Azacycloalkane compounds as well as pharmaceutical composition and use thereof

Abstract

Disclosed in the present invention are azacycloalkane compounds as well as a pharmaceutical composition and the use thereof. The present invention provides the use of the compounds represented by formula (I) or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising the compounds represented by formula (I) as an opioid receptor agonist. When the compounds are used as opioid receptor agonists, the compounds do not cause constipation and intestinal function disorder side effects, do not cause addiction, and thus can be used as pain relieving drugs.

Description

Azacycloalkane compounds, pharmaceutical compositions and uses thereof

[0001] This application claims priority to Chinese patent application 2024106287687 with a filing date of 2024 / 5 / 21. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to an azacycloalkane compound, a pharmaceutical composition and uses thereof. BACKGROUND

[0003] The International Association for the Study of Pain (IASP) considers pain to be the "fifth vital sign" after respiration, pulse, temperature and blood pressure. Pain is an unpleasant feeling or sensation associated with actual or potential tissue damage. If the pain lasts for more than a month, or beyond the expected duration of the acute process of injury, healing and repair, it becomes chronic pain, usually lasting for months, years or decades.

[0004] Opioid receptors are a class of G protein-coupled receptors widely present in the central nervous system and peripheral tissues, which are involved in a variety of physiological and pathological processes. In the transmission and regulation of pain, opioid receptors play a crucial role. There are multiple types of opioid receptors, among which the classic opioid receptors include μ, κ and δ (doi.org / 10.1038 / s41583-018-0028-x). Analgesics act on opioid receptors in the central nervous system, especially after agonizing the μ receptor in the opioid receptor, the process of pain signal transmission up the central nervous system pathway is inhibited, resulting in a very low or completely filtered pain signal intensity transmitted to the cerebral cortex, thus achieving a reduction or disappearance of pain sensation experienced by the patient, that is, playing a role in analgesia. Opioid drugs such as morphine and codeine can inhibit the transmission of pain signals by acting on opioid receptors, and have analgesic effects. Morphine is an agonist of μ, κ and δ receptors, and the intensity of action on the three receptor subtypes decreases in turn. However, opioid drugs have a certain addictive property, and long-term use can lead to drug dependence and tolerance. In addition, opioid drugs can also cause central and intestinal side effects such as respiratory depression, sedation, addiction and constipation (doi.org / 10.1038 / s41598-018-27313-4). Constipation, as the most common side effect of opioid drugs, can seriously affect the quality of life of patients (DOI: 10.1097 / AJP.0000000000000852). Therefore, it is an urgent problem to develop opioid receptor agonists that overcome the side effect of constipation. SUMMARY

[0005] The present application relates to a series of azacycloalkane compounds and their use in the preparation of drugs for the treatment of diseases related to opioid receptor agonists. Specifically, the present application relates to a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof.

[0006] The present application provides a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof, as an opioid receptor agonist.

[0007] wherein n1 is 0 or 1;

[0008] R1 is selected from the group consisting of hydrogen, hydroxyl, amine, thiol, C1-C6 alkoxy, C1-C6 alkylamine, nitrogen-containing C1-C6 heteroalkyl, oxygen-containing C1-C6 heteroalkyl, sulfur-containing C1-C6 heteroalkyl, halogen, C1-C6 carboxyl, C1-C6 amide, C2-C6 ester, and C2-C6 ester substituted with 1, 2, or 3 halogens;

[0009] R2 is selected from the group consisting of:

[0010] unsubstituted or substituted C6-C 18 aryl, unsubstituted or substituted C3-C 18 heteroaryl, C1-C6 alkyl substituted with a carbonyl, unsubstituted or substituted C3-C8 cycloalkane, and unsubstituted or substituted C4-C8 aliphatic heterocycle; wherein the substitution is mono-, di-, tri-, or tetra-substitution with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkyl substituted with 1, 2, or 3 halogens, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with 1, 2, or 3 halogens, C1-C6 alkoxy, C1-C6 alkoxy substituted with 1, 2, or 3 halogens, sulfur-containing C1-C6 heteroalkyl, C1-C6 alkylthiol, C1-C6 alkylthiol substituted with 1, 2, or 3 halogens, C1-C6 sulfoxide, C1-C6 sulfone, hydroxyl, cyano, nitro, urea, oxygen-containing C1-C6 heteroalkyl, amine, nitrogen-containing C1-C6 heteroalkyl, C1-C6 alkylamine, C1-C6 alkylamine substituted with 1, 2, or 3 halogens, C1-C6 carboxyl, C1-C6 amide, C2-C6 ester, and urea substituted with 0, 1, 2, or 3 halogen-substituted C1-C6 alkyl groups;

