Arylalkylamine compounds, processes for their preparation and uses thereof

Abstract

The present application relates to arylalkylamine compounds, and preparation methods and uses thereof, the arylalkylamine compounds of the present application have the following formula (I): wherein X, Y are as defined in the specification. The compounds of the present application have excellent CaSR agonistic activity, high bioavailability, high in vivo metabolic stability, and high safety.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and in particular relates to an arylalkylamine compound, a preparation method thereof and a use of the arylalkylamine compound in allosteric agonism of a calcium-sensing receptor (Cacium-sensing receptor, CaSR). BACKGROUND

[0002] Chronic kidney disease (CKD) is a kidney disease caused by various reasons leading to kidney damage or decreased kidney function, which can cause a series of compensatory diseases, and secondary hyperparathyroidism (SHPT) is a common complication, which is clinically manifested as mineral metabolism abnormalities such as calcium and phosphorus, elevated parathyroid hormone (PTH), parathyroid hyperplasia and adenoma, various bone diseases and cardiovascular calcification, etc. According to the statistical data of the seventeenth "World Kidney Day" in 2022, 10% of the world's population suffers from CKD, and it is expected to rise to 17% in 10 years. SHPT is the third largest endocrine gland disease in the world, and has gradually become a common and frequently-occurring disease that seriously affects human health.

[0003] PTH is a basic single-chain polypeptide hormone secreted by parathyroid chief cells. Its main function is to mobilize bone calcium into blood, promote the reabsorption of calcium ions and the excretion of phosphate in the renal tubules, increase the concentration of blood calcium, and decrease the concentration of blood phosphorus. The main target organs of its action are bone and kidney.

[0004] CaSR belongs to the C family of G protein-coupled receptors (GPCRs), and the CaSR distributed on the parathyroid cells can sense the extracellular Ca 2+ concentration, negatively feedback regulate the secretion and synthesis of PTH, and further regulate the concentration of calcium and phosphorus in blood.

[0005] At present, the methods for treating SHPT at home and abroad mainly include hemodialysis, phosphorus binding agents, vitamin D drugs, calcium mimetic drugs and surgical operation. However, hemodialysis, phosphorus binding agents, vitamin D drugs and surgical operation have the disadvantages of high cost, narrow treatment window, incomplete treatment, easy recurrence and intolerance, etc., while calcium mimetic drugs directly act on CaSR, can effectively control the synthesis and secretion of PTH, and further continuously and stably control the calcium and phosphorus levels of patients, thus having more clinical advantages.

[0006] In the 1990s, NPS Pharmaceuticals developed NPS R-568 (WO9602492 A1) from Fendiline, a calcium antagonist drug for treating angina pectoris, which has good in vitro activity and safety. However, due to its low oral bioavailability (<5%) and easy in vivo metabolic inactivation, it was forced to terminate the phase II clinical study stage (Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6 [J]. Pharmacogenetics. 2001, 11:573-585). NPS Pharmaceuticals successfully developed the first calcimimetic drug, Cinacalcet hydrochloride (US 6011068 A), to overcome the shortcomings of NPS R-568. It was approved for marketing in the United States in March 2004 and in Japan in October 2007. Although Cinacalcet hydrochloride has good therapeutic effects, it has the disadvantages of low bioavailability (<20%), causing hypocalcemia, strong CYP2D6 inhibition, and severe upper gastrointestinal adverse reactions, such as an upper gastrointestinal adverse reaction rate of up to 60%, with a proportion of nausea and vomiting of more than 30% (Calcimimetic and calcilytic drugs for treating bone and mineral-related disorders [J]. Best Practice & Research Clinical Endocrinology & Metabolism. 2013, 27:373-384). These shortcomings limit the improvement of its clinical treatment dose. Mitsubishi Tanabe Pharma Co., Ltd. successfully developed the calcimimetic drug Evocalcet (WO2005115975) to overcome the shortcomings of Cinacalcet hydrochloride. It was first approved for marketing in Japan in March 2018. According to the Evocalcet review report, its adverse reactions mainly include hypocalcemia, vomiting, nausea, chills, QT prolongation, mood disorders, arrhythmia, blood pressure drop, and spasm (Orkedia tablet 1 mg, same tablet 2 mg review result report. March 2018).

[0007]

[0008] With the aggravation of population aging in China, the number of patients with SHPT is increasing, and this part of patients needs to take calcium mimetic drugs for long-term maintenance treatment. However, the existing drugs have low oral bioavailability and are easy to be metabolized in vivo, and there are some adverse reactions, such as gastrointestinal discomfort, hypocalcemia, etc., which seriously affect the quality of life of patients. Therefore, it is of extremely important clinical value and social value to develop calcium mimetic drugs with higher activity and safety, especially arylalkylamine compounds, for the treatment of SHPT in patients. SUMMARY

[0009] In order to solve the defects of the prior art, the present application aims to provide an arylalkylamine compound with higher activity and safety. The compound of the present application has excellent CaSR agonistic activity, high bioavailability, high in vivo metabolic stability, and high safety. The present application is realized by the following technical scheme.

[0010] In one aspect, the present application provides a compound having the structure shown in formula (I) or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof:

[0011]

[0012] wherein X is selected from a chemical bond, C1-C6 alkylene (such as -CH2-), -CO-, -CONH- and -NHCO-;

[0013] Y is selected from formula (1), formula (2) and formula (3);

[0014]

[0015] In formula (1), R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from a hydrogen atom;

[0016] unsubstituted or substituted C 2-6 carboxylic acid group, wherein the substituent of the substituted C 2-6 carboxylic acid group is selected from C 1-6 alkyl, amino, halogen, cyano, nitro, oxygen, C 2-6 carboxylic acid group, hydroxyl, C 3-6 cycloalkyl, C 1-6 alkoxy and halogenated C 1-6 alkoxy;

[0017] C 1-7alkoxy (the alkyl group can be a cycloalkyl or an alkyl group), which can be substituted by a substituent selected from the group consisting of halogen, cyano, nitro, oxygen, C 1-6 carboxylic acid group, amine group, C 3-6 cycloalkyl, aryl C 1-6 alkyloxy (e.g. benzyloxy), hydroxy, C 1-6 alkoxy, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy;

[0018] aryloxy or aryl C 1-6 alkyloxy, e.g. phenoxy or benzyloxy, the aryl group of the aryloxy or aryl C 1-6 alkyloxy can be substituted by a substituent selected from the group consisting of halogen, halogenated C 1-6 alkyl, C 1-6 carboxylic acid group (e.g. -COOH);

[0019] ester group, e.g. methyl ester group, ethyl ester group, which can be substituted by a substituent selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, halogen;

[0020] halogen;

[0021] C 1-6 alkyl;

[0022] halogenated C 1-6 alkyl;

[0023] 4-6-membered heterocyclic hydrocarbon group selected from 1, 2 or 3 heteroatoms among N, O, S, which can be substituted by C 1-6 carboxylic acid group, e.g. -COOH;

[0024] 4-6-membered heteroaryl group selected from 1, 2 or 3 heteroatoms among N, O, S, which can be substituted by C 1-6 carboxylic acid group, e.g. -COOH;

[0025] aryl group, wherein the aryl group is selected from phenyl, which can be substituted by a substituent selected from the group consisting of halogen, halogenated C 1-6 alkyl.

[0026] with the proviso that: 1) R 1 , R 2 , R 3 , R 4 , R 5 are not simultaneously H;

[0027] 2) when the substituent is an unsubstituted or substituted C 2-6 carboxylic acid group, the substitution site is R 2 -R 4 , and R 1-R 5 at least 2 of which are not H;

[0028] In formula (2), the A ring is selected from the following substituents: a 6-membered cycloalkyl group, a 4-12-membered heterocycloalkyl group selected from 1, 2, 3, 4, 5, 6 heteroatoms among N and O; and a 5-6-membered heteroaryl group selected from 1, 2 heteroatoms among N and O;

[0029] R 6 selected from a hydrogen atom, a halogen and a C 1-6 alkyl group;

[0030] R 7 selected from an oxo group, a C 1-6 carboxylic acid group, a carbonyl group and a halogenated C 1-6 alkylcarbonyl group;

[0031] In formula (3), the B ring is a bridged or spiro ring, for example a bicyclo[l,l,l], bicyclo[2,2,2], bicyclo[2,2,l], spiro[2,4], spiro[2,5], spiro[4,5], preferably a bicyclo[2,2,2], spiro[4,5].

[0032] R 8 is a C 1-6 carboxylic acid group, for example -COOH.

[0033] Preferably, X is selected from a chemical bond, a C1-C4 alkylene group (for example -CH2-), -CO- and -CONH-;

[0034] Preferably, X is a chemical bond.

[0035] Preferably, Y is selected from formula (1) and formula (2).

[0036] Preferably, Y is selected from formula (1).

[0037] Preferably, in formula (1), R 1 , R 5 are selected from H, a halogen (for example F, Cl), a C 1-6 alkyl group (for example methyl, ethyl), a C 1-6 alkoxy group (for example methoxy, ethoxy).

[0038] Preferably, in formula (1), R 1 , R 5 are selected from H, a halogen (for example F, Cl), a C 1-6 alkyl group (for example methyl, ethyl).

[0039] Preferably, in formula (1), R 2 -R 4 satisfies one of the following conditions:

[0040] i) R2 -R 4 at least one of which is unsubstituted or substituted C 2-6 carboxylic acid group, preferably acetic acid group, and R 1 -R 5 at least two of which are not H. That is, at least in the para or meta position is an acetic acid group (i.e., -CH2COOH), and at least one other position is substituted.

[0041] ii) R 2 -R 4 at least one of which is -COOR 9 or -(CH)2COOR 9 wherein R 9 is C 1-3 alkyl, or C 3-5 cycloalkyl, and -(CH)2COOR 9 may be substituted with C 1-3 alkyl or C 3-5 cycloalkyl. iii) R 2 -R 4 at least two of which are C 1-6 alkoxy, which C 1-6 alkoxy may be independently substituted with C 1-6 alkoxy, hydroxy, C 1-6 carboxylic acid group (e.g., -COOH), aryl C 1-6 alkyloxy (e.g., benzyloxy), halogen, halogenated C 1-6 alkyl.

[0042] iv) R 2 -R 4 at least one of which is oxo C 1-6 carboxylic acid group, which C 1-6 carboxylic acid group (e.g., acetic acid group) may be substituted with C 1-6 alkyl.

[0043] Preferably, in formula (1), R 2 -R 4 at least one of which is unsubstituted or substituted acetic acid group, and R 1 -R 5 at least two of which are not H. That is, at least in the para or meta position is an acetic acid group (i.e., -CH2COOH), and at least one other position is substituted.

[0044] Preferably, in formula (2), the A ring is selected from the following substituents: 5-12 membered heterocycloalkyl selected from 1, 2, 3, 4 heteroatoms of O; and 5-6 membered heteroaryl selected from 1 heteroatom of N;

[0045] Preferably, in formula (2), R 6 is selected from a hydrogen atom;

[0046] Preferably, in formula (2), R 7 is selected from C 1-6 arboxylic acid group, e.g. formyl, and a carbonyl group (C=0);

[0047] Preferably, in formula (3), preferably is bis[2,2,2] or spiro[4,5].

[0048] Preferably, in formula (3), R 8 is C 1-6 arboxylic acid group, e.g. formyl.

[0049] In one embodiment, X is selected from a chemical bond, C1-C4 alkylene (e.g. -CH2-), -CO- and -CONH-; Y is selected from formula (1); R 1 , R 5 is selected from H, halogen (e.g. F, CI), C 1-6 alkyl (e.g. methyl, ethyl), C 1-6 alkoxy (e.g. methoxy, ethoxy); R 2 -R 4 satisfies one of the following conditions:

[0050] i) R 2 -R 4 is unsubstituted or substituted C 2-6 arboxylic acid group, preferably acetic acid group, and R 1 -R 5 is not H. I.e. at least in para or meta position is acetic acid group (i.e. -CH2COOH) and at least one other position is substituted.

[0051] ii) R 2 -R 4 is at least one -COOR 9 or -(CH)2COOR 9 , wherein R 9 is C 1-3 alkyl or C 3-5 cycloalkyl, and -(CH)2COOR 9 may be substituted with C 1-3 alkyl or C 3-5 cycloalkyl.

[0052] iii) R 2 -R 4 is at least two C 1-6 alkoxy groups, which C 1-6 alkoxy groups may be independently substituted with C 1-6 alkoxy, hydroxyl, C 1-6carboxylic acid group (e.g., -COOH), aryl C 1-6 alkyloxy (e.g., benzyloxy), halogen, haloC 1-6 alkyl-substituted.

[0053] iv) R 2 -R 4 at least one of which is an oxyC 1-6 carboxylic acid group, as appropriate, the C 1-6 carboxylic acid group (e.g., acetoxy) can be alkyl-substituted. 1-6

[0054] In one embodiment, X is selected from the group consisting of a bond, C1-C4 alkylene (e.g., -CH2-), -CO-, and -CONH-; Y is selected from formula (1); R 1 , R 5 is selected from the group consisting of H, halogen (e.g., F, Cl), C 1-6 alkyl (e.g., methyl, ethyl); R 2 -R 4 at least one of which is an acetoxy group, and R 1 -R 5 at least 2 of which are not H. That is, at least in the para or meta position is an acetoxy group (i.e., -CH2COOH), and at least one other position is substituted.

[0055] In one embodiment, X is selected from the group consisting of a bond, C1-C4 alkylene (e.g., -CH2-), -CO-, and -CONH-; Y is selected from formula (2); the A ring is selected from the group consisting of 5-12 membered heterocycloalkyl groups selected from 1, 2, 3, 4 heteroatoms in O; and 5-6 membered heteroaryl groups selected from 1 heteroatom in N; R 6 is selected from the group consisting of a hydrogen atom; R 7 is selected from the group consisting of C 1-6 carboxylic acid group (e.g., -COOH), and carbonyl (C=O).

[0056] In one embodiment, X is selected from the group consisting of a bond, C1-C4 alkylene (e.g., -CH2-), -CO-, and -CONH-; Y is selected from formula (3); the B ring is bicyclo[2,2,2], spiro[4,5]. R 8 is C 1-6 carboxylic acid group, e.g., -COOH.

[0057] In one embodiment, X is selected from the group consisting of a bond, C1-C4 alkylene (e.g., -CH2-), -CO-, and -CONH-; Y is selected from:

[0058]

[0059] ​

[0060]

[0061] In one embodiment, the compound of formula (I) is selected from:

[0062]

[0063]

[0064]

[0065]

[0066] The compound of general formula (I) of the present application can be in free form or in a pharmaceutically acceptable salt form. The pharmaceutically acceptable inorganic acid salts, such as hydrochloride, sulfate, phosphate, or hydrobromide, and the like. The pharmaceutically acceptable organic acid salts, such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or maleate, and the like. In addition, when the compound has an acidic group such as carboxyl group, a salt with metal ion, such as sodium salt, potassium salt, calcium salt, and the like, alkali metal salt or alkaline earth metal salt can be formed.

[0067] In another aspect, the present application provides a process for preparing the compound of formula (I) as described above, which comprises the step of reacting a compound of formula 1 with a compound of formula (II) to form a compound of formula (I):

[0068]

[0069] wherein X, Y are as defined above, and Z represents a leaving group selected from halogen, hydroxyl, lower alkylsulfonyloxy (e.g. C 1-6 alkylsulfonyloxy), sulfonyloxy, and the like, preferably Br, Cl, trifluoromethylsulfonyloxy.

[0070] In still another aspect, the present application provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0071] In particular, the compound of formula (I) or a pharmaceutically acceptable salt thereof, as an effective ingredient for medical use, can be used together with an inert carrier suitable for each administration method, and can be formulated into a conventional pharmaceutical preparation such as a tablet, granule, capsule, powder, solution, suspension, emulsion, injection, etc. When used as a solid preparation, the inert carrier includes a binder (acacia, gelatin, sorbitol, polyvinylpyrrolidone, etc.), an excipient (lactose, galactose, corn starch, sorbitol, etc.), a lubricant (magnesium stearate, talc, polyethylene glycol, etc.), a disintegrant (potato starch, etc.), etc. When used as an injection, it can be formulated with distilled water for injection, physiological saline, an aqueous glucose solution, etc.

[0072] The compound of formula (I) or a pharmaceutically acceptable salt thereof for medical use according to the present application can be administered orally, intravenously, intramuscularly, subcutaneously, transdermally, etc., and the administration dose and volume can be determined according to the characteristics of the drug, the administration route, the age, body weight, or disease state of the patient, etc.

[0073] The present application provides the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof, or a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient. It produces various pharmacological effects by activating CaSR, and is used for preventing and treating diseases related to CaSR, such as inhibiting the production of PTH, regulating the calcium and phosphorus levels in blood, treating primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis), parathyroid adenoma, parathyroid hyperplasia, parathyroid cancer, vascular calcification and valve calcification, abnormal calcium homeostasis (e.g., hypercalcemia), abnormal phosphorus homeostasis (e.g., hypophosphatemia), bone-related diseases or complications caused by hyperparathyroidism, chronic kidney disease, or parathyroid cancer, bone loss after kidney transplantation, osteogenesis imperfecta, renal osteodystrophy, cardiovascular complications caused by hyperparathyroidism or chronic kidney disease, Ca 2+ Certain malignancies of abnormally high.

[0074] The following terms are used in the specification and claims, unless otherwise indicated, have the meanings given below.

[0075] The present application includes all stereoisomer forms of the compounds described. Unless specified to the contrary, the present application is intended to encompass all such isomeric forms of the compounds. The asymmetric centers in the compounds of the present application can each be of the (R) or (S) configuration, independently of one another. Where the bond to the chiral carbon is represented in the structural formula of the application as a straight line, it is to be understood that both the (R) and (S) configurations of the chiral carbon are included in the formula. Where a particular configuration is depicted, it is meant to refer to the enantiomer (R) or (S). Similarly, where a compound name is recited without the chiral designation of the chiral carbon, it is to be understood that both the (R) and (S) configurations of the chiral carbon are included by the name. The preparation of particular stereoisomers or mixtures thereof can be identified in embodiments where such stereoisomers or mixtures thereof are obtained, but this in no way limits the scope of the disclosure to include all stereoisomers and mixtures thereof.

[0076] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0077] The term "alkyl" means an alkane-derived hydrocarbyl group comprising only carbon and hydrogen atoms in its backbone, having no unsaturation, having from 1 to 6 carbon atoms, and being attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), and the like. Unless stated otherwise or indicated by context, all alkyl groups described or claimed herein can be straight, branched, or cyclic, substituted or unsubstituted.

[0078] "Cycloalkyl" means a saturated monocyclic or polycyclic cyclic hydrocarbyl group, which can be combined with other groups. Monocyclic cyclic hydrocarbyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferred are 3-8 membered cycloalkyl groups. More preferred are 3-6 membered cycloalkyl groups.

[0079] The term "alkoxy" means an alkyl group linked by an oxygen bond. Non-limiting examples of such groups are methoxy, ethoxy, and propoxy, and the like. Unless stated otherwise or indicated by context, all alkoxy groups described or claimed herein can be straight or branched, substituted or unsubstituted.

[0080] The term "haloalkyl" means an alkyl group as defined above substituted with one or more halogen atoms as defined above. Preferably, haloalkyl groups can be mono-haloalkyl, di-haloalkyl, or poly-haloalkyl groups including per-haloalkyl groups. Mono-haloalkyl groups can have one iodine atom, bromine atom, chlorine atom, or fluorine atom. Di-haloalkyl and poly-haloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Unless stated otherwise or indicated by context, all haloalkyl groups described or claimed herein can be straight or branched, substituted or unsubstituted.

[0081] The term "haloalkoxy" refers to an alkoxy group as defined above, which is substituted by one or more halogen atoms as defined above.

[0082] The term "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, which can include a spiro or bridged ring system, having from 3 to 15 carbon atoms, 3 to 10 carbon atoms, or 5 to 7 carbon atoms, and which is saturated or unsaturated, and which is connected to the rest of the molecule by a single bond. Unless specifically indicated otherwise in the specification, a cycloalkyl group can optionally be substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thia, cyano, nitro, and the like. The term "heterocycloalkyl" is a cycloalkyl group as defined above containing a heteroatom in the ring, which can be selected from N, O, S, and the number of heteroatoms can be 1, 2, 3, 4, 5, 6, and the like.

[0083] The term "aryl" refers to a monocyclic or polycyclic carbocyclic ring system having one or more fused or non-fused aromatic rings, including but not limited to phenyl. The term "heteroaryl" is an aryl group as defined above containing a heteroatom in the aromatic ring, which can be selected from N, O, S, and the number of heteroatoms can be 1, 2, 3, 4, 5, 6, and the like. Including but not limited to naphthyl, indenyl, pyridine, pyrazine, pyridazine, thiophene, pyrrole, furan, imidazole, pyrazole, thiazole, oxazole, and the like.

[0084] The term "carboxyl" is a basic functional group in organic chemistry, consisting of one carbon atom, two oxygen atoms, and one hydrogen atom, with the chemical formula -COOH.C 1-6 carboxyl, C 2-6 carboxyl is a lower alkyl further containing a carboxyl group.C 1-6 carboxyl can be formyl (e.g., -COOH), acetyl, propionyl, butyryl, valeryl, hexanoyl.C 2-6 carboxyl can be acetyl, propionyl, butyryl, valeryl, hexanoyl.

[0085] The term "aryloxy" refers to an aryl-O- group, such as phenoxy, naphthoxy. The term "arylalkyloxy" refers to an aryl lower alkyl-O- group, such as benzyloxy. 1-4 alkyloxy" refers to an aryl lower alkyl-O- group, such as benzyloxy.

[0086] The term "ester" refers to a group comprising -COOM (where M is typically an alkyl group or other non-H group).

[0087] The term "oxyc 1-6 carboxyl" refers to an oxo group substituted by a C 1-6 carboxyl, such as -O-CH2COOH, -O-CH(CH3)COOH.

[0088] The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption of the active ingredient so as to realize its biological activity.

[0089] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure that is safe and effective for use in a mammal and has the desired biological activity.

[0090] The compound of formula (I) or a pharmaceutically acceptable salt thereof of the present application, as an effective ingredient, inhibits the synthesis and secretion of parathyroid hormone by allosterically activating CaSR on parathyroid cells, thereby reducing the parathyroid hormone level in blood, and thus stably maintaining the blood calcium and phosphorus concentrations, and can be used for preventing or treating hyperparathyroidism, has an excellent CaSR allosteric agonistic effect and reduces the PTH action in vivo. The compound is confirmed to have a CaSR allosteric activation effect and reduce the PTH action in vivo of a model rat through a CaSR allosteric activation effect experiment, an SD rat adenine model, or an SD rat 5 / 6 nephrectomy model.

[0091] The compound of formula (I) or a pharmaceutically acceptable salt thereof of the present application, as an effective ingredient, not only has excellent activity, but also has certain metabolic stability in vivo. The present application has conducted a rat liver microsomal incubation experiment to verify that the compound indeed has metabolic stability.

[0092] The compound of formula (I) or a pharmaceutically acceptable salt thereof of the present application, as an effective ingredient, not only has an excellent CaSR activation effect, but also has high safety.

[0093] Compared with the prior art, the present application not only has excellent activity and good safety, but also has high metabolic stability in vivo and high relative bioavailability in vivo. Specific implementation method

[0094] The present disclosure is further described below in conjunction with examples, but these examples do not limit the scope of the present disclosure.

[0095] The known starting materials of the present disclosure can be synthesized according to methods known in the art or purchased from chemical companies such as Sigma-Aldrich, B&J, Merck, Aldrich, and Bide.

[0096] Unless otherwise specified in the examples, the solution refers to aqueous solution, room temperature refers to 20-30℃, inert gas refers to argon or nitrogen, the developing solvent for thin layer chromatography (TLC) monitoring reaction and column chromatography purification is dichloromethane / methanol system, n-hexane / ethyl acetate system, petroleum ether / ethyl acetate system, petroleum ether / ethyl acetate / methanol system, etc., the component ratio of the system is adjusted according to the polarity of the compound, and a small amount of triethylamine and basic or acidic reagents such as acetic acid can also be added for adjustment.

[0097] Unless otherwise specified in the examples, the mass spectrometer (Mass spectrum, MS), nuclear magnetic resonance (Nuclear Magnetic Resonance, NMR) and high performance liquid chromatography (High performance liquid chromatography, HPLC) used for structure confirmation are Agilent InfinityLab LC / MSD iQ G6160A, Bruker AVANCE 400 or Bruke AVANCE NEO 600 and Shimadzu LC-2010AHT, respectively. The determination solvent of NMR is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) or deuterated heavy water (D2O), and the internal standard is tetramethylsilane (TMS).

[0098] Example 1: Synthesis of (3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}pyrrolidine dihydrochloride (1)

[0099] The synthesis route is as follows:

[0100]

[0101] Step 1: 2-nitrobenzenesulfonic acid-(3R)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}pyrrolidin-3-yl ester (3)

[0102] 500 mL three-necked flask, compound 2 (25.00 g, 0.13 mol), triethylamine (17.57 g, 0.17 mol), trimethylamine hydrochloride (2.55 g, 0.03 mol) and dichloromethane 125 mL were added and stirred; cooled to 0-10 °C, 2-nitrobenzenesulfonyl chloride (32.55 g, 0.15 mol) in dichloromethane 125 mL was added dropwise; after the reaction was completed, 150 mL of purified water was added, and the pH was adjusted to 2.0-4.0 with 6N hydrochloric acid; stand until obvious layering, separate phases, retain the organic phase, extract the aqueous phase with 50 mL of dichloromethane once, combine the organic phases, dry over anhydrous sodium sulfate, filter; the filtrate was concentrated under reduced pressure to constant weight to give compound 3 (47.40 g, y = 95%). LCMS (ESI) m / z: 373.1 [M+H] + .

[0103] Step 2: (3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester (4)

[0104] 100 mL three-necked flask, compound 3 (45.00 g, 0.12 mol), (1R)-1-(naphthalen-1-yl)ethan-1-amine (17.60 g, 0.10 mol), potassium phosphate (21.23 g, 0.10 mol) and acetonitrile 150 mL were added, and the temperature was raised to 75 °C, and stirred for 24 h; cool to room temperature, filter, wash the filter cake with 60 mL of acetonitrile, concentrate under reduced pressure to remove solvent; add 90 mL of ethyl acetate and 90 mL of saturated brine and stir for 0.5 h, stand until obvious layering, separate phases, retain the organic phase, extract the aqueous phase with 45 mL of ethyl acetate once, combine the organic phases, dry over anhydrous sodium sulfate, concentrate the filtrate under reduced pressure to constant weight to give compound 4 (32.62 g, y = 96%). LCMS (ESI) m / z: 341.2 [M+H] + .

[0105] Step 3: (3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydropyrrole dihydrochloride (1)

[0106] 500 mL three-necked flask, compound 4 (30.00 g, 0.09 mol) and ethyl acetate 150 mL were added and stirred, cooled to 0-10 °C, 22.5 mL of concentrated hydrochloric acid was added dropwise, after dropping, stirred for 0.5 h, the temperature was raised to 55 °C and reacted for 2.0 h; cool to room temperature, filter, wash the filter cake with 50 mL of ethyl acetate, dry at 45 °C to constant weight to give compound 1 (19.87 g, y = 92%). LCMS (ESI) m / z: 241.2 [M+H] + . 1H NMR (400 MHz, MeOH-d4): δ 8.29 (d, J = 8.8 Hz, 1H), 8.04-7.97 (m, 2H), 7.94 (d, J = 7.2 Hz, 1H), 7.72-7.58 (m, 3H), 5.60-5.51 (m, 1H), 3.98-3.87 (m, 1H), 3.65-3.54 (m, 1H), 3.51-3.38 (m, 2H), 3.29-3.20 (m, 1H), 2.55-2.44 (m, 1H), 2.43-2.32 (m, 1H), 1.89 (d, J = 6.8 Hz, 3H).

[0107] Example 2: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-methoxyphenyl}acetic acid (A1)

[0108] The synthetic route is as follows:

[0109]

[0110] Step 1: (5-bromo-2-methoxyphenyl) ethyl acetate (A1-2)

[0111] 500 mL three-necked flask, compound A1-1 (5.00 g, 20.40 mmol) and anhydrous ethanol 50 mL were added and stirred; 2 mL of concentrated sulfuric acid was slowly added dropwise, and the reaction was refluxed at elevated temperature for 3.0 h; cooled to room temperature, concentrated under reduced pressure to remove solvent, added 50 mL of ethyl acetate and 50 mL of purified water and stirred, added saturated sodium carbonate solution dropwise to adjust pH to 8.0, stood until obvious layering, separated the phases, retained the organic phase, extracted the aqueous phase with 50 mL of ethyl acetate once, combined the organic phases, dried with anhydrous sodium sulfate, filtered; the filtrate was concentrated under reduced pressure to constant weight to obtain compound A1-2 (5.13 g, y = 92%). LCMS (ESI) m / z: 273.0 [M+H] + .

[0112] Step 2: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-methoxyphenyl} ethyl acetate (A1-3)

[0113] 100 mL single necked flask, was charged with free compound 1 (0.77 g, 3.19 mmol), compound A1-2 (1.05 g, 3.83 mmol), Pd(OAc)2(35.92 mg, 0.16 mmol), X-Phos (76.21 g, 0.16 mmol), Cs2CO3(3.12 g, 9.57 mmol) and 20 mL of toluene, replaced with nitrogen three times, warmed to 100 °C and stirred for 12.0 h, cooled to room temperature, added 30 mL of saturated brine and stirred, allowed to settle to distinct layers, separated the layers, retained the organic layer, extracted the aqueous layer with 20 mL of ethyl acetate once, combined the organic layers, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure to no solvent take off, purified the residue by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 80 / 20→ 50 / 50), concentrated under reduced pressure to yield compound A1-3 (0.81 g, y = 59%). LCMS (ESI) m / z: 433.2 [M+H] + .

