H),6.50-6.59(m,2H),4.29-4. 21(m,2H),4.20-4.09(m,1H),3.21-3.08(m,1H),2.82-2.68(m,2H),2.67-2 .58(m,1H),2.22-2.10(m,1H),1.99(s,3H),1.79(s,3H),0.72-0.26(m,4H).

[0475] MS(M+H) + :438

[0476] Embodiment 25

[0477] 2-Cyano-1-(3-((dimethylamino)(thiophen-3-yl)methyl)pentan-3-yl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 25

[0478]

[0479] Step 1: 2-Ethyl N 1 , N 1 Preparation of dimethyl-1-(thiophen-3-yl)butane-1,2-diamine (JH-77-16) 25a

[0480] 2-(Dimethylamino)-2-(thiophen-3-yl)acetonitrile (513 mg, 3.1 mmol) was dissolved in dry THF (10 mL), stirred at -70 °C, and Ti(O i Pr) 4 (1.08g, 3.72mmol), then ethylmagnesium bromide (13mL, 13mmol) was added dropwise to the above-mentioned reaction solution at -70℃. After the addition, the mixture was returned to room temperature and reacted for 2h. Then water (3mL) was added dropwise under ice bath to quench the reaction, EA (20mL) was added to dilute, pH was adjusted to 1-2 with HCl (1N), and the separated aqueous phase was adjusted to pH 10-11 with NaOH (5N), extracted with EA (20mLx3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was mixed with silica gel and column chromatography (MeOH:DCM=1:15) was performed to obtain 170mg of the product as a light yellow solid, with a yield of 24.3%.

[0481] MS(M+H) + :227

[0482] Step 2: Preparation of 2-cyano-1-(3-((dimethylamino)(thiophen-3-yl)methyl)pentan-3-yl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 25

[0483] 2-Ethyl N 1 , N 1 Dimethyl-1-(thiophen-3-yl)butane-1,2-diamine and phenyl-N′-cyano-N-(1,2,3,4-tetrahydronaphthalen-2-yl)carbamide ester were synthesized according to the method of the above example.

[0484] 1 H NMR (400 MHz, DMSO-d 6)δ:7.44(dd,J=7.2,4.0Hz,1H),7.31(s,1H),7.14-7.12(m,1H),7.08-7.04(m,4H),6.5 9(s,1H),5.24(d,J=4.6Hz,1H),3.87-3.80(m,1H),3.75(d,J=9.6Hz,1H),2.96(dd,J=16 .4,4.5Hz,1H),2.84-2.73(m,2H),2.57-2.53(m,1H),2.06(s,3H),2.02(s,3H),1.94-1 .91(m,1H),1.81-1.76(m,2H),1.69-1.60(m,2H),1.50-1.41(m,1H),0.77-0.68(m,6H).

[0485] MS(M+H) + :424

[0486] Embodiment 26

[0487] Preparation of (4-((S)-2-(1-(2-cyano-3-((S)-1,2,3,4-tetrahydro-naphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl)boronic acid p-toluenesulfonate

[0488]

[0489] (4-((S)-2-(1-(2-cyano-3-((S)-1,2,3,4-tetrahydro-naphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl)boronic acid (6.7 mg, 0.015 mmol) was dissolved in DCM (1 mL), and a solution of p-toluenesulfonic acid (2.85 mg, 0.015 mmol) in THF (0.6 mL) was added and stirred for 1 h. The solvent was concentrated by rotary evaporation, and EA (0.3 mL) and n-hexane (3 mL) were added for slurrying. 9.1 mg of white solid, i.e., compound 26, was obtained. Yield: 98.3%.

[0490] 1 H NMR (400 MHz, DMSO-d 6)δ:9.06(s,1H),8.02(s,2H),7.76(d,J=7.6Hz,2H),7.45(d,J=8.0Hz,2H),7.34(d, J=7.7Hz,2H),7.28(s,1H),7.10-7.07(m,6H),4.05-3.95(m,1H),3.55-3.49(m,1H) ,3.16-3.04(m,2H),3.00-2.70(m,10H),2.27(s,3H),2.03-1.94(m,1H),1.85-1.75 (m,1H),1.20-1.12(m,1H),1.02-0.97(m,1H),0.89-0.81(m,1H),0.79-0.72(m,1H).

[0491] Embodiment 27

[0492] Preparation of (4-((S)-2-(1-((2-cyano-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl)borate disodium salt

[0493]

[0494] (4-((S)-2-(1-(2-cyano-3-((S)-1,2,3,4-tetrahydro-naphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl)boronic acid (16.3 mg, 0.036 mmol) was placed in an eggplant-shaped bottle, water (3 mL) was added, and then an aqueous NaOH solution (0.2 mmol / mL, 0.36 mL) was added and stirred for 1 h. The solvent was concentrated by rotary evaporation, EA (0.3 mL) was added, and n-hexane (3 mL) was used for slurrying to obtain 17.2 mg of a white solid, i.e., compound 27. Yield: 96%.

[0495] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.80-7.65(m,2H),7.53(d,J=6.9Hz,1H),7.30-7.20(s,1H),7.06-6.94(m,7H),3.98- 3.75(m,2H),2.85-2.73(m,5H),2.28-2.06(m,8H),2.01-1.93(m,1H),0.65-0.35(m,4H).

[0496] Embodiment 28

[0497] 4-((S)-2-(1-(2-cyano-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(dimethylamino)ethyl)phenyl acetate

[0498]

[0499] 2-Cyano-1-(1-((S)-1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine (43) (50 mg, 0.12 mmol) was dissolved in DCM (0.5 mL) and pyridine (20 mg, 0.24 mmol) was added. Then acetic anhydride (12 mg, 0.12 mmol) was added and the reaction was stirred at room temperature for 1 h. Acetic anhydride (8 mg, 0.08 mmol) was added and the stirring was continued for 2 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted with EA (20 mL x 3). The organic phases were combined, washed once with saturated ammonium chloride solution (20 mL), washed once with saturated sodium bicarbonate solution (20 mL), washed once with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated on a preparative TLC plate (MeOH:DCM=1:20) to obtain 50 mg of a light yellow solid. Yield: 90%. The product was prepared again as 27 mg of white solid, namely compound 28. Yield: 49.0%.