[0011] selected from the group consisting of:

[0012] unsubstituted or substituted C6-C 18 aryl and unsubstituted or substituted C3-C 18heteroaryl; wherein the substituents are single, double, triple or quadruple, and the substituents are selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2 or 3 halogens, C3-C8cycloalkyl, C3-C8cycloalkyl substituted with 1, 2 or 3 halogens, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2 or 3 halogens, sulfur containing C1-C6heteroalkyl, C1-C6alkylmercapto, C1-C6alkylmercapto substituted with 1, 2 or 3 halogens, C1-C6sulfoxide, C1-C6sulfone, hydroxyl, cyano, nitro, ureido, oxygen containing C1-C6heteroalkyl, aminyl, nitrogen containing C1-C6heteroalkyl, C1-C6alkylaminyl, C1-C6alkylaminyl substituted with 1, 2 or 3 halogens, C1-C6carboxyl, C1-C6amide, C2-C6ester, and ureido substituted with 0, 1, 2 or 3 halogen substituted C1-C6alkyl;

[0013] The sulfur containing C1-C6heteroalkyl contains 1 S heteroatom which can replace a C atom in the alkyl chain at positions allowed by normal valence and the S atom is not directly attached to the group being substituted;

[0014] The oxygen containing C1-C6heteroalkyl contains 1 O heteroatom which can replace a C atom in the alkyl chain at positions allowed by normal valence and the O atom is not directly attached to the group being substituted;

[0015] The nitrogen containing C1-C6heteroalkyl contains 1 N heteroatom which can replace a C atom in the alkyl chain at positions allowed by normal valence and the N atom is not directly attached to the group being substituted;

[0016] The C4-C8aliphatic heterocycle has 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S and P.

[0017] The C3-C8cycloalkyl is a saturated or partially saturated cyclic hydrocarbon group having 3, 4, 5, 6, 7 or 8 carbon atoms. 18 The aromatic heterocycle has 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S.

[0018] In some embodiments, certain groups in the compounds of Formula I, or pharmaceutically acceptable salts thereof, have the following definitions, and definitions for groups not mentioned are as described in any of the aspects of the application (hereinafter referred to as "in some embodiments"):

[0019] In some embodiments, the C1-C6alkyl can be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl or i-hexyl.

[0020] In some embodiments, the C1-C6 alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, n-hexyloxy, or isohexyloxy.

[0021] In some embodiments, the C1-C6 alkylamino group may be methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentamino, isopentamino, neopentamino, n-hexylamino, or isohexylamino.

[0022] In some embodiments, the C1-C6 alkyl mercapto group may be methyl mercapto, ethmerothiol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-pentanol, isopentanol, neopentanol, n-hexyl mercapto, or isohexyl mercapto.

[0023] In some embodiments, the C2-C6 ester group may be -CO2C1-C5 alkyl or -OCOC1-C5 alkyl.

[0024] In some embodiments, the alkyl group in the -CO2C1-C5 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or isopentyl.

[0025] In some embodiments, the -OCOC1-C5 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or isopentyl.

[0026] In some embodiments, the halogen may be fluorine, chlorine, bromine, or iodine.

[0027] In some embodiments, the sulfur-containing C1-C6 heteroalkyl group may be -CH2-S-CH3, -CH2CH2-S-CH3, -CH2CH2-S-CH2CH3, -CH2CH2-S-CH2CH2CH3, -CH2CH2CH2-S-CH2CH3, or -CH2CH2CH2-S-CH2CH2CH3.

[0028] In some embodiments, the oxygen-containing Ci-C6heteroalkyl group can be -CH2-OH, -CH2CH2-OH, -CH2CH2CH2-OH, -CH2CH2CH2CH2-OH, -CH2CH2CH2CH2CH2-OH, -CH2CH2CH2CH2CH2CH2-OH, -CH2-O-CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2CH2-O-CH2CH2CH3, -CH2CH2CH2-O-CH2CH3, or -CH2CH2CH2-O-CH2CH2CH3.