[0114] Step 3: {5-[(3S)-3-{[(1R)-1-(Naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- methoxyphenyl}acetic acid (A1)

[0115] 100 mL single necked flask, was charged with A1-3 (0.80 g, 1.85 mmol), sodium hydroxide (0.15 g, 3.70 mmol), purified water 10 mL and ethanol 10 mL, warmed and stirred at 60 °C for 3.0 h, cooled to room temperature, adjusted the pH to solid precipitated out clearly with 1 N hydrochloric acid, filtered, washed the filter cake with 10 mL of purified water, air dried at 45 °C to constant weight to yield compound A1 (0.58 g, y = 77%). LCMS (ESI) m / z: 405.3 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 8.32 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 7.3 Hz, 1H), 7.50 (q, J = 8.9, 7.6 Hz, 3H), 6.76 (d, J = 8.3 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 6.46 (s, 1H), 4.72 (q, J = 6.6 Hz, 1H), 3.63 (s, 3H), 3.38 (s, 2H), 3.29 - 3.22 (m, 2H), 3.15 (q, J = 7.2 Hz, 2H), 3.05 (dd, J = 9.8, 5.8 Hz, 1H), 1.93 (dt, J = 13.4, 6.8 Hz, 1H), 1.78 (dq, J = 14.1, 7.2 Hz, 1H), 1.40 (d, J = 6.5 Hz, 3H).

[0116] Example 3: Synthesis of {2-ethoxy-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A2)

[0117] The synthetic route is as follows.

[0118]

[0119] Step 1: (5-bromo-2-ethoxyphenyl) ethanoate (A2-2)

[0120] A 500 mL three-necked flask was charged with compound A2-1 (2.00 g, 7.72 mmol), potassium carbonate (1.07 g, 7.72 mmol), ethyl bromide (1.68 g, 15.44 mmol) and acetonitrile 50 mL was stirred, 60 °C reaction for 24.0 h; cooled to room temperature, concentrated to no solvent evaporation under reduced pressure, added 50 mL of ethyl acetate and 50 mL of purified water was stirred, placed to obvious layering, separated, the organic phase was reserved, the aqueous phase was extracted with 50 mL of ethyl acetate once, the combined organic phase was dried over anhydrous sodium sulfate and filtered; the filtrate was concentrated to constant weight under reduced pressure to give compound A2-2 (1.95 g, y = 88%). LCMS (ESI) m / z: 287.0 [M+H] + .

[0121] Step 2: {2-ethoxy-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid ethyl ester (A2-3)

[0122] 100 mL single necked flask, add free compound 1 (0.77 g, 3.19 mmol), compound A2-2 (1.10 g, 3.83 mmol), Pd(OAc)2(35.92 mg, 0.16 mmol), X-Phos (76.21 g, 0.16 mmol), Cs2CO3(3.12 g, 9.57 mmol) and 20 mL of toluene, synthesis and work-up procedure refer to compound A1-3, get compound A2-3 (0.91 g, y = 64%). LCMS (ESI) m / z: 447.3 [M+H] + .

[0123] Step 3: {2-ethoxy-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}acetic acid (A2)

[0124] 100 mL single necked flask, add A2-3 (0.50 g, 1.12 mmol), sodium hydroxide (0.13 g, 3.36 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound A2 (0.19 g, y = 41%). LCMS (ESI) m / z: 419.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.2 Hz, 1H), 7.97 - 7.91 (m, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.53 (qd, J = 9.3, 7.7, 5.5 Hz, 3H), 6.79 (d, J = 8.7 Hz, 1H), 6.35 (d, J = 2.9 Hz, 1H), 6.29 (dd, J = 8.7, 2.9 Hz, 1H), 4.78 (q, J = 6.5 Hz, 1H), 3.86 (q, J = 6.9 Hz, 2H), 3.42 (s, 2H), 3.25 (q, J = 7.2, 5.4 Hz, 3H), 3.05 (d, J = 8.1 Hz, 1H), 2.95 (q, J = 4.3 Hz, 1H), 2.07 - 1.98 (m, 1H), 1.90 (dt, J = 13.0, 6.9 Hz, 1H), 1.42 (d, J = 6.5 Hz, 3H), 1.23 (t, J = 6.9 Hz, 3H).

[0125] Example 4: Synthesis of {2-ethoxy-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A3)

[0126] The synthesis route is as follows:

[0127]

[0128] Step 1: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- (prop-2-yloxy)phenyl}acetic acid ethyl ester (A3-2)

[0129] 100 mL single necked flask, add free compound 1 (0.77 g, 3.19 mmol), compound A3-1 (1.15 g, 3.83 mmol), Pd(OAc)2(35.92 mg, 0.16 mmol), X-Phos (76.21 g, 0.16 mmol), Cs2CO3(3.12 g, 9.57 mmol) and 20 mL of toluene, synthesis and work-up procedure refer to compound A1-3, get compound A3-2 (0.85 g, y = 48%). LCMS (ESI) m / z: 461.3 [M+H] + .

[0130] Step 2: {2-ethoxy-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}acetic acid (A3)

[0131] 100 mL single necked flask, add A3-2 (0.85 g, 1.84 mmol), sodium hydroxide (0.15 g, 3.68 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound A3 (0.41 g, y = 52%). LCMS (ESI) m / z: 433.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.36 - 8.29 (m, 1H), 7.95 (dd, J = 7.2, 2.2 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 7.1 Hz, 1H), 7.54 (tdd, J = 9.5, 7.6, 4.3 Hz, 3H), 6.81 (d, J = 8.7 Hz, 1H), 6.35 (d, J = 2.9 Hz, 1H), 6.30 (dd, J = 8.7, 3.0 Hz, 1H), 4.75 (q, J = 6.5 Hz, 1H), 4.31 (hept, J = 6.0 Hz, 1H), 3.42 (s, 2H), 3.26 (tt, J = 9.9, 5.8 Hz, 3H), 3.08 (dd, J = 8.8, 6.9 Hz, 1H), 2.95 (q, J = 3.8 Hz, 1H), 2.03 (dt, J = 11.7, 6.0 Hz, 1H), 1.90 (dt, J = 12.3, 6.9 Hz, 1H), 1.41 (d, J = 6.5 Hz, 3H), 1.19 (d, J = 6.0 Hz, 6H).

[0132] Example 5: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-(propyloxy)phenyl}acetic acid (A4)

[0133] The synthetic route is as follows:

[0134]

[0135] Step 1: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2- (propyloxy)phenyl}acetic acid ethyl ester (A4-2)

[0136] 100 mL single necked flask, free compound 1 (0.77 g, 3.19 mmol), compound A4-1 (1.15 g, 3.83 mmol), Pd(OAc)2(35.92 mg, 0.16 mmol), X-Phos (76.21 g, 0.16 mmol), Cs2CO3(3.12 g, 9.57 mmol) and 20 mL of toluene, synthesis and workup procedure refer to compound A1-3, compound A4-2 (0.93 g, y = 63%) was obtained. LCMS (ESI) m / z: 461.3 [M+H] + .

[0137] Step 2: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- (propyloxy)phenyl}acetic acid (A4)

[0138] 100 mL single necked flask was charged with A4-2 (0.85 g, 1.84 mmol), sodium hydroxide (0.15 g, 3.68 mmol), purified water 10 mL and ethanol 10 mL, synthesis and workup procedure refer to compound A1 to give compound A4 (0.58 g, y = 73%). LCMS (ESI) m / z: 433.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 8.1 Hz, 1H), 7.96 - 7.89 (m, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.51 (ddt, J = 12.1, 7.7, 3.4 Hz, 3H), 6.76 (d, J = 8.7 Hz, 1H), 6.33 (d, J = 2.9 Hz, 1H), 6.27 (dd, J = 8.8, 2.9 Hz, 1H), 4.74 (q, J = 6.5 Hz, 1H), 3.76 (d, J = 6.2 Hz, 2H), 3.41 (s, 2H), 3.23 (dd, J = 7.7, 4.4 Hz, 3H), 3.02 (q, J = 7.8 Hz, 1H), 2.96 - 2.86 (m, 1H), 2.00 (dd, J = 11.6, 6.0 Hz, 1H), 1.87 (dt, J = 12.3, 6.8 Hz, 1H), 1.62 (h, J = 7.0 Hz, 2H), 1.40 (d, J = 6.5 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H).

[0139] Example 6: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-[(2-methoxyethyl)oxy]phenyl}acetic acid (A5)

[0140] The synthesis route is as follows:

[0141]

[0142] Step 1: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-[(2- methoxyethyl)oxy]phenyl}acetic acid ethyl ester (A5-2)

[0143] 100 mL single necked flask, add free compound 1 (0.77 g, 3.19 mmol), compound A5-1 (1.21 g, 3.83 mmol), Pd(OAc)2(35.92 mg, 0.16 mmol), X-Phos (76.21 g, 0.16 mmol), Cs2CO3(3.12 g, 9.57 mmol) and 20 mL of toluene, synthesis and work-up procedure refer to compound A1-3, get compound A5-2 (1.17 g, y = 77%). LCMS (ESI) m / z: 477.3 [M+H] + .

[0144] Step 2: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- [(2-methoxyethyl)oxy]phenyl}acetic acid (A5)

[0145] 100 mL single necked flask, add A5-2 (0.65 g, 1.36 mmol), sodium hydroxide (0.16 g, 4.10 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound A5 (0.24 g, y = 39%). LCMS (ESI) m / z: 449.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.32 (d, J = 8.3 Hz, 1H), 7.95-7.91 (m, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.79-7.75 (m, 1H), 7.51 (ddd, J = 10.7, 8.1, 4.9 Hz, 3H), 6.81 (d, J = 8.8 Hz, 1H), 6.35 (d, J = 3.0 Hz, 1H), 6.29 (dd, J = 8.8, 2.9 Hz, 1H), 4.77 (s, 1H), 3.93 (t, J = 4.8 Hz, 2H), 3.57 (t, J = 4.8 Hz, 2H), 3.45 (s, 2H), 3.29 (s, 3H), 3.26 (t, J = 6.8 Hz, 3H), 3.06 (q, J = 7.7 Hz, 1H), 2.97 (s, 1H), 2.05-1.99 (m, 1H), 1.91 (s, 1H), 1.42 (d, J = 6.5 Hz, 3H).

[0146] Example 7: Synthesis of {2-[(2-hydroxyethyl)oxy]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A6)

[0147] The synthesis route is as follows:

[0148]

[0149] Step 1: Acetic acid-2-{[2-(2-ethoxy-2-oxoethyl)-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]oxy}ethyl ester (A6-2)

[0150] 100 mL single necked flask, add free compound 1 (0.77 g, 3.19 mmol), compound A6-1 (1.32 g, 3.83 mmol), Pd(OAc)2(35.92 mg, 0.16 mmol), X-Phos (76.21 g, 0.16 mmol), Cs2CO3(3.12 g, 9.57 mmol) and 20 mL of toluene, synthesis and work-up procedure refer to compound A1-3, get compound A6-2 (1.03 g, y = 64%). LCMS (ESI) m / z: 505.3 [M+H] + .

[0151] Step 2: {2-[(2-Hydroxyethyl)oxy]-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A6)

[0152] 100 mL single necked flask, add A6-2 (1.00 g, 1.98 mmol), sodium hydroxide (0.20 g, 5.00 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound A6 (0.33 g, y = 38%). LCMS (ESI) m / z: 435.3 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 8.32 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.51 (p, J = 7.2 Hz, 3H), 6.79 (d, J = 8.6 Hz, 1H), 6.35 (s, 1H), 6.27 (d, J = 8.8 Hz, 1H), 4.73 (q, J = 6.6 Hz, 1H), 3.85 (t, J = 5.2 Hz, 2H), 3.62 (t, J = 5.3 Hz, 2H), 3.44 (s, 2H), 3.24 (q, J = 6.3 Hz, 3H), 3.05 (q, J = 7.9 Hz, 1H), 2.96 - 2.91 (m, 1H), 2.00 (d, J = 8.4 Hz, 1H), 1.88 (dd, J = 14.7, 8.1 Hz, 1H), 1.40 (d, J = 6.4 Hz, 3H).

[0153] Example 8: Synthesis of [2-(butyloxy)-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (A7)

[0154] The synthetic route is as follows:

[0155]

[0156] Step 1: Acetic acid-2-{[2-(2-ethoxy-2-oxoethyl)-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]oxy}ethyl ester (A7-2)

[0157] 100 mL single necked flask, free compound 1 (0.77 g, 3.19 mmol), compound A7-1 (1.21 g, 3.83 mmol), Pd(OAc)2(35.92 mg, 0.16 mmol), X-Phos (76.21 g, 0.16 mmol), Cs2CO3(3.12 g, 9.57 mmol), and 20 mL of toluene, synthesis and workup procedure refer to compound A1-3, to give compound A7-2 (0.77 g, y = 51%). LCMS (ESI) m / z: 475.3 [M+H] + .

[0158] Step 2: [2-(butyloxy)-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]phenyl]acetic acid ethyl ester (A7)

[0159] 100 mL single necked flask was charged with A7-2 (0.70 g, 1.48 mmol), sodium hydroxide (0.20 g, 5.00 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work up procedure was referenced to compound A1 to get compound A7 (0.24 g, y = 37%). LCMS (ESI) m / z: 447.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.31 (d, J = 8.3 Hz, 1H), 7.92 (dd, J = 7.8, 1.7 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.1 Hz, 1H), 7.55 - 7.47 (m, 3H), 6.71 (d, J = 8.7 Hz, 1H), 6.38 (d, J = 3.0 Hz, 1H), 6.21 (dd, J = 8.7, 3.0 Hz, 1H), 4.72 (q, J = 6.5 Hz, 1H), 3.78 (t, J = 6.4 Hz, 2H), 3.22 (tt, J = 12.9, 6.8 Hz, 3H), 3.03 (q, J = 7.7 Hz, 1H), 2.92 (dd, J = 8.2, 4.9 Hz, 1H), 2.00 (dq, J = 12.0, 6.0 Hz, 1H), 1.89 - 1.81 (m, 1H), 1.77 (s, 2H), 1.65 - 1.57 (m, 2H), 1.40 (dd, J = 10.4, 7.0 Hz, 5H), 0.90 (t, J = 7.4 Hz, 3H).

[0160] Example 9: Synthesis of [2-(Cyclopentyloxy)-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (A8)

[0161] The synthesis route is as follows:

[0162]

[0163] Step 1: [2-(Cyclopentyloxy)-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid ethyl ester (A8-2)

[0164] 100 mL single necked flask, add free compound 1 (0.77 g, 3.19 mmol), compound A8-1 (1.25 g, 3.83 mmol), Pd(OAc)2(35.92 mg, 0.16 mmol), X-Phos (76.21 g, 0.16 mmol), Cs2CO3(3.12 g, 9.57 mmol) and 20 mL of toluene, synthesis and post-processing operations refer to compound A1-3, to get compound A8-2 (1.26 g, y = 81%). LCMS (ESI) m / z: 487.3 [M+H] + .

[0165] Step 2: [2-(Cyclopentyloxy)-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (A8)

[0166] 100 mL single necked flask, add A8-2 (1.20 g, 2.47 mmol), sodium hydroxide (0.32 g, 8.00 mmol), purified water 10 mL and ethanol 10 mL, synthesis and post-processing operations refer to compound A1, to get compound A8 (0.17 g, y = 15%). LCMS (ESI) m / z: 459.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.30 (d, J = 8.1 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.49 (dq, J = 22.0, 7.3 Hz, 3H), 6.68 (d, J = 8.2 Hz, 1H), 6.53 (dd, J = 8.0, 2.0 Hz, 1H), 6.46 (d, J = 2.1 Hz, 1H), 4.69 (q, J = 6.6 Hz, 1H), 4.65 (td, J = 5.6, 2.7 Hz, 1H), 3.35 (s, 2H), 3.30 (dd, J = 9.6, 6.5 Hz, 1H), 3.24 (td, J = 8.6, 5.2 Hz, 1H), 3.17 (dq, J = 13.0, 7.1, 6.6 Hz, 2H), 3.04 (dd, J = 9.7, 6.1 Hz, 1H), 1.94 (dq, J = 12.4, 6.3 Hz, 1H), 1.76 (dp, J = 15.7, 5.3, 4.3 Hz, 3H), 1.68 - 1.57 (m, 4H), 1.50 (dq, J = 10.9, 6.8 Hz, 2H), 1.39 (d, J = 6.5 Hz, 3H).

[0167] Example 10: Synthesis of [2-(Cyclohexyloxy)-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (A9)

[0168] The synthetic route is as follows:

[0169]

[0170] Step 1: [2-(Cyclohexyloxy)-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl] ethyl acetate (A9-2)

[0171] Into a 100 mL single necked flask, was placed free compound 1 (0.77 g, 3.19 mmol), compound A9-1 (1.31 g, 3.83 mmol), Pd(OAc)2(35.92 mg, 0.16 mmol), X-Phos (76.21 g, 0.16 mmol), Cs2CO3(3.12 g, 9.57 mmol) and 20 mL of toluene, synthesis and work-up procedure refer to compound A1-3 to give compound A9-2 (0.42 g, y = 26%). LCMS (ESI) m / z: 501.3 [M+H] + .

[0172] Step 2: [2-(Cyclohexyloxy)-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (A9)

[0173] Into a 100 mL single necked flask, was placed A9-2 (0.42 g, 0.84 mmol), sodium hydroxide (0.16 g, 4.00 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1 to give compound A9 (0.17 g, y = 43%). LCMS (ESI) m / z: 473.4 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 8.31 (d, J = 8.1 Hz, 1H), 7.94 - 7.88 (m, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.54 - 7.44 (m, 3H), 6.73 (d, J = 8.2 Hz, 1H), 6.52 (dd, J = 8.1, 2.0 Hz, 1H), 6.47 (d, J = 2.1 Hz, 1H), 4.69 (q, J = 6.6 Hz, 1H), 4.11 (dq, J = 8.6, 4.0 Hz, 1H), 3.36 (s, 2H), 3.31 (dd, J = 9.7, 6.5 Hz, 1H), 3.25 (td, J = 8.5, 5.0 Hz, 1H), 3.19 (dt, J = 16.7, 7.0 Hz, 2H), 3.04 (dd, J = 9.7, 6.2 Hz, 1H), 1.95 (dq, J = 12.4, 6.4 Hz, 1H), 1.83 - 1.72 (m, 3H), 1.63 (tt, J = 9.0, 5.1, 4.6 Hz, 2H), 1.50 - 1.44 (m, 1H), 1.39 (d, J = 6.5 Hz, 3H), 1.27 (p, J = 9.3 Hz, 4H), 1.19 (s, 1H).

[0174] Example 11: Synthesis of {2-[(cyclohexylmethyl)oxy]-5-[(3S)-3-{[(1R)-1- (naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A10)

[0175] The synthetic route is as follows:

[0176]

[0177] Step 1: {2-[(cyclohexylmethyl)oxy]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid ethyl ester (A10-2)

[0178] 100 mL single necked flask was charged with free compound 1 (0.77 g, 3.19 mmol), compound A10-1 (1.36 g, 3.83 mmol), Pd(OAc)2(35.92 mg, 0.16 mmol), X-Phos (76.21 g, 0.16 mmol), Cs2CO3(3.12 g, 9.57 mmol) and 20 mL of toluene, synthesis and workup procedure was referenced to compound A1-3 to give compound A10-2 (0.87 g, y = 53%). LCMS (ESI) m / z: 515.4 [M+H] + .

[0179] Step 2: {2-[(Cyclohexylmethyl)oxy]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A10)

[0180] 100 mL single necked flask was charged with A10-2 (0.85 g, 1.65 mmol), sodium hydroxide (0.20 g, 5.00 mmol), purified water 10 mL and ethanol 10 mL, synthesis and workup procedure refer to compound A1 to give compound A10 (0.27 g, y = 34%). LCMS (ESI) m / z: 487.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.31 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 7.8, 1.8 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.57 - 7.47 (m, 3H), 6.87 (d, J = 8.2 Hz, 1H), 5.92 (dd, J = 8.2, 2.3 Hz, 1H), 5.89 (d, J = 2.3 Hz, 1H), 4.73 (q, J = 6.6 Hz, 1H), 3.70 (s, 1H), 3.32 (s, 2H), 3.29 (td, J = 8.5, 4.6 Hz, 1H), 3.23 (p, J = 6.3 Hz, 1H), 3.18 (dd, J = 9.3, 6.6 Hz, 1H), 3.08 (dt, J = 9.3, 7.3 Hz, 1H), 2.91 (dd, J = 9.3, 5.9 Hz, 1H), 2.06 - 1.98 (m, 1H), 1.87 (dq, J = 12.0, 7.5 Hz, 1H), 1.78 (dd, J = 12.8, 3.7 Hz, 2H), 1.74 - 1.69 (m, 1H), 1.71 - 1.65 (m, 2H), 1.65 (dq, J = 12.2, 3.4, 2.8 Hz, 1H), 1.41 (d, J = 6.5 Hz, 3H), 1.29 - 1.11 (m, 3H), 1.10 - 1.00 (m, 2H).

[0181] Example 12: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-(phenyloxy)phenyl}acetic acid (A11)

[0182] The synthesis route is as follows:

[0183]

[0184] Step 1: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- (phenyloxy)phenyl}acetic acid ethyl ester (A11-2)

[0185] 100 mL single necked flask, add free compound 1 (0.77 g, 3.19 mmol), compound A11-1 (1.28 g, 3.83 mmol), Pd(OAc)2(35.92 mg, 0.16 mmol), X-Phos (76.21 g, 0.16 mmol), Cs2CO3(3.12 g, 9.57 mmol) and 20 mL of toluene, synthesis and work-up procedure refer to compound A1-3, get compound A11-2 (0.81 g, y = 76%). LCMS (ESI) m / z: 495.3 [M+H] + .

[0186] Step 2: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- (phenyloxy)phenyl}acetic acid (A11)

[0187] 100 mL single necked flask, add A11-2 (0.80 g, 1.62 mmol), sodium hydroxide (0.20 g, 5.00 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound A11 (0.63 g, y = 34%). LCMS (ESI) m / z: 467.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 8.1 Hz, 1H), 7.93 (dd, J = 7.5, 2.0 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.52 (dtt, J = 9.4, 6.9, 3.5 Hz, 3H), 7.31 - 7.22 (m, 2H), 6.98 (t, J = 7.3 Hz, 1H), 6.82 - 6.75 (m, 2H), 6.75 (d, J = 8.8 Hz, 1H), 6.43 (d, J = 2.9 Hz, 1H), 6.36 (dd, J = 8.8, 2.9 Hz, 1H), 4.76 (q, J = 6.5 Hz, 1H), 3.37 (s, 2H), 3.29 (qd, J = 10.7, 9.4, 4.8 Hz, 3H), 3.10 (dt, J = 9.3, 7.2 Hz, 1H), 3.01 (p, J = 5.0, 4.4 Hz, 1H), 2.07 - 1.98 (m, 1H), 1.91 (dq, J = 13.9, 7.1 Hz, 1H), 1.41 (d, J = 6.5 Hz, 3H).

[0188] Example 13: Synthesis of {2-[(3-fluorophenyl)oxy]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A12):

[0189] The synthesis route is as follows:

[0190]

[0191] Step 1: {5-bromo-2-[(3-fluorophenyl)oxy]phenyl} ethanoate (A12-2)

[0192] 100 mL single necked flask, compound A12-1 (2.00 g, 7.72 mmol), m-fluorophenylboronic acid (1.19 g, 8.49 mmol), copper acetate (1.54 g, 8.49 mmol), triethylamine (2.34 g, 23.16 mmol) and 20 mL dichloromethane were added, the reaction was replaced three times with oxygen, stirred for 12.0 h, 30 mL saturated brine was added and stirred, allowed to stand until clear separation, the organic phase was separated, the water phase was extracted with 20 mL dichloromethane once, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure until solvent was distilled off, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / dichloromethane: 99 / 1→50 / 50), concentrated under reduced pressure to give compound A12-2 (0.61 g, y = 22%). LCMS (ESI) m / z: 353.0 [M+H] + .

[0193] Step 2: {2-[(3-fluorophenyl)oxy]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid ethyl ester (A12-3)

[0194] Into a 100 mL single necked flask, was added free compound 1 (0.41 g, 1.69 mmol), compound A12-2 (0.61 g, 1.69 mmol), Pd(OAc)2(35.92 mg, 0.16 mmol), X-Phos (76.21 g, 0.16 mmol), Cs2CO3(1.66 g, 5.09 mmol) and 20 mL of toluene, synthesis and work-up procedure refer to compound A1-3, to give compound A12-3 (0.73 g, y = 84%). LCMS (ESI) m / z: 513.2 [M+H] + .

[0195] Step 3: {2-[(3-fluorophenyl)oxy]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A12)

[0196] Into a 100 mL single necked flask, was added A12-3 (0.73 g, 1.42 mmol), sodium hydroxide (0.16 g, 4.00 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, to give compound A12 (0.61 g, y = 87%). LCMS (ESI) m / z: 485.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.1 Hz, 1H), 8.01 - 7.88 (m, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.51 (dt, J = 12.8, 6.0 Hz, 3H), 7.30 (q, J = 7.9 Hz, 1H), 6.82 (dd, J = 8.7, 3.8 Hz, 2H), 6.66 (s, 1H), 6.56 (dd, J = 10.9, 2.5 Hz, 1H), 6.44 (d, J = 2.9 Hz, 1H), 6.38 (dd, J = 8.8, 3.0 Hz, 1H), 4.75 (q, J = 6.5 Hz, 1H), 3.38 (s, 2H), 3.30 (td, J = 12.9, 12.2, 5.5 Hz, 3H), 3.11 (q, J = 7.7 Hz, 1H), 3.01 (dd, J = 8.4, 4.6 Hz, 1H), 2.03 (dd, J = 12.4, 6.3 Hz, 1H), 1.92 (p, J = 6.3, 5.6 Hz, 1H), 1.41 (d, J = 6.5 Hz, 3H).

[0197] Example 14: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-{[3-(trifluoromethyl)phenyl]oxy}phenyl}acetic acid (A13)

[0198] The synthetic route is as follows:

[0199]

[0200] Step 1: (5-bromo-2-{[3-(trifluoromethyl)phenyl]oxy}phenyl) ethanoate (A13-2)

[0201] 100 mL single necked flask was charged with compound A13-1 (2.00 g, 7.72 mmol), (3- (trifluoromethyl)phenyl)boronic acid (1.61 g, 8.49 mmol), copper acetate (1.54 g, 8.49 mmol), triethylamine (2.34 g, 23.16 mmol) and 20 mL dichloromethane. The synthesis and workup procedure was referenced to compound A12-2 to give compound A13-2 (0.90 g, y = 29%). LCMS (ESI) m / z: 403.0 [M+H] + .

[0202] Step 2: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-{[3- (trifluoromethyl)phenyl]oxy}phenyl}acetic acid ethyl ester (A13-3)

[0203] 100 mL single necked flask, add free compound 1 (0.54 g, 2.24 mmol), compound A13-2 (0.90 g, 2.24 mmol), Pd(OAc)2(49.39 mg, 0.22 mmol), X-Phos (104.88 mg, 0.22 mmol), Cs2CO3(1.82 g, 5.60 mmol) and 20 mL of toluene, synthesis and work-up procedure refer to compound A1-3, get compound A13-3 (0.95 g, y = 79%). LCMS (ESI) m / z: 563.2 [M+H] + .

[0204] Step 3: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-{[3- (trifluoromethyl)phenyl]oxy}phenyl}acetic acid (A13)

[0205] 100 mL single necked flask, add A13-3 (0.95 g, 1.69 mmol), sodium hydroxide (0.34 g, 8.45 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound A13 (0.30 g, y = 32%). LCMS (ESI) m / z: 535.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 8.2 Hz, 1H), 7.92 (dd, J = 7.6, 1.9 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.57 - 7.46 (m, 4H), 7.32 (d, J = 7.8 Hz, 1H), 7.11 (dd, J = 8.3, 2.5 Hz, 1H), 7.01 (t, J = 2.1 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.43 (d, J = 2.8 Hz, 1H), 6.33 (dd, J = 8.8, 2.9 Hz, 1H), 4.76 (q, J = 6.5 Hz, 1H), 3.28 (d, J = 12.7 Hz, 5H), 3.03 (dd, J = 28.5, 5.9 Hz, 2H), 2.05 - 1.98 (m, 1H), 1.94 - 1.86 (m, 1H), 1.41 (d, J = 6.5 Hz, 3H).

[0206] Example 15: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-(1,4-oxazin-4-yl)phenyl}acetic acid (A14)

[0207] The synthetic route is as follows:

[0208]

[0209] Step 1: [5-bromo-2-(l,4-oxazepan-4-yl)phenyl] acetic acid ethyl ester (A14-1)

[0210] Into a 250 mL single necked flask, was placed compound 3 (7.00 g, 25.22 mmol), morpholine (2.09 g, 23.99 mmol), Pd(OAc)2(0.56 g, 2.49 mmol), X-Phos (1.21 mg, 2.49 mmol), Cs2CO3(24.65 g, 75.65 mmol) and 70 mL of toluene, synthesis and work-up procedure refer to compound A1-3, to give compound A14-1 (2.0 g, y = 28%). LCMS (ESI) m / z: 328.0 [M+H] + .

[0211] Step 2: {5-[(3S)-3-{[(lR)-l-(naphthalen-l-yl)ethyl]amino}tetrahydro-lH-pyrrol-l-yl]-2- (l,4-oxazepan-4-yl)phenyl} acetic acid ethyl ester (A14-2)

[0212] Into a 100 mL single necked flask, was placed free compound 1 (1.70 g, 7.07 mmol), compound A14-1 (2.00 g, 7.05 mmol), Pd(OAc)2(0.16 g, 0.70 mmol), X-Phos (0.34 g, 0.70 mmol), Cs2CO3(6.89 g, 21.15 mmol) and 50 mL of toluene, synthesis and work-up procedure refer to compound A1-3, to give compound A14-2 (2.20 g, y = 64%). LCMS (ESI) m / z: 488.3 [M+H] + .