[0500] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.63(s,1H),7.34(d,J=8.2Hz,3H),7.06(s,4H),6.98(d,J=8.0Hz,2H), 3.96(s,1H),3.04-2.95(m,1H),2.92-2.79(m,3H),2.75(dd,J=14.3,6.5Hz ,1H),2.63(dd,J=16.2,7.5Hz,1H),2.34(s,1H),2.21(s,3H),2.10(s,6H), 2.01-1.94(m,1H),1.78-1.73(m,1H),0.71-0.63(m,2H),0.45-0.40(m,2H).

[0501] MS(M+H) + :460.

[0502] Embodiment 29

[0503] 4-((S)-2-(1-(2-cyano-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidino)cyclopropyl)-2-(phosphodimethylamino)ethyl)phenyldihydro

[0504]

[0505] 2-Cyano-1-(1-((S)-1-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)cyclopropyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine (43) (112 mg, 0.27 mmol) was dissolved in DCM (3 mL), and triethylamine (55 mg, 0.54 mmol) was added. Then phosphorus oxychloride (60 mg, 0.41 mmol) was added and the reaction was stirred at room temperature for 1 h. NaHCO was added 3 Aqueous solution (3 mL) was stirred at room temperature for 40 min. Then, the pH value was adjusted to about 3-4 with HCl (1 N) and stirred at room temperature for 2 h. The low boiling point solvent was then spun off and the remaining mother liquor was directly separated by preparative HPLC. The product was obtained as 20 mg of white solid, i.e., compound 29. Yield: 15.5%.

[0506] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.50(s,1H),7.21(d,J=8.0Hz,2H),7.06-7.02(m,5H),4.00(s,1H),2.98-2.82(m,5H),2.74-2. 70(m,1H),2.48(s,6H),2.31-2.28(m,1H),2.01-1.96(m,1H),1.78-1.70(m,1H),0.95-0.55(m,4H).

[0507] MS(M+H) + :498.

[0508] Embodiment 30

[0509] Preparation of 2-cyano-1-(1-((1S)-1-(dimethylamino)-2-(1H-indazol-5-yl)ethyl)cyclopropyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine

[0510]

[0511] Step 1: Preparation of tert-butyl (1-((1S)-1-amino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)cyclopropyl)carbamate (30a)

[0512] Dissolve tert-butyl 1-(1-amino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)cyclopropyl)carbamate (2.9 g, 7.24 mmol) (5f) in 20 mL of a mixed solvent of EtOH:MeCN=1:9. Slowly drop a mixed solution of L-(-)-di-p-methoxybenzoyltartaric acid in EtOH:MeCN=1:9 to the solution under stirring at room temperature. Stir at room temperature for 20 minutes to produce a large amount of white solid. Raise the temperature to 80°C and continue stirring for 30 minutes. Cool the suspension to room temperature within 30 minutes, filter and dry to obtain a white solid. Recrystallize the white solid twice using 20 mL of a mixed solvent of EtOH:MeCN=1:9 according to the above operation to obtain 1.8 g of a white solid. Place the white solid in a single-mouth bottle, add 30 mL of dichloromethane, and slowly add 1N NaOH aqueous solution to adjust the pH to 8-9. The aqueous phase was extracted with DCM, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 800 mg of a white solid with a yield of 28% and ee% = 93%. (CHIRALPAK AD-H, (n-hexane: ethanol = 4:1) + 0.1% TEA, 1 mL / min).

[0513] MS(M+H) + :401.

[0514] Step 2: Preparation of 2-cyano-1-(1-((1S)-1-(dimethylamino)-2-(1H-indazol-5-yl)ethyl)cyclopropyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine (30)

[0515] The synthesis method of 30a to 30 is the same as that of Example 1.

[0516] 1 H NMR (400 MHz, DMSO-d 6 )δ12.90(s,1H),8.69(s,1H),7.94(s,1H),7.68(s,1H),7.40(d,J=8.5Hz,1H),7. 35(s,1H),7.29(d,J=8.6Hz,1H),7.06(s,4H),3.96(s,1H),3.05-2.90(m,2H),2. 90-2.74(m,3H),2.63(dd,J=16.3,7.5Hz,1H),2.39(s,1H),2.12(s,6H),2.03-1. 92(m,1H),1.87(s,1H),1.82-1.70(m,1H),0.78-0.56(m,2H),0.47-0.33(m,2H).

[0517] MS(M+H)+ :442.

[0518] Embodiment 31

[0519] 2-Cyano-1-(1-(1-((S)-1-(dimethylamino)-2-(1H-indol-5-yl)ethyl)cyclopropyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine

[0520]

[0521] Step 1: Synthesis of tert-butyl 5-formyl-1H-indole-1-carboxylate (31a)

[0522] 5-Indolecarboxaldehyde (4.42 g, 30.5 mmol) was dissolved in DCM (70 mL), DMAP (370 mg, 0.3 mmol) was added, and (Boc) was added. 2 O (7.0 g, 32 mmol) was stirred at room temperature for 1 h. The raw material point disappeared under TLC monitoring (PE:EA=3:1), and the reaction was completed. DCM (50 mL) was added, washed with 0.5 N hydrochloric acid (50 mL*1), and saturated NaHCO 3 The solution was washed (50 mL*1), dried over anhydrous sodium sulfate, and concentrated to obtain 8.4 g of a crude product. Yield: 100%.

[0523] MS(M+H) + :246

[0524] Step 2: Synthesis of tert-butyl 5-(hydroxymethyl)-1H-indole-1-carboxylate (31b)

[0525] 5-Formyl-1H-indole-1-carboxylic acid tert-butyl ester (8.2 g, 33.47 mmol) was added to THF (50 mL) and stirred to dissolve. Then MeOH (20 mL) was added and the mixture was cooled to 0-5°C in an ice-water bath under nitrogen protection. NaBH 4 (400 mg, 10.52 mmol), remove the ice bath after addition, stir at room temperature for 1 h, TLC monitoring (PE:EA = 3:1) shows that the raw material point disappears, and the reaction is complete. 4 Cl aqueous solution (50 mL), then add water (20 mL), stir at room temperature for 5-10 min, extract with EA (70 mL*3), wash with saturated brine (50 mL*1), dry over anhydrous sodium sulfate, and purify by column chromatography (PE:EA=3:1) to obtain 7.24 g of colorless oily liquid, with a yield of 85.4%.

[0526] MS(M+H) + :248

[0527] 1 H NMR (400 MHz, CDCl 3 )δ8.11(d,J=7.7Hz,1H),7.63-7.51(m,2H),7.30(d,J=8.4Hz,1H),6.55(d,J=2.9Hz,1H),4.76(s,2H),1.67(s,9H).