[0029] In some embodiments, the nitrogen-containing Ci-C6heteroalkyl group can be -CH2-NH2, -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH2CH2CH2CH2-NH2, -CH2CH2CH2CH2CH2-NH2, -CH2CH2CH2CH2CH2CH2-NH2, -CH2-NH-CH3, -CH2CH2-NH-CH3, -CH2-N-(CH3)2, -CH2CH2-NH-CH2CH3, -CH2CH2-N-(CH3)2, -CH2CH2-NH-CH2CH2CH3, -CH2CH2CH2-N-(CH3)2, -CH2CH2CH2-NH-CH2CH3, -CH2CH2CH2-NH-CH2CH2CH3, or -CH2CH2CH2CH2-N-(CH3)2.

[0030] In some embodiments, the Ci-C6sulfoxide group can be a methylsulfoxide group, an ethylsulfoxide group, an n-propylsulfoxide group, an i-propylsulfoxide group, an n-butylsulfoxide group, an i-butylsulfoxide group, a sec-butylsulfoxide group, a t-butylsulfoxide group, an n-pentylsulfoxide group, an i-pentylsulfoxide group, a neopentylsulfoxide group, an n-hexylsulfoxide group, or an i-hexylsulfoxide group.

[0031] In some embodiments, the Ci-C6sulfoxide group can be a methylsulfoxide group, an ethylsulfoxide group, an n-propylsulfoxide group, an i-propylsulfoxide group, an n-butylsulfoxide group, an i-butylsulfoxide group, a sec-butylsulfoxide group, a t-butylsulfoxide group, an n-pentylsulfoxide group, an i-pentylsulfoxide group, a neopentylsulfoxide group, an n-hexylsulfoxide group, or an i-hexylsulfoxide group.

[0032] In some embodiments, the C1-C6 carboxyl group can be -COOH, -CH2COOH, -CH(CH3)COOH, -CH2CH2COOH, -CH(CH3)CH2COOH, -CH2CH(CH3)COOH, -C(CH3)2COOH, -CH2CH2CH2COOH, -CH(CH3)CH2CH2COOH, -CH2CH(CH3)CH2COOH, -CH2CH2CH(CH3)COOH, -C(CH3)2CH2CH2COOH, -CH2C(CH3)2CH2COOH, -CH2CH2C(CH3)2COOH, -CH(CH3)CH(CH3)CH2COOH, -CH(CH3)CH2CH(CH3)COOH, -CH2CH(CH3)CH(CH3)COOH, -CH2CH2CH2CH2COOH, -CH(CH3)CH2CH2CH2COOH, -CH2CH(CH3)CH2CH2COOH, -CH2CH2CH(CH3)CH2COOH, -CH2CH2CH2CH(CH3)COOH, or -CH2CH2CH2CH2CH2COOH.

[0033] In some embodiments, the C1-C6 amido group can be -CONHC1-C5 alkyl, -CON(C1-C3 alkyl)2, -NHCOC1-C5 alkyl, or -N(C1-C2 alkyl)COC1-C3 alkyl.

[0034] In some embodiments, the C1-C5 alkyl in the -CONHC1-C5 alkyl group can be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, or neopentyl.

[0035] In some embodiments, the C1-C5 alkyl in the -NHCOC1-C5 alkyl group can be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, or i-pentyl, or neopentyl.

[0036] In some embodiments, the C1-C3 alkyl in the -CON(C1-C3 alkyl)2 group can be methyl, ethyl, n-propyl, or i-propyl.

[0037] In some embodiments, the C1-C3 alkyl in the -N(C1-C2 alkyl)COC1-C3 alkyl group can be methyl, ethyl, n-propyl, or i-propyl.

[0038] In some embodiments, the C1-C2 alkyl in the -N(C1-C2 alkyl)COC1-C3 alkyl group can be methyl or ethyl.

[0039] In some embodiments, the C3-C8 cycloalkyl group can be cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane.

[0040] In some embodiments, the heteroatom of the C4-C8 aliphatic heterocycle can be independently selected from N and / or O.

[0041] In some embodiments, the number of heteroatoms of the C4-C8 aliphatic heterocycle can be 1 or 2.

[0042] In some embodiments, the C4-C8 aliphatic heterocycle can be a 3-6 membered aliphatic heterocycle.