[0213] Step 3: {5-[(3S)-3-{[(lR)-l-(naphthalen-l-yl)ethyl]amino}tetrahydro-lH-pyrrol-l-yl]-2- (l,4-oxazepan-4-yl)phenyl} acetic acid (A14)

[0214] Into a 100 mL single necked flask, was placed A14-2 (2.20 g, 4.51 mmol), sodium hydroxide (0.90 g, 22.5 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, to give compound A14 (1.00 g, y = 48%). LCMS (ESI) m / z: 460.3 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 7.4, 2.0 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.58 - 7.46 (m, 3H), 7.01 (d, J = 9.3 Hz, 1H), 6.32 (dd, J = 6.2, 2.9 Hz, 2H), 4.75 (q, J = 6.5 Hz, 1H), 3.64 (dd, J = 5.8, 3.2 Hz, 4H), 3.51 (s, 2H), 3.25 (dd, J = 11.5, 5.1 Hz, 3H), 3.04 (q, J = 7.8 Hz, 1H), 2.99 - 2.89 (m, 1H), 2.66 (t, J = 4.5 Hz, 4H), 2.01 (dd, J = 12.0, 6.2 Hz, 1H), 1.87 (dd, J = 12.2, 6.5 Hz, 1H), 1.40 (d, J = 6.5 Hz, 3H).

[0215] Example 16: Synthesis of {2,4-difluoro-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A15)

[0216] The synthetic route is as follows:

[0217]

[0218] Step 1: 5-bromo-1-(bromomethyl)-2,4-difluorobenzene (A15-2)

[0219] 250 mL single necked flask, compound A15-1 (10.00 g, 48.30 mmol), dibenzoyl peroxide (1.12 g, 4.62 mmol) and 100 mL dichloromethane were stirred, cooled to 0 °C, N-bromosuccinimide (9.02 g, 50.68 mmol) was added portionwise, after addition, 40 °C was stirred overnight, 50 mL purified water was added and stirred, stood until obvious layering, the organic phase was reserved, 50 mL dichloromethane was added to the aqueous phase once, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until solvent was distilled out, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→10 / 90), concentrated under reduced pressure to give compound A15-2 (12.80 g, y = 87%). LCMS (ESI) m / z: 284.8 [M+H] + .

[0220] Step 2: (5-bromo-2,4-difluorophenyl)acetonitrile (A15-3)

[0221] 500 mL single neck flask, add compound A15-2 (12.80 g, 44.77 mmol), TMSCN (13.32 g, 134.26 mmol), TBAF (23.41 g, 89.54 mmol) and 150 mL acetonitrile, stir the reaction at 50 °C for 4.0 h, concentrate under reduced pressure to no solvent evaporate obviously, add 50 mL ethyl acetate and 50 mL purified water, stir, stand until obvious layering, separate the phases, retain the organic phase, extract the aqueous phase with 50 mL ethyl acetate once, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to no solvent evaporate, obtain residue A15-3 (11.50 g, not calculated yield) for use in the next step directly. LCMS (ESI) m / z: 231.9 [M+H] + .

[0222] Step 3: (5-bromo-2,4-difluorophenyl)acetic acid (A15-4)

[0223] 100 mL single neck flask, add A15-3 (11.50 g, 49.48 mmol), sodium hydroxide (5.94 g, 148.5 mmol), 60 mL purified water and 60 mL ethanol, stir the reaction at 50 °C overnight, cool to room temperature, concentrate under reduced pressure to no solvent evaporate obviously, adjust pH to 4.0-6.0 with 6N hydrochloric acid, extract with 50 mL ethyl acetate twice, concentrate under reduced pressure, purify the residue by column chromatography (200-300 mesh silica gel, dichloromethane / methanol: 99 / 1→90 / 10), obtain compound A15-4 (3.00 g, y = 24%). LCMS (ESI) m / z: 250.9 [M+H] + .

[0224] Step 4: (5-bromo-2,4-difluorophenyl) ethyl acetate (A15-5)

[0225] 100 mL three-neck flask, add A15-4 (3.00 g, 11.95 mmol) and 60 mL ethanol, stir, cool to 0 °C, dropwise add thionyl chloride (4.26 g, 35.81 mmol), reflux the reaction overnight, cool to room temperature, concentrate under reduced pressure to no solvent evaporate obviously, add 50 mL ethyl acetate and 50 mL purified water, stir, stand until obvious layering, separate the phases, retain the organic phase, extract the aqueous phase with 20 mL ethyl acetate once, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to no solvent evaporate, purify the residue by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→10 / 90), concentrate under reduced pressure, obtain compound A15-5 (1.50 g, y = 45%). LCMS (ESI) m / z: 279.0 [M+H] + .

[0226] Step 5: {2,4-difluoro-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl} ethyl acetate (A15-6)

[0227] 100 mL single necked flask was charged with free compound 1 (1.29 g, 5.37 mmol), compound A15-5 (1.50 g, 5.37 mmol), Pd(OAc)2(0.12 g, 0.54 mmol), X-Phos (0.26 g, 0.54 mmol), Cs2CO3(5.25 g, 16.11 mmol) and 50 mL of toluene, synthesis and work up procedure refer to compound A1-3 to give compound A15-6 (0.80 g, y = 34%). LCMS (ESI) m / z: 439.2 [M+H] + .

[0228] Step 6: {2,4-difluoro-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl} acetic acid (A15)

[0229] 100 mL single necked flask was charged with A15-6 (0.80 g, 1.82 mmol), sodium hydroxide (0.38 g, 9.60 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work up procedure refer to compound A1 to give compound A15 (0.24 g, y = 32%). LCMS (ESI) m / z: 411.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.2 Hz, 1H), 7.96 - 7.90 (m, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.0 Hz, 1H), 7.58 - 7.46 (m, 3H), 6.88 (dt, J = 13.2, 9.1 Hz, 1H), 6.63 - 6.54 (m, 1H), 4.71 (q, J = 6.5 Hz, 1H), 3.29 (dd, J = 9.6, 3.9 Hz, 2H), 3.15 (td, J = 14.8, 12.2, 6.9 Hz, 4H), 3.05 (d, J = 7.6 Hz, 1H), 1.94 (dq, J = 12.6, 6.4 Hz, 1H), 1.82 (dq, J = 13.2, 7.1 Hz, 1H), 1.39 (d, J = 6.5 Hz, 3H).

[0230] Example 17: Synthesis of {2-fluoro-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl} acetic acid (A16)

[0231] The synthetic route is as follows:

[0232]

[0233] Step 1: (5-bromo-2-fluorophenyl) ethanoate (A16-2)

[0234] Into a 250 mL single necked flask, was placed compound A16-1 (5.00 g, 21.46 mmol) and 60 mL of ethanol, stirred, synthesis and work-up procedure refer to compound A1-2, to give compound A16-2 (5.50 g, y = 98%). LCMS (ESI) m / z: 261.0 [M+H] + .

[0235] Step 2: {2-fluoro-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}acetic acid ethyl ester (A16-3)

[0236] Into a 100 mL single necked flask, was placed free compound 1 (1.84 g, 7.66 mmol), compound A16-2 (2.00 g, 7.66 mmol), Pd(OAc)2 (0.17 g, 0.77 mmol), X-Phos (0.37 g, 0.77 mmol), Cs2CO3 (7.49 g, 22.99 mmol) and 50 mL of toluene, stirred, synthesis and work-up procedure refer to compound A1-3, to give compound A16-3 (2.70 g, y = 84%). LCMS (ESI) m / z: 421.2 [M+H] + .

[0237] Step 3: {2-fluoro-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}acetic acid (A16)

[0238] Into a 100 mL single necked flask, was placed A16-3 (2.70 g, 6.42 mmol), sodium hydroxide (1.28 g, 32.00 mmol), purified water 10 mL and ethanol 10 mL, stirred, synthesis and work-up procedure refer to compound A1, to give compound A16 (1.00 g, y = 40%). LCMS (ESI) m / z: 393.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.3 Hz, 1H), 7.93 (dd, J = 7.8, 1.8 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.53 (qd, J = 7.7, 7.2, 5.1 Hz, 3H), 6.89 (t, J = 9.2 Hz, 1H), 6.33 (dd, J = 6.4, 2.9 Hz, 1H), 6.27 (dt, J = 9.1, 3.6 Hz, 1H), 4.86 (q, J = 6.5 Hz, 1H), 3.43 (s, 2H), 3.32 (h, J = 8.3, 7.4 Hz, 1H), 3.24 (t, J = 8.4 Hz, 2H), 3.01 (q, J = 8.1 Hz, 2H), 2.02 (p, J = 6.3 Hz, 1H), 1.92 (dq, J = 15.0, 7.5 Hz, 1H), 1.45 (d, J = 6.5 Hz, 3H).

[0239] Example 18: Synthesis of {3-fluoro-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A17)

[0240] The synthetic route is as follows:

[0241]

[0242] Step 1: (3-bromo-5-fluorophenyl) ethanoate (A17-2)

[0243] 250 mL single necked flask, compound A17-1 (2.50 g, 10.73 mmol) and 60 mL ethanol were stirred, cooled to 0 °C, 2 mL concentrated sulfuric acid was added dropwise, the synthesis and post-processing operations were referred to compound A1-2, compound A17-2 (2.75 g, y = 98%) was obtained. LCMS (ESI) m / z: 261.0 [M+H] + .

[0244] Step 2: {5-fluoro-3-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]phenyl}acetic acid ethyl ester (A17-3)

[0245] 100 mL single necked flask, add free compound 1 (1.84 g, 7.66 mmol), compound A17-2 (2.00 g, 7.66 mmol), Pd(OAc)2(0.17 g, 0.77 mmol), X-Phos (0.37 g, 0.77 mmol), Cs2CO3(7.49 g, 22.99 mmol) and 50 mL of toluene, synthesis and work-up procedure refer to compound A1-3, get compound A17-3 (1.50 g, y = 47%). LCMS (ESI) m / z: 421.2 [M+H] + .

[0246] Step 3: {3-fluoro-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}acetic acid (A17)

[0247] 100 mL single necked flask, add compound A17-3 (1.00 g, 2.38 mmol), sodium hydroxide (0.71 g, 17.83 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound A17 (0.69 g, y = 69%). LCMS (ESI) m / z: 393.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.33 - 8.26 (m, 1H), 7.93 (dd, J = 6.9, 2.4 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.52 (dq, J = 10.9, 7.4, 6.2 Hz, 3H), 6.25 (d, J = 9.6 Hz, 1H), 6.16 (s, 1H), 6.08 (dt, J = 12.3, 2.4 Hz, 1H), 4.76 (q, J = 6.5 Hz, 1H), 3.45 (s, 2H), 3.37 - 3.28 (m, 1H), 3.27 (dd, J = 8.7, 5.9 Hz, 2H), 3.09 (dt, J = 9.3, 7.1 Hz, 1H), 3.00 (q, J = 6.1, 3.7 Hz, 1H), 2.01 (dq, J = 12.1, 6.0 Hz, 1H), 1.90 (dq, J = 13.3, 7.2 Hz, 1H), 1.41 (d, J = 6.4 Hz, 3H).

[0248] Example 19: Synthesis of {2-fluoro-3-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A18)

[0249] The synthesis route is as follows:

[0250]

[0251] Step 1: (3-bromo-2-fluorophenyl) ethyl acetate (A18-2)

[0252] 250 mL single necked flask, was charged with compound A18-1 (1.50 g, 6.64 mmol) and 60 mL of ethanol was stirred, synthesis and post-processing operations refer to compound A1-2, compound A18-2 (1.30 g, y = 77%) was obtained. LCMS (ESI) m / z: 261.0 [M+H] + .

[0253] Step 2: {2-fluoro-3-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl] phenyl} acetic acid ethyl ester (A18-3)

[0254] 100 mL single necked flask, was charged with free compound 1 (1.20 g, 4.99 mmol), compound A18-2 (1.30 g, 4.99 mmol), Pd(OAc)2(0.11 g, 0.50 mmol), X-Phos (0.24 g, 0.50 mmol), Cs2CO3(4.90 g, 15.04 mmol) and 50 mL of toluene was stirred, synthesis and post-processing operations refer to compound A1-3, compound A18-3 (0.70 g, y = 33%) was obtained. LCMS (ESI) m / z: 421.2 [M+H] + .

[0255] Step 3: {2-fluoro-3-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl] phenyl} acetic acid (A18)

[0256] 100 mL single necked flask, was charged with A18-3 (0.70 g, 1.66 mmol), sodium hydroxide (0.33 g, 8.35 mmol), purified water 10 mL and ethanol 10 mL, synthesis and post-processing operations refer to compound A1, compound A18 (0.45 g, y = 69%) was obtained. LCMS (ESI) m / z: 393.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 8.1 Hz, 1H), 7.93 (dd, J = 7.4, 2.0 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.72 (dd, J = 7.3, 1.2 Hz, 1H), 7.58 - 7.46 (m, 3H), 6.89 (t, J = 7.8 Hz, 1H), 6.60 - 6.53 (m, 1H), 6.57 - 6.48 (m, 1H), 4.78 (q, J = 6.5 Hz, 1H), 3.49 (d, J = 2.1 Hz, 2H), 3.34 (ddt, J = 9.1, 6.4, 3.7 Hz, 2H), 3.27 - 3.09 (m, 3H), 1.96 (dq, J = 12.3, 6.1 Hz, 1H), 1.86 (dq, J = 13.9, 7.2 Hz, 1H), 1.42 (d, J = 6.5 Hz, 3H).

[0257] Example 20: Synthesis of {2-fluoro-3-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A19)

[0258] The synthetic route is as follows:

[0259]

[0260] Step 1: (3-bromo-2-fluorophenyl) ethyl acetate (A19-2)

[0261] 250 mL single necked flask, compound A19-1 (1.50 g, 6.64 mmol) and 60 mL ethanol were stirred, synthesis and post-treatment operation refer to compound A1-2, compound A19-2 (0.98 g, y = 57%) was obtained. LCMS (ESI) m / z: 261.0 [M+H] + .

[0262] Step 2: {2-fluoro-3-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]phenyl}acetic acid ethyl ester (A19-3)

[0263] 100 mL single necked flask, add free compound 1 (0.83 g, 3.46 mmol), compound A19-2 (0.90 g, 3.46 mmol), Pd(OAc)2(0.11 g, 0.50 mmol), X-Phos (0.24 g, 0.50 mmol), Cs2CO3(4.90 g, 15.04 mmol) and 50 mL of toluene, synthesis and post-treatment operation refer to compound A1-3, get compound A19-3 (0.62 g, y = 43%). LCMS (ESI) m / z: 421.2 [M+H] + .

[0264] Step 3: {2-fluoro-3-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H- pyrrol-1-yl]phenyl}acetic acid (A19)

[0265] 100 mL single necked flask, add A19-3 (0.62 g, 1.48 mmol), sodium hydroxide (0.33 g, 8.35 mmol), purified water 10 mL and ethanol 10 mL, synthesis and post-treatment operation refer to compound A1, get compound A19 (0.40 g, y = 62%). LCMS (ESI) m / z: 393.3 [M+H] + . 1 H NMR (400 MHz, D2O) δ 7.59 (s, 1H), 7.33 (s, 1H), 7.15 (s, 2H), 7.07 (s, 1H), 6.95 (s, 1H), 6.83 (s, 1H), 6.46 (s, 1H), 6.32 (s, 1H), 6.17 (s, 1H), 4.39 (s, 1H), 3.19 (s, 2H), 2.66 (d, J = 44.6 Hz, 4H), 2.30 (s, 1H), 1.30 (s, 2H), 1.14 (s, 3H).

[0266] Example 21: Synthesis of {2-chloro-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A20)

[0267] The synthesis route is as follows:

[0268]

[0269] Step 1: {2-chloro-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H- pyrrol-1-yl]phenyl} ethyl acetate (A20-2)

[0270] 100 mL single necked flask, add free compound 1 (1.40 g, 5.82 mmol), compound A20-1 (1.50 g, 5.69 mmol), Pd(OAc)2(0.11 g, 0.50 mmol), X-Phos (0.24 g, 0.50 mmol), Cs2CO3(4.90 g, 15.04 mmol) and 50 mL of toluene, synthesis and work-up procedure refer to compound A1-3, get compound A20-2 (0.80 g, y = 33%). LCMS (ESI) m / z: 437.2 [M+H] + .

[0271] Step 3: {2-chloro-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}acetic acid (A20)

[0272] 100 mL single necked flask, add A20-2 (0.80 g, 1.89 mmol), sodium hydroxide (0.38 g, 9.5 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound A20 (0.50 g, y = 65%). LCMS (ESI) m / z: 409.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.3 Hz, 1H), 7.98 (dd, J = 7.8, 1.7 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 7.1 Hz, 1H), 7.64 - 7.51 (m, 3H), 7.16 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 2.9 Hz, 1H), 6.40 (dd, J = 8.8, 2.9 Hz, 1H), 5.01 (d, J = 7.4 Hz, 1H), 3.60 (s, 2H), 3.52 (s, 1H), 3.37 (ddd, J = 13.8, 9.3, 6.1 Hz, 2H), 3.19 - 3.07 (m, 2H), 2.18 - 2.00 (m, 2H), 1.54 (d, J = 6.5 Hz, 3H).

[0273] Example 22: Synthesis of {4-chloro-3-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A21)

[0274] The synthesis route is as follows:

[0275]

[0276] Step 1: {4-chloro-3-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H- pyrrol-1-yl]phenyl} ethyl acetate (A21-2)

[0277] 100 mL single necked flask was charged with free compound 1 (2.10 g, 8.74 mmol), compound A21-1 (2.00 g, 7.21 mmol), Pd(OAc)2(0.08 g, 0.36 mmol), X-Phos (0.20 g, 0.42 mmol), Cs2CO3(2.30 g, 7.06 mmol) and 50 mL of toluene, synthesis and work up procedure refer to compound A1-3 to give compound A21-2 (0.80 g, y = 33%). LCMS (ESI) m / z: 437.2 [M+H] + Step 3: {4-chloro-3-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H- pyrrol-1-yl]phenyl} acetic acid (A21)

[0278] 100 mL single necked flask was charged with A21-2 (0.80 g, 1.89 mmol), sodium hydroxide (0.38 g, 9.5 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work up procedure refer to compound A1 to give compound A21 (0.50 g, y = 65%). LCMS (ESI) m / z: 409.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8.5 Hz, 1H), 7.96 (dd, J = 17.9, 8.0 Hz, 2H), 7.75 (d, J = 7.3 Hz, 1H), 7.67 - 7.53 (m, 3H), 7.19 (d, J = 8.0 Hz, 1H), 6.79 - 6.71 (m, 2H), 5.17 (d, J = 6.9 Hz, 1H), 3.57 (t, J = 7.0 Hz, 1H), 3.43 (s, 2H), 3.37 - 3.08 (m, 4H), 2.14 (s, 1H), 2.02 (s, 1H), 1.62 (d, J = 6.5 Hz, 3H).

[0279] Example 23: Synthesis of [2-(3-fluorophenyl)-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl] acetic acid (A22)

[0280] The synthesis route is as follows:

[0281]

[0282] Step 1: (2-bromo-5-chlorophenyl) ethyl acetate (A22-1)

[0283] 500 mL single necked flask was charged with compound 3 (25.0 g, 100.20 mmol) and 200 mL of ethanol was stirred, synthesis and work up procedure was referred to compound A1-2 to get compound A22-1 (27.0 g, y = 97%). LCMS (ESI) m / z: 277.0 [M+H] + .

[0284] Step 2: [5-chloro-2-(3-fluorophenyl)phenyl] ethyl acetate (A22-2)

[0285] 100 mL single necked flask was charged with compound A22-1 (2.00 g, 7.21 mmol), m-fluorophenylboronic acid (1.21 g, 8.65 mmol), Pd(PPh3)2Cl2 (0.25 g, 0.36 mmol), potassium carbonate (2.99 g, 21.63 mmol), 1,4-dioxane 20 mL and purified water 2 mL, was purged with nitrogen three times, temperature was raised to 80 °C and stirred overnight. Temperature was lowered to room temperature, purified water and ethyl acetate was added and extracted twice, organic layer was combined, dried and concentrated, crude was purified by column chromatography (200-300 mesh silica gel, petroleum ether / dichloromethane: 80 / 20→60 / 40) to get compound A22-2 (2.00 g, y = 95%). LCMS (ESI) m / z: 293.1 [M+H] + .

[0286] Step 3: [2-(3-fluorophenyl)-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl] ethyl acetate (A22-3)

[0287] 100 mL single necked flask was charged with free compound 1 (1.64 g, 6.82 mmol), compound A22-2 (2.00 g, 6.83 mmol), Pd(OAc)2 (0.15 g, 0.68 mmol), X-Phos (0.33 g, 0.68 mmol), Cs2CO3 (6.66 g, 20.44 mmol) and 50 mL of toluene synthesis and work up procedure was referred to compound A1-3 to get compound A22-3 (2.90 g, y = 86%). LCMS (ESI) m / z: 497.3 [M+H] + Step 3: [2-(3-fluorophenyl)-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl] acetic acid (A22)

[0288] 100 mL single necked flask, add A22-3 (2.90 g, 5.84 mmol), sodium hydroxide (1.17 g, 29.25 mmol), purified water 10 mL and ethanol 20 mL, synthesis and post-processing operation for reference compound A1, compound A22 (2.50 g, y = 91%) was obtained. LCMS (ESI) m / z: 469.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.54 (dq, J = 13.7, 6.8 Hz, 3H), 7.38 (d, J = 7.2 Hz, 1H), 7.11 - 7.02 (m, 3H), 6.99 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.0 Hz, 2H), 4.92 (d, J = 6.6 Hz, 1H), 3.56 - 3.16 (m, 5H), 3.10 - 3.02 (m, 2H), 2.06 (s, 1H), 1.96 (s, 1H), 1.48 (d, J = 6.5 Hz, 3H).

[0289] Example 24: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-[3-(trifluoromethyl)phenyl]phenyl}acetic acid (A23)

[0290] The synthesis route is as follows:

[0291]

[0292] Step 1: {5-chloro-2-[3-(trifluoromethyl)phenyl]phenyl} ethyl acetate (A23-1)

[0293] 100 mL single necked flask, add compound 3 (2.00 g, 7.21 mmol), [3- (trifluoromethyl)phenyl]boronic acid (1.64 g, 8.63 mmol), Pd(PPh3)2Cl2(0.25 g, 0.36 mmol), potassium carbonate (2.99 g, 21.63 mmol), 1,4-dioxane 20 mL and purified water 2 mL, synthesis and post-processing operation for reference compound A22-2, compound A23-1 (2.40 g, y = 93%) was obtained. LCMS (ESI) m / z: 343.1 [M+H] + .

[0294] Step 2: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-[3- (trifluoromethyl)phenyl]phenyl} acetic acid ethyl ester (A23-2)

[0295] 100 mL single necked flask was charged with free compound 1 (1.68 g, 6.99 mmol), compound A23-1 (2.40 g, 7.00 mmol), Pd(OAc)2(0.16 g, 0.70 mmol), X-Phos (0.33 g, 0.70 mmol), Cs2CO3(6.84 g, 20.99 mmol) and 50 mL of toluene, synthesis and work up procedure refer to compound A1-3 to give compound A23-2 (2.90 g, y = 76%). LCMS (ESI) m / z: 497.3 [M+H] + .

[0296] Step 3: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-[3- (trifluoromethyl)phenyl]phenyl} acetic acid (A23)

[0297] 100 mL single necked flask was charged with A23-2 (2.90 g, 5.31 mmol), sodium hydroxide (1.06 g, 26.50 mmol), purified water 10 mL and ethanol 20 mL, synthesis and work up procedure refer to compound A1 to give compound A23 (2.73 g, y = 98%). LCMS (ESI) m / z: 519.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.31 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.75 (d, J = 6.6 Hz, 1H), 7.69 (d, J = 5.5 Hz, 2H), 7.60 (s, 2H), 7.53 (dd, J = 15.9, 8.1 Hz, 3H), 7.02 (dd, J = 8.5, 3.5 Hz, 1H), 6.46 (s, 1H), 6.39 (d, J = 8.6 Hz, 1H), 4.75 (q, J = 7.3 Hz, 1H), 3.35 (dt, J = 23.4, 7.3 Hz, 2H), 3.27 (s, 3H), 3.16 - 3.11 (m, 1H), 3.03 (q, J = 9.1, 6.8 Hz, 1H), 2.04 (dd, J = 13.2, 7.3 Hz, 1H), 1.95 - 1.87 (m, 1H), 1.41 (dd, J = 6.9, 3.5 Hz, 3H).

[0298] Example 25: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-[4-(trifluoromethyl)phenyl}phenyl}acetic acid (A24)

[0299] The synthetic route is as follows:

[0300]

[0301] Step 1: {5-chloro-2-[4-(trifluoromethyl)phenyl]phenyl} ethyl acetate (A24-1)

[0302] 100 mL single necked flask, add compound 3 (2.00 g, 7.21 mmol), [4- (trifluoromethyl)phenyl]boronic acid (1.64 g, 8.63 mmol), Pd(PPh3)2Cl2(0.25 g, 0.36 mmol), potassium carbonate (2.99 g, 21.63 mmol), 1,4-dioxane 20 mL and purified water 2 mL, synthesis and post-processing operations refer to compound A22-2, to get compound A24-1 (2.40 g, y = 97%). LCMS (ESI) m / z: 343.1 [M+H] + .

[0303] Step 2: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-[4-(trifluoromethyl)phenyl}phenyl} ethyl acetate (A24-2)

[0304] 100 mL single necked flask, add free compound 1 (1.68 g, 6.99 mmol), compound A24-1 (2.40 g, 7.00 mmol), Pd(OAc)2(0.16 g, 0.70 mmol), X-Phos (0.33 g, 0.70 mmol), Cs2CO3(6.84 g, 20.99 mmol) and 50 mL of toluene, synthesis and post-processing operations refer to compound A1-3, to get compound A24-2 (3.00 g, y = 78%). LCMS (ESI) m / z: 497.3 [M+H] + .

[0305] Step 3: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-[4-(trifluoromethyl)phenyl}phenyl}acetic acid (A24)

[0306] 100 mL single necked flask was charged with A24-2 (2.90 g, 5.31 mmol), sodium hydroxide (1.06 g, 26.50 mmol), purified water 10 mL and ethanol 20 mL, synthesis and work up procedure refer to compound A1, afforded compound A24 (2.81 g, y = 98%). LCMS (ESI) m / z: 519.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.2 Hz, 1H), 7.94 (dd, J = 7.7, 1.8 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.73 (dd, J = 10.8, 7.6 Hz, 3H), 7.53 (ddq, J = 14.1, 6.9, 3.8, 2.5 Hz, 3H), 7.47 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.44 (d, J = 8.2 Hz, 2H), 4.80 (q, J = 6.4 Hz, 1H), 3.45 (s, 2H), 3.42 - 3.33 (m, 1H), 3.32 (t, J = 7.8 Hz, 2H), 3.13 (d, J = 8.7 Hz, 1H), 3.08 - 3.01 (m, 1H), 2.05 (dd, J = 11.8, 6.2 Hz, 1H), 1.94 (dt, J = 12.6, 6.4 Hz, 1H), 1.43 (d, J = 6.5 Hz, 3H).

[0307] Example 26: Synthesis of [2-(furan-2-yl)-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (A25)

[0308] The synthesis route is as follows:

[0309]

[0310] Step 1: [5-chloro-2-(furan-2-yl)phenyl]acetic acid ethyl ester (A25-1)

[0311] 100 mL single necked flask, add compound 3 (2.00 g, 7.21 mmol), 2-furanboronic acid (0.97 g, 8.67 mmol), Pd(PPh3)4(0.42 g, 0.36 mmol), K2CO3(2.99 g, 21.63 mmol), 1,4-dioxane 20 mL and purified water 2 mL, replace three times nitrogen, warm up to 80 °C and react overnight. Cool down to room temperature, add purified water and extract twice with ethyl acetate, combine the organic phase, dry and concentrate, the crude product is purified by column chromatography (silica gel 200-300 mesh, petroleum ether / dichloromethane: 80 / 20→60 / 40) to give compound A25-1 (1.80 g, y = 94%). LCMS (ESI) m / z: 265.1 [M+H] + .

[0312] Step 2: [2-(Furan-2-yl)-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl] acetic acid ethyl ester (A25-2)

[0313] 100 mL single necked flask, add free compound 1 (1.80 g, 7.49 mmol), compound A25-1 (1.80 g, 6.80 mmol), Pd(OAc)2(0.15 g, 0.68 mmol), X-Phos (0.32 g, 0.68 mmol), Cs2CO3(6.65 g, 20.41 mmol) and 50 mL of toluene, synthesis and work-up procedure refer to compound A1-3 to give compound A25-2 (1.40 g, y = 44%). LCMS (ESI) m / z: 469.3 [M+H] + .

[0314] Step 3: [2-(Furan-2-yl)-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl] acetic acid (A25)

[0315] 100 mL single necked flask, add A25-2 (1.40 g, 2.99 mmol), NaOH (0.60 g, 14.93 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1 to give compound A25 (1.02 g, y = 72%). LCMS (ESI) m / z: 441.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 8.2 Hz, 1H), 7.96 - 7.90 (m, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.57 - 7.47 (m, 3H), 7.38 (d, J = 8.5 Hz, 1H), 6.50 (t, J = 2.7 Hz, 1H), 6.45 - 6.35 (m, 3H), 4.75 (q, J = 6.5 Hz, 1H), 3.63 (s, 2H), 3.41 - 3.20 (m, 3H), 3.13 (q, J = 7.8 Hz, 1H), 3.03 (dd, J = 9.3, 5.6 Hz, 1H), 2.09 - 1.98 (m, 1H), 1.90 (dq, J = 14.5, 7.5 Hz, 1H), 1.41 (d, J = 6.5 Hz, 3H).

[0316] Example 27: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-(1,3-oxazol-5-yl)phenyl}acetic acid (A26)

[0317] The synthetic route is as follows:

[0318]

[0319] Step 1: [5-chloro-2-(oxazol-2-yl)phenyl]acetic acid ethyl ester (A26-1)

[0320] 250 mL single necked flask, compound 3 (8.50 g, 30.63 mmol), oxazole (2.11 g, 30.55 mmol), Pd(OAc)2(0.69 g, 3.07 mmol), X-Phos (1.46 g, 3.07 mmol), Cs2CO3(29.93 g, 91.86 mmol) and 100 mL of toluene, synthesis and workup procedure refer to compound A1-3, compound A26-1 (0.25 g, y = 3%) was obtained. LCMS (ESI) m / z: 281.0 [M+H] + .