[0528] Step 3: Synthesis of tert-butyl 5-(bromomethyl)-1H-indole-1-carboxylate (31c)

[0529] 5-(Hydroxymethyl)-1H-indole-1-carboxylic acid tert-butyl ester (4.3 g, 17.4 mmol) was prepared according to the method of Example 1b to obtain 5.144 g of light yellow viscous liquid. The yield was 95.6%.

[0530] Step 4: Synthesis of tert-butyl 5-(2-cyano-2-(((diphenylmethylene)amino)ethyl)-1H-indole-1-carboxylate (31d)

[0531] Tert-butyl 5-(bromomethyl)-1H-indole-1-carboxylate was prepared according to the method of Example 1c. Yield: 99%.

[0532] MS(M+H) + :450

[0533] 1 H NMR (400 MHz, CDCl 3 )δ8.00(d,J=8.1Hz,1H),7.65-7.58(m,2H),7.55(d,J=3.4Hz,1H),7.46-7.30(m,6H),7.26(d,J=4.2Hz,1H),7.01(dd,J=8.5,1.4H z,1H),6.81(d,J=6.9Hz,2H),6.46(d,J=3.6Hz,1H),4.44(dd,J=7.9,6.2Hz,1H),3.31(ddd,J=21.4,13.5,7.1Hz,2H),1.65(s,9H).

[0534] Step 5: tert-Butyl 5-(2-(1-(aminocyclopropyl)-2-)(((diphenylmethylene)amino)ethyl)-1H-indole-1-carboxylate (31e)

[0535] Tert-butyl 5-(2-cyano-2-(((diphenylmethylene)amino)ethyl)-1H-indole-1-carboxylate (5.9 g, 13.14 mmol) was prepared according to the method of Example 1d to obtain 3.6 g, yield: 57.2%.

[0536] MS(M+H) + :480

[0537] Step 6: Synthesis of tert-butyl 5-(2-(1-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-2-((diphenylmethylene)amino)ethyl)-1H-indole-1-carboxylate (31f)

[0538] Tert-butyl 5-(2-(1-(aminocyclopropyl)-2-)(((diphenylmethylene)amino)ethyl)-1H-indole-1-carboxylate (3.6 g, 7.5 mmol) was prepared according to the method of Example 1e to give 2.066 g, yield: 47.5%.

[0539] MS(M+H) + :580

[0540] 1 H NMR (400 MHz, CDCl 3 )δ7.90(d,J=7.4Hz,1H),7.53(d,J=8.5Hz,3H),7.42-7.14(m,6H),7.06(d,J=7.0Hz,2H),6.92(d,J=8.4Hz,1H),6.39(d,J=3.5Hz,1H) ,6.24(s,1H),3.26(s,1H),3.18(d,J=12.9Hz,1H),3.07-2.95(m,1H),1.65(s,9H),1.41(s,9H),1.05(s,1H),0.70(d,J=10.9Hz,3H).

[0541] Step 7: Synthesis of tert-butyl 5-(2-amino-2-(1-(((tert-butoxycarbonyl)amino)cyclopropyl)ethyl)-1H-indole-1-carboxylate (31 g)

[0542] Tert-butyl 5-(2-(1-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-2-((diphenylmethylene)amino)ethyl)-1H-indole-1-carboxylate (2.06 g, 3.56 mmol) was prepared according to the synthetic method of Example 1f to give 1.55 g of an off-white solid. Yield: 100%.

[0543] MS(M+H) + :416

[0544] Step 8: (S)-tert-butyl 5-(2-amino-2-(1-(((tert-butoxycarbonyl)amino)cyclopropyl)ethyl)-1H-indole-1-carboxylate (31h)

[0545] 5-(2-amino-2-(1-(((tert-butoxycarbonyl)amino)cyclopropyl)ethyl)-1H-indole-1-carboxylic acid tert-butyl ester (1.5 g, 3.6 mmol) was separated according to the method of Example 30a to obtain 480 mg of white solid (S)-5-(2-amino-2-(1-(((tert-butoxycarbonyl)amino)cyclopropyl)ethyl)-1H-indole-1-carboxylic acid tert-butyl ester L-(-)-di-p-methoxybenzoyl tartrate. Yield: 40.2%, ee.: 99%.

[0546] Chiral HPLC analysis conditions:

[0547] Instrument: Agilent 1100

[0548] Chromatographic column: CHIRALPAK IC, 4.6mm*250mm, 5.0μm,

[0549] Mobile phase: (n-hexane: ethanol = 4:1) + 0.1% TEA isocratic elution

[0550] Flow rate: 1mL / min

[0551] Detection wavelength: 220nm

[0552] Step 9: Synthesis of (S)-tert-butyl 5-(2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-2-(dimethylamino)ethyl)-1H-indole-1-carboxylate (31i)

[0553] 10% K was added to tert-butyl (S)-5-(2-amino-2-(1-(((tert-butoxycarbonyl)amino)cyclopropyl)ethyl)-1H-indole-1-carboxylate L-(-)-di-p-methoxybenzoyl tartrate (400 mg, 0.48 mmol). 2 CO 3 The aqueous solution (20 mL) was stirred, EA (10 mL) was added and stirred until the solid dissolved, the layers were separated, the aqueous layer was extracted with EA (20 mL*2), the EA layers were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, and concentrated to obtain 200 mg of a colorless viscous liquid. MeCN (2 mL), water (1 mL), and 37% formaldehyde solution (190 mg, 2.4 mmol) were added to the viscous liquid and stirred at room temperature, and NaBH(OAc) was added. 3 (306 mg, 1.44 mmol) was stirred at room temperature for 10 min, and the reaction was completed under TLC monitoring (DCM:MeOH=10:1). Saturated NaHCO 3 The solution (15 mL) was extracted with EA (15 mL*3), washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, and concentrated to obtain 210 mg of a light yellow viscous liquid. The yield was 98.3%.

[0554] MS(M+H) + :444

[0555] Step 10: Synthesis of (S)-1-(1-(dimethylamino)-2-(1H-indol-5-yl)ethyl)cyclopropylamine (31j)

[0556] Dissolve (S)-tert-butyl 5-(2-(1-(((tert-butoxycarbonyl)amino)cyclopropyl)-2-(dimethylamino)ethyl)-1H-indole-1-carboxylate (180 mg, 0.41 mmol) in DCM (2 mL), add TFA (1 mL) under stirring at room temperature, stir at room temperature for 2.5 h, monitor by LC-MS, and the reaction is complete. Add ice water (15 mL), extract with DCM (10 mL*1), and add 20% K 2 CO 3 Adjust pH to 12, add sodium chloride to saturation, extract with THF (10 mL*5), dry over anhydrous sodium sulfate overnight, filter, and concentrate the filtrate to obtain 104 mg of a yellow viscous crude product.