[0043] In some embodiments, the C4-C8 aliphatic heterocycle refers to a group formed by a heterocyclic compound without aromatic characteristics, such as piperidine, piperazine, dioxane or morpholine.

[0044] In some embodiments, the C6-C 18 The aryl group can be phenyl, naphthyl or biphenyl.

[0045] In some embodiments, the C3-C 18 The heteroaryl group can be a 5-10 membered heteroaryl group, preferably a 5-6 membered heteroaryl group.

[0046] In some embodiments, the C3-C 18 The heteroatom of the heteroaryl group can be independently selected from one or two of N, O and S.

[0047] In some embodiments, the C3-C 18 The heteroaryl group refers to a monocyclic or polycyclic aromatic heterocycle, and at least one heteroatom exists in the ring, such as furanyl, pyranyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl or tetrazolyl.

[0048] In some embodiments, n1 is 0 or 1.

[0049] In some embodiments, R1 is selected from hydrogen, hydroxyl and C2-C6 ester group, preferably R1 is hydroxyl.

[0050] In some embodiments, R2 is selected from the following groups:

[0051] (1) unsubstituted or substituted phenyl; wherein substituted is mono-, di-, tri-, or tetra-substituted with substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogen, C3-C8cycloalkyl, C3-C8cycloalkyl substituted with 1, 2, or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2, or 3 halogen, C1-C3heteroalkyl containing sulfur, C1-C6alkylmercapto, C1-C6alkylmercapto substituted with 1, 2, or 3 halogen, C1-C6sulfoxide, C1-C6sulfone, hydroxyl, cyano, nitro, ureido, C1-C6heteroalkyl containing oxygen, aminyl, C1-C6heteroalkyl containing nitrogen, C1-C6alkylaminyl substituted with 1, 2, or 3 halogen, C1-C6alkylaminyl, C1-C6carboxyl, C1-C6amido, C2-C6ester, and ureido substituted with 0, 1, 2, or 3 C1-C6alkyl substituted with halogen;

[0052] (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein substituted is mono-, di-, or tri-substituted with substituents selected from the group consisting of halogen, C1-C6alkyl, cyano, nitro, C1-C6alkyl substituted with 1, 2, or 3 halogen, C3-C8cycloalkyl, C3-C8cycloalkyl substituted with 1, 2, or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2, or 3 halogen, C1-C3heteroalkyl containing sulfur, C1-C6alkylmercapto, C1-C6alkylmercapto substituted with 1, 2, or 3 halogen, C1-C6sulfoxide, C1-C6sulfone, hydroxyl, C1-C6heteroalkyl containing oxygen, aminyl, C1-C6heteroalkyl containing nitrogen, C1-C6alkylaminyl substituted with 1, 2, or 3 halogen, C1-C6alkylaminyl, C1-C6carboxyl, C2-C6ester, C1-C6amido, and ureido substituted with 0, 1, 2, or 3 C1-C6alkyl substituted with halogen;

[0053] (3) unsubstituted or substituted biphenyl; wherein substituted is mono-, di-, tri-, tetra- to octa-substituted; substituents selected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2, or 3 halogen, C1-C6alkylmercapto, C1-C6alkylmercapto substituted with 1, 2, or 3 halogen, C1-C6sulfoxide, C1-C6sulfone, hydroxyl, C1-C6heteroalkyl containing oxygen, aminyl, C1-C6heteroalkyl containing nitrogen, C1-C6alkylaminyl substituted with 1, 2, or 3 halogen, C1-C6alkylaminyl, C1-C6carboxyl, C2-C6ester, C1-C6amido, and ureido substituted with 0, 1, 2, or 3 C1-C6alkyl substituted with halogen;

[0054] (4) unsubstituted or substituted naphthyl; wherein the substitution is mono-, di- or tri- substitution; wherein the substituents are selected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6alkyl substituted with 1, 2 or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2 or 3 halogen, C1-C6alkylmercapto, C1-C6alkylmercapto substituted with 1, 2 or 3 halogen, C1-C6sulfinyl, C1-C6sulfone, hydroxy, oxygen containing C1-C6heteroalkyl, aminyl, nitrogen containing C1-C6heteroalkyl, C1-C6alkylaminyl, C1-C6alkylaminyl substituted with 1, 2 or 3 halogen, C1-C6carboxyl, C2-C6ester, C1-C6amido and ureido substituted with C1-C6alkyl substituted with 0, 1, 2 or 3 halogen;