[0321] Step 2: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-(1,3-oxazol-5-yl)phenyl}acetic acid ethyl ester (A26-2)

[0322] 100 mL single necked flask, add free compound 1 (0.23 g, 0.94 mmol), compound A26-1 (0.25 g, 0.94 mmol), Pd(OAc)2(21 mg, 0.10 mmol), X-Phos (45 mg, 0.10 mmol), Cs2CO3(0.92 g, 2.82 mmol) and 10 mL toluene, synthesis and work-up procedure refer to compound A1-3, get compound A26-2 (0.17 g, y = 38%). LCMS (ESI) m / z: 470.2 [M+H] + .

[0323] Step 3: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- (1,3-oxazol-5-yl)phenyl}acetic acid (A26)

[0324] 100 mL single necked flask, add A26-2 (170.00 mg, 0.6 mmol), sodium hydroxide (72.40 mg, 1.81 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound A26 (74.00 mg, y = 46%). LCMS (ESI) m / z: 442.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.2 Hz, 1H), 8.02 (s, 1H), 7.98 - 7.91 (m, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.0, 4.9 Hz, 2H), 7.59 - 7.48 (m, 3H), 7.24 (s, 1H), 6.49 (dd, J = 8.7, 2.5 Hz, 1H), 6.43 (d, J = 2.5 Hz, 1H), 4.78 (d, J = 6.8 Hz, 1H), 4.01 (s, 2H), 3.41 (td, J = 9.8, 9.4, 6.5 Hz, 2H), 3.31 (s, 1H), 3.26 - 3.15 (m, 1H), 3.11 (dd, J = 9.9, 5.4 Hz, 1H), 2.10 - 2.01 (m, 1H), 1.96 (p, J = 6.5, 6.1 Hz, 1H), 1.42 (d, J = 6.5 Hz, 3H).

[0325] Example 28: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]-2-(thiophen-2-yl)phenyl}acetic acid (A27)

[0326] The synthesis route is as follows:

[0327]

[0328] Step 1: [5-chloro-2-(thiophen-2-yl)phenyl]acetic acid ethyl ester (A27-1)

[0329] Into a 100 mL single necked flask, was placed compound 3 (2.00 g, 7.21 mmol), 2- thiopheneboronic acid (0.92 g, 7.19 mmol), tetrakis(triphenylphosphine)palladium (0.42 g, 0.36 mmol), potassium carbonate (2.99 g, 21.63 mmol), 1,4-dioxane 20 mL and purified water 2 mL, synthesis and work up procedure refer to compound A26-1 to afford compound A27-1 (1.60 g, y = 79%). LCMS (ESI) m / z: 281.0 [M+H] + .

[0330] Step 2: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- (thiophen-2-yl)phenyl}acetic acid ethyl ester (A27-2)

[0331] Into a 100 mL single necked flask, was placed free compound 1 (1.17 g, 4.87 mmol), compound A27-1 (1.50 g, 5.34 mmol), Pd(OAc)2 (0.55 g, 2.45 mmol), X-Phos (0.32 g, 0.68 mmol), Cs2CO3 (4.76 g, 14.61 mmol) and 50 mL of toluene, synthesis and work up procedure refer to compound A1-3 to afford compound A27-2 (1.20 g, y = 46%). LCMS (ESI) m / z: 485.2 [M+H] + .

[0332] Step 3: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- (thiophen-2-yl)phenyl}acetic acid (A27)

[0333] Into a 100 mL single necked flask, was placed A27-2 (1.20 g, 2.48 mmol), sodium hydroxide (0.50 g, 12.50 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work up procedure refer to compound A1 to afford compound A27 (0.25 g, y = 61%). LCMS (ESI) m / z: 457.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.5 Hz, 1H), 8.09 - 8.01 (m, 2H), 7.84 (d, J = 7.1 Hz, 1H), 7.74 - 7.60 (m, 3H), 7.48 (d, J = 5.2 Hz, 1H), 7.22 (d, J = 9.1 Hz, 1H), 7.09 (dd, J = 5.2, 3.5 Hz, 1H), 6.96 (d, J = 3.5 Hz, 1H), 6.58 - 6.51 (m, 2H), 5.45 (d, J = 7.0 Hz, 1H), 4.00 - 3.93 (m, 1H), 3.53 - 3.45 (m, 2H), 3.41 (dd, J = 10.7, 5.2 Hz, 1H), 3.25 (q, J = 7.9 Hz, 1H), 2.30 (d, J = 6.9 Hz, 2H), 1.74 (d, J = 6.5 Hz, 3H).

[0334] Example 29: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-[(2,2,2-trifluoroethyl)oxy]phenyl}acetic acid (A28)

[0335] The synthetic route is as follows:

[0336]

[0337] Step 1: {5-Bromo-2-[(2,2,2-trifluoroethyl)oxy]phenyl}acetic acid methyl ester (A28-2)

[0338] 100 mL single necked flask, compound A28-1 (2.00 g, 8.16 mmol), 2,2,2- trifluoroethyl trifluoromethanesulfonate (2.08 g, 8.98 mmol), cesium carbonate (4.00 g, 12.24 mmol) and DMF 20 mL stirred overnight, 150 mL purified water and 50 mL ethyl acetate were added to extract, dried, concentrated, the crude product was purified by column chromatography (200-300 mesh silica gel, petroleum ether / dichloromethane: 80 / 20→60 / 40) to give compound A28-2 (1.90 g, y = 71%). LCMS (ESI) m / z: 327.0 [M+H] + .

[0339] Step 2: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-[(2,2,2-trifluoroethyl)oxy]phenyl}acetic acid methyl ester (A28-3)

[0340] 100 mL single necked flask, add free compound 1 (1.00 g, 4.16 mmol), compound A28-2 (1.63 g, 4.99 mmol), Pd(OAc)2(0.02 g, 0.08 mmol), X-Phos (0.02 g, 0.08 mmol), Cs2CO3(4.00 g, 12.50 mmol) and 50 mL toluene, synthesis and work-up procedure refer to compound A1-3, get compound A28-3 (1.00 g, y = 50%). LCMS (ESI) m / z: 487.2 [M+H] + .

[0341] Step 3: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- [(2,2,2-trifluoroethyl)oxy]phenyl}acetic acid (A28)

[0342] 100 mL single necked flask, add A28-3 (1.00 g, 2.06 mmol), sodium hydroxide (0.41 g, 10.30 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound A28 (0.46 g, y = 73%). LCMS (ESI) m / z: 473.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 7.9 Hz, 1H), 7.93 (dd, J = 7.5, 2.1 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.52 (qd, J = 7.3, 5.4 Hz, 3H), 6.91 (d, J = 8.8 Hz, 1H), 6.35 (d, J = 2.9 Hz, 1H), 6.30 (dd, J = 8.8, 2.9 Hz, 1H), 4.75 (q, J = 6.5 Hz, 1H), 4.48 (q, J = 8.9 Hz, 2H), 3.46 (s, 2H), 3.25 (t, J = 6.5 Hz, 3H), 3.06 (q, J = 7.7 Hz, 1H), 3.00 - 2.90 (m, 1H), 2.06 - 1.96 (m, 1H), 1.88 (dq, J = 13.7, 7.2 Hz, 1H), 1.41 (d, J = 6.5 Hz, 3H).

[0343] Example 30: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]-3-(propyloxy)phenyl}acetic acid (A29)

[0344] The synthesis route is as follows:

[0345]

[0346] Step 1: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-3- (propyloxy)phenyl}acetic acid ethyl ester (A29-2)

[0347] 100 mL single necked flask, add free compound 1 (1.00 g, 4.16 mmol), compound A29-1 (1.50 g, 4.99 mmol), Pd(OAc)2(0.02 g, 0.08 mmol), X-Phos (0.02 g, 0.08 mmol), Cs2CO3(4.00 g, 12.50 mmol) and 50 mL of toluene, synthesis and work-up procedure refer to compound A1-3, get compound A29-2 (1.70 g, y = 89%). LCMS (ESI) m / z: 461.3 [M+H] + .

[0348] Step 2: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-3- (propyloxy)phenyl}acetic acid (A29)

[0349] 100 mL single necked flask, add A29-2 (1.00 g, 2.17 mmol), sodium hydroxide (0.40 g, 10.00 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound A29 (0.46 g, y = 20%). LCMS (ESI) m / z: 433.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.55 (s, 3H), 6.09 (s, 1H), 5.98 (s, 1H), 5.86 (s, 1H), 4.83 (s, 1H), 3.85 (t, J = 6.5 Hz, 2H), 3.40 (s, 2H), 3.35 (s, 2H), 3.12 (q, J = 7.8 Hz, 1H), 3.04 (s, 1H), 2.03 (d, J = 16.3 Hz, 2H), 1.71 (h, J = 7.1 Hz, 2H), 1.47 (s, 3H), 0.98 (t, J = 7.4 Hz, 3H).

[0350] Example 31: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-(1,3-thiazin-5-yl)phenyl}acetic acid (A30)

[0351] The synthetic route is as follows:

[0352]

[0353] Step 1: [5-chloro-2-(1,3-thiazin-5-yl)phenyl] ethanoate (A30-1)

[0354] 100 mL single necked flask, add compound 3 (2.00 g, 7.21 mmol), thiazole-5- boronic acid pinacol ester (0.92 g, 7.59 mmol), tetra(triphenylphosphine)palladium (0.42 g, 0.36 mmol), potassium carbonate (2.99 g, 21.63 mmol), 1,4-dioxane 20 mL and purified water 2 mL, synthesis and post-treatment operation refer to compound A26-1, get compound A30-1 (0.15 g, y = 7%). LCMS (ESI) m / z: 282.0 [M+H] + .

[0355] Step 2: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]- 2-(1,3-thiazin-5-yl)phenyl} ethanoate (A30-2)

[0356] 50 mL single necked flask, add free compound 1 (0.13 mg, 0.53 mmol), compound A30-1 (0.15 g, 0.53 mmol), Pd(OAc)2 (12 mg, 0.05 mmol), X-Phos (25 mg, 0.05 mmol), Cs2CO3 (0.52 g, 1.60 mmol) and 10 mL toluene, synthesis and post-treatment operation refer to compound A1-3, get compound A30-2 (0.10 g, y = 39%). LCMS (ESI) m / z: 486.2 [M+H] + .

[0357] Step 3: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]- 2-(1,3-thiazin-5-yl)phenyl} acetic acid (A30)

[0358] 100 mL single necked flask, was added A30-2 (0.10 g, 0.21 mmol), sodium hydroxide (0.05 g, 1.25 mmol), purified water 10 mL and ethanol 10 mL, synthesis and post-processing operations refer to compound A1, compound A30 (40.0 mg, y = 42%) was obtained. LCMS (ESI) m / z: 458.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.25 (d, J = 8.6 Hz, 1H), 7.98 (t, J = 7.9 Hz, 2H), 7.77 (d, J = 7.3 Hz, 1H), 7.68 (s, 1H), 7.61 (t, J = 8.8 Hz, 3H), 7.17 (d, J = 8.3 Hz, 1H), 6.51 - 6.43 (m, 2H), 5.29 (d, J = 6.5 Hz, 1H), 3.82 - 3.75 (m, 1H), 3.54 (s, 2H), 3.47 - 3.38 (m, 2H), 3.28 (dd, J = 11.0, 5.6 Hz, 1H), 3.16 (d, J = 8.5 Hz, 1H), 2.28 - 2.16 (m, 2H), 1.67 (d, J = 6.6 Hz, 3H).

[0359] Example 32: Synthesis of 5-[2-(carboxymethyl)-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]thiophene-2-carboxylic acid (A31)

[0360] The synthesis route is as follows:

[0361]

[0362] Step 1: 5-[4-chloro-2-(2-ethoxy-2-oxoethyl)phenyl]thiophene-2-carboxylic acid ethyl ester (A31-1)

[0363] 100 mL single necked flask, was added compound 3 (2.78 g, 13.90 mmol), [5- (ethoxycarbonyl)thiophen-2-yl]boronic acid (2.00 g, 7.21 mmol), tetraphenylphosphonium palladium (0.58 g, 0.50 mmol), potassium carbonate (3.04 g, 30.04 mmol), 1,4-dioxane 20 mL and purified water 2 mL, synthesis and post-processing operations refer to compound A26-1, compound A31-1 (2.50 g, y = 71%) was obtained. LCMS (ESI) m / z: 353.1 [M+H] + .

[0364] Step 2: {2-[5-(Ethoxycarbonyl)thiophen-2-yl]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl} ethanoate (A31-2)

[0365] 250 mL single necked flask was charged with free compound 1 (1.70 g, 7.07 mmol), compound A31-1 (2.50 g, 7.07 mmol), Pd(OAc)2 (80 mg, 0.36 mmol), X-Phos (25 mg, 0.36 mmol), Cs2CO3 (6.90 g, 21.18 mmol) and 50 mL of toluene, synthesis and work up procedure refer to compound A1-3 to give compound A31-2 (1.50 g, y = 38%). LCMS (ESI) m / z: 557.2 [M+H] + .

[0366] Step 3: 5-[2-(Carboxymethyl)-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro- 1H-pyrrol-1-yl]phenyl]thiophene-2-carboxylic acid (A31)

[0367] 100 mL single necked flask was charged with A31-2 (1.50 g, 2.69 mmol), sodium hydroxide (0.54 g, 13.48 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work up procedure refer to compound A1 to give compound A31 (551.0 mg, y = 41%). LCMS (ESI) m / z: 501.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.4 Hz, 1H), 8.00 - 7.92 (m, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 7.3 Hz, 1H), 7.61 - 7.48 (m, 4H), 7.22 (d, J = 8.9 Hz, 1H), 6.98 (d, J = 3.8 Hz, 1H), 6.45 (d, J = 7.0 Hz, 2H), 4.90 (d, J = 6.8 Hz, 1H), 3.63 (s, 2H), 3.41 (s, 3H), 3.20 - 3.09 (m, 2H), 2.01 (m, 2H), 1.48 (d, J = 6.5 Hz, 3H).

[0368] Example 33: Synthesis of [2-(5-Fluoropyridin-3-yl)-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (A32)

[0369] The synthetic route is as follows:

[0370]

[0371] Step 1: [5-chloro-2-(5-fluoropyridin-3-yl)phenyl]acetic acid ethyl ester (A32-1)

[0372] Into a 100 mL single-necked flask, compound 3 (2.00 g, 7.21 mmol), 5-fluoro-3- pyridineboronic acid (1.22 g, 8.66 mmol), Pd(PPh3)2Cl2(253 mg, 0.36 mmol), potassium carbonate (2.99 g, 21.63 mmol), 1,4-dioxane 20 mL and purified water 2 mL, synthesis and post-processing operations refer to compound A22-2, to obtain compound A32-1 (1.92 g, y = 91%). LCMS (ESI) m / z: 294.1 [M+H] + .

[0373] Step 2: {2-[5-(ethoxycarbonyl)thiophen-2-yl]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid ethyl ester (A32-2)

[0374] Into a 250 mL single-necked flask, free compound 1 (1.53 g, 6.37 mmol), compound A32-1 (1.92 g, 6.37 mmol), Pd(OAc)2(143 mg, 0.64 mmol), X-Phos (304 mg, 0.64 mmol), Cs2CO3(6.23 g, 19.12 mmol) and 50 mL of toluene, synthesis and post-processing operations refer to compound A1-3, to obtain compound A32-2 (2.30 g, y = 71%). LCMS (ESI) m / z: 498.2 [M+H] + .

[0375] Step 3: [2-(5-fluoropyridin-3-yl)-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (A32)

[0376] Into a 100 mL single-necked flask, A32-2 (2.30 g, 4.62 mmol), sodium hydroxide (0.92 g, 23.10 mmol), purified water 10 mL and ethanol 10 mL, synthesis and post-processing operations refer to compound A1, to obtain compound A32 (1.94 g, y = 89%). LCMS (ESI) m / z: 470.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 2.8 Hz, 1H), 8.35 - 8.27 (m, 2H), 7.94 (dd, J = 7.8, 1.9 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.63 (dt, J = 10.1, 2.3 Hz, 1H), 7.59 - 7.48 (m, 3H), 7.07 (s, 1H), 6.46 (dd, J = 5.8, 2.7 Hz, 2H), 4.78 (q, J = 6.5 Hz, 1H), 3.47 (s, 2H), 3.30 (m, 3H), 3.15 (q, J = 7.7 Hz, 1H), 3.05 (dd, J = 9.0, 5.2 Hz, 1H), 2.05 (dd, J = 12.0, 6.2 Hz, 1H), 1.93 (dq, J = 13.6, 7.2 Hz, 1H), 1.42 (d, J = 6.5 Hz, 3H).

[0377] Example 34: Synthesis of {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-[2-(methylamino)ethyl]phenyl}acetic acid (A33)

[0378] The synthetic route is as follows:

[0379]

[0380] Step 1: (5-bromo-2-{[2-(methylamino)ethyl]oxy}phenyl) ethanoate (A33-1)

[0381] 100 mL single necked flask, add compound A33-1 (2.00 g, 5.46 mmol), methylamine hydrochloride (0.55 g, 8.14 mmol), potassium carbonate (2.20 g, 15.92 mmol) and acetonitrile 20 mL, stir, warm to 60 °C, react overnight. Cool to room temperature, add purified water and extract twice with ethyl acetate, combine the organic phase, dry and concentrate to give compound A33-1 (1.30 g, y = 77%). LCMS (ESI) m / z: 316.0 [M+H] + .

[0382] Step 2: [2-({2-[acetyl(methyl)amino]ethyl}oxy)-5-bromophenyl] ethanoate (A33-2)

[0383] 100 mL single neck flask, add compound 33-1 (1.30 g, 4.11 mmol), acetyl chloride (380 mg, 4.84 mmol), triethylamine (830 mg, 8.20 mmol) and dichloromethane 25 mL, stir reaction 3.0 h, add 50 mL purified water, stand to separate, dry, concentrate, get compound A33-2 (1.42 g, y = 95%). LCMS (ESI) m / z: 358.1 [M+H] + .

[0384] Step 3: Ethyl (2-{2-[acetyl(methyl)amino]ethyl}-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl)acetate (A33-3)

[0385] 250 mL single neck flask, add free compound 1 (940 mg, 3.90 mmol), compound A33-2 (1.40 g, 3.90 mmol), Pd(OAc)2(90 mg, 0.40 mmol), X-Phos (180 mg, 0.40 mmol), Cs2CO3(3.80 g, 11.66 mmol) and 50 mL toluene, synthesis and post-processing operation reference compound A1-3, get compound A33-3 (1.20 g, y = 60%). LCMS (ESI) m / z: 502.3 [M+H] + .

[0386] Step 4: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- [2-(methylamino)ethyl]phenyl}acetic acid (A33)

[0387] 100 mL single neck flask, add compound A33-3 (1.20 g, 2.32 mmol), sodium hydroxide (1.85 g, 46.26 mmol), purified water 10 mL and ethanol 10 mL, synthesis and post-processing operation reference compound A1, get compound A33 (0.21 g, y = 21%). LCMS (ESI) m / z: 432.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 8.5 Hz, 1H), 8.07 - 8.00 (m, 2H), 7.98 (d, J = 7.3 Hz, 1H), 7.65 (ddt, J = 14.9, 12.6, 7.0 Hz, 3H), 6.91 (d, J = 8.7 Hz, 1H), 6.49 - 6.40 (m, 2H), 5.41 (q, J = 6.7 Hz, 1H), 4.10 (t, J = 5.0 Hz, 2H), 3.83 (d, J = 6.5 Hz, 1H), 3.58 (s, 2H), 3.47 - 3.31 (m, 3H), 3.26 (t, J = 5.0 Hz, 2H), 3.10 (q, J = 8.0 Hz, 1H), 2.63 (s, 3H), 2.35 - 2.17 (m, 2H), 1.74 (d, J = 6.5 Hz, 3H).

[0388] Example 35: Synthesis of {2-[(2-ethoxyethyl)oxy]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A34)

[0389] The synthetic route is as follows:

[0390]

[0391] Step 1: {2-[(2-ethoxyethyl)oxy]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid ethyl ester (A34-2)

[0392] 250 mL single necked flask, free compound 1 (1.10 g, 4.54 mmol), compound A34-1 (1.50 g, 4.54 mmol), Pd(OAc)2(102 mg, 0.45 mmol), X-Phos (216 mg, 0.45 mmol), Cs2CO3(4.43 g, 11.66 mmol) and 50 mL of toluene, synthesis and workup procedure refer to compound A1-3, compound A34-2 (1.90 g, y = 86%) was obtained. LCMS (ESI) m / z: 502.3 [M+H] + .

[0393] Step 2: {2-[(2-ethoxyethyl)oxy]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (A34)

[0394] 100 mL single necked flask was charged with A34-2 (1.90 g, 3.87 mmol), sodium hydroxide (0.77 g, 19.25 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work up procedure refer to compound A1 to get compound A34 (388 mg, y = 22%). LCMS (ESI) m / z: 463.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 8.6 Hz, 1H), 8.08 - 8.02 (m, 2H), 7.83 (d, J = 7.2 Hz, 1H), 7.67 (dq, J = 14.3, 7.7, 7.2 Hz, 3H), 6.88 (d, J = 8.6 Hz, 1H), 6.50 - 6.41 (m, 2H), 5.43 (d, J = 6.7 Hz, 1H), 3.99 - 3.93 (m, 2H), 3.92 - 3.85 (m, 1H), 3.62 (t, J = 4.8 Hz, 2H), 3.54 - 3.42 (m, 5H), 3.40 (d, J = 6.1 Hz, 1H), 3.34 (d, J = 5.1 Hz, 1H), 3.13 (d, J = 8.3 Hz, 1H), 2.26 (d, J = 7.0 Hz, 2H), 1.73 (d, J = 6.6 Hz, 3H), 1.12 (t, J = 7.0 Hz, 3H).

[0395] Example 36: Synthesis of {[2-(carboxymethyl)-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]oxy}acetic acid (A35)

[0396] The synthesis route is as follows:

[0397]

[0398] Step 1: {5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]-2-{[2-(1,4-oxazepan-4-yl)-2-oxovinyl]oxy}phenyl} ethyl acetate (A35-2)

[0399] 250 mL single necked flask, was charged with free compound 1 (4.79 g, 19.93 mmol), compound A35-1 (7.70 g, 19.93 mmol), Pd(OAc)2 (447 mg, 1.99 mmol), X-Phos (949 mg, 1.99 mmol), Cs2CO3 (19.48 g, 59.79 mmol) and 50 mL of toluene, synthesis and work-up procedure refer to compound A1-3, to give compound A35-2 (4.20 g, y = 39%). LCMS (ESI) m / z: 546.3 [M+H] + .

[0400] Step 2: {[2-(carboxymethyl)-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]oxy}acetic acid (A35)

[0401] 100 mL single necked flask, was charged with A35-2 (2.00 g, 3.67 mmol), sodium hydroxide (733 mg, 18.33 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, to give compound A35 (330 mg, y = 20%). LCMS (ESI) m / z: 449.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 5.8 Hz, 3H), 6.75 (d, J = 8.8 Hz, 1H), 6.34 (s, 1H), 6.29 (d, J = 8.9 Hz, 1H), 4.84 (s, 1H), 4.36 (s, 2H), 3.52 (s, 2H), 3.27 (m, 3H), 3.06 (m, 2H), 2.08 - 1.87 (m, 2H), 1.45 (d, J = 5.3 Hz, 3H).

[0402] Example 37: Synthesis of {2-fluoro-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (B1)

[0403] The synthesis route is as follows:

[0404]

[0405] Step 1: (3-bromo-2-fluorophenyl) ethyl acetate (B1-2)

[0406] 250 mL single necked flask, add compound B1-1 (2.00 g, 8.58 mmol) and 60 mL ethanol, stir, cool to 0 °C, dropwise add concentrated sulfuric acid 1 mL, synthesis and workup procedure refer to compound A1-2, get compound B1-2 (2.00 g, y = 89%). LCMS (ESI) m / z: 261.0 [M+H] + .

[0407] Step 2: {2-Fluoro-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}acetic acid ethyl ester (B1-3)

[0408] 250 mL single necked flask, add free compound 1 (1.00 g, 4.16 mmol), compound B1-2 (1.31 g, 4.99 mmol), Pd(OAc)2 (50 mg, 0.20 mmol), X-Phos (100 mg, 0.20 mmol), Cs2CO3 (4.10 g, 12.48 mmol) and 50 mL toluene, synthesis and workup procedure refer to compound A1-3, get compound B1-3 (0.70 g, y = 40%). LCMS (ESI) m / z: 421.2 [M+H] + .

[0409] Step 3: {2-Fluoro-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}acetic acid (B1)

[0410] 100 mL single necked flask, add B1-3 (0.60 g, 1.43 mmol), sodium hydroxide (572 mg, 14.3 mmol), purified water 10 mL and ethanol 10 mL, synthesis and workup procedure refer to compound A1, get compound B1 (0.30 g, y = 53%). LCMS (ESI) m / z: 393.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.34 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 8.6 Hz, 2H), 7.56 (dd, J = 14.2, 5.9 Hz, 3H), 7.05 (t, J = 8.6 Hz, 1H), 6.24 (d, J = 8.9 Hz, 2H), 4.96 (s, 1H), 3.43 (s, 3H), 3.36 (q, J = 7.7 Hz, 2H), 3.13 (q, J = 7.8 Hz, 2H), 2.07 (m, 2H), 1.52 (s, 3H).

[0411] Example 38: Synthesis of {3-fluoro-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (B2)

[0412] The synthetic route is as follows:

[0413]

[0414] Step 1: (4-bromo-3-fluorophenyl) ethyl acetate (B2-2)

[0415] Into a 250 mL single necked flask, was placed compound B2-1 (2.00 g, 8.58 mmol) and 60 mL of ethanol was stirred and cooled to 0 °C, 1 mL of concentrated sulfuric acid was added dropwise, the synthesis and workup procedure was referenced to compound A1-2 to give compound B2-2 (1.80 g, y = 81%). LCMS (ESI) m / z: 261.0 [M+H] + .

[0416] Step 2: {3-fluoro-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]phenyl} ethyl acetate (B2-3)

[0417] Into a 250 mL single necked flask, was placed free compound 1 (1.00 g, 4.16 mmol), compound B2-2 (1.31 g, 4.99 mmol), Pd(OAc)2 (50 mg, 0.20 mmol), X-Phos (100 mg, 0.20 mmol), Cs2CO3 (4.10 g, 12.48 mmol) and 50 mL of toluene, the synthesis and workup procedure was referenced to compound A1-3 to give compound B2-3 (0.89 g, y = 51%). LCMS (ESI) m / z: 421.2 [M+H] + .

[0418] Step 3: {2-fluoro-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]phenyl} acetic acid (B2)

[0419] Into a 100 mL single necked flask, was placed B2-3 (0.80 g, 1.90 mmol), sodium hydroxide (760 mg, 19.0 mmol), purified water 10 mL and ethanol 10 mL, the synthesis and workup procedure was referenced to compound A1 to give compound B2 (0.39 g, y = 52%). LCMS (ESI) m / z: 393.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.33 - 8.26 (m, 1H), 7.93 (dd, J = 7.0, 2.3 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.51 (dtd, J = 10.2, 7.2, 4.8 Hz, 3H), 6.91 (dd, J = 14.9, 2.0 Hz, 1H), 6.85 (dd, J = 8.2, 2.0 Hz, 1H), 6.56 (t, J = 9.0 Hz, 1H), 4.72 (q, J = 6.6 Hz, 1H), 3.42 - 3.28 (m, 4H), 3.19 (p, J = 6.9, 5.9 Hz, 2H), 3.09 (ddd, J = 8.9, 5.7, 2.7 Hz, 1H), 1.96 (dq, J = 12.3, 6.1 Hz, 1H), 1.83 (dq, J = 13.6, 7.2 Hz, 1H), 1.40 (d, J = 6.5 Hz, 3H).

[0420] Example 39: Synthesis of {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-3-methylphenyl}acetic acid (B3)

[0421] The synthetic route is as follows:

[0422]

[0423] Step 1: (4-bromo-3-methylphenyl) ethanoate (B3-2)

[0424] 250 mL single necked flask, compound B3-1 (1.00 g, 4.37 mmol) and 60 mL ethanol were stirred, cooled to 0 °C, 1 mL concentrated sulfuric acid was added dropwise, the synthesis and post-processing operation was referred to compound A1-2, compound B3-2 (0.87 g, y = 77%) was obtained. LCMS (ESI) m / z: 257.0 [M+H] + .

[0425] Step 2: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-3- methylphenyl} ethanoate (B3-3)

[0426] 250 mL single necked flask, add free compound 1 (1.00 g, 4.16 mmol), compound B3-2 (1.28 g, 4.99 mmol), Pd(OAc)2(50 mg, 0.20 mmol), X-Phos (100 mg, 0.20 mmol), Cs2CO3(4.10 g, 12.48 mmol) and 50 mL of toluene, synthesis and work-up procedure refer to compound A1-3, get compound B3-3 (0.73 g, y = 42%). LCMS (ESI) m / z: 417.2 [M+H] + .

[0427] Step 3: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-3- methylphenyl}acetic acid (B3)

[0428] 100 mL single necked flask, add B3-3 (0.70 g, 1.68 mmol), sodium hydroxide (0.34 g, 8.40 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound B3 (0.44 g, y = 67%). LCMS (ESI) m / z: 389.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.0 Hz, 1H), 7.93 (dd, J = 7.3, 2.1 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.51 (qd, J = 8.1, 7.3, 2.3 Hz, 3H), 6.97 - 6.86 (m, 2H), 6.71 - 6.64 (m, 1H), 4.71 (q, J = 6.5 Hz, 1H), 3.38 (s, 2H), 3.18 (s, 1H), 3.13 - 3.06 (m, 2H), 3.02 (m, 1H), 2.92 (dd, J = 9.2, 6.3 Hz, 1H), 2.11 (s, 3H), 1.99 (dq, J = 12.6, 6.5 Hz, 1H), 1.86 - 1.73 (m, 1H), 1.41 (d, J = 6.5 Hz, 3H).

[0429] Example 40: Synthesis of {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]-2-methylphenyl}acetic acid (B4):

[0430] The synthesis route is as follows:

[0431]

[0432] Step 1: (4-bromo-2-methylphenyl) ethyl acetate (B4-2)

[0433] 250 mL single neck flask, compound B4-1 (1.00 g, 4.37 mmol) and 60 mL ethanol were stirred, cooled to 0 °C, 1 mL of concentrated sulfuric acid was added dropwise, synthesis and post-processing operations refer to compound A1-2, compound B4-2 (0.93 g, y = 83%) was obtained. LCMS (ESI) m / z: 257.0 [M+H] + .