[0557] MS(M+H) + :244

[0558] Step 11: 2-Cyano-1-(1-(1-((S)-1-(dimethylamino)-2-(1H-indol-5-yl)ethyl)cyclopropyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine (31)

[0559] (S)-1-(1-(Dimethylamino)-2-(1H-indol-5-yl)ethyl)cyclopropylamine (63j) (100 mg, 0.41 mmol) was prepared according to the preparation method of Example 1 to obtain 30 mg of white solid, namely compound 31, with a yield of 16.6%.

[0560] MS(M+H) + :441

[0561] 1 H NMR (400 MHz, DMSO-d 6)δ10.91(s,1H),8.78(s,1H),7.44(s,1H),7.33-7.19(m,3H),7.12-6.95(m ,5H),6.30(s,1H),3.96(s,1H),3.03-2.90(m,2H),2.87-2.76(m,3H),2.62( dd,J=16.3,7.4Hz,1H),2.39(s,1H),2.11(s,6H),1.97(s,1H),1.75(dd,J= 12.7,7.4Hz,1H),0.72(s,1H),0.61(d,J=4.7Hz,1H),0.42(d,J=8.5Hz,2H).

[0562] Embodiment 32

[0563] 2-Cyano-1-(1-(1-(dimethylamino)-2-(3,5-dichloro-4-hydroxyphenyl)ethyl)cyclopropyl)-3-(S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine

[0564]

[0565] Step 1: Preparation of 4-(tert-butyldimethylsilyloxy)-3,5-dichloro-benzoic acid methyl ester 32c

[0566] Dissolve 4-hydroxy-3,5-dichloro-benzoic acid methyl ester (5g, 22.6mmol) in DCM (50mL), cool to 0℃, add imidazole (3.85g, 56.5mmol) and stir for 5 minutes, then add tert-butyldimethylsilyl chloride (4.69g, 31.1mmol). Stir at room temperature for 2 hours, TLC detection reaction is complete, add water (50mL) to quench the reaction, and stir for 5 minutes. Separate the organic phase and extract with DCM, combine the organic phases, wash with water and saturated brine in turn, and dry over anhydrous sodium sulfate. After concentration, filter with a silica gel short column, rinse with EA:PE=1:10 mixed solution (250mL), and concentrate the filtrate to obtain 8.3g of yellow oily crude product, which is directly used in the next step without further purification.

[0567] The crude product of 4-(tert-butyldimethylsilyloxy)-3,5-dichloro-benzoic acid methyl ester was dissolved in anhydrous THF (80mL), cooled to 0°C, and a THF solution of lithium aluminum tetrahydride (9.0mL, 2.5M, 22.6mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature and reacted for 30 minutes. TLC detected that the reaction was complete, the reaction system was cooled to 0°C, and sodium sulfate decahydrate solid was slowly added until no bubbles were generated, followed by EA (50mL) and water (100mL), and stirred for 10 minutes. The organic phase was separated, and the aqueous phase was extracted twice with EA. The organic phases were combined, washed with water and saturated brine respectively, and dried over anhydrous sodium sulfate. After filtration and concentration, 7.62g of yellow oily crude product was obtained, and the crude product was directly used in the next step without separation.

[0568] The crude product of 1-(4-(tert-butyldimethylsilyloxy)-3,5-dichloro-phenyl)methanol was dissolved in DCM (80 mL) and N 2 After protection, Ph 3 P (7.40 g, 28.2 mmol) and NBS (5.02 g, 28.2 mmol) were stirred at room temperature for one hour. The reaction was complete after TLC detection, the solvent was dried, and column chromatography (100% PE) was used to separate 5.95 g of light yellow liquid. The three-step yield was 71%.

[0569] 1 H NMR (400 MHz, CDCl 3 )δ:7.29(s,2H),4.36(s,3H),1.05(s,9H),0.29(s,6H).

[0570] Step 2: Preparation of 2-((benzhydryl)amino)-3-(4-(tert-butyldimethylsilyloxy)-3,5-dichloro-phenyl)propionitrile 32d

[0571] Dissolve dibenzylideneaminoacetonitrile (3.23 g, 14.7 mmol) in THF (40 mL) and add N 2 After protection, the mixture was stirred at -78°C, and LDA (15.4 mL, 7.7 mmol, 2.0 M in THF) was slowly added dropwise, followed by a solution of (4-(bromomethyl)-2,6-dichlorophenoxy)tert-butyldimethylsilane (5.71 g, 15.4 mmol) in THF (20 mL). The mixture was naturally heated to 0°C and stirred for 1 hour. The reaction was complete by TLC detection, and a saturated ammonium chloride solution (50 mL) was added to quench the reaction. The organic phase was separated, and the aqueous phase was extracted twice with EA. The organic phases were combined, washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After filtration and concentration, the mixture was separated by column chromatography (EA:PE=1:5) to obtain 4.6 g of a white solid with a yield of 58.6%.

[0572] 1 H NMR (400 MHz, CDCl 3 )δ:7.58(d,J=7.5Hz,2H),7.55-7.40(m,4H),7.35(t,J=7.4Hz,2H),6.99(s,2H),6.91( s,2H),4.36(t,J=6.8Hz,1H),3.11(d,J=6.8Hz,2H),1.02(s,9H),0.25(d,J=3.0Hz,6H).

[0573] MS(M+H) + :509.

[0574] Step 3: Preparation of tert-butyl (1-(1-((diphenylmethylene)amino)-2-(4-(tert-butyldimethylsilyloxy)-3,5-dichloro-phenyl)-ethyl)cyclopropyl)carbamate 32f

[0575] 2-((Benzhydryl)amino)-3-(4-(tert-butyldimethylsilyloxy)-3,5-dichloro-phenyl)propionitrile (4.4 g, 8.63 mmol) was dissolved in dry THF (20 mL). 2 Under protection, the temperature was lowered to -78°C. Ti(O i Pr) 4 (2.70 g, 9.51 mmol), then slowly add ethylmagnesium bromide (19 mL, 19 mmol, 1.0 M in THF). After the addition, the reaction system was returned to room temperature and stirred for 1 hour. The reaction system was cooled to 0°C and BF 3 E 2 O (2.45g, 17.2mmol), return to room temperature and stir for 1 hour. LCMS shows that the raw material reacts completely and the product is generated. Saturated sodium bicarbonate solution is added to quench the reaction (50mL). The organic phase is separated, the aqueous phase is extracted twice with EA, the organic phases are combined, washed with water and saturated brine respectively, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product of 32e is obtained as a yellow oil. The crude product of 32e is dissolved in ethanol (30mL), di-tert-butyl dicarbonate (2.2g, 10.1mmol) is added, and stirred overnight. TLC detection shows that the reaction is complete. After the solvent is dried, column chromatography is performed (EA:PE=1:20) to obtain 1.4g of a light yellow solid, with a two-step yield of 25.3%.