[0055] (5) C1-C6alkyl substituted with a carbonyl group, wherein the carbonyl group is -(C=O)R3, wherein R3is selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1-3 halogen, hydroxy, oxygen containing C1-C6heteroalkyl, aminyl, nitrogen containing C1-C6heteroalkyl and C1-C6alkylaminyl; said sulfur containing C1-C6heteroalkyl is an alkyl chain with 1 S heteroatom which can replace a C atom in the alkyl chain at positions allowed by normal valency and the S atom is not directly attached to the substituted group;

[0056] said oxygen containing C1-C6heteroalkyl is an alkyl chain with 1 O heteroatom which can replace a C atom in the alkyl chain at positions allowed by normal valency and the O atom is not directly attached to the substituted group;

[0057] said nitrogen containing C1-C6heteroalkyl is an alkyl chain with 1 N heteroatom which can replace a C atom in the alkyl chain at positions allowed by normal valency and the N atom is not directly attached to the substituted group.

[0058] In some embodiments, R2is selected from the following groups:

[0059] (1) substituted phenyl; wherein the substitution is mono-, di-, tri- or tetra- substitution, and the substituents are selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2 or 3 halogen, C1-C6alkoxy, C1-C6alkylmercapto, cyano, C2-C6ester and ureido substituted with C 1- C6alkyl;

[0060] (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from 2-pyridyl, 3-pyridyl or 4-pyridyl; wherein the substitution comprises mono-, di- or tri- substitution, and the substituents are selected from the group consisting of halogen, C1-C6alkyl, cyano, C1-C6alkyl substituted with 1, 2 or 3 halogen and C2-C6ester;

[0061] (3) unsubstituted or substituted biphenyl; wherein substituted is mono, di, tri, tetra to octa substitution; and wherein substituents are selected from the group consisting of halogen and C1-C6 alkyl substituted with 1, 2, or 3 halogen;

[0062] (4) unsubstituted or substituted naphthyl; wherein substituted is mono; and wherein substituents are C1-C6 alkoxy;

[0063] (5) C1-C6 alkyl substituted with carbonyl, wherein carbonyl is -(C=0)R3, wherein R3 is C1-C6 alkylamino.

[0064] In some embodiments, R2 is selected from the group consisting of:

[0065] (1) substituted phenyl; wherein substituted is mono, di, tri, or tetra substitution; and wherein substituents are selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkyl substituted with 1, 2, or 3 halogen, C1-C6 alkoxy, and C1-C6 alkylthio; 1- C6 alkyl substituted ureido;

[0066] (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein substituted is mono, di, or tri substitution; and wherein substituents are selected from the group consisting of halogen and cyano;

[0067] (3) unsubstituted or substituted biphenyl; wherein substituted includes mono, di, tri, tetra to octa substitution; and wherein substituents are halogen;

[0068] (4) naphthyl.

[0069] In some embodiments, R2 is selected from the group consisting of:

[0070] (1) substituted phenyl; wherein substituted is mono, di, tri, or tetra substitution; and wherein substituents are selected from the group consisting of halogen, cyano, C1-C6 alkyl, C1-C6 alkyl substituted with 1, 2, or 3 halogen, and C1-C6 alkoxy;

[0071] (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein substituted is mono, di, or tri substitution; and wherein substituents are halogen;

[0072] (3) unsubstituted or substituted naphthyl; wherein substituted is mono substitution; and wherein substituents are C1-C6 alkoxy.

[0073] In some embodiments, R2 is selected from the group consisting of:

[0074] (1) substituted phenyl; wherein substituted is mono, di, or tri substitution; and wherein substituents are selected from the group consisting of halogen, cyano, C1-C6 alkyl, C1-C6 alkyl substituted with 1, 2, or 3 halogen, C1-C6 alkylthio, and C1-C6 alkoxy;

[0075] (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein substitution is mono-substitution and the substituent is selected from halogen;

[0076] (3) unsubstituted or substituted biphenyl; wherein substitution is mono-substitution; and the substituent is halogen;

[0077] (4) unsubstituted or substituted naphthyl; wherein substitution is mono-substitution; and the substituent is C1-C6alkoxy.