[0434] Step 2: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-3- methylphenyl} ethyl acetate (B4-3)

[0435] 250 mL single neck flask, free compound 1 (1.00 g, 4.16 mmol), compound B4-2 (1.28 g, 4.99 mmol), Pd(OAc)2 (50 mg, 0.20 mmol), X-Phos (100 mg, 0.20 mmol), Cs2CO3 (4.10 g, 12.48 mmol) and 50 mL toluene were added, synthesis and post-processing operations refer to compound A1-3, compound B4-3 (0.73 g, y = 42%) was obtained. LCMS (ESI) m / z: 417.2 [M+H] + .

[0436] Step 3: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- methylphenyl} acetic acid (B4)

[0437] 100 mL single neck flask, B4-3 (0.50 g, 1.20 mmol), sodium hydroxide (0.24 g, 6.00 mmol), purified water 5 mL and ethanol 5 mL were added, synthesis and post-processing operations refer to compound A1, compound B4 (0.32 g, y = 69%) was obtained. LCMS (ESI) m / z: 389.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.0 Hz, 1H), 7.92 (dd, J = 7.3, 2.1 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.53 (qd, J = 8.1, 7.3, 2.3 Hz, 3H), 6.97 - 6.86 (m, 2H), 6.71 - 6.64 (m, 1H), 4.71 (q, J = 6.5 Hz, 1H), 3.38 (s, 2H), 3.18 (s, 1H), 3.13 - 3.06 (m, 2H), 3.02 (m, 1H), 2.91 (dd, J = 9.2, 6.3 Hz, 1H), 2.10 (s, 3H), 1.99 (dq, J = 12.6, 6.5 Hz, 1H), 1.86 - 1.72 (m, 1H), 1.43 (d, J = 6.5 Hz, 3H).

[0438] Example 41: Synthesis of {2,6-difluoro-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (B5)

[0439] The synthetic route is as follows:

[0440]

[0441] Step 1: {2,6-difluoro-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro- 1H-pyrrol-1-yl]phenyl} ethyl acetate (B5-2)

[0442] 250 mL single necked flask, free compound 1 (861 mg, 3.58 mmol), compound B5-1 (1.00 g, 3.58 mmol), Pd(OAc)2(80 mg, 0.36 mmol), X-Phos (171 mg, 0.36 mmol), Cs2CO3(3.50 g, 10.74 mmol) and 50 mL of toluene, synthesis and workup procedure refer to compound A1-3, compound B5-2 (1.44 g, y = 74%) was obtained. LCMS (ESI) m / z: 439.2 [M+H] + .

[0443] Step 2: {2,6-difluoro-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro- 1H-pyrrol-1-yl]phenyl} acetic acid (B5)

[0444] 100 mL single necked flask, add B5-2 (1.44 g, 3.28 mmol), sodium hydroxide (0.66 g, 16.43 mmol), purified water 5 mL and ethanol 5 mL, synthesis and post-processing operation reference compound A1, get compound B5 (1.25 g, y = 93%). LCMS (ESI) m / z: 411.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.94 (s, 1H), 7.85-7.78 (m, 1H), 7.73 (dd, J = 10.9, 6.0 Hz, 1H), 7.57-7.47 (m, J = 6.5, 5.5 Hz, 3H), 6.08 (dq, J = 10.2, 5.2 Hz, 2H), 4.75 (dd, J = 11.7, 6.0 Hz, 1H), 3.42 (q, J = 5.5, 5.0 Hz, 2H), 3.37-3.23 (m, 3H), 3.11 (s, 1H), 2.99 (s, 1H), 2.05-1.98 (m, 1H), 1.94-1.88 (m, 1H), 1.42 (p, J = 5.7 Hz, 3H).

[0445] Example 42: Synthesis of {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-3-methoxyphenyl}acetic acid (B6)

[0446] The synthesis route is as follows:

[0447]

[0448] Step 1: methyl 4-bromo-3-methoxybenzoate (B6-2)

[0449] 100 mL single necked flask, add free compound B6-1 (10.00 g, 0.046 mol), methyl iodide (19.62 g, 0.14 mol), potassium carbonate (25.47 g, 0.18 mol) and 50 mL DMF stirring reaction overnight, add 500 mL saturated brine and 100 mL ethyl acetate stirring, standing to obvious layering, phase separation, retain the organic phase, 50 mL ethyl acetate extract the aqueous phase twice, combine the organic phase, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to distill off the solvent, get compound B6-2 (10.50 g, y = 93%). LCMS (ESI) m / z: 245.0 [M+H] + .

[0450] Step 2: (4-bromo-3-methoxyphenyl)methanol (B6-3)

[0451] A 500 mL three-necked flask was charged with compound B6-2 (10.50 g, 23.8 mmol) and 100 mL of anhydrous tetrahydrofuran and stirred, cooled to 0 °C, lithium aluminum hydride (1.95 g, 51.4 mmol) was added portionwise, the reaction was maintained for 4.0 h, 150 mL of 1 N hydrochloric acid was added slowly and stirred, left to stand until clear separation, the organic phase was retained, the aqueous phase was extracted twice with 50 mL of ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure until solvent evaporation, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→80 / 20), concentrated under reduced pressure to give compound B6-3 (5.80 g, y = 62%). LCMS (ESI) m / z: 217.0 [M+H] + .

[0452] Step 3: 1-bromo-4-(bromomethyl)-2-methoxybenzene (B6-4)

[0453] A 500 mL three-necked flask was charged with compound B6-3 (5.00 g, 23.00 mmol), triphenylphosphine (7.30 g, 27.60 mmol), carbon tetrabromide (8.40 g, 25.30 mmol) and 100 mL of dichloromethane and stirred overnight, the filtrate was concentrated under reduced pressure until solvent evaporation, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→85 / 15), concentrated under reduced pressure to give compound B6-4 (5.80 g, y = 90%). LCMS (ESI) m / z: 279.0 [M+H] + .

[0454] Step 4: (4-bromo-3-methoxyphenyl)acetonitrile (B6-5)

[0455] A 500 mL three-necked flask was charged with compound B6-4 (5.00 g, 17.9 mmol), TBAF (5.60 g, 21.4 mmol) and 50 mL of acetonitrile and stirred, cooled to 0 °C, TMSCN (2.13 g, 21.4 mmol) was added portionwise, stirred overnight, the filtrate was concentrated under reduced pressure until solvent evaporation, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→85 / 15), concentrated under reduced pressure to give compound B6-5 (3.60 g, y = 89%). LCMS (ESI) m / z: 226.0 [M+H] + .

[0456] Step 5: (4-bromo-3-methoxyphenyl) ethyl acetate (B6-6)

[0457] 500 mL three-necked flask, compound B6-5 (3.00 g, 13.27 mmol) and 50 mL of ethanol were added and stirred, cooled to 0 °C, dropwise added 7.5 mL of concentrated sulfuric acid, synthesis and post-processing operation for reference compound A1-2, compound B6-6 (3.20 g, y = 88%) was obtained. LCMS (ESI) m / z: 273.0 [M+H] + .

[0458] Step 6: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-3- methoxyphenyl}acetic acid ethyl ester (B6-7)

[0459] 100 mL single-necked flask, free compound 1 (1.00 g, 4.61 mmol), compound B6-6 (1.10 g, 4.99 mmol), Pd(OAc)2(19 mg, 0.08 mmol), X-Phos (40 mg, 0.08 mmol), Cs2CO3(4.00 g, 12.50 mmol) and 20 mL of toluene were added, synthesis and post-processing operation for reference compound A1-3, compound B6-7 (1.20 g, y = 67%) was obtained. LCMS (ESI) m / z: 433.2 [M+H] + .

[0460] Step 7: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-3- methoxyphenyl}acetic acid (B6)

[0461] 100 mL single-necked flask, B6-7 (1.00 g, 2.31 mmol), sodium hydroxide (0.28 g, 6.93 mmol), purified water 5 mL and ethanol 5 mL were added, synthesis and post-processing operation for reference compound A1, compound B6 (0.31 g, y = 33%) was obtained. LCMS (ESI) m / z: 405.2 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 8.32 (d, J = 8.2 Hz, 1H), 7.92 (dd, J = 7.7, 1.8 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.72 (dd, J = 7.3, 1.2 Hz, 1H), 7.55 - 7.46 (m, 3H), 6.73 (d, J = 2.0 Hz, 1H), 6.65 (dd, J = 8.1, 1.9 Hz, 1H), 6.48 (d, J = 8.1 Hz, 1H), 4.71 (s, 1H), 3.64 (s, 3H), 3.40 (s, 2H), 3.22 (dt, J = 7.9, 6.0 Hz, 2H), 3.14 (dt, J = 9.4, 6.8 Hz, 2H), 3.01 (t, J = 7.9 Hz, 1H), 1.93 (dt, J = 13.2, 6.6 Hz, 1H), 1.77 (dd, J = 12.5, 6.7 Hz, 1H), 1.40 (d, J = 6.6 Hz, 3H).

[0462] Example 43: Synthesis of {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-methoxyphenyl}acetic acid (B7)

[0463] The synthetic route is as follows:

[0464]

[0465] Step 1: 4-bromo-2-methoxyphenyl ethanoate (B7-2)

[0466] A 500 mL three-necked flask was charged with compound B7-1 (10.00 g, 40.80 mmol) and 80 mL of ethanol, stirred, cooled to 0 °C, and 1.5 mL of concentrated sulfuric acid was added dropwise. The synthesis and post-processing operations were referred to compound A1-2 to obtain compound B7-2 (10.50 g, y = 94%). LCMS (ESI) m / z: 245.0 [M+H] + .

[0467] Step 2: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2- methoxyphenyl}acetic acid ethyl ester (B7-3)

[0468] 100 mL single necked flask was charged with free compound 1 (1.47 g, 6.11 mmol), compound B7-2 (2.00 g, 7.32 mmol), Pd(OAc)2 (70 mg, 0.31 mmol), X-Phos (150 mg, 0.31 mmol), Cs2CO3 (5.96 g, 12.50 mmol) and 20 mL of toluene, synthesis and work up procedure refer to compound A1-3 to give compound B7-3 (1.60 g, y = 61%). LCMS (ESI) m / z: 433.2 [M+H] + .

[0469] Step 3: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- methoxyphenyl}acetic acid ethyl ester (B7)

[0470] 100 mL single necked flask was charged with B7-3 (1.60 g, 3.70 mmol), sodium hydroxide (0.59 g, 14.75 mmol), purified water 5 mL and ethanol 5 mL, synthesis and work up procedure refer to compound A1 to give compound B7 (0.50 g, y = 33%). LCMS (ESI) m / z: 405.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.33 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.51 (q, J = 7.9, 6.8 Hz, 3H), 6.88 (d, J = 8.2 Hz, 1H), 5.98 (d, J = 2.3 Hz, 1H), 5.96 (dd, J = 8.4, 2.2 Hz, 1H), 4.76 (s, 1H), 3.70 (s, 3H), 3.32 (s, 4H), 3.12 (dt, J = 9.2, 7.3 Hz, 1H), 2.99 (s, 1H), 2.04 (s, 1H), 1.91 (s, 1H), 1.42 (s, 3H).

[0471] Example 44: Synthesis of {2-ethoxy-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (B8)

[0472] The synthesis route is as follows:

[0473]

[0474] Step 1: 4-bromo-2-ethoxybenzoic acid ethyl ester (B8-1)

[0475] 250 mL three-necked flask, compound 4 (2.00 g, 7.72 mmol), potassium carbonate (3.20 g, 23.00 mmol), ethyl bromide (0.93 g, 8.40 mmol) and 50 mL of acetonitrile were added, the synthesis and post-processing operations were referenced to compound A2-2, and compound B8-1 (2.02 g, y = 91%) was obtained. LCMS (ESI) m / z: 287.0 [M+H] + .

[0476] Step 2: {2-Ethoxy-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}acetic acid ethyl ester (B8-2)

[0477] 100 mL single-necked flask, free compound 1 (1.00 g, 4.16 mmol), compound B8-1 (2.00 g, 7.32 mmol), Pd(OAc)2 (70 mg, 0.31 mmol), X-Phos (150 mg, 0.31 mmol), Cs2CO3 (4.51 g, 13.90 mmol) and 20 mL of toluene were added, the synthesis and post-processing operations were referenced to compound A1-3, and compound B8-2 (1.60 g, y = 86%) was obtained. LCMS (ESI) m / z: 447.3 [M+H] + .

[0478] Step 3: {2-Ethoxy-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}acetic acid (B8)

[0479] 100 mL single-necked flask, B8-2 (1.60 g, 3.53 mmol), sodium hydroxide (0.60 g, 15.00 mmol), purified water 10 mL and ethanol 10 mL were added, the synthesis and post-processing operations were referenced to compound A1, and compound B8 (0.52 g, y = 35%) was obtained. LCMS (ESI) m / z: 419.2 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 11.70 (s, 1H), 10.23 (s, 1H), 9.78 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 8.12 (s, 1H), 8.02 (t, J = 8.9 Hz, 2H), 7.64 (d, J = 7.5 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.02 (d, J = 9.1 Hz, 2H), 5.42 (s, 1H), 3.96 (q, J = 7.0 Hz, 2H), 3.82 (s, 1H), 3.40 (t, J = 7.1 Hz, 3H), 3.15 (q, J = 8.1 Hz, 1H), 2.34 (s, 1H), 2.26 (s, 1H), 1.76 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H).

[0480] Example 45: Synthesis of {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-(propan-2-yloxy)phenyl}acetic acid (B9)

[0481] The synthetic route is as follows:

[0482]

[0483] Step 1: [4-bromo-2-(propan-2-yloxy)phenyl]acetic acid ethyl ester (B9-1)

[0484] Into a 250 mL three-necked flask, was placed compound 4 (2.00 g, 7.72 mmol), potassium carbonate (3.20 g, 23.15 mmol), bromoisopropane (1.04 g, 8.49 mmol) and 50 mL of acetonitrile. The synthesis and work-up procedure was referenced to compound A2-2 to give compound B9-1 (1.95 g, y = 84%). LCMS (ESI) m / z: 301.0 [M+H] + .

[0485] Step 2: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2- (propan-2-yloxy)phenyl}acetic acid ethyl ester (B9-2)

[0486] 100 mL single necked flask, add free compound 1 (0.80 g, 3.32 mmol), compound B9-1 (1.20 g, 3.32 mmol), Pd(OAc)2(40 mg, 0.16 mmol), X-Phos (80 mg, 0.16 mmol), Cs2CO3(3.25 g, 9.96 mmol) and 20 mL of toluene, synthesis and work-up procedure refer to compound A1-3, get compound B9-2 (0.80 g, y = 52%). LCMS (ESI) m / z: 461.3 [M+H] + .

[0487] Step 3: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- (prop-2-yloxy)phenyl}acetic acid (B9)

[0488] 100 mL single necked flask, add B9-2 (0.80 g, 1.70 mmol), sodium hydroxide (0.20 g, 5.20 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound B9 (0.50 g, y = 68%). LCMS (ESI) m / z: 433.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.32 (d, J = 8.0 Hz, 1H), 7.92 (dd, J = 7.2, 2.3 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.51 (qd, J = 7.2, 5.1 Hz, 3H), 6.87 (d, J = 8.7 Hz, 1H), 5.94 (dq, J = 4.4, 2.3 Hz, 2H), 4.73 (d, J = 6.9 Hz, 1H), 4.47 (hept, J = 6.0 Hz, 1H), 3.29 (d, J = 4.1 Hz, 3H), 3.24 (t, J = 6.3 Hz, 1H), 3.20 (dd, J = 9.0, 6.6 Hz, 1H), 3.09 (dt, J = 9.1, 7.2 Hz, 1H), 2.92 (dd, J = 9.1, 5.5 Hz, 1H), 2.02 (dd, J = 12.2, 6.3 Hz, 1H), 1.87 (s, 1H), 1.40 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.0 Hz, 6H).

[0489] Example 46: Synthesis of {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]-2-(propyloxy)phenyl}acetic acid (B10)

[0490] The synthetic route is as follows:

[0491]

[0492] Step 1: [4-bromo-2-(propyloxy)phenyl]acetic acid ethyl ester (B10-1)

[0493] Into a 250 mL three-necked flask, was placed compound 4 (2.00 g, 7.72 mmol), potassium carbonate (3.20 g, 23.15 mmol), n-propyl bromide (1.04 g, 8.49 mmol) and 50 mL of acetonitrile. The synthesis and work-up procedure was referenced to compound A2-2 to give compound B10-1 (1.57 g, y = 68%). LCMS (ESI) m / z: 301.0 [M+H] + .

[0494] Step 2: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- (propyloxy)phenyl}acetic acid ethyl ester (B10-2)

[0495] Into a 100 mL single-necked flask, was placed free compound 1 (1.04 g, 4.31 mmol), compound B10-1 (1.57 g, 5.20 mmol), Pd(OAc)2 (50 mg, 0.22 mmol), X-Phos (100 mg, 0.22 mmol), Cs2CO3 (4.25 g, 13.04 mmol) and 20 mL of toluene. The synthesis and work-up procedure was referenced to compound A1-3 to give compound B10-2 (0.45 g, y = 23%). LCMS (ESI) m / z: 461.3 [M+H] + .

[0496] Step 3: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- (propyloxy)phenyl}acetic acid (B10)

[0497] Into a 100 mL single-necked flask, was placed B10-2 (0.45 g, 0.98 mmol), sodium hydroxide (0.12 g, 3.00 mmol), purified water 10 mL and ethanol 10 mL. The synthesis and work-up procedure was referenced to compound A1 to give compound B10 (0.38 g, y = 90%). LCMS (ESI) m / z: 433.2 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 8.33 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.52 (dt, J = 15.4, 8.8 Hz, 3H), 6.88 (d, J = 8.3 Hz, 1H), 5.95 (s, 2H), 4.78 (s, 1H), 3.84 (t, J = 6.3 Hz, 2H), 3.32 (s, 4H), 3.27 (s, 1H), 3.11 (q, J = 7.8 Hz, 1H), 2.99 (s, 1H), 2.06 (s, 1H), 1.94 (s, 1H), 1.68 (h, J = 6.7 Hz, 2H), 1.44 (s, 3H), 0.97 (t, J = 7.4 Hz, 3H).

[0498] Example 47: Synthesis of {2-[(2-hydroxyethyl)oxy]-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (B11)

[0499] The synthetic route is as follows:

[0500]

[0501] Step 1: Acetic acid-2-{[5-bromo-2-(2-ethoxy-2-oxoethyl)phenyl]oxy}ethyl ester (B11-1)

[0502] A 250 mL three-necked flask was charged with compound 4 (1.60 g, 6.17 mmol), potassium carbonate (2.55 g, 18.50 mmol), acetic acid-2-bromoethyl ester (1.04 g, 7.41 mmol) and 50 mL of acetonitrile. The synthesis and workup procedure was referenced to compound A2-2 to give compound B11-1 (1.20 g, y = 62%). LCMS (ESI) m / z: 301.0 [M+H] + .

[0503] Step 2: Acetic acid-2-{[2-(2-ethoxy-2-oxoethyl)-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]oxy}ethyl ester (B11-2)

[0504] 100 mL single necked flask, add free compound 1 (0.91 g, 3.79 mmol), compound B11-1 (1.10 g, 3.79 mmol), Pd(OAc)2(40 mg, 0.19 mmol), X-Phos (90 mg, 0.19 mmol), Cs2CO3(3.70 g, 11.40 mmol) and 20 mL of toluene, synthesis and work-up procedure refer to compound A1-3, get compound B11-2 (1.01 g, y = 53%). LCMS (ESI) m / z: 505.3 [M+H] + .

[0505] Step 3: {2-[(2-Hydroxyethyl)oxy]-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (B11)

[0506] 100 mL single necked flask, add B11-2 (0.50 g, 0.99 mmol), sodium hydroxide (0.20 g, 4.95 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work-up procedure refer to compound A1, get compound B11 (0.40 g, y = 85%). LCMS (ESI) m / z: 435.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.34 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.54 (dq, J = 15.6, 7.1 Hz, 3H), 6.90 (d, J = 8.1 Hz, 1H), 6.01 - 5.95 (m, 2H), 4.91 - 4.88 (m, 1H), 3.92 (t, J = 5.4 Hz, 2H), 3.68 (t, J = 5.3 Hz, 2H), 3.45 (q, J = 7.0 Hz, 1H), 3.38 (s, 2H), 3.36 - 3.31 (m, 1H), 3.28 (s, 1H), 3.17 - 2.96 (m, 2H), 2.10 - 2.04 (m, 1H), 1.97 (s, 1H), 1.50 (s, 3H).

[0507] Example 48: Synthesis of {4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-[(2-methoxyethyl)oxy]phenyl}acetic acid (B12)

[0508] The synthesis route is as follows:

[0509]

[0510] Step 1: {4-bromo-2-[(2-methoxyethyl)oxy]phenyl}acetic acid ethyl ester (B12-1)

[0511] 250 mL single necked flask was charged with compound 4 (1.60 g, 6.17 mmol), potassium carbonate (2.55 g, 18.50 mmol), 1-bromo-2-methoxyethane (1.23 g, 7.41 mmol) and 50 mL of acetonitrile, synthesis and work up procedure refer to compound A2-2 to give compound B12-1 (1.10 g, y = 54%). LCMS (ESI) m / z: 317.0 [M+H] + .

[0512] Step 2: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- [(2-methoxyethyl)oxy]phenyl}acetic acid ethyl ester (B12-2)

[0513] 100 mL single necked flask was charged with free compound 1 (0.80 g, 3.32 mmol), compound B12-1 (1.10 g, 3.32 mmol), Pd(OAc)2 (36 mg, 0.16 mmol), X-Phos (76 mg, 0.16 mmol), Cs2CO3 (4.10 g, 9.96 mmol) and 20 mL of toluene, synthesis and work up procedure refer to compound A1-3 to give compound B12-2 (0.40 g, y = 25%). LCMS (ESI) m / z: 477.3 [M+H] + .

[0514] Step 3: {2-[(2-hydroxyethyl)oxy]-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro- 1H-pyrrol-1-yl]phenyl}acetic acid (B12)

[0515] 50 mL single necked flask was charged with B12-2 (0.40 g, 0.84 mmol), sodium hydroxide (0.34 g, 8.40 mmol), purified water 5 mL and ethanol 5 mL, synthesis and work up procedure refer to compound A1 to give compound B12 (0.11 g, y = 29%). LCMS (ESI) m / z: 449.2 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 8.33 (d, J = 8.2 Hz, 1H), 7.96-7.91 (m, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.56-7.48 (m, 3H), 6.89 (d, J = 8.2 Hz, 1H), 6.00 (d, J = 2.3 Hz, 1H), 5.97 (dd, J = 8.1, 2.3 Hz, 1H), 4.78 (s, 1H), 4.02 (t, J = 4.7 Hz, 2H), 3.62 (t, J = 4.7 Hz, 2H), 3.33 (d, J = 14.0 Hz, 6H), 3.28 (s, 2H), 3.11 (q, J = 7.8 Hz, 1H), 2.99 (s, 1H), 2.07-2.01 (m, 1H), 1.94-1.90 (m, 1H), 1.43 (s, 3H).

[0516] Example 49: Synthesis of [2-(butyloxy)-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (B13)

[0517] The synthetic route is as follows:

[0518]

[0519] Step 1: [4-bromo-2-(butyloxy)phenyl]acetic acid ethyl ester (B13-1)

[0520] A 250 mL three-necked flask was charged with compound 4 (2.00 g, 7.72 mmol), potassium carbonate (3.19 g, 23.08 mmol), 1-bromobutane (1.27 g, 9.27 mmol) and 50 mL of acetonitrile. The synthesis and workup procedure was referenced to compound A2-2 to give compound B13-1 (1.52 g, y = 62%). LCMS (ESI) m / z: 315.1 [M+H] + .

[0521] Step 2: [2-(butyloxy)-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]phenyl]acetic acid ethyl ester (B13-2)

[0522] 100 mL single necked flask was charged with free compound 1 (1.14 g, 4.74 mmol), compound B13-1 (1.50 g, 4.76 mmol), Pd(OAc)2(50 mg, 0.22 mmol), X-Phos (110 mg, 0.23 mmol), Cs2CO3(4.64 g, 14.24 mmol) and 20 mL of toluene, synthesis and work up procedure refer to compound A1-3 to give compound B13-2 (1.08 g, y = 41%). LCMS (ESI) m / z: 475.3 [M+H] + .

[0523] Step 3: [2-(Butyloxy)-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H- pyrrol-1-yl]phenyl]acetic acid (B13)

[0524] 50 mL single necked flask was charged with B13-2 (1.00 g, 1.93 mmol), sodium hydroxide (0.77 g, 19.30 mmol), purified water 5 mL and ethanol 5 mL, synthesis and work up procedure refer to compound A1 to give compound B13 (0.91 g, y = 94%). LCMS (ESI) m / z: 447.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.32 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.51 (p, J = 7.1 Hz, 3H), 6.87 (d, J = 8.0 Hz, 1H), 5.93 (d, J = 9.8 Hz, 2H), 4.73 (q, J = 6.5 Hz, 1H), 3.87 (t, J = 6.4 Hz, 2H), 3.30 (s, 3H), 3.23 (d, J = 6.2 Hz, 2H), 3.10 (q, J = 7.8 Hz, 1H), 2.94 (t, J = 6.2 Hz, 1H), 2.02 (dq, J = 12.1, 6.0 Hz, 1H), 1.88 (dt, J = 12.3, 7.1 Hz, 1H), 1.65 (p, J = 6.7 Hz, 2H), 1.42 (dd, J = 15.6, 7.1 Hz, 5H), 0.92 (t, J = 7.5 Hz, 3H).

[0525] Example 50: Synthesis of [2-(Cyclopentyloxy)-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (B14)

[0526] The synthesis route is as follows:

[0527]

[0528] Step 1: [4-bromo-2-(cyclopentyloxy)phenyl]acetic acid ethyl ester (B14-1)

[0529] Into a 250 mL flask, was placed compound 4 (1.50 g, 5.71 mmol), potassium carbonate (2.40 g, 17.00 mmol), bromocyclopentane (1.07 g, 8.70 mmol) and 50 mL of acetonitrile. The synthesis and work up procedure was referenced to compound A2-2 to yield compound B14-1 (1.20 g, y = 64%). LCMS (ESI) m / z: 327.1 [M+H] + .

[0530] Step 2: [2-(cyclopentyloxy)-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid ethyl ester (B14-2)

[0531] Into a 100 mL flask, was placed free compound 1 (0.74 g, 3.10 mmol), compound B14-1 (1.20 g, 3.70 mmol), Pd(OAc)2 (40 mg, 0.15 mmol), X-Phos (80 mg, 0.15 mmol), Cs2CO3 (3.00 g, 9.20 mmol) and 20 mL of toluene. The synthesis and work up procedure was referenced to compound A1-3 to yield compound B14-2 (0.85 g, y = 56%). LCMS (ESI) m / z: 487.3 [M+H] + .

[0532] Step 3: [2-(cyclopentyloxy)-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (B14)

[0533] Into a 50 mL flask, was placed B14-2 (0.85 g, 1.70 mmol), sodium hydroxide (0.21 g, 5.20 mmol), purified water 5 mL and ethanol 5 mL. The synthesis and work up procedure was referenced to compound A1 to yield compound B14 (0.57 g, y = 73%). LCMS (ESI) m / z: 459.3 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 8.33 (d, J = 8.0 Hz, 1H), 7.92 (dd, J = 7.3, 2.1 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.1 Hz, 1H), 7.50 (tt, J = 7.6, 3.5 Hz, 3H), 6.85 (d, J = 8.0 Hz, 1H), 5.94 - 5.88 (m, 2H), 4.76 - 4.70 (m, 2H), 3.30 - 3.22 (m, 4H), 3.19 (dd, J = 9.3, 6.6 Hz, 1H), 3.09 (dt, J = 9.1, 7.2 Hz, 1H), 2.91 (dd, J = 9.3, 5.7 Hz, 1H), 2.02 (td, J = 13.7, 13.0, 7.0 Hz, 1H), 1.92 - 1.83 (m, 1H), 1.78 (dt, J = 11.1, 4.9 Hz, 2H), 1.68 (s, 2H), 1.73 - 1.63 (m, 2H), 1.55 (dtd, J = 10.7, 7.4, 3.8 Hz, 2H), 1.40 (d, J = 6.5 Hz, 3H).

[0534] Example 51: Synthesis of [2-(Cyclohexyloxy)-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (B15)

[0535] The synthetic route is as follows:

[0536]

[0537] Step 1: [4-Bromo-2-(cyclohexyloxy)phenyl] acetic acid ethyl ester (B15-1)

[0538] Into a 250 mL three-necked flask, was placed compound 4 (4.50 g, 17.37 mmol), potassium carbonate (7.20 g, 52.10 mmol), bromocyclohexane (28.32 g, 173.68 mmol) and 50 mL of acetonitrile. The synthesis and workup procedure was referenced to compound A2-2 to give compound B15-1 (2.40 g, y = 40%). LCMS (ESI) m / z: 341.1 [M+H] + .

[0539] Step 2: [2-(Cyclohexyloxy)-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid ethyl ester (B15-2)

[0540] 100 mL single necked flask was charged with free compound 1 (1.35 g, 5.62 mmol), compound B15-1 (2.40 g, 6.76 mmol), Pd(OAc)2(60 mg, 0.27 mmol), X-Phos (140 mg, 0.27 mmol), Cs2CO3(5.50 g, 9.20 mmol) and 20 mL of toluene, synthesis and work up procedure refer to compound A1-3 to give compound B15-2 (0.41 g, y = 14%). LCMS (ESI) m / z: 501.3 [M+H] + .