[0576] 1H NMR (400MHz, CDCl 3)δ:7.53(d,J=7.4Hz,2H),7.38-7.25(m,6H),6.85(s,2H),6.47(s,2H),5.17(s,1H),3.19(s,1H),3.0 5-2.90(m,1H),2.89–2.75(m,1H),1.45(s,9H),1.03(s,10H),0.71(s,3H),0.25(s,3H),0.23(s,3H).

[0577] MS(M+H) + :639.

[0578] Step 4: Preparation of tert-butyl (1-(1-(dimethylamino)-2-(4-(tert-butyldimethylsilyloxy)-3,5-dichloro-phenyl)ethyl)cyclopropyl)carbamate 32h

[0579] Dissolve tert-butyl (1-(1-((diphenylmethylene)amino)-2-(4-(tert-butyldimethylsilyloxy)-3,5-dichloro-phenyl)-ethyl)cyclopropyl)carbamate (1.4 g, 2.19 mmol) in methanol (10 mL), add potassium acetate (279 mg, 2.85 mmol) and hydroxylamine hydrochloride (160 mg, 2.30 mmol) to the reaction solution in sequence, and stir at room temperature for 20 minutes. TLC detection shows that the reaction is complete, and sodium bicarbonate solution (10 mL) is added to quench the reaction, and EA (20 mL x 3) is used for extraction, and the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 32 g of crude product. 32 g of the crude product was dissolved in a mixed solvent of acetonitrile (10 mL) and water (5 mL), cooled to 0 °C, and 37% formaldehyde aqueous solution (888 mg, 11.0 mmol) and NaBH(OAc) were added to the reaction solution in sequence. 3 (1.4 g, 6.57 mmol), stirred at room temperature for 30 minutes. LCMS showed that the raw material disappeared and the product was generated. Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution to quench the reaction, and DCM (10 mL x 2) was used for extraction. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, column chromatography (DCM: MeOH = 10: 1) was used to separate 882 mg of a light yellow oil, with a two-step yield of 80%.

[0580] 1H NMR (400MHz, CDCl 3)δ:7.17(s,2H),5.10–4.90(m,2H),2.81(s,2H),2.45(s,6H),1.53–1.42( m,12H),1.04(s,6H),0.91(s,2H),0.77(s,1H),0.47(s,1H),0.27(s,6H).

[0581] MS(M+H) + :503.

[0582] Step 5: Preparation of 1-(1-(dimethylamino)-2-(4-hydroxy-3,5-dichloro-phenyl)ethyl)cyclopropylamine hydrochloride 32i

[0583] Dissolve tert-butyl (1-(1-(dimethylamino)-2-(4-(tert-butyldimethylsilyloxy)-3,5-dichloro-phenyl)ethyl)cyclopropyl)carbamate (480 mg, 0.953 mmol) in DCM (3 mL), add a solution of hydrochloric acid in dioxane (4N, 3 mL) to the reaction solution, and stir at room temperature for 1 hour. LCMS shows that the reaction of the raw materials is complete and the product is generated. The solvent is dried to obtain 1-(1-(dimethylamino)-2-(4-hydroxy-3,5-dichloro-phenyl)ethyl)cyclopropylamine.

[0584] MS(M+H) + :403.

[0585] Step 6: Preparation of 2-cyano-1-(1-(1-(dimethylamino)-2-(4-hydroxy-3,5-dichloro-phenyl)ethyl)cyclopropyl)-3-(S-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine 32

[0586] 1-(1-(dimethylamino)-2-(4-hydroxy-3,5-dichloro-phenyl)ethyl)cyclopropylamine (160 mg, 0.396 mmol) and phenyl N'-cyano-N-(S)-(1,2,3,4-tetrahydronaphthalen-2-yl)carbamide ester (127 mg, 0.436 mmol) were dissolved in DMSO (2.5 mL), triethylamine (80 mg, 0.792 mmol) was added to the reaction solution, and the temperature was raised to 80 ° C for 2 hours. LCMS detection showed that the product was generated, and saturated ammonium chloride solution (25 mL) was added to quench the reaction (25 mL), and the aqueous phase was extracted with DCM (15 mL x 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, column chromatography separation (EA: PE = 1: 1) was obtained to obtain 84 mg of a white solid, which was prepared by HPLC and freeze-dried to obtain 34 mg of a white solid, i.e., compound 32. Yield: 14.3%.

[0587] 1H NMR (400MHz, DMSO-d6) δ: 8.62 (d, J = 31.5Hz, 1H), 7.39 (d, J = 11.9Hz, 1H), 7. 33(d,J=4.5Hz,2H),7.07(s,4H),4.02(d,J=52.7Hz,2H),3.07–2.93(m,2H) ,2.88–2.57(m,4H),2.23(d,J=37.4Hz,1H),2.11(s,3H),1.87(s,3H),1.77 (d,J=6.6Hz,2H),0.79(s,1H),0.72–0.59(m,1H),0.54(s,1H),0.40(s,1H).

[0588] MS(M+H) + :486.

[0589] Embodiment 33:

[0590] 2-Cyano-1-(1-(1-(dimethylamino)-2-(4-hydroxy-3,5-dimethylphenyl)ethyl)cyclopropyl)-3-(S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine

[0591]

[0592] The synthesis was carried out according to the route of Example 32 above using (4-(bromomethyl)-2,6-dimethylphenoxy)tert-butyldimethylsilane as the starting material.

[0593] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.79(d,J=25.7Hz,1H),7.26(d,J=10.0Hz,1H),7.09(s,4H),6.82(d,J=7.2Hz,2H),4.04(d,J=52.3Hz,1H),3.03(t,J=12.3Hz,1H),2.84( s,2H),2.78–2.55(m,4H),2.27(d,J=37.0Hz,2H),2.11(s,9H),1.89(s ,3H),1.78(d,J=6.8Hz,1H),0.88–0.61(m,2H),0.48(d,J=29.1Hz,2H).

[0594] MS(M+H) + :446.