[0541] Step 3: [2-(Cyclohexyloxy)-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl]acetic acid (B15)

[0542] 50 mL single necked flask was charged with B15-2 (0.40 g, 0.80 mmol), sodium hydroxide (0.13 g, 3.25 mmol), purified water 5 mL and ethanol 5 mL, synthesis and work up procedure refer to compound A1 to give compound B15 (90 mg, y = 24%). LCMS (ESI) m / z: 473.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.31 (d, J = 8.1 Hz, 1H), 7.94 - 7.88 (m, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.54 - 7.44 (m, 3H), 6.73 (d, J = 8.2 Hz, 1H), 6.52 (dd, J = 8.1, 2.0 Hz, 1H), 6.47 (d, J = 2.1 Hz, 1H), 4.69 (q, J = 6.6 Hz, 1H), 4.11 (dq, J = 8.6, 4.0 Hz, 1H), 3.36 (s, 2H), 3.31 (dd, J = 9.7, 6.5 Hz, 1H), 3.25 (td, J = 8.5, 5.0 Hz, 1H), 3.19 (dt, J = 16.7, 7.0 Hz, 2H), 3.04 (dd, J = 9.7, 6.2 Hz, 1H), 1.95 (dq, J = 12.4, 6.4 Hz, 1H), 1.83 - 1.72 (m, 3H), 1.63 (tt, J = 9.0, 5.1, 4.6 Hz, 2H), 1.50 - 1.44 (m, 1H), 1.39 (d, J = 6.5 Hz, 3H), 1.27 (p, J = 9.3 Hz, 4H), 1.19 (s, 1H).

[0543] Example 52: Synthesis of {2-[(cyclohexylmethyl)oxy]-4-[(3S)-3-{[(1R)-1- (naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (B16)

[0544] The synthetic route is as follows:

[0545]

[0546] Step 1: {4-bromo-2-[(cyclohexylmethyl)oxy]phenyl}acetic acid ethyl ester (B16-1)

[0547] Into a 250 mL three-necked flask, was placed compound 4 (1.35 g, 5.17 mmol), potassium carbonate (2.14 g, 15.48 mmol), bromomethylcyclohexane (1.84 g, 10.33 mmol) and 50 mL of acetonitrile. The synthesis and work-up procedure was referenced to compound A2-2 to give compound B16-1 (1.75 g, y = 95%). LCMS (ESI) m / z: 355.1 [M+H] + .

[0548] Step 2: {2-[(cyclohexylmethyl)oxy]-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid ethyl ester (B16-2)

[0549] Into a 100 mL single-necked flask, was placed free compound 1 (1.00 g, 4.28 mmol), compound B16-1 (1.75 g, 5.13 mmol), Pd(OAc)2 (60 mg, 0.27 mmol), X-Phos (140 mg, 0.27 mmol), Cs2CO3 (4.18 g, 12.83 mmol) and 20 mL of toluene. The synthesis and work-up procedure was referenced to compound A1-3 to give compound B16-2 (0.72 g, y = 32%). LCMS (ESI) m / z: 515.3 [M+H] + .

[0550] Step 3: {2-[(cyclohexylmethyl)oxy]-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}acetic acid (B16)

[0551] Into a 50 mL single-necked flask, was placed B16-2 (0.70 g, 1.36 mmol), sodium hydroxide (0.16 g, 4.00 mmol), purified water 5 mL and ethanol 5 mL. The synthesis and work-up procedure was referenced to compound A1 to give compound B16 (203 mg, y = 30%). LCMS (ESI) m / z: 487.3 [M+H]+ . 1 H NMR (600 MHz, DMSO-d6) δ 8.32 (d, J = 8.1 Hz, 1H), 7.92 (dd, J = 7.5, 1.9 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.1 Hz, 1H), 7.55 - 7.47 (m, 3H), 6.86 (d, J = 8.1 Hz, 1H), 5.94 - 5.89 (m, 2H), 4.73 (q, J = 6.5 Hz, 1H), 3.69 - 3.63 (m, 2H), 3.31 - 3.27 (m, 3H), 3.22 (q, J = 6.6, 5.6 Hz, 2H), 3.10 (dt, J = 9.2, 7.3 Hz, 1H), 2.93 (h, J = 5.0, 4.6 Hz, 1H), 2.02 (dq, J = 12.0, 6.0 Hz, 1H), 1.87 (dq, J = 12.0, 7.0 Hz, 1H), 1.78 (dd, J = 12.7, 3.6 Hz, 2H), 1.74 - 1.62 (m, 4H), 1.40 (d, J = 6.5 Hz, 3H), 1.30 - 1.11 (m, 3H), 1.06 (qd, J = 11.5, 10.9, 6.0 Hz, 2H).

[0552] Example 53: Synthesis of ethyl 2-(2-ethoxy-2-oxoethyl)-5-[(3S)-3-{[(1R)-1- (naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]benzoate (B17)

[0553] The synthetic route is as follows:

[0554]

[0555] Step 1: 5-bromo-2-(carboxymethyl)benzoic acid (B17-2)

[0556] A 250 mL three-necked flask was charged with compound B17-1 (5.00 g, 27.77 mmol), potassium bromate (6.90 g, 41.32 mmol) and 50 mL purified water, stirred, cooled to 0 °C, slowly added concentrated sulfuric acid (13.6 g, 138.66 mmol), after adding, 90 °C for 2.0 h, cooled to room temperature, poured into ice water, stirred for 1.0 h, filtered, the filter cake was washed with water and dried to give compound B17-2 (4.00 g, y = 56%). LCMS (ESI) m / z: 259.0 [M+H] + .

[0557] Step 2: ethyl 5-bromo-2-(2-ethoxy-2-oxoethyl)benzoate (B17-3)

[0558] 250 mL three-necked flask, compound B17-2 (4.00 g, 15.51 mmol) and 50 mL of ethanol were stirred, cooled to 0 °C, and 2.0 mL of concentrated sulfuric acid was added dropwise slowly. The synthesis and post-processing operations were referred to compound A1-2 to obtain compound B17-3 (2.50 g, y = 51%). LCMS (ESI) m / z: 515.3 [M+H] + .

[0559] Step 3: Ethyl 2-(2-ethoxy-2-oxoethyl)-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]benzoate (B17)

[0560] 100 mL single-necked flask, free compound 1 (1.90 g, 7.90 mmol), compound B17-3 (2.50 g, 7.96 mmol), Pd(OAc)2(90 mg, 0.40 mmol), X-Phos (191 mg, 0.40 mmol), Cs2CO3(5.20 g, 15.96 mmol) and 50 mL of toluene were added. The synthesis and post-processing operations were referred to compound A1-3 to obtain compound B17 (0.80 g, y = 21%). LCMS (ESI) m / z: 475.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (dd, J = 7.0, 2.6 Hz, 1H), 7.98 - 7.89 (m, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.58 - 7.47 (m, 3H), 7.10 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 2.7 Hz, 1H), 6.60 (dd, J = 8.4, 2.7 Hz, 1H), 4.75 (q, J = 6.4 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.81 (s, 2H), 3.36 (s, 1H), 3.36 - 3.23 (m, 2H), 3.15 (dt, J = 9.3, 7.1 Hz, 1H), 3.03 (p, J = 4.7 Hz, 1H), 2.08 - 1.98 (m, 1H), 1.92 (dq, J = 12.7, 6.9 Hz, 1H), 1.41 (d, J = 6.5 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H).

[0561] Example 54: Synthesis of 1-{4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl}cyclobutane-1-carboxylic acid (B18)

[0562] The synthesis route is as follows:

[0563]

[0564] Step 1: 1-(4-bromophenyl)cyclobutane-1-carboxylate (B18-2)

[0565] 250 mL three-necked flask, compound B18-1 (5.00 g, 19.60 mmol) and 50 mL anhydrous ethanol were stirred, cooled to 0 °C, 1 mL concentrated sulfuric acid was added dropwise slowly, the synthesis and post-processing operation were referred to compound A1-2, and compound B18-2 (5.10 g, y = 92%) was obtained. LCMS (ESI) m / z: 283.0 [M+H] + .

[0566] Step 2: 1-{4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1- yl]phenyl}cyclobutane-1-carboxylate (B18)

[0567] 500 mL single-necked flask, free compound 1 (4.75 g, 19.68 mmol), compound B18-2 (5.30 g, 19.68 mmol), Pd(OAc)2 (442 mg, 1.97 mmol), X-Phos (938 mg, 1.97 mmol), Cs2CO3 (19.25 g, 59.08 mmol) and 100 mL toluene were added, the synthesis and post-processing operation were referred to compound A1-3, and compound B18 (7.50 g, y = 89%) was obtained. LCMS (ESI) m / z: 443.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.4 Hz, 1H), 8.07 - 7.99 (m, 3H), 7.65 (dq, J = 15.4, 6.7 Hz, 3H), 7.13 - 7.06 (m, 2H), 6.55 - 6.47 (m, 2H), 5.43 (q, J = 6.3 Hz, 1H), 3.83 (d, J = 6.6 Hz, 1H), 3.52 (s, 3H), 3.52 - 3.46 (m, 1H), 3.46 - 3.37 (m, 2H), 3.21 - 3.10 (m, 1H), 2.70 - 2.59 (m, 2H), 2.41 - 2.28 (m, 3H), 2.25 (h, J = 7.0 Hz, 1H), 1.85 (m, 1H), 1.75 (d, J = 6.7 Hz, 4H).

[0568] Example 55: Synthesis of {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-(trifluoromethyl)phenyl}acetic acid (B19)

[0569] The synthetic route is as follows:

[0570]

[0571] Step 1: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2- (trifluoromethyl)phenyl} ethyl acetate (B19-2)

[0572] 250 mL single necked flask, free compound 1 (1.60 g, 6.66 mmol), compound B19-1 (1.90 g, 6.11 mmol), Pd(OAc)2(137 mg, 0.61 mmol), X-Phos (291 mg, 0.61 mmol), Cs2CO3(6.00 g, 18.42 mmol) and 50 mL of toluene, synthesis and workup procedure refer to compound A1-3, compound B19-2 (1.90 g, y = 66%) was obtained. LCMS (ESI) m / z: 471.2 [M+H] + .

[0573] Step 3: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2- (trifluoromethyl)phenyl} acetic acid (B19)

[0574] 50 mL single necked flask was charged with B19-2 (1.90 g, 4.04 mmol), sodium hydroxide (0.81 g, 20.3 mmol), purified water 10 mL and ethanol 10 mL, synthesis and workup procedure refer to compound A1 to get compound B19 (1.20 g, y = 67%). LCMS (ESI) m / z: 443.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.2 Hz, 1H), 7.97 (dd, J = 7.6, 1.9 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.57 (m, 3H), 7.23 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 8.5, 2.6 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H), 5.03 (d, J = 7.4 Hz, 1H), 3.62 - 3.57 (m, 2H), 3.40 (dd, J = 9.5, 6.3 Hz, 2H), 3.18 (qd, J = 7.2, 3.9 Hz, 2H), 2.18 - 2.08 (m, 3H), 1.55 (d, J = 6.5 Hz, 3H).

[0575] Example 56: Synthesis of methyl 2-{4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}-2-methylpropanoate (B20)

[0576] The synthesis route is as follows:

[0577]

[0578] Step 1: Methyl 2-{4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]phenyl}-2-methylpropanoate (B20)

[0579] 250 mL single necked flask was charged with free compound 1 (1.00 g, 4.16 mmol), compound B20-1 (1.40 g, 5.41 mmol), Pd(OAc)2 (40 mg, 0.17 mmol), X-Phos (85 mg, 0.17 mmol), Cs2CO3 (4.40 g, 13.50 mmol) and 50 mL of toluene, synthesis and workup procedure refer to compound A1-3 to get compound B20 (1.44 g, y = 83%). LCMS (ESI) m / z: 417.2 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 10.36 (dt, J = 12.5, 6.0 Hz, 1H), 9.95 (dt, J = 12.5, 6.3 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 8.19 (d, J = 7.2 Hz, 1H), 8.01 (dd, J = 12.5, 8.1 Hz, 2H), 7.64 (td, J = 7.5, 4.8 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 8.5 Hz, 2H), 6.46 (d, J = 8.4 Hz, 2H), 5.42 (p, J = 6.4 Hz, 1H), 3.78 (p, J = 6.4 Hz, 1H), 3.53 (s, 3H), 3.47 (d, J = 6.4 Hz, 2H), 3.42 (td, J = 8.7, 4.9 Hz, 1H), 3.13 (q, J = 7.9 Hz, 1H), 2.38 (dq, J = 14.7, 7.6, 6.8 Hz, 1H), 2.22 (ddt, J = 12.7, 7.8, 3.7 Hz, 1H), 1.76 (d, J = 6.6 Hz, 3H), 1.44 (s, 6H).

[0580] Example 57: Synthesis of methyl 1-{4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}cyclopropane-1-carboxylate (B21)

[0581] The synthesis route is as follows:

[0582]

[0583] Step 1: methyl 1-{4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]phenyl}cyclopropane-1-carboxylate (B21)

[0584] 50 mL single necked flask, add free compound 1 (0.50 g, 2.08 mmol), compound B21-1 (1.40 g, 2.49 mmol), Pd(OAc)2(10 mg, 0.05 mmol), X-Phos (24 mg, 0.05 mmol), Cs2CO3(2.20 g, 6.76 mmol) and 10 mL of toluene, synthesis and workup procedure refer to compound A1-3, get compound B21 (0.71 g, y = 83%). LCMS (ESI) m / z: 415.2 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 10.27 (d, J = 10.7 Hz, 1H), 9.91 - 9.86 (m, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.16 (d, J = 7.3 Hz, 1H), 8.02 (dd, J = 11.8, 8.1 Hz, 2H), 7.65 (td, J = 7.6, 5.1 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H), 6.44 (d, J = 8.3 Hz, 2H), 5.42 (q, J = 6.5 Hz, 1H), 3.80 (p, J = 6.5 Hz, 1H), 3.51 - 3.50 (m, 1H), 3.50 (s, 3H), 3.53 - 3.39 (m, 2H), 3.15 (q, J = 7.9 Hz, 1H), 2.37 (dq, J = 14.4, 7.3 Hz, 1H), 2.27 - 2.19 (m, 1H), 1.76 (d, J = 6.6 Hz, 3H), 1.40 (q, J = 3.6 Hz, 2H), 1.07 (q, J = 3.7 Hz, 2H).

[0585] Example 58: Synthesis of 1-{[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]carbonyl}bicyclo[2.2.2]octane-4-carboxylic acid (C1)

[0586] The synthesis route is as follows:

[0587]

[0588] Step 1: 1-{[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1- yl]carbonyl}bicyclo[2.2.2]octane-4-carboxylic acid methyl ester (C1-1)

[0589] 250 mL single necked flask, add free compound 1 (1.00 g, 4.16 mmol), compound 5 (1.06 g, 4.99 mmol), triethylamine (1.68 g, 16.64 mmol) and 50 mL dichloromethane, stir, add HATU (2.37 g, 6.24 mmol) portion wise, stir overnight, add 50 mL saturated brine, stir, allow to settle into distinct layers, separate phases, retain organic phase, extract aqueous phase twice with 30 mL dichloromethane, combine organic phases, dry over anhydrous sodium sulfate, filter, concentrate filtrate under reduced pressure to remove solvent, purify residue by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrate under reduced pressure to give compound C1-1 (0.76 g, y = 42%). LCMS (ESI) m / z: 435.3 [M+H]+ .

[0590] Step 2: 1-{[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]carbonyl}bicyclo[2.2.2]octane-4-carboxylic acid (C1)

[0591] 50 mL single necked flask, was added C1-1 (0.70 g, 1.61 mmol), sodium hydroxide (0.32 g, 8.06 mmol), purified water 10 mL and ethanol 10 mL, synthesis and workup procedure refer to compound A1, to give compound C1 (0.45 g, y = 66 %). LCMS (ESI) m / z: 421.2 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.92 (dd, J = 7.8, 1.7 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 7.1 Hz, 1H), 7.51 (ddt, J = 12.9, 8.1, 3.8 Hz, 3H), 4.66 (q, J = 6.6 Hz, 1H), 3.15 (m, 4H), 1.93 - 1.31 (m, 18H).

[0592] Example 59: Synthesis of 1-{[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]methyl}bicyclo[2.2.2]octane-4-carboxylic acid (C2)

[0593] The synthesis route is as follows:

[0594]

[0595] Step 1: 1-(hydroxymethyl)bicyclo[2.2.2]octane-4-carboxylic acid methyl ester (C2-1)

[0596] 250 mL single necked flask, was added compound 5 (4.00 g, 18.85 mmol) and 50 mL tetrahydrofuran stirred, 14.2 mL 2M borane complex dimethylsulfide in tetrahydrofuran was added portionwise, refluxed for 2.0 h, cooled to room temperature, 15 mL methanol was added slowly stirred for 0.5 h, the filtrate was concentrated under reduced pressure to distill off solvent, to give compound C2-1 (3.36 g, y = 90 %). LCMS (ESI) m / z: 199.1 [M+H] + .

[0597] Step 2: 1-(oxymethyl)bicyclo[2.2.2]octane-4-carboxylic acid methyl ester (C2-2)

[0598] 500 mL three-necked flask, DMSO (1.89 g, 24.19 mmol) and 50 mL dichloromethane were added and stirred, replaced with nitrogen for three times, cooled to below -65 °C, oxalyl chloride (2.82 g, 22.22 mmol) was added dropwise slowly, after dropwise addition, 0.5 h was allowed to react, 50 mL dichloromethane solution of compound C2-1 (3.30 g, 16.66 mmol) was added dropwise, after dropwise addition, 0.5 h was allowed to react, triethylamine (6.13 g, 60.58 mmol) was added dropwise, after dropwise addition, 1.0 h was allowed to react at room temperature, 150 mL purified water was added and stirred, allowed to stand until obvious layer separation, the phases were separated, the organic phase was retained, the aqueous phase was extracted with 50 mL dichloromethane twice, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until solvent evaporation, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure to obtain compound C2-2 (1.24 g, y = 38%). LCMS (ESI) m / z: 197.1 [M+H] + .

[0599] Step 3: Methyl 1-{[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]methyl}bicyclo[2.2.2]octane-4-carboxylate (C2-3)

[0600] 250 mL single-necked flask, free compound 1 (1.50 g, 6.24 mmol), compound C2-2 (1.20 g, 6.24 mmol) and 50 mL dichloromethane were added and stirred, sodium triacetoxyborohydride (4.86 g, 22.93 mmol) was added in portions, and the reaction was allowed to proceed at room temperature overnight, 50 mL purified water was added and stirred, allowed to stand until obvious layer separation, the phases were separated, the organic phase was retained, the aqueous phase was extracted with 50 mL dichloromethane twice, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until solvent evaporation, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure to obtain compound C2-3 (1.05 g, y = 40%). LCMS (ESI) m / z: 421.3 [M+H] + .

[0601] Step 4: 1-{[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]carbonyl}bicyclo[2.2.2]octane-4-carboxylic acid (C2)

[0602] 50 mL single necked flask was charged with C2-3 (1.00 g, 2.38 mmol), sodium hydroxide (0.48 g, 11.90 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work up procedure refer to compound A1, afforded compound C2 (0.80 g, y = 83%). LCMS (ESI) m / z: 407.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 8.1 Hz, 1H), 7.95 - 7.88 (m, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 7.1 Hz, 1H), 7.50 (qd, J = 8.0, 7.5, 2.3 Hz, 3H), 4.59 (q, J = 6.5 Hz, 1H), 2.97 (q, J = 6.7 Hz, 1H), 2.55 (d, J = 6.5 Hz, 1H), 2.45 (q, J = 7.7 Hz, 1H), 2.27 (dd, J = 9.2, 5.9 Hz, 1H), 2.04 (dt, J = 23.7, 11.8 Hz, 2H), 1.76 (dq, J = 13.9, 7.3 Hz, 1H), 1.58 (dd, J = 10.5, 5.6 Hz, 7H), 1.36 (d, J = 6.5 Hz, 3H), 1.27 (m, 7H).

[0603] Example 60: Synthesis of (3S)-1-{3,4-bis[(2-methoxyethyl)oxy]phenyl}-3-{[(1R)-1- (naphthalen-1-yl)ethyl]amino}pyrrolidine hydrochloride (D1)

[0604] The synthesis route is as follows:

[0605]

[0606] Step 1: 4-bromo-1,2-bis[(2-methoxyethyl)oxy]benzene (D1-1)

[0607] 250 mL single necked flask was charged with compound 6 (4.00 g, 21.00 mmol), 1-bromo-2-methoxyethane (11.50 g, 82.00 mmol), potassium carbonate (13.37 g, 60.00 mmol) and 50 mL acetonitrile, synthesis and work up procedure refer to compound A2-2, afforded compound D1-1 (2.20 g, y = 36%). LCMS (ESI) m / z: 305.0 [M+H] + .

[0608] Step 2: (3S)-1-{3,4-bis[(2-methoxyethyl)oxy]phenyl}-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}pyrrolidine hydrochloride (D1)

[0609] 250 mL single necked flask charged with free compound 1 (1.00 g, 4.20 mmol), compound D1-1 (1.50 g, 4.90 mmol), Pd(OAc)2(50 mg, 0.21 mmol), X-Phos (100 mg, 0.21 mmol), Cs2CO3(4.10 g, 12.60 mmol) and 50 mL of toluene, replaced with nitrogen three times, warmed to 100 °C and stirred overnight, cooled to room temperature, stirred with 20 mL of saturated brine, allowed to settle into layers, separated, retained the organic phase, extracted the aqueous phase with 50 mL of ethyl acetate once, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure until solvent was distilled off, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure, salted out, and dried under a blast of air at 45 °C until constant weight to give compound D1 (0.75 g, y = 36%). LCMS (ESI) m / z: 465.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.95 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 7.3 Hz, 1H), 8.04 (t, J = 7.5 Hz, 2H), 7.71 - 7.58 (m, 3H), 6.86 (d, J = 8.6 Hz, 1H), 6.26 (s, 1H), 6.15 - 6.08 (m, 1H), 5.44 (t, J = 6.7 Hz, 1H), 4.08 (dd, J = 5.6, 3.8 Hz, 2H), 3.97 (dd, J = 5.7, 3.8 Hz, 2H), 3.84 - 3.77 (m, 1H), 3.70 - 3.63 (m, 2H), 3.63 - 3.56 (m, 2H), 3.45 (qd, J = 6.5, 4.3, 3.0 Hz, 3H), 3.32 (d, J = 12.2 Hz, 6H), 3.15 (dd, J = 10.1, 6.4 Hz, 1H), 2.41 (dq, J = 14.5, 7.3 Hz, 1H), 2.25 (dq, J = 12.9, 7.1 Hz, 1H), 1.79 (d, J = 6.5 Hz, 3H).

[0610] Example 61: Synthesis of (3S)-1-{3,4-bis[(2-methoxyethyl)oxy]phenyl}-3-{[(1R)-1- (naphthalen-1-yl)ethyl]amino}pyrrolidine hydrochloride (D2)

[0611] The synthetic route is as follows:

[0612]

[0613] Step 1: Acetic acid-2-({2-[(2-acetyloxyethyl)oxy]-5-bromophenyl}oxy)ethyl ester (D2-1)

[0614] Into a 250 mL single necked flask, was placed compound 6 (3.00 g, 15.87 mmol), acetic acid-2-bromoethyl ester (10.60 g, 63.47 mmol), potassium carbonate (10.11 g, 73.15 mmol) and 50 mL of acetonitrile. The synthesis and workup procedure was referenced to compound A2-2 to yield compound D2-1 (1.10 g, y = 36%). LCMS (ESI) m / z: 361.0 [M+H] + .

[0615] Step 2: Acetic acid-2-({2-[(2-acetyloxyethyl)oxy]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}oxy)ethyl ester (D2-2)

[0616] Into a 250 mL single necked flask, was placed free compound 1 (0.50 g, 2.08 mmol), compound D2-1 (0.90 g, 2.50 mmol), Pd(OAc)2 (50 mg, 0.21 mmol), X-Phos (100 mg, 0.21 mmol), Cs2CO3 (4.10 g, 12.60 mmol) and 50 mL of toluene. The synthesis and workup procedure was referenced to compound A1-3 to yield compound D2-2 (0.57 g, y = 53%). LCMS (ESI) m / z: 521.3 [M+H] + .

[0617] Step 3: 2-({2-[(2-Hydroxyethyl)oxy]-5-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}oxy)ethan-1-ol hydrochloride (D2)

[0618] 100 mL single necked flask, add compound D2-2 (0.50 g, 0.96 mmol), sodium hydroxide (0.19 g, 4.80 mmol), purified water 10 mL and ethanol 10 mL, stir the reaction at 45 °C overnight, cool to room temperature, concentrate under reduced pressure to no solvent evaporate, add 30 mL ethyl acetate and 30 mL saturated brine, stir, stand to obvious layer separation, separate phases, dry over anhydrous sodium sulfate, filter, salt with hydrochloric acid, dry at 45 °C under a blast of air to constant weight, to give compound D2 (0.16 g, y = 35%). LCMS (ESI) m / z: 437.3 [M+H] + . 1 HNMR (600 MHz, DMSO-d6) δ 10.13 (dd, J = 12.4, 6.2 Hz, 1H), 9.72 (dt, J = 12.5, 6.5 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 7.3 Hz, 1H), 8.03 (t, J = 8.7 Hz, 2H), 7.69 - 7.63 (m, 2H), 7.61 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.16 (d, J = 2.7 Hz, 1H), 6.03 (dd, J = 8.7, 2.7 Hz, 1H), 5.41 (p, J = 6.4 Hz, 1H), 3.97 (dt, J = 10.5, 5.2 Hz, 3H), 3.85 (t, J = 5.2 Hz, 2H), 3.83 - 3.76 (m, 1H), 3.71 (t, J = 5.2 Hz, 3H), 3.62 (t, J = 5.2 Hz, 3H), 3.38 (t, J = 5.1 Hz, 2H), 3.11 (q, J = 7.9 Hz, 1H), 2.33 (dq, J = 14.5, 7.3 Hz, 1H), 2.23 (dtd, J = 12.6, 7.6, 4.8 Hz, 1H), 1.76 (d, J = 6.6 Hz, 3H).

[0619] Example 62: Synthesis of (3S)-1-(3-{[2-(benzyloxy)ethyl]oxy}-4-[(2- methoxyethyl)oxy]phenyl)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}pyrrolidine hydrochloride (D3):

[0620] The synthesis route is as follows:

[0621]

[0622] Step 1: 1-(2-{[2-(benzyloxy)ethyl]oxy}-4-bromophenyl)ethan-1-one (D3-2)

[0623] 250 mL single necked flask, compound D3-2 (12.00 g, 27.32 mmol) and 100 mL dichloromethane were added and stirred, m-chloroperoxybenzoic acid (23.70 g, 137.34 mmol) was added portion wise, the reaction was allowed to proceed overnight, 50 mL purified water was added, saturated sodium carbonate was used to adjust the pH to 8.0, the mixture was allowed to stand until clear separation was observed, the organic phase was retained, the aqueous phase was extracted with 50 mL dichloromethane once, the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure until no solvent was distilled out, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure to give compound D3-3 (12.10 g, y = 96%). LCMS (ESI) m / z: 365.0 [M+H] + .

[0624] Step 2: Acetic acid-2-{[2-(benzyloxy)ethyl]oxy}-4-bromophenyl ester (D3-3)

[0625] 250 mL single necked flask, compound D3-2 (12.00 g, 27.32 mmol) and 100 mL dichloromethane were added and stirred, m-chloroperoxybenzoic acid (23.70 g, 137.34 mmol) was added portion wise, the reaction was allowed to proceed overnight, 50 mL purified water was added, saturated sodium carbonate was used to adjust the pH to 8.0, the mixture was allowed to stand until clear separation was observed, the organic phase was retained, the aqueous phase was extracted with 50 mL dichloromethane once, the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure until no solvent was distilled out, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure to give compound D3-3 (12.10 g, y = 96%). LCMS (ESI) m / z: 365.0 [M+H] + .

[0626] Step 3: 2-{[2-(benzyloxy)ethyl]oxy}-4-bromophenol (D3-4)

[0627] 250 mL single necked flask, compound D3-3 (12.10 g, 33.13 mmol), sodium hydroxide (6.62 g, 165.50 mmol) in 50 mL purified water and 50 mL ethanol were added and stirred at 45 °C overnight, the mixture was allowed to cool to room temperature, concentrated under reduced pressure until no solvent was distilled out, 1 N hydrochloric acid was used to adjust the pH until the solid precipitated out, the mixture was filtered, the solid was dried under a blast of air at 45 °C until the constant weight was achieved to give compound D3-4 (10.10 g, y = 95%). LCMS (ESI) m / z: 323.0 [M+H] + .

[0628] Step 4: 2-{[2-(benzyloxy)ethyl]oxy}-4-bromo-1-[(2-methoxyethyl)oxy]benzene (D3-5)

[0629] 100 mL single necked flask, was added compound D3-4 (1.00 g, 3.10 mmol), sodium hydroxide (0.52 g, 3.71 mmol), 2-bromoethyl methyl ether (0.52 g, 3.71 mmol) and acetonitrile 25 mL, synthesis and work-up procedure refer to compound A2-2, to give compound D3-5 (0.55 g, y = 47%). LCMS (ESI) m / z: 381.1 [M+H] + .

[0630] Step 5: (3S)-1-(3-{[2-(benzyloxy)ethyl]oxy}-4-[(2-methoxyethyl)oxy]phenyl)-3-{[(1R)-1- (naphthalen-1-yl)ethyl]amino}pyrrolidine hydrochloride (D3)

[0631] 250 mL single necked flask, was added free compound 1 (0.35 g, 1.45 mmol), compound D3-5 (0.55 g, 1.45 mmol), Pd(OAc)2(50 mg, 0.21 mmol), X-Phos (100 mg, 0.21 mmol), Cs2CO3(1.42 g, 4.35 mmol) and 50 mL toluene, synthesis and work-up procedure refer to compound D1, to give compound D3 (0.33 g, y = 39%). LCMS (ESI) m / z: 541.3 [M+H] + . 1H NMR (600 MHz, CDC13) δ 10.75 (s, 1H), 10.46 (s, 1H), 8.31 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.96-7.89 (m, 2H), 7.68-7.58 (m, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.33-7.24 (m, 4H), 7.23 (td, J = 6.1, 2.5 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 5.97 (d, J = 2.8 Hz, 1H), 5.89 (dd, J = 8.8, 2.8 Hz, 1H), 5.29 (s, 1H), 4.55 (s, 2H), 4.05 (dt, J = 8.0, 4.0 Hz, 1H), 4.04-3.99 (m, 1H), 3.96 (dd, J = 5.7, 4.1 Hz, 2H), 3.74 (t, J = 5.0 Hz, 2H), 3.71 (dd, J = 10.0, 6.7 Hz, 1H), 3.57 (dd, J = 5.7, 4.1 Hz, 2H), 3.52-3.47 (m, 1H), 3.43 (td, J = 9.1, 4.0 Hz, 1H), 3.33 (s, 3H), 3.27 (dd, J = 9.9, 7.1 Hz, 1H), 2.99 (q, J = 8.0 Hz, 1H), 2.57 (dq, J = 12.7, 8.0 Hz, 1H), 2.24-2.16 (m, 1H), 2.06-2.01 (m, 3H).