[0595] Embodiment 34:

[0596] Synthesis of (S)-2-cyano-1-(2,3-dihydro-1H-indan-2-yl)-3-(1-(1-(1-dimethylamino)-2-(1H-indazol-5-yl)ethyl)cyclopropyl)guanidine

[0597]

[0598] (S)-1-(1-(dimethylamino)-2-(1H-indazol-5-yl)ethyl)cyclopropylamine (100 mg, 0.41 mmol) and phenyl N'-cyano-N-(2,3-dihydro-1H-indan-2-yl)carbamate (102 mg, 0.37 mmol) were prepared according to the above Example 1 to obtain a white solid: 40 mg. Purification by preparative liquid phase gave a white solid: 12 mg, yield: 7%.

[0599] 1 H NMR (400 MHz, DMSO-d 6 )δ12.92(s,1H),9.16(s,1H),7.95(s,1H),7.67(s,1H),7.43-7.36(m,2H),7.29( s,1H),7.27-7.24(m,2H),7.17-7.13(m,2H),4.45-4.36(m,1H),3.27-3.16(m,2H ),2.98-2.90(m,1H),2.86-2.81(m,1H),2.80-2.71(m,2H),2.37(s,1H),1.89(s, 6H),0.81-0.74(m,1H),0.69-0.61(m,1H),0.55-0.48(m,1H),0.47-0.38(m,1H).

[0600] MS(M+H) + :428.

[0601] Embodiment 35:

[0602] 2-Cyano-1-(1-(1-(dimethylamino)-2-(4-hydroxy-3-(trifluoromethyl)phenyl)-1-(dimethylamino)ethyl)cyclopropyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)guanidine

[0603]

[0604] The synthesis was carried out according to the route of Example 32 using (4-(bromomethyl)-2-(trifluoromethyl)phenoxy)tert-butyldimethylsilane as the starting material.

[0605] 1 H NMR (400 MHz, DMSO-d6 )δ8.65(d,J=31.9Hz,2H),7.43-7.31(m,3H),7.07(s,3H),6.88(s,1H),4.03(d,J=51.7Hz,1H),2.99(d,J=13.5Hz,1H),2.82(s,3H),2.75-2. 60(m,2H),2.26(d,J=37.9Hz,1H),2.10(s,3H),1.96(s,1H),1.87(s,3 H),1.77(d,J=6.3Hz,1H),0.81(s,1H),0.74-0.50(m,2H),0.42(s,1H).

[0606] MS(M+H) + :486

[0607] Biological evaluation

[0608] Test Example 1: MOR cAMP agonist activity screening experiment

[0609] 1.1 Experimental Purpose

[0610] This experiment is to test the agonist effect of compounds on MOR. 50 The in vitro activity of the compounds was evaluated by the size of Emax.

[0611] 1.2 Experimental methods

[0612] MOR activated by compounds can regulate the level of intracellular cAMP. Using HTRF (Homogeneous Time-Resolved Fluorescence) technology, the cAMP detection kit of Cisbio can be used to detect the level of cAMP in hMOR cells after compound stimulation. The detection principle of the cAMP detection kit is based on the competition method. The kit contains Eu-labeled cAMP antibody and d2-labeled cAMP. The antibody can recognize cAMP and bring Eu and d2 close. After Eu is excited, its energy can be resonantly transferred to d2 to generate a signal. When cAMP is produced in the cell, it competes with d2-labeled cAMP for binding to the antibody binding site, increasing the distance between the latter and Eu, making it impossible to generate energy transfer, and thus the signal decreases. Based on the experimental signal data, the cAMP stimulating effect of the test compound on hMOR can be analyzed.

[0613] 1.3 Experimental Materials

[0614]

[0615]

[0616] 1.4 Experimental procedures

[0617] Compound formulation

[0618] The compound samples were first dissolved in DMSO to a storage concentration of 30 mM. A sample dilution series was prepared on a 384-well LDV plate (Labcyte #LP-0200), with the starting concentration point of 2 mM, 3.162-fold gradient dilution, and a total of 11 concentration points; the sample dilution series was transferred to a 384-well experimental plate (Corning, #3824) using an Echo machine, with 50 nL transferred to each well; 50 nL of positive control or negative control was transferred to the corresponding position of the 384-well experimental plate using an Echo machine.

[0619] Compounds agonistic effect on MOR

[0620] Prepare the assay buffer (Assay Buffer: 1x HBSS (+ / +), containing 20mM HEPES) and stimulator buffer (Stimulation Buffer: 3μM NKH477, 200μM IBMX dissolved in assay buffer) required for the experiment. Add 5μL of stimulator buffer to each well of the 384-well assay plate (with 50nL of compound in the well), and then add 5μL of cell suspension (suspended in assay buffer), with 10,000 cells / well; place the assay plate in a 5% carbon dioxide, 37 degrees Celsius constant temperature incubator for 40 minutes. During the incubation period, prepare the cAMP standard concentration curve assay plate, with the first concentration point at 2848nM, 4-fold gradient dilution, a total of 16 test concentrations, and 3 replicates for each concentration point. After the incubation is completed, add cAMP detection reagent (Cisbio #62AM4PEJ) to the test sample test plate and the cAMP standard concentration curve test plate: first add 5 μL / well D2 reagent, then add 5 μL / well Cryptate reagent. Then let the test plate stand at room temperature and read on Envision after 60 minutes.

[0621] Test Example 2: MORβ-arrestin agonist activity screening experiment

[0622] 2.1 Experimental Purpose

[0623] This experiment is to test the agonist effect of compounds on MORβ-arrestin. 50 The size of Emax was used to evaluate the in vitro activity of the compound.

[0624] 2.2 Experimental methods

[0625] The μ-opioid receptor (MOR) and β-arrestin expressed by the cells used in this experiment were labeled with partial amino acid fragments of β-galactosidase. When the MOR receptor was activated by the compound and recruited β-arrestin, the amino acid fragments of β-galactosidase carried by both were able to form a complete and active β-galactosidase. Therefore, the stimulatory effect of the compound on MORβ-arrestin can be evaluated by detecting the fluorescence intensity produced by the hydrolysis of the substrate by β-galactosidase.

[0626] 2.3 Experimental Materials

[0627]

[0628] 2.4 Experimental procedures

[0629] Compound formulation

[0630] The compound samples were dissolved in DMSO to a storage concentration of 30 mM; a sample dilution series was prepared on a 384-well LDV plate (Labcyte #LP-0200), with a starting concentration of 2 mM, 3.162-fold gradient dilution, and a total of 11 concentration points; the sample dilution series was transferred to a 384-well experimental plate (PerkinElmer, #6007680) using an Echo machine, with 100 nL transferred to each well; 100 nL of positive control or negative control was transferred to the corresponding position of the 384-well experimental plate using an Echo machine.