[0632] Example 63: Synthesis of (3S)-1-(4-{[2-(benzyloxy)ethyl]oxy}-3-[(2- methoxyethyl)oxy]phenyl)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}pyrrolidine hydrochloride (D4)

[0633] The synthetic route is as follows:

[0634]

[0635] Step 1: 1-(2-{[2-(benzyloxy)ethyl]oxy}-5-bromophenyl)ethan-1-one (D4-2)

[0636] 250 mL single necked flask was charged with compound D4-1 (5.00 g, 14.32 mmol), benzyl 2-bromoethyl ether (3.69 g, 17.18 mmol), potassium carbonate (3.96 g, 28.64 mmol) and 50 mL of acetonitrile, synthesis and workup procedure was referenced to compound A2-2 to yield compound D4-2 (3.15 g, y = 63%). LCMS (ESI) m / z: 349.0 [M+H] + .

[0637] Step 2: Acetic acid-2-{[2-(benzyloxy)ethyl]oxy}-5-bromophenyl ester (D4-3)

[0638] 250 mL single neck flask was charged with compound D4-2 (3.00 g, 8.60 mmol) and 50 mL of dichloromethane was stirred, m-chloroperoxybenzoic acid (1.78 g, 10.32 mmol) was added portion wise, reaction was allowed to proceed overnight, 50 mL of purified water was added, pH was adjusted to 8.0 using saturated sodium carbonate, allowed to stand until clear separation, phases were separated, organic phase was retained, aqueous phase was extracted with 50 mL of dichloromethane once, combined organic phase was dried over anhydrous sodium sulfate, filtered, filtrate was concentrated under reduced pressure to distill off solvents, residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure to obtain compound D4-3 (2.26 g, y = 72%). LCMS (ESI) m / z: 365.0 [M+H] + .

[0639] Step 3: 2-{[2-(benzyloxy)ethyl]oxy}-5-bromophenol (D4-4)

[0640] 250 mL single neck flask was charged with compound D4-3 (2.00 g, 6.19 mmol), sodium hydroxide (0.50 g, 12.38 mmol) in 50 mL of purified water and 50 mL of ethanol was stirred, reaction was allowed to proceed overnight at 45 °C, cooled to room temperature, concentrated under reduced pressure to distill off solvents, pH was adjusted to solid came out clearly using 1 N hydrochloric acid, filtered, air dried at 45 °C to constant weight to obtain compound D4-4 (1.74 g, y = 87%). LCMS (ESI) m / z: 323.0 [M+H] + .

[0641] Step 4: 1-{[2-(benzyloxy)ethyl]oxy}-4-bromo-2-[(2-methoxyethyl)oxy]benzene (D4-5)

[0642] 100 mL single neck flask was charged with compound D4-4 (1.00 g, 3.10 mmol), sodium hydroxide (0.52 g, 3.71 mmol), 2-bromoethyl methyl ether (0.52 g, 3.71 mmol) and 25 mL of acetonitrile was stirred, reaction was allowed to proceed overnight by increasing temperature to 65 °C, cooled to room temperature, concentrated under reduced pressure to distill off solvents, 10 mL of purified water was added, 1 N hydrochloric acid was added drop wise until solid came out clearly, filtered, air dried at 45 °C to constant weight to obtain compound D4-5 (0.57 g, y = 48%). LCMS (ESI) m / z: 381.1 [M+H] + .

[0643] Step 5: (3S)-1-(3-{[2-(benzyloxy)ethyl]oxy}-4-[(2-methoxyethyl)oxy]phenyl)-3-{[(1R)-1- (naphthalen-1-yl)ethyl]amino}pyrrolidine hydrochloride (D4)

[0644] 250 mL single necked flask was charged with free compound 1 (0.35 g, 1.45 mmol), compound D4-5 (0.55 g, 1.45 mmol), Pd(OAc)2(50 mg, 0.21 mmol), X-Phos (100 mg, 0.21 mmol), Cs2CO3(1.42 g, 4.35 mmol) and 50 mL of toluene, synthesis and work up procedure was referenced to compound D1 to give compound D4 (0.44 g, y = 39%). LCMS (ESI) m / z: 541.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.35 (t, J = 8.1 Hz, 1H), 8.04 (dd, J = 8.1, 5.8 Hz, 2H), 8.02 - 7.94 (m, 1H), 7.67 (q, J = 8.4 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.39 - 7.32 (m, 4H), 7.32 - 7.27 (m, 1H), 6.83 (dd, J = 8.8, 2.8 Hz, 1H), 6.16 (q, J = 2.6 Hz, 1H), 6.04 (dd, J = 8.8, 2.6 Hz, 1H), 5.42 (q, J = 7.4, 6.7 Hz, 1H), 4.54 (d, J = 2.3 Hz, 2H), 4.06 (dd, J = 5.9, 3.6 Hz, 2H), 4.01 (dd, J = 5.9, 3.5 Hz, 2H), 3.85 (p, J = 6.7 Hz, 1H), 3.77 - 3.71 (m, 1H), 3.71 - 3.66 (m, 5H), 3.64 (dd, J = 5.8, 3.5 Hz, 2H), 3.36 (pt, J = 11.2, 5.4 Hz, 3H), 3.11 (q, J = 7.9 Hz, 1H), 2.34 - 2.23 (m, 2H), 1.76 (d, J = 4.5 Hz, 3H).

[0645] Example 64: Synthesis of (3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}-1-{3-[(2- methoxyethyl)oxy]-5-{[(2,2,2-trifluoroethyl)oxy]methyl}phenyl}pyrrolidine hydrochloride (D5)

[0646] The synthesis route is as follows:

[0647]

[0648] Step 1: (3S)-1-(3-{[2-(benzyloxy)ethyl]oxy}-4-[(2-methoxyethyl)oxy]phenyl)-3-{[(1R)-1- (naphthalen-1-yl)ethyl]amino}pyrrolidine hydrochloride (D5)

[0649] 250 mL single necked flask was charged with free compound 1 (1.00 g, 4.16 mmol), compound D5-1 (1.71 g, 4.99 mmol), Pd(OAc)2(50 mg, 0.21 mmol), X-Phos (100 mg, 0.21 mmol), Cs2CO3(4.00 g, 12.50 mmol) and 50 mL of toluene, synthesis and workup procedure refer to compound D1 to give compound D5 (1.69 g, y = 81%). LCMS (ESI) m / z: 503.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.62 (s, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.06 - 8.00 (m, 3H), 7.69 - 7.63 (m, 2H), 7.61 (t, J = 7.4 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H), 6.12 (d, J = 1.9 Hz, 1H), 6.04 - 6.00 (m, 1H), 5.42 (q, J = 6.6 Hz, 1H), 4.54 (s, 2H), 4.08 - 4.00 (m, 4H), 3.88 (p, J = 6.4 Hz, 1H), 3.66 - 3.61 (m, 2H), 3.52 (dd, J = 10.5, 7.1 Hz, 1H), 3.44 (ddt, J = 16.3, 10.7, 5.3 Hz, 2H), 3.30 (s, 3H), 3.18 (q, J = 8.0 Hz, 1H), 2.37 - 2.22 (m, 2H), 1.75 (d, J = 6.6 Hz, 3H).

[0650] Example 65: Synthesis of (3S)-1-(2,3-dihydrobenzo[2,1-b][1,4]dioxin-6-yl)-3-{[(1R)-1- (naphthalen-1-yl)ethyl]amino}pyrrolidine hydrochloride (E1)

[0651] Synthetic route is as follows:

[0652]

[0653] Step 1: (3S)-1-(2,3-dihydrobenzo[2,1-b][1,4]dioxin-6-yl)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}pyrrolidine (E1)

[0654] 100 mL single necked flask, add free compound 1 (1.00 g, 4.16 mmol), E1-1 (1.07 g, 4.99 mmol), Pd(OAc)2(20 mg, 0.08 mmol), X-Phos (40 mg, 0.08 mmol), Cs2CO3(4.00 g, 12.50 mmol) and 50 mL of toluene, synthesis and work-up procedure refer to compound D1, get compound E1 (0.79 g, y = 46%). LCMS (ESI) m / z: 375.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.5 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.87 (d, J = 7.3 Hz, 1H), 7.64 (tt, J = 11.2, 7.0 Hz, 3H), 6.69 (d, J = 8.5 Hz, 1H), 6.12 - 6.03 (m, 2H), 5.38 (q, J = 6.6 Hz, 1H), 4.16 (dd, J = 5.5, 2.7 Hz, 2H), 4.10 (dd, J = 5.8, 2.7 Hz, 2H), 3.81 (q, J = 6.6 Hz, 1H), 3.34 (dt, J = 8.7, 6.7 Hz, 2H), 3.26 (dd, J = 10.4, 5.5 Hz, 1H), 3.06 (q, J = 7.9 Hz, 1H), 2.23 (q, J = 7.0 Hz, 2H), 1.72 (d, J = 6.5 Hz, 3H).

[0655] Example 66: Synthesis of (3S)-1-(benzo[d][1,3]dioxol-5-yl)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}pyrrolidine hydrochloride (E2)

[0656] The synthesis route is as follows:

[0657]

[0658] Step 1: (3S)-1-(benzo[d][1,3]dioxol-5-yl)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}pyrrolidine hydrochloride (E2)

[0659] 100 mL single necked flask, to free compound 1 (1.00 g, 4.16 mmol), E2-1 (1.00 g, 4.99 mmol), Pd(OAc)2(20 mg, 0.08 mmol), X-Phos (40 mg, 0.08 mmol), Cs2CO3(4.00 g, 12.50 mmol) and 50 mL of toluene, synthesis and work-up procedure refer to compound D1, to get compound E2 (0.79 g, y = 83%). LCMS (ESI) m / z: 361.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 10.30 (dt, J = 12.3, 6.2 Hz, 1H), 9.85 (dt, J = 12.4, 6.4 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.16 (d, J = 7.3 Hz, 1H), 8.05 - 7.99 (m, 2H), 7.65 (ddd, J = 8.1, 6.9, 5.1 Hz, 2H), 7.61 (td, J = 7.4, 6.6, 1.1 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 2.4 Hz, 1H), 5.93 (dd, J = 8.4, 2.4 Hz, 1H), 5.87 (q, J = 1.0 Hz, 2H), 5.40 (p, J = 6.4 Hz, 1H), 3.79 (p, J = 6.5 Hz, 1H), 3.44 (s, 2H), 3.37 (td, J = 8.7, 4.7 Hz, 1H), 3.09 (dt, J = 9.2, 7.6 Hz, 1H), 2.35 (ddd, J = 15.1, 13.3, 7.4 Hz, 1H), 2.22 (dtd, J = 12.5, 7.6, 4.6 Hz, 1H), 1.76 (d, J = 6.6 Hz, 3H).

[0660] Example 67: Synthesis of (3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}-1-{2,5,8,11- tetraoxabicyclo[10.4.0]hexadeca-1(16),12(13),14-trien-14-yl}tetrahydropyrrole hydrochloride (E3)

[0661] The synthesis route is as follows:

[0662]

[0663] Step 1: (3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}-1-{2,5,8,11-tetraoxabicyclo[10.4.0]hexadeca-1(16),12(13),14-trien-14-yl}tetrahydropyrrole hydrochloride (E3)

[0664] 100 mL single necked flask, add free compound 1 (0.50 g, 2.08 mmol), E3-1 (0.76 g, 2.50 mmol), Pd(OAc)2(20 mg, 0.08 mmol), X-Phos (40 mg, 0.08 mmol), Cs2CO3(2.00 g, 6.25 mmol) and 50 mL of toluene, synthesis and work-up procedure refer to compound D1, get compound E3 (0.79 g, y = 47%). LCMS (ESI) m / z: 463.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 10.37 (dt, J = 12.1, 6.0 Hz, 1H), 9.90 (dt, J = 12.4, 6.4 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 7.1 Hz, 1H), 8.05 - 7.98 (m, 2H), 7.68 - 7.56 (m, 3H), 6.88 (d, J = 8.7 Hz, 1H), 6.18 (d, J = 2.8 Hz, 1H), 6.07 (dd, J = 8.7, 2.7 Hz, 1H), 5.40 (q, J = 6.5 Hz, 1H), 4.06 (dd, J = 5.3, 3.5 Hz, 2H), 3.99 - 3.92 (m, 2H), 3.79 (p, J = 6.5 Hz, 1H), 3.76 - 3.70 (m, 2H), 3.63 (d, J = 10.2 Hz, 6H), 3.43 (dd, J = 9.0, 4.4 Hz, 1H), 3.43 - 3.36 (m, 2H), 3.11 (dt, J = 9.3, 7.5 Hz, 1H), 2.41 - 2.32 (m, 1H), 2.23 (dtd, J = 12.6, 7.5, 4.7 Hz, 1H), 1.77 (d, J = 6.6 Hz, 3H).

[0665] Example 68: Synthesis of (3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}-1-{2,5,8- trioxabicyclo[7.4.0]trideca-1(13),9(10),11-trien-11-yl}tetrahydropyrrole hydrochloride (E4)

[0666] The synthesis route is as follows:

[0667]

[0668] Step 1: (3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}-1-{2,5,8-trioxabicyclo[7.4.0]trideca- 1(13),9(10),11-trien-11-yl}tetrahydropyrrole hydrochloride hydrochloride (E4)

[0669] 100 mL single necked flask was charged with free compound 1 (0.50 g, 2.08 mmol), E4-1 (0.56 g, 2.19 mmol), Pd(OAc)2(20 mg, 0.08 mmol), X-Phos (40 mg, 0.08 mmol), Cs2CO3(2.00 g, 6.25 mmol) and 50 mL of toluene, synthesis and workup procedure refer to compound D1, to give compound E4 (0.39 g, y = 44%). LCMS (ESI) m / z: 419.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 10.49 (dt, J = 12.2, 5.9 Hz, 1H), 10.04 (dt, J = 12.3, 6.3 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.23 (d, J = 7.3 Hz, 1H), 8.02 (dd, J = 13.7, 8.1 Hz, 2H), 7.65 (q, J = 7.2 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.17 (d, J = 9.4 Hz, 2H), 5.39 (q, J = 6.5 Hz, 1H), 4.36 (t, J = 4.1 Hz, 2H), 4.02 (dd, J = 5.8, 3.0 Hz, 2H), 3.77 (dq, J = 13.5, 4.8, 4.1 Hz, 5H), 3.47 (d, J = 6.5 Hz, 2H), 3.40 (td, J = 8.7, 4.7 Hz, 1H), 3.11 (q, J = 8.0 Hz, 1H), 2.39 (dq, J = 14.7, 7.5 Hz, 1H), 2.21 (td, J = 10.5, 8.2, 4.6 Hz, 1H), 1.77 (d, J = 6.6 Hz, 3H).

[0670] Example 69: Synthesis of 6-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-3,4-dihydro-2H-chromen-2-one (E5)

[0671] The synthesis route is as follows:

[0672]

[0673] Step 1: (2E)-3-{5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-2-methoxyphenyl}prop-2-enoic acid methyl ester (E5-2)

[0674] 500 mL single necked flask, compound 1 (13.50 g, 31.35 mmol), E5-1 (8.80 g, 32.46 mmol), Pd(OAc)2(730 mg, 3.25 mmol), X-Phos (1.55 g, 3.25 mmol), Cs2CO3(31.73 g, 97.39 mmol) and 100 mL of toluene were added, synthesis and work-up procedure refer to compound A1-3, compound E5-2 (13.50 g, y = 96%) was obtained. LCMS (ESI) m / z: 431.2 [M+H] + .

[0675] Step 2: (2E)-3-{5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-methoxyphenyl}prop-2-enoic acid methyl ester (E5-3)

[0676] 500 mL single necked flask, compound E5-2 (13.50 g, 31.36 mmol), 10% palladium on carbon (60% water content) and 100 mL of methanol were added, replaced with nitrogen for three times, then replaced with hydrogen for three times, stirred at room temperature, reaction overnight, filtered (diatomite helped to filter, waste palladium on carbon was recycled), the filtrate was concentrated under reduced pressure to no solvent evaporated, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure, compound E5-3 (3.50 g, y = 28%) was obtained. LCMS (ESI) m / z: 433.2 [M+H] + .

[0677] Step 3: 3-{5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2-methoxyphenyl}propanoic acid methyl ester (E5-4)

[0678] 500 mL single necked flask, compound E5-3 (3.50 g, 8.09 mmol) and 100 mL of dichloromethane were added and stirred, cooled to 0 °C, boron tribromide (3.50 g, 24.27 mmol) was added dropwise, after dropwise, stirred at room temperature for 2.0 h, cooled to 0 °C, quenched with methanol dropwise, concentrated under reduced pressure to no solvent evaporated, dichloromethane 50 mL and purified water 50 mL were added and stirred, stood until obvious layering, separated, concentrated under reduced pressure to no solvent evaporated, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure, compound E5-4 (0.66 g, y = 20%) was obtained. LCMS (ESI) m / z: 419.2 [M+H] + .

[0679] Step 4: 3-{2-hydroxy-5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl}propanoic acid (E5-5)

[0680] 500 mL single necked flask, was charged with compound E5-4 (0.66 g, 1.58 mmol), sodium hydroxide (0.19 g, 4.75 mmol), purified water 10 mL and ethanol 10 mL was stirred, reaction was allowed to proceed overnight, 1 N hydrochloric acid was added drop wise till solid was precipitated, filtered, the filter cake was dried under blast of air at 45 °C to constant weight to get compound E5-5 (0.52 g, y = 81 %). LCMS (ESI) m / z: 405.2 [M+H] + .

[0681] Step 5: 6-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]- 3,4-dihydro-2H-chromen-2-one (E5)

[0682] 250 mL single necked flask, was charged with compound E5-5 (0.50 g, 1.24 mmol), PYBOP (1.05 g, 2.02 mmol), triethylamine (0.48 g, 3.71 mmol) and dichloromethane 50 mL was stirred overnight, 50 mL saturated brine was added and stirred, allowed to settle to get distinct layers, phases were separated, organic phase was retained, aqueous phase was extracted with dichloromethane 50 mL once, combined organic phase was dried over anhydrous sodium sulfate, filtered, filtrate was concentrated under reduced pressure to distill off solvent, residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure to get compound E5 (81.42 mg, y = 17 %). LCMS (ESI) m / z: 387.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.52 (dd, J = 8.7, 6.3 Hz, 3H), 7.33 (d, J = 8.7 Hz, 1H), 6.77 (s, 1H), 6.41 - 6.32 (m, 2H), 4.80 (t, J = 6.7 Hz, 1H), 3.31 (dd, J = 9.5, 5.2 Hz, 3H), 3.14 - 3.01 (m, 2H), 2.04 (s, 1H), 1.88 (s, 1H), 1.43 (d, J = 6.5 Hz, 3H).

[0683] Example 70: Synthesis of 6-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-1H-indole-3-carboxylic acid (E6)

[0684] The synthesis route is as follows:

[0685]

[0686] Step 1: 6-Bromoindole-1-carboxylic acid-2-methylprop-2-yl ester (E6-2)

[0687] Into a 500 mL single necked flask was placed compound E6-1 (5.00 g, 25.50 mmol), (Boc)20 (8.35 g, 38.26 mmol), DMAP (311 mg, 2.55 mmol), triethylamine (7.74 g, 76.49 mmol) and dichloromethane 100 mL stirred and reacted overnight, added 150 mL purified water stirred, allowed to stand until clear separation, separated the phases, retained the organic phase, extracted the aqueous phase with dichloromethane 50 mL once, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure until solvent evaporation, purified the residue by column chromatography (silica gel 200-300 mesh, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure, formed the hydrochloride salt, dried under a blast of air at 45 °C, obtained compound E6-2 (6.50 g, y = 86%). LCMS (ESI) m / z: 296.0 [M+H] + .

[0688] Step 2: 6-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl] indole-1-carboxylic acid-2-methylprop-2-yl ester (E6-3)

[0689] Into a 250 mL single necked flask was placed free compound 1 (3.40 g, 14.14 mmol), E6-2 (5.00 g, 16.88 mmol), Pd(OAc)2 (100 mg, 0.40 mmol), X-Phos (200 mg, 0.40 mmol), Cs2CO3 (13.80 g, 42.36 mmol) and 50 mL toluene, replaced three times with nitrogen, stirred and reacted overnight at 100 °C, cooled to room temperature, added 20 mL saturated brine stirred, allowed to stand until clear separation, separated the phases, retained the organic phase, extracted the aqueous phase with ethyl acetate 50 mL once, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure until solvent evaporation, purified the residue by column chromatography (silica gel 200-300 mesh, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure, obtained compound E6-3 (2.36 g, y = 36%). LCMS (ESI) m / z: 456.3 [M+H]+ .

[0690] Step 3: 6-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-3- (trifluoroacetyl)indole-1 -carboxylic acid-2-methylprop-2-yl ester (E6-4)

[0691] 250 mL single necked flask, was charged with compound E6-3 (2.30 g, 5.05 mmol) and DMF 25 mL stirred, cooled to 0 °C, trifluoroacetic anhydride (2.12 g, 10.09 mmol) was added drop wise, after drop wise addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for 4.0 h, 150 mL saturated brine and 50 mL ethyl acetate was added stirred, allowed to stand until clear separation was observed, phases were separated, the organic phase was retained, the aqueous phase was extracted with 50 mL ethyl acetate twice, the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to remove solvent, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure to obtain compound E6-4 (1.20 g, y = 43%). LCMS (ESI) m / z: 552.1 [M+H] + .

[0692] Step 4: 6-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-1H- indole-3-carboxylic acid (E6)

[0693] 250 mL single necked flask, was charged with compound E6-4 (1.00 g, 1.81 mmol), sodium hydroxide (0.36 g, 9.05 mmol) in purified water 40 mL and DMF 5 mL stirred, allowed to warm to 100 °C and stirred overnight, cooled to room temperature, 50 mL ethyl acetate was added stirred, allowed to stand until clear separation was observed, phases were separated, the organic phase was retained, the aqueous phase was extracted with 50 mL ethyl acetate twice, the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to remove solvent, the residue was purified by column chromatography (200-300 mesh silica gel, dichloromethane / methanol: 100 / 0→90 / 10), concentrated under reduced pressure to obtain compound E6 (0.17 g, y = 23%). LCMS (ESI) m / z: 400.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.52 (dd, J = 8.7, 6.3 Hz, 3H), 7.33 (d, J = 8.7 Hz, 1H), 6.77 (s, 1H), 6.41 - 6.32 (m, 2H), 4.80 (t, J = 6.7 Hz, 1H), 3.31 (dd, J = 9.5, 5.2 Hz, 3H), 3.14 - 3.01 (m, 2H), 2.04 (s, 1H), 1.88 (s, 1H), 1.43 (d, J = 6.5 Hz, 3H).

[0694] Example 71: Synthesis of 6-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]-2,3-dihydro-1H-2-oxo(E7)

[0695] The synthesis route is as follows:

[0696]

[0697] Step 1: {4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-2- nitrophenyl}acetic acid methyl ester (E7-2)

[0698] 500 mL single necked flask, free compound 1 (5.00 g, 18.06 mmol), compound E7-1 (5.00 g, 18.24 mmol), Pd(OAc)2(100 mg, 0.40 mmol), X-Phos (200 mg, 0.40 mmol), Cs2CO3(13.80 g, 42.36 mmol) and 50 mL of toluene, synthesis and workup procedure refer to compound A1-3, compound E7-2 (2.34 g, y = 30%) was obtained. LCMS (ESI) m / z: 434.3 [M+H] + .

[0699] Step 2: {2-amino-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl] phenyl}acetic acid methyl ester (E7-3)

[0700] 250 mL single neck flask, compound E7-2 (2.00 g, 4.62 mmol) and methanol 50 mL were stirred, replaced with nitrogen for three times, 10% palladium on carbon (0.2 g, water content 60%) was added, replaced with hydrogen for three times, stirred at room temperature overnight, filtered (diatomite as filter aid, waste palladium on carbon was recycled), 50 mL methanol was used to rinse, the filtrate was concentrated under reduced pressure to remove solvent, the residue was purified by column chromatography (200-300 mesh silica gel, dichloromethane / methanol: 100 / 0→90 / 10), concentrated under reduced pressure to give compound E7-3 (0.60 g, y = 32%). LCMS (ESI) m / z: 404.2 [M+H] + .

[0701] Step 3: 6-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]- 2,3-dihydro-1H-2-oxo (E7)

[0702] 50 mL single neck flask, compound E7-3 (0.66 g, 1.20 mmol) and methanol 10 mL were stirred, heated to reflux and stirred overnight, cooled to room temperature, the filtrate was concentrated under reduced pressure to remove solvent, the residue was purified by column chromatography (200-300 mesh silica gel, dichloromethane / methanol: 100 / 0→95 / 5), concentrated under reduced pressure to give compound E7 (0.22 g, y = 46%). LCMS (ESI) m / z: 372.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.26 (d, J = 8.2 Hz, 1H), 7.92 (dd, J = 7.9, 2.6 Hz, 1H), 7.81 (dd, J = 8.3, 2.5 Hz, 1H), 7.71 (dd, J = 7.3, 2.5 Hz, 1H), 7.52 (pd, J = 6.8, 5.9, 2.3 Hz, 3H), 6.98 (dd, J = 8.2, 2.5 Hz, 1H), 6.14 - 6.05 (m, 2H), 4.88 - 4.84 (m, 1H), 3.34 (dd, J = 3.4, 1.7 Hz, 5H), 3.17 - 3.00 (m, 2H), 2.15 (q, J = 7.8, 5.5 Hz, 1H), 1.96 (ddt, J = 12.0, 8.0, 4.9 Hz, 1H), 1.55 (dd, J = 6.7, 2.5 Hz, 3H).

[0703] Example 72: Synthesis of 7-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]quinoline-4-carboxylic acid (E8)

[0704] The synthetic route is as follows:

[0705]

[0706] Step 1: 7-bromoquinoline-2,4-dicarboxylic acid (E8-2)

[0707] Into a 500 mL single-neck flask, was placed compound E8-1 (5.00 g, 18.24 mmol), sodium pyruvate (2.92 g, 26.54 mmol), sodium hydroxide (5.3 g, 0.13 mol) and purified water 100 mL, stirred, refluxed for 4.0 h, cooled to room temperature, added 1 N hydrochloric acid dropwise until solid was observed to precipitate, filtered, washed with 50 mL of purified water, and dried at 45 °C under a blast of air to constant weight to give compound E8-2 (4.64 g, 86%). LCMS (ESI) m / z: 295.9 [M+H] + .

[0708] Step 2: 7-bromoquinoline-4-carboxylic acid (E8-3)

[0709] Into a 250 mL single-neck flask, was placed compound E8-2 (4.5 g, 15.20 mmol) and diphenyl ether 50 mL, stirred, replaced with nitrogen three times, warmed to 210 °C for 5.0 h, cooled to room temperature, filtered, washed with 50 mL of petroleum ether, and dried at 45 °C under a blast of air to constant weight to give compound E8-3 (3.32 g, y = 87%). LCMS (ESI) m / z: 252.0 [M+H] + .

[0710] Step 3: ethyl 7-bromoquinoline-4-carboxylate (E8-4)

[0711] Into a 50 mL single-neck flask, was placed compound E8-3 (3.30 g, 13.15 mmol) and methanol 10 mL, stirred, cooled to 0 °C, added thionyl chloride (1.84 g, 15.50 mmol) dropwise, warmed to reflux for overnight, cooled to room temperature, the filtrate was concentrated under reduced pressure to distill off the solvent, to give compound E8-4 (3.38 g, y = 92%). LCMS (ESI) m / z: 280.0 [M+H] + .

[0712] Step 4: methyl 7-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]quinoline-4-carboxylate (E8-5)

[0713] A 500 mL single necked flask was charged with free compound 1 (2.58 g, 10.75 mmol), compound E8-4 (3.00 g, 10.75 mmol), Pd(OAc)2(242.47 mg, 1.08 mmol), X-Phos (514.84 mg, 1.08 mmol), Cs2CO3(13.80 g, 42.36 mmol) and 50 mL of toluene, synthesis and work up procedure refer to compound A1-3 to give compound E8-5 (1.01 g, y = 22%). LCMS (ESI) m / z: 426.2 [M+H] + .

[0714] Step 5: 7-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl] quinoline-4-carboxylic acid (E8)

[0715] A 500 mL single necked flask was charged with compound E8-5 (1.00 g, 2.35 mmol), sodium hydroxide (0.47 g, 11.75 mmol), purified water 10 mL and ethanol 10 mL, synthesis and work up procedure refer to compound A1 to give compound E8 (0.44 g, y = 45%). LCMS (ESI) m / z: 412.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 4.6 Hz, 1H), 8.40 - 8.30 (m, 2H), 7.98 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.57 (t, J = 8.3 Hz, 3H), 7.28 (d, J = 4.6 Hz, 1H), 7.04 (d, J = 9.3 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 5.03 (s, 1H), 3.54 (s, 3H), 3.31 (s, 2H), 2.15 (s, 2H), 1.54 (d, J = 6.4 Hz, 3H).