[0631] Compounds agonistic effect on MORβ-arrestin

[0632] Prepare the detection reagent (Path Hunter Detection Reagent) required for the experiment. The preparation method refers to the instructions of the Path Hunter kit, Galacton Star: Emerald II: PathHunter Cell Assay Buffer = 1:5:19. Suspend the cells with DPBS solution, and add 20μL of MOR beta-arrestin cell suspension to each well of the 384-well experimental plate (100nL of compound in the well), with 7500 cells / well, and incubate at room temperature in the dark for 2 hours. Then add 6μL / well of detection reagent to the 384-well experimental plate and incubate at room temperature in the dark for 1 hour. After incubation, read the reading on Envision.

[0633] Test Case 1 and Test Case 2 Results: The data read from the above two tests are processed by software and EC is calculated 50, Emax% value; Emax% is the maximum effect of the compound on activating cAMP and β-arrestin signaling pathways (with DAMGO as 100%); the "Bias Factor" is calculated according to the formula provided in reference Cell.2017171(5):1165-1175.

[0634] Table 1

[0635]

[0636]

[0637] Conclusion: The compounds provided by the present invention retain excellent G protein pathway agonist activity, while having low agonist activity on the β-Arrestin 2 signaling pathway, and the "Bias Factor" is significantly increased by 1-3 orders of magnitude compared with the classical MOR biased ligands PZM21 and TRV130.

[0638] Test Example 3: Pharmacokinetics of the compounds of the present invention in mice

[0639] Experimental method: Healthy male C57 mice were randomly divided into groups, 3 mice in each group, and the test compound was intravenously injected at a dose of 10 mg / kg. Each test compound was dissolved in physiological saline to prepare a solution of a certain concentration for administration. Fasting but not drinking water for 12-14 hours one day before administration, and feeding 4 hours after administration. 0.030 mL of blood was collected from each animal through the eye socket each time, and EDTAK 2 Anticoagulation, collection time points are 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after administration of the test substance. Blood samples were placed on ice after collection and centrifuged within 30 minutes to separate plasma (centrifugation conditions: 5000 rpm, 10 minutes, 4°C). Stored at -80°C before analysis.

[0640] Test Example 3 results: see Table 2 below.

[0641] Table 2

[0642]

[0643] Conclusion: The compounds provided by the present invention have excellent metabolic characteristics. Compared with the control PZM21, the plasma exposure (AUC) was greatly increased, the clearance rate (CL) was reduced by 3-10 times, and the half-life (T 1 / 2 )extend.

[0644] Test Example 4: hERG potassium channel inhibition experiment of the compounds of the present invention

[0645] 4.1 Experimental Purpose

[0646] The blocking effect of the compounds of the present invention on hERG potassium current was tested using fully automated patch clamp on a stable cell line transfected with hERG potassium channel.

[0647] 4.2 Experimental Methods

[0648] 4.2.1 Cell preparation

[0649] CHO-hERG cells were cultured at 175 cm 2 When the cell density in the culture flask grows to 60-80%, remove the culture medium, wash once with 7 ml PBS (Phosphate Buffered Saline), and then add 3 ml Detachin for digestion.

[0650] After digestion is complete, add 7 ml of culture medium to neutralize, then centrifuge, remove the supernatant, and add 5 ml of culture medium to resuspend to ensure that the cell density is 2-5×10 6 / ml.

[0651] 4.2.2 Solution preparation

[0652]

[0653] 4.2.3 Electrophysiological recording process

[0654] The single cell high impedance sealing and whole cell pattern formation process are all completed automatically by the Qpatch instrument. After obtaining the recording mode, the cell is clamped at -80 mV. Before giving a 5-second +40 mV depolarizing stimulus, a 50-millisecond -50 mV pre-voltage is given, and then repolarized to -50 mV for 5 seconds, and then returned to -80 mV. This voltage stimulus is applied every 15 seconds. After recording for 2 minutes, the extracellular solution is given for 5 minutes, and then the drug administration process begins. The compound concentration starts from the lowest test concentration, and each test concentration is given for 2.5 minutes. After all concentrations are given continuously, the positive control compound 3μM Cisapride is given. At least 3 cells (n≥3) are tested for each concentration.

[0655] 4.2.4 Compound preparation

[0656] The 20 mM compound stock solution was diluted with extracellular fluid, 5 μL of the 20 mM compound stock solution was added to 2495 μL of extracellular fluid, diluted 500 times to 40 μM, and then serially diluted 3 times in the extracellular fluid containing 0.2% DMSO to obtain the final concentration to be tested.

[0657] The highest tested concentration was 40 μM, followed by 6 concentrations including 40, 13.33, 4.44, 1.48, 0.49, and 0.16 μM.

[0658] The DMSO content in the final test concentration did not exceed 0.2%, and this concentration of DMSO had no effect on the hERG potassium channel.

[0659] 4.3 Data Analysis

[0660] The experimental data were analyzed by XLFit software.

[0661] 4.4 Experimental Results

[0662] Compound 17 22 PZM21 Cispride <![CDATA[IC 50 (μM)]]> 9.4 21.4 2-4 0.043

[0663] Conclusion: The hERG potassium channel inhibitory activity of the compounds provided by the present invention is significantly lower than the literature value reported for PZM21 [IC 50 2 to 4 μM, Nature. 2016 537(7619):185-190], with a lower risk of cardiotoxicity.

[0664] Test Example 5: In vivo analgesic experiment of the compound of the present invention (Hot Plate experiment)

[0665] 5.1 Compounds and Animals

[0666] Morphine was diluted with 0.9% saline, and other test compounds were prepared with 5% DMSO and 5% Solutol HS-15 and then diluted with 0.9% saline. Adult male Swiss mice weighing 18–25 g were used as experimental animals and administered subcutaneously.

[0667] 5.2 Experimental methods

[0668] Experimental Methods Reference Journal of Ethnopharmacology 196:151-159, pain reflexes in response to heat stimulation by hot plates were measured using a YLS-6B intelligent hot plate analgesia instrument (Device Station, Shandong Academy of Medical Sciences, Shandong, China). The hot plate surface was heated to a constant temperature of 50 ± 0.1 °C, measured by a built-in digital thermometer with an accuracy of 0.1 °C. During the experiment, mice were placed on the hot plate surrounded by a transparent acrylic cage, and the start / stop button on the timer was activated. The researchers measured the latency of the hind paw licking or jumping (the action that occurred first) (Paw Lick Latency).

[0669] 5.3 Experimental Results

[0670] like Figure 1As shown, compared with the blank control group (Vehicle), at the same dose, Example Compound 30 (codenamed JH-77-14-SS) and Example Compound 19 (codenamed JH-75-45-AB) significantly prolonged the latency of the mouse hind paw licking at 0.5h after injection, and the maximum extension range reached 99.0% and 60.8%, respectively, which were significantly higher than the 42.9% of the positive control PZM21 (codenamed JH-28-234). In addition, Example Compound 30 (codenamed JH-77-14-SS) also showed a longer analgesic time than morphine.

[0671] Conclusion: In the mouse hot plate test (Hot Plate), the analgesic effect of the compound provided by the present invention is better than that of PZM21.

[0672] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound represented by formula (I) or its meso form, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, Ring A is selected from the following group: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 4-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; the substitution refers to substitution by one or more substituents selected from the following group: hydrogen, hydroxyl, halogen, -B(OH)2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkyloxy, -OC(O)R 5 and G is selected from the following group: CR 7 R 8 and NR 2 ; R 2 Selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy and cyano; R 3 and R 4 Each is independently selected from the following group: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, or R 3 and R 4 The carbon atoms to which they are attached are closed to form a 3-6 membered cycloalkyl group; R 5 Selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy; Each R 6 are the same or different and are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy and halogen; R 7 and R 8 The same or different, and each independently selected from the following group: H, NO2, C1-C6 alkyl, halogenated C1-C6 alkyl; n is 0, 1, 2 or 3; q is 0, 1, 2, 3, or 4; Z is selected from the following group: NR 11 , O, S and CR 9 R 10 ; R 9 , R 10 , R 11 Each is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy and cyano; t is 0, 1, 2, or 3.

2. The compound of formula (I) according to claim 1, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from the following group: G is selected from the group consisting of CHNO2 and NR 2 ; Each R 1 are the same or different and are each independently selected from the following group: hydrogen, hydroxyl, halogen, -B(OH)2, C1-C6 alkyl, -CF3, -OC(O)R 5 and R 2 Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy and cyano; R 3 and R 4 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R 3 and R 4 The carbon atoms to which they are attached are closed to form a 3-6 membered cycloalkyl group; R 5 is hydrogen or C1-C6 alkyl; Each R 6 are the same or different and are each independently selected from the group consisting of hydrogen, C1-C6 alkyl and halogen; m is 0, 1, 2, 3, 4 or 5; n is 0 or 1; q is 0, 1, 2, 3, or 4; Z is selected from the group consisting of O and CH2; t is 0, 1, or 2.

3. The compound of formula (I) according to claim 1 or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is a substituted C6-C10 aryl group, wherein the substitution refers to substitution by m substituents selected from the group consisting of hydrogen, hydroxyl, halogen, -B(OH)2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy, -OC(O)R 5 and m is 0, 1, 2, 3, 4 or 5; G is selected from the following group: CR 7 R 8 and NR 2 ; R 2 Selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy and cyano; R 3 and R 4 Each is independently selected from the following group: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, or R 3 and R 4 The carbon atoms to which they are attached are closed to form a 3-6 membered cycloalkyl group; R 5 Selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy; Each R 6 are the same or different and are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy and halogen; R 7 and R 8 The same or different, and each independently selected from the following group: H, NO2, C1-C6 alkyl, halogenated C1-C6 alkyl; n is 0, 1, 2 or 3; q is 0, 1, 2, 3, or 4; Z is selected from the following group: NR 11 , O, S and CR 9 R 10 ; R 9 , R 10 , R 11 Each is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy and cyano; t is 0, 1, 2, or 3.

4. The compound of formula (I) according to claim 1, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is a substituted or unsubstituted 4-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; the substitution refers to substitution by one or more substituents selected from the following group: hydrogen, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy; G is selected from the following group: CR 7 R 8 and NR 2 ; R 2 Selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy and cyano; R 3 and R 4 Each is independently selected from the following group: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, or R 3 and R 4 The carbon atoms to which they are attached are closed to form a 3-6 membered cycloalkyl group; Each R 6 are the same or different and are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy and halogen; R 7 and R 8 The same or different, and each independently selected from the following group: H, NO2, C1-C6 alkyl, halogenated C1-C6 alkyl; n is 0, 1, 2 or 3; q is 0, 1, 2, 3, or 4; Z is selected from the following group: NR 11 , O, S and CR 9 R 10 ; R 9 , R 10 , R 11 Each is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkoxy and cyano; t is 0, 1, 2, or 3.

5. The compound of formula (I) according to claim 4, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from the following group:

6. The compound of formula (I) according to claim 1, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The compound or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt is selected from the following group:

7. A pharmaceutical composition, characterized in that It comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more compounds of formula (I) according to claim 1 or their racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

8. A method for preparing the compound of formula (I) according to claim 1 or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The method is selected from the group consisting of: Method 1: including the steps: (i-1) the compound represented by formula A or its salt, the compound represented by formula B or its salt, and Reaction to obtain a compound of formula I-1, wherein the reaction order of the compound of formula A or its salt and the compound of formula B or its salt can be interchanged; Among them, Ring A, G, R 3 , R 4 , R 6 , Z, t, q, n as described in claim 1; M is selected from the group consisting of -S-(C1-C6 alkyl), -O-(C6-C10 aryl); Method 2: including the following steps: (ii-1) reacting the compound represented by formula A or a salt thereof with the compound represented by formula C or a salt thereof to obtain the compound represented by formula I-2; Among them, Ring A, R 2 , R 3 , R 4 , R 6 , Z, t, q, n as described in claim 1; M is selected from the group consisting of -S-(C1-C6 alkyl), -O-(C6-C10 aryl); Method 3: including the following steps: (iii-1) reacting the compound represented by formula D or a salt thereof with the compound represented by formula E or a salt thereof to obtain a compound represented by formula I-3; Among them, Ring A, R 3 , R 4 , R 6 , Z, t, q, n as described in claim 1; M is -S-(C1-C6 alkyl); Q is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy.

9. Use of a compound of formula (I) according to claim 1 or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Used for preparing a medicament for preventing and / or treating pain or pain-related diseases.

10. The use according to claim 9, characterized in that The pain or pain-related disease is a pain disease associated with MOR receptors.

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