[0716] Example 73: Synthesis of 5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-1,3-dihydro-2-benzofuran-1-one (E9)

[0717] The synthesis route is as follows:

[0718]

[0719] Step 1: 5-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]- 1,3-dihydro-2-benzofuran-1-one (E9)

[0720] 100 mL single necked flask was charged with free compound 1 (0.50 g, 2.08 mmol), compound E9-1 (0.53 g, 2.49 mmol), Pd2(dba)3 (100 mg, 0.11 mmol), BINAP (0.13 g, 0.21 mmol), Cs2CO3 (2.03 g, 6.23 mmol) and 20 mL of toluene, synthesis and work up procedure refer to compound A1-3 to give compound E9 (0.31 g, y = 39%). LCMS (ESI) m / z: 373.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.37 (d, J = 8.6 Hz, 1H), 8.04 (dd, J = 9.8, 7.9 Hz, 3H), 7.72 - 7.60 (m, 4H), 6.71 (dd, J = 8.6, 2.1 Hz, 1H), 6.65 (d, J = 2.1 Hz, 1H), 5.44 (q, J = 6.7 Hz, 1H), 5.26 (s, 2H), 3.96 (p, J = 6.5 Hz, 1H), 3.75 (dd, J = 11.0, 7.1 Hz, 1H), 3.60 (dt, J = 10.6, 4.1 Hz, 2H), 3.34 (dt, J = 10.0, 7.5 Hz, 1H), 2.41 (dq, J = 14.6, 7.4, 6.6 Hz, 1H), 2.37 - 2.28 (m, 1H), 1.77 (d, J = 6.6 Hz, 3H).

[0721] Example 74: Synthesis of 7-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H- pyrrol-1-yl]-1,2-dihydroquinolin-2-one (E10)

[0722] The synthesis route is as follows:

[0723]

[0724] Step 1: (2E)-3-{4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]- 2-nitrophenyl}prop-2-enoic acid methyl ester (E10-2)

[0725] 500 mL single necked flask, add free compound 1 (2.00 g, 8.32 mmol), compound E10-1 (2.85 g, 9.98 mmol), Pd2(dba)3 (186 mg, 0.83 mmol), BINAP (395 mg, 0.83 mmol), Cs2CO3 (8.13 g, 24.96 mmol) and 50 mL of toluene, synthesis and post-processing operation according to compound A1-3, compound E10-2 (2.55 g, y = 69%) was obtained. LCMS (ESI) m / z: 446.2 [M+H] + .

[0726] Step 2: (2E)-3-{2-amino-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl}prop-2-enoic acid methyl ester (E10-3)

[0727] 250 mL single necked flask, add compound E10-2 (2.50 g, 5.62 mmol) and 50 mL of ethanol, replace three times of nitrogen, add 10% palladium carbon (0.25 g, 60% of water content), replace three times of hydrogen, stir overnight at room temperature, reaction is completed, replace three times of nitrogen, filter (diatomite filter aid, recover palladium carbon), 20 mL of ethanol elution, concentrate the filtrate under reduced pressure to no solvent evaporation, compound E10-3 (1.42 g, y = 61%) was obtained. LCMS (ESI) m / z: 416.2 [M+H] + .

[0728] Step 3: 7-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-1,2- dihydroquinolin-2-one (E10)

[0729] 100 mL single necked flask, add compound E10-3 (1.40 g, 3.37 mmol) and 50 mL of methanol, stir, replace three times of nitrogen, heat to reflux reaction, reaction is completed, concentrate the filtrate under reduced pressure to no solvent evaporation, the residue is purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrate under reduced pressure, compound E10 (0.34 g, y = 26%) was obtained. LCMS (ESI) m / z: 384.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 8.5 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.83 (d, J = 7.3 Hz, 1H), 7.63 (ddd, J = 19.2, 9.7, 5.8 Hz, 3H), 6.99 - 6.93 (m, 1H), 6.13 (dd, J = 8.1, 2.3 Hz, 1H), 6.08 (s, 1H), 5.37 (d, J = 6.8 Hz, 1H), 3.82 (p, J = 6.6 Hz, 1H), 3.46 - 3.26 (m, 3H), 3.09 (q, J = 7.9 Hz, 1H), 2.71 (t, J = 7.5 Hz, 2H), 2.38 (t, J = 7.5 Hz, 2H), 2.24 (q, J = 7.3 Hz, 2H), 1.72 (d, J = 6.5 Hz, 3H).

[0730] Example 75: Synthesis of 7-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-1,2,3,4-tetrahydronaphthalen-1-one (E11)

[0731] The synthetic route is as follows:

[0732]

[0733] Step 1: 8-Oximinotetrahydro-2-naphthalenecarboxylic acid trifluoromethanesulfonate (E11-2)

[0734] 250 mL single necked flask, compound E11-1 (5.00 g, 30.83 mmol) and pyridine 20 mL were added and stirred, cooled to 0 °C, trifluoromethanesulfonic anhydride (9.57 g, 33.91 mmol) was added dropwise, after dropwise, the reaction was carried out at room temperature for 1.0 h, 100 mL purified water and 50 mL ethyl acetate were added and stirred, and then allowed to stand until the layers were clearly separated, the organic phase was retained, the water phase was extracted with 50 mL ethyl acetate once, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until the solvent was distilled out, and the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure to obtain compound E11-2 (8.30 g, y = 92%). LCMS (ESI) m / z: 295.0 [M+H] + .

[0735] Step 2: 7-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-1,2,3,4-tetrahydronaphthalen-1-one (E11)

[0736] 100 mL single necked flask, was charged with free compound 1 (1.00 g, 4.16 mmol), compound E11-2 (1.60 g, 5.41 mmol), Pd(OAc)2(20 mg, 0.08 mmol), X-Phos (50 mg, 0.08 mmol), Cs2CO3(4.40 g, 13.50 mmol) and 50 mL of toluene, was flushed with nitrogen three times, was warmed to 100 °C and stirred overnight, was cooled to room temperature, was stirred with 20 mL of saturated brine, was allowed to stand until clear separation, was separated, the organic phase was retained, the aqueous phase was extracted with 50 mL of ethyl acetate once, the combined organic phases were dried over anhydrous sodium sulfate, were filtered, and the filtrate was concentrated under reduced pressure until solvent was distilled off, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), and was concentrated under reduced pressure to give compound E11 (0.22 g, y = 14%). LCMS (ESI) m / z: 385.2 [M+H] + .

[0737] Example 76: Synthesis of 6-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-1,2,3,4-tetrahydronaphthalen-1-one (E12)

[0738] The synthesis route is as follows:

[0739]

[0740] Step 1: 5-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (E12-2)

[0741] 250 mL single necked flask, was charged with compound E12-1 (5.00 g, 30.83 mmol) and pyridine 20 mL was stirred and cooled to 0 °C, trifluoromethanesulfonic anhydride (9.57 g, 33.91 mmol) was added dropwise, the synthesis and workup procedure was referenced to compound E11-2 to give compound E12-2 (7.40 g, y = 82%). LCMS (ESI) m / z: 295.0 [M+H] + .

[0742] Step 2: 6-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]-1,2,3,4-tetrahydronaphthalen-1-one (E12)

[0743] 100 mL single necked flask was charged with free compound 1 (1.00 g, 4.16 mmol), compound E12-2 (1.60 g, 5.41 mmol), Pd(OAc)2(20 mg, 0.08 mmol), X-Phos (50 mg, 0.08 mmol), Cs2CO3(4.40 g, 13.50 mmol) and 50 mL of toluene, synthesis and work up procedure refer to compound E11 to give compound E12 (0.28 g, y = 18%). LCMS (ESI) m / z: 385.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.39 (d, J = 8.6 Hz, 1H), 8.18 (t, J = 7.6 Hz, 1H), 8.02 (dd, J = 11.6, 8.1 Hz, 2H), 7.65 (q, J = 7.4 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 6.79 (dt, J = 8.5, 2.5 Hz, 1H), 5.44 (q, J = 6.5 Hz, 1H), 3.87 - 3.79 (m, 1H), 3.54 (dt, J = 11.8, 4.4 Hz, 2H), 3.47 (td, J = 8.7, 4.6 Hz, 1H), 3.21 - 3.14 (m, 1H), 2.81 (t, J = 6.0 Hz, 2H), 2.54 (t, J = 6.4 Hz, 2H), 2.40 (dd, J = 12.7, 7.9 Hz, 1H), 2.29 - 2.21 (m, 1H), 1.97 (d, J = 6.2 Hz, 1H), 1.77 (d, J = 6.6 Hz, 3H).

[0744] Example 77: Synthesis of 2,2,2-trifluoro-1-{6-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]-1H-indol-3-yl}ethan-1-one (E13)

[0745] The synthesis route is as follows:

[0746]

[0747] Step 1: 2,2,2-trifluoro-1-{6-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro- 1H-pyrrol-1-yl]-1H-indol-3-yl}ethan-1-one (E13)

[0748] 100 mL single necked flask, was added free compound 1 (1.00 g, 4.16 mmol), compound E13-1 (1.46 g, 4.99 mmol), Pd(OAc)2(20 mg, 0.08 mmol), X-Phos (50 mg, 0.08 mmol), Cs2CO3(4.00 g, 12.50 mmol) and 50 mL of toluene, synthesis and work-up procedure refer to compound E11, to give compound E13 (0.21 g, y = 11%). LCMS (ESI) m / z: 452.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.13 - 8.01 (m, 3H), 7.88 (d, J = 7.4 Hz, 1H), 7.73 - 7.59 (m, 4H), 7.40 (s, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.54 (d, J = 3.0 Hz, 1H), 6.06 (d, J = 7.0 Hz, 1H), 4.23 (d, J = 9.2 Hz, 2H), 3.86 - 3.76 (m, 2H), 3.47 (q, J = 9.5 Hz, 1H), 1.96 (d, J = 6.7 Hz, 3H), 1.83 (dd, J = 14.6, 7.5 Hz, 1H), 0.93 (s, 1H).

[0749] Example 78: Synthesis of (2R)-2-({4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}oxy)propanoic acid (F1)

[0750] The synthesis route is as follows:

[0751]

[0752] Step 1: (2R)-2-[(4-bromophenyl)oxy]propionic acid ethyl ester (F1-2)

[0753] 100 mL single necked flask, was added compound F1-1 (0.95 g, 5.52 mmol), (2S)-2-bromo propionic acid ethyl ester (1.00 g, 5.52 mmol), potassium carbonate (2.30 g, 16.64 mmol) and 10 mL of acetonitrile, warmed to 80 °C for overnight, cooled to room temperature, filtered, 10 mL of acetonitrile was used to rinse, the filtrate was concentrated under reduced pressure to no solvent evaporated, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure to give compound F1-2 (0.42 g, y = 28%). LCMS (ESI) m / z: 273.0 [M+H] + .

[0754] Step 2: (2R)-2-({4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl}oxy)propanoic acid ethyl ester (F1-3)

[0755] Into a 100 mL single necked flask, was placed compound 1 (0.34 g, 1.40 mmol), compound F1-2 (0.40 g, 1.47 mmol), Pd(OAc)2(20 mg, 0.08 mmol), X-Phos (50 mg, 0.08 mmol), Cs2CO3(2.00 g, 6.25 mmol) and 50 mL of toluene, flushed with nitrogen three times, warmed to 100 °C and stirred overnight, cooled to room temperature, stirred with 20 mL of saturated brine, allowed to stand until clear separation, separated, retained the organic phase, extracted the aqueous phase with 50 mL of ethyl acetate once, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure until solvent was distilled off, the residue was purified by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate: 95 / 5→75 / 25), concentrated under reduced pressure to give compound F1-3 (0.26 g, y = 41%). LCMS (ESI) m / z: 452.2 [M+H] + .

[0756] Step 3: (2R)-2-({4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl}oxy)propanoic acid (F1)

[0757] Into a 100 mL single necked flask, was placed compound F1-3 (0.20 g, 0.44 mmol), sodium hydroxide (80.50 mg, 2.21 mmol), purified water 5 mL and ethanol 5 mL, stirred, warmed to 40 °C and stirred overnight, cooled to room temperature, added 1 N hydrochloric acid drop wise until solid was evident, filtered, rinsed with 5 mL of purified water, air dried at 45 °C until constant weight to give compound F1 (0.12 g, y = 65%). LCMS (ESI) m / z: 405.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.59 - 7.49 (m, 3H), 6.74 (d, J = 8.3 Hz, 2H), 6.38 (d, J = 8.3 Hz, 2H), 4.80 (d, J = 6.9 Hz, 1H), 4.57 (q, J = 6.7 Hz, 1H), 3.27 (dq, J = 12.9, 6.9, 6.3 Hz, 3H), 3.07 (t, J = 7.9 Hz, 1H), 2.97 (s, 1H), 2.03 (s, 1H), 1.96 - 1.88 (m, 1H), 1.43 (d, J = 6.6 Hz, 6H).

[0758] Example 79: Synthesis of (2S)-2-({3-fluoro-4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}oxy)propanoic acid (F2)

[0759] The synthetic route is as follows:

[0760]

[0761] Step 1: (2S)-2-[(4-bromo-3-fluorophenyl)oxy]propanoic acid ethyl ester (F2-2)

[0762] 100 mL single necked flask, compound F2-1 (0.95 g, 5.52 mmol), (2R)-2-bromoethyl propionate (1.00 g, 5.52 mmol), potassium carbonate (2.30 g, 16.64 mmol) and acetonitrile 10 mL, synthesis and workup procedure refer to compound F1-2, compound F2-2 (0.56 g, y = 35%) was obtained. LCMS (ESI) m / z: 291.0 [M+H] + .

[0763] Step 2: (2S)-2-({3-fluoro-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro- 1H-pyrrol-1-yl]phenyl}oxy)propanoic acid ethyl ester (F2-3)

[0764] 100 mL single necked flask, compound 1 (0.36 g, 1.50 mmol), compound F2-2 (0.44 g, 1.50 mmol), Pd(OAc)2(20 mg, 0.08 mmol), X-Phos (50 mg, 0.08 mmol), Cs2CO3(2.00 g, 6.25 mmol) and 50 mL of toluene, synthesis and work up procedure refer to compound F1-3, compound F2-3 (0.45 g, y = 66%) was obtained. LCMS (ESI) m / z: 452.2 [M+H] + .

[0765] Step 3: (2S)-2-({3-fluoro-4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl}oxy)propanoic acid (F2)

[0766] 100 mL single necked flask, compound F2-3 (0.30 g, 0.66 mmol), sodium hydroxide (132.74 mg, 3.32 mmol), purified water 5 mL and ethanol 5 mL, synthesis and work up procedure refer to compound F1, compound F2 (0.16 g, y = 58%) was obtained. LCMS (ESI) m / z: 423.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.58 (h, J = 6.1, 5.4 Hz, 3H), 6.71 - 6.58 (m, 2H), 6.56 (d, J = 8.7 Hz, 1H), 5.05 (d, J = 7.0 Hz, 1H), 4.59 (s, 1H), 3.43 (s, 1H), 3.26 (d, J = 9.0 Hz, 2H), 3.18 (s, 1H), 3.08 (q, J = 7.9 Hz, 1H), 2.02 (q, J = 7.4 Hz, 2H), 1.55 (d, J = 6.4 Hz, 3H), 1.42 (d, J = 6.7 Hz, 3H).

[0767] Example 80: Synthesis of (2R)-2-({3-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl}oxy)propanoic acid (F3)

[0768] The synthesis route is as follows:

[0769]

[0770] Step 1: (2R)-2-[(4-bromophenyl)oxy]propionic acid ethyl ester (F3-2)

[0771] 100 mL single necked flask, compound F3-1 (0.95 g, 5.52 mmol), (2S)-2-bromo propionic acid ethyl ester (1.00 g, 5.52 mmol), potassium carbonate (2.30 g, 16.64 mmol) and acetonitrile 10 mL were added, synthesis and work up procedure refer to compound F1-2 to get compound F3-2 (0.48 g, y = 28 %). LCMS (ESI) m / z: 273.0 [M+H] + .

[0772] Step 2: (2R)-2-({3-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}oxy)propanoic acid ethyl ester (F3-3)

[0773] 100 mL single necked flask, compound 1 (0.34 g, 1.40 mmol), compound F3-2 (0.40 g, 1.47 mmol), Pd(OAc)2 (20 mg, 0.08 mmol), X-Phos (50 mg, 0.08 mmol), Cs2CO3 (2.00 g, 6.25 mmol) and 50 mL toluene were added, synthesis and work up procedure refer to compound F1-3 to get compound F3-3 (0.30 g, y = 48 %). LCMS (ESI) m / z: 452.2 [M+H] + .

[0774] Step 3: (2R)-2-({3-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}oxy)propanoic acid (F3)

[0775] 100 mL single necked flask, compound F3-3 (0.20 g, 0.44 mmol), sodium hydroxide (80.50 mg, 2.21 mmol), purified water 5 mL and ethanol 5 mL were added, synthesis and work up procedure refer to compound F1 to get compound F3 (124.74 mg, y = 70 %). LCMS (ESI) m / z: 405.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.62 - 7.50 (m, 3H), 6.99 (t, J = 8.1 Hz, 1H), 6.09 (dd, J = 8.1, 2.3 Hz, 1H), 6.06 - 6.00 (m, 1H), 5.95 (d, J = 2.4 Hz, 1H), 4.95 (q, J = 6.5 Hz, 1H), 4.65 (q, J = 6.7 Hz, 1H), 3.41 (q, J = 6.5 Hz, 1H), 3.29 (dd, J = 9.7, 6.1 Hz, 2H), 3.07 (dq, J = 8.7, 4.6, 3.6 Hz, 2H), 2.03 (dh, J = 27.6, 6.3 Hz, 2H), 1.49 (d, J = 6.4 Hz, 3H), 1.44 (d, J = 6.7 Hz, 3H).

[0776] Example 81: Synthesis of (2S)-2-({4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}oxy)propanoic acid (F4)

[0777] The synthetic route is as follows:

[0778]

[0779] Step 1: (2S)-2-({4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}oxy)propanoic acid ethyl ester (F4-2)

[0780] 100 mL single necked flask, compound 1 (0.36 g, 1.50 mmol), compound F4-1 (0.41 g, 1.50 mmol), Pd(OAc)2(20 mg, 0.08 mmol), X-Phos (50 mg, 0.08 mmol), Cs2CO3(2.00 g, 6.25 mmol) and 25 mL of toluene, synthesis and workup procedure refer to compound F1-3, compound F4-2 (0.36 g, y = 53%) was obtained. LCMS (ESI) m / z: 452.2 [M+H] + .

[0781] Step 2: (2S)-2-({4-[(3S)-3-{[(1R)-1-(naphthalen-1- yl)ethyl]amino}tetrahydro-1H-pyrrol-1-yl]phenyl}oxy)propanoic acid (F4)

[0782] 100 mL single necked flask, was added compound F4-2 (0.20 g, 0.44 mmol), sodium hydroxide (80.50 mg, 2.21 mmol), purified water 5 mL and ethanol 5 mL, synthesis and work-up procedure refer to compound F1, to get compound F4 (98.01 mg, y = 55%). LCMS (ESI) m / z: 405.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.5 Hz, 1H), 8.06 (dd, J = 8.2, 3.5 Hz, 2H), 7.84 (d, J = 7.3 Hz, 1H), 7.70 (t, J = 3.8 Hz, 1H), 7.70 - 7.60 (m, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 8.9 Hz, 2H), 5.44 (d, J = 6.8 Hz, 1H), 4.66 (q, J = 6.7 Hz, 1H), 3.92 (q, J = 6.3 Hz, 1H), 3.48 (dd, J = 10.4, 7.0 Hz, 1H), 3.44 - 3.29 (m, 2H), 3.13 (q, J = 7.9 Hz, 1H), 2.27 (t, J = 7.5 Hz, 2H), 1.73 (d, J = 6.5 Hz, 3H), 1.46 (d, J = 6.7 Hz, 3H).

[0783] Example 82: Synthesis of ({4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1-yl]phenyl}oxy)acetic acid (F5)

[0784] The synthesis route is as follows:

[0785]

[0786] Step 1: ({4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino} tetrahydro-1H-pyrrol-1- yl]phenyl}oxy)acetic acid ethyl ester (F5-2)

[0787] 500 mL single necked flask, was added compound 1 (0.50 g, 2.08 mmol), compound F5-1 (0.57 g, 2.20 mmol), Pd(OAc)2 (50 mg, 0.22 mmol), X-Phos (106 mg, 0.22 mmol), Cs2CO3 (2.03 g, 6.24 mmol) and 20 mL toluene, synthesis and work-up procedure refer to compound F1-3, to get compound F5-2 (0.50 g, y = 58%). LCMS (ESI) m / z: 419.2 [M+H] + .

[0788] Step 3: ({4-[(3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}tetrahydro-1H-pyrrol-1- yl]phenyl}oxy)acetic acid (F5)

[0789] 100 mL single neck flask, add compound F5-3 (0.30 g, 0.72 mmol), sodium hydroxide (144.00 mg, 3.60 mmol), purified water 5 mL and ethanol 5 mL, synthesis and post-processing operation according to compound F1, get compound F5 (95.72 mg, y = 34%). LCMS (ESI) m / z: 391.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 8.3 Hz, 1H), 7.96 (dd, J = 7.9, 1.7 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.62 - 7.50 (m, 3H), 6.72 (d, J = 8.9 Hz, 2H), 6.36 (d, J = 8.7 Hz, 2H), 5.00 (t, J = 6.4 Hz, 1H), 4.26 (d, J = 3.8 Hz, 2H), 3.40 (d, J = 7.8 Hz, 1H), 3.22 (dd, J = 9.3, 6.6 Hz, 2H), 3.04 (d, J = 10.2 Hz, 1H), 2.99 (d, J = 8.4 Hz, 1H), 2.07 - 1.99 (m, 2H), 1.52 (dd, J = 6.8, 2.3 Hz, 3H).

[0790] Experimental Example 1: CaSR Allosteric Activation Effect in Vitro Experiment

[0791] CaSR belongs to the C family of G protein-coupled receptors (GPCRs). When extracellular Ca 2+ or compound activates CaSR on the cell, the intracellular Ca 2+ concentration increases. Therefore, the hCaSR-CHO cell line is applied, and the intracellular Ca 2+ concentration is used as an indicator. By detecting the change of intracellular Ca 2+ concentration, the allosteric activation effect of the compound on CaSR is evaluated.

[0792] I. Experimental Steps:

[0793] a) Pre-plating preparation: 12 h before cell plating, 0.1 mg / ml polylysine was used to coat the 384-well cell culture plate.

[0794] b) Cell plating: Resuspend the digested CHO-CaSR cells with complete medium, count by cell counter and adjust the cell density to 5x10 5 cells / mL, and inoculate 25μL cell suspension per well. After cell inoculation, place the plate in 37℃, 5% CO2 incubator for 18h.

[0795] c) Compound preparation: Dilute the test compound to the desired concentration (10μM, 2μM, 400nM, 80nM, 16nM, 3.2nM and 0.64nM) by serial dilution, and add to the 384-well compound plate, ready for use. Here, since there are already 25μL Fluo-4 NW reagent in the cell culture plate to be tested, the instrument is set to give a dose of 20μL, so the concentration of the compound in the compound plate at this time is 2.25 times the actual test concentration, i.e. the concentration of 10μM compound in the well is 22.5μM, and so on.

[0796] d) Reagent preparation: According to the requirements of the kit Fluo-4 NW Calcium Assay Kits (Thermo, F36206), add 1mL assay buffer to Component B to prepare a 250mM probenecid solution; then take 100μL probenecid solution and add to 10mL assay buffer, mix well and add to Component A to prepare 1X dye loading solution ready for use.

[0797] e) Add fluorescent dye: Discard the complete medium, and use the multidrop automatic dispenser to add 25μL 1X dye loading solution to the 384-well plate, place in the dark at 37℃ for 30min, transfer to room temperature for another 30min, and then transfer to the Fliper Tetra (Molecular Devices) instrument.

[0798] f) Read raw experimental data: Add 20μL test compound solution, set the excitation wavelength to 470-495nm, detect the emission light in the range of 515-575nm, and after the instrument quality control plate is read and determined to be correct, start the detection, with a continuous detection time of 660 seconds, and after reading is complete, export the values.

[0799] g) Data processing: the maximum fluorescence value (MAX, take the average value of 40 sec-80 sec) minus the minimum fluorescence value (MIN, take the average value of 14 sec-21 sec) after the drug concentration, the fluorescence intensity change value is obtained, which represents the intracellular calcium signal change. Using GraphPad Prism, the drug concentration is used as the horizontal coordinate, and the fluorescence intensity change is used as the vertical coordinate to plot, and the EC 50 value of the compound is calculated.

[0800] II. Experimental results: the EC50 of the compound verified by the present application is shown in Table 1.

[0801] Table 1

[0802]

[0803]

[0804]

[0805] Experimental Example 2: Inhibition of PTH in blood in vivo experiment

[0806] Using a rat adenine model as an animal model of hyperparathyroidism, and using parathyroid hormone (PTH) in blood as an index, the ELISA enzyme immunoassay method is used, and by detecting the change of PTH concentration in rat plasma before and after giving the compound, the in vivo activity of the compound is evaluated.

[0807] Rat adenine model experiment steps

[0808] SPF level male 7-8 week old SD rats are used. First, normal feed is adapted for feeding for 1 week; second, special feed (adenine 0.75%, calcium 0.5% and total phosphorus 1.2%) is fed for 2 weeks, about 400 μL of blood is collected from the tail vein, centrifuged at 12000 rpm for 3 minutes, and plasma samples are obtained, and the concentration of full-length PTH (1-84) in plasma is detected by MicroVue Intact PTH EIA-96Test (Quidel, catalog No. 60-2500); third, according to the PTH concentration level of the rats, the rats are grouped, and the average PTH concentration of each group of rats is basically the same; finally, a single or continuous multiple dose of the compound to be tested is given, and blood samples are collected at different time points before and after administration, about 400 μL each time, centrifuged at 12000 rpm for 3 minutes, and plasma samples are obtained, stored at -80℃ (or -20℃) or directly detected for PTH content by ELISA. According to the method, it is confirmed that the compound has the effect of reducing the PTH level in the blood of adenine model rats.

[0809] The results of the compound verified by the present application to reduce the PTH level in the blood of adenine model rats are shown in Table 2.

[0810] Table 2

[0811]

[0812]

[0813] Note: The efficiency of reducing PTH 1 h after administration compared with 0 h PTH concentration.

[0814] Experimental Example 3: Rat liver microsomal stability test

[0815] Incubate rat liver microsomes, testosterone (positive control), tolbutamide (internal standard), test compound and PBS (pH 7.4) at a certain concentration at 37°C, quench with methanol at 0, 5, 10, 20, 30 and 60 minutes, respectively, pretreat the samples, and detect by LC-MS method, and plot the data (test compound peak area / internal standard peak area as the vertical coordinate and time as the horizontal coordinate) to obtain t 1 / 2 The results are shown in Table 3.

[0816] Table 3

[0817]

[0818] Note: The liver microsomal stability test is affected by the activity of liver microsomes, and the longest incubation time in vitro test is 60 min, t 1 / 2 > 60 min is estimated to have high metabolic stability in vivo.

[0819] Experimental Example 4: SD rat pharmacokinetic experiment

[0820] I. Experimental steps:

[0821] 1) Animal information: SD normal rats, 7-8 weeks old, male, 3-5 rats / group

[0822] 2) Dosing information: single gavage, fasting for more than 12 h before administration.

[0823] 3) Blood sampling points: before administration and 0.25, 0.5, 1, 2, 4, 6, 8, 24 h after administration, 100 μL of whole blood was taken from the tail vein at each time point.

[0824] 4) Sample processing and storage: after blood sampling, transfer to 1.5 mL EP tube, 50 μL per tube, 2 tubes per sample, complete centrifugation within 2 h, whole blood samples were stored in ice bath before centrifugation, centrifugation conditions: 4000 r / min, 2-8°C, 10 min. After aspirating the supernatant, if not detected immediately, store at -80°C or below.

[0825] 5) Detection

[0826] a) Chromatographic column: Infinitylab poroshell 120 SB C18 2.1*100mm, 2.7pm; column temperature: 30°C; flow rate: 0.3ml / min; run time: 9.5min; post run time: 2min; injection volume: 2pL; mobile phase: methanol-0.1% formic acid. Gradient elution was performed according to the following table:

[0827]

[0828] b) Mass spectrometry conditions:

[0829]

[0830]

[0831] c) Preparation of stock solutions, working solution samples:

[0832] All prepared stock solutions were stored in -80-C refrigerator, working solutions were placed in 4-C refrigerator. Evocalcet stock solution (0.2mg / mL): precisely weigh 10mg of the product into a 50ml volumetric flask, dissolve with methanol and dilute to the mark, shake well, and it is ready. (Compound stock solution preparation is the same as Evocalcet) Preparation of standard solutions: precisely measure each stock solution and dilute with 50% methanol to the concentration of 80, 200, 1000, 5000, 10000, 20000, 40000ng / mL for Evocalcet, 093-125, 093-130; 64, 160, 800, 4000, 8000, 16000, 32000ng / mL for 093-062.

[0833] Preparation of clenbuterol hydrochloride solution: precisely weigh 10mg of clenbuterol hydrochloride into a 10ml volumetric flask, dissolve with methanol and dilute to the mark, shake well, and it is ready. Clenbuterol hydrochloride stock solution (1.0mg / mL). Precisely measure the stock solution and dilute with methanol to the concentration of 2000ng / mL for the internal standard working solution.

[0834] d) Sample processing procedure:

[0835] Standard curve sample processing: take 90pL of blank matrix, add 10pL of each standard series solution, 50pL of internal standard solution, vortex mix for 30s, add 350pL of methanol to precipitate the protein solution, vortex mix, centrifuge the sample at 12000rpm for 10min, take 200pL of supernatant and mix with 600pL of water, take the supernatant for analysis.

[0836] Blood sample processing: take 50 μL of plasma sample, add 25 μL of internal standard solution, vortex mix for 30 s, add 175 μL of methanol protein precipitation solution, vortex mix, centrifuge the sample in a centrifuge at 12000 rpm for 10 min, take 100 μL of supernatant, add 300 μL of water, mix, take the supernatant for sample analysis.

[0837] II. Experimental results

[0838] The results are shown in Table 4.

[0839] Table 4

[0840]

Claims

1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt or stereoisomer thereof. 。 2. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier or excipient.

3. Use of a compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition of claim 2 for the manufacture of a medicament for the prevention and / or treatment of a disease associated with CaSR.

4. Use according to claim 3, wherein, the disease is selected from the group consisting of primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism.

5. The use according to claim 3, wherein, the disease is selected from the group consisting of hypercalcemia, hypophosphatemia.

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