[0078] In some embodiments, is selected from the group consisting of:

[0079] (1) substituted phenyl; wherein substitution is mono-, di-, or tri-substitution; and the substituents are selected from halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2, or 3 halogen, C1-C6alkylamino, C3-C8cycloalkyl, C1-C6alkylmercapto, C1-C6sulfoxide, C1-C6sulfone, and cyano; wherein the amine group can be substituted with 0-3 C1-C6alkyl substituted with halogen;

[0080] (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from 2-pyridyl, 3-pyridyl, and 4-pyridyl; wherein substitution is mono-, di-, or tri-substitution; and the substituents are selected from halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2, or 3 halogen, C1-C6alkylamino, C1-C6alkylmercapto, C1-C6sulfoxide, C1-C6sulfone, and cyano.

[0081] In some embodiments, is selected from the group consisting of:

[0082] (1) substituted phenyl; wherein substitution is mono-, di-, or tri-substitution; and the substituents are selected from halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogen, cyano, C1-C6alkoxy, C1-C6alkylamino, C1-C6alkylmercapto, and C1-C6heteroalkyl containing sulfur; wherein the amine group is substituted with C1-C6alkyl;

[0083] (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from 2-pyridyl, 3-pyridyl, and 4-pyridyl; wherein substitution is mono-, di-, or tri-substitution; and the substituents are halogen.

[0084] In some embodiments, substituted phenyl; wherein the substitution is mono-, di-, or tri-substitution; and the substituents are selected from the group consisting of halogen, cyano, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogen, C1-C6alkoxy, and C1-C6alkylmercapto.

[0085] In some embodiments, substituted phenyl; wherein the substitution is mono-, di-, or tri-substitution; and the substituents are selected from the group consisting of halogen, cyano, and C1-C6alkoxy.

[0086] In some embodiments, substituted phenyl; wherein the substitution is mono-, di-, or tri-substitution; and the substituents are selected from the group consisting of halogen, cyano, and C1-C6alkoxy.

[0087] In some embodiments, R1is preferably selected from the group consisting of hydroxyl and C2-C3ester.

[0088] R2is preferably selected from the group consisting of:

[0089] (1) substituted phenyl; wherein the substitution is mono-, di-, tri-, or tetra-substitution; and the substituents are selected from the group consisting of halogen, C1-C3alkyl substituted with 1-3 halogen, C1-C3alkoxy, C1-C3alkoxy substituted with 1, 2, or 3 halogen, C1-C3alkylmercapto, sulfur-containing C1-C3heteroalkyl, hydroxyl, oxygen-containing C1-C3heteroalkyl, aminyl, nitrogen-containing C1-C3heteroalkyl, C1-C3alkylaminyl, C1-C3carboxyl, C2-C3ester, C1-C3amide, ureido, cyano, and ureido substituted with 0, 1, 2, or 3 halogen-substituted C1-C3alkyl;

[0090] (2) substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl; wherein the substitution comprises mono-, di-, or tri-substitution; and the substituents are selected from the group consisting of halogen, C1-C3alkyl substituted with 1, 2, or 3 halogen, C1-C3alkoxy, C1-C3alkoxy substituted with 1, 2, or 3 halogen, C1-C3alkylmercapto, sulfur-containing C1-C3heteroalkyl, hydroxyl, oxygen-containing C1-C3heteroalkyl, aminyl, C1-C3alkylaminyl, nitrogen-containing C1-C3heteroalkyl, C1-C3carboxyl, C2-C3ester, C1-C3amide, ureido, cyano, and ureido substituted with 0, 1, 2, or 3 halogen-substituted C1-C3alkyl;

[0091] (3) unsubstituted or substituted biphenyl; wherein the substitution is mono-, di-, or tri-substitution; and wherein the substituents are selected from the group consisting of halogen, C1-C3 alkyl substituted with 1, 2, or 3 halogens, C1-C3 alkoxy, C1-C3 alkoxy substituted with 1, 2, or 3 halogens, C1-C3 alkylmercapto, sulfur-containing C1-C3 heteroalkyl, hydroxyl, oxygen-containing C1-C3 heteroalkyl, aminyl, nitrogen-containing C1-C3 heteroalkyl, C1-C3 alkylaminyl, C1-C3 carboxyl, C2-C3 ester, C1-C3 amido, ureido, cyano, and ureido substituted with 0, 1, 2, or 3 halogen-substituted C1-C3 alkyl;

[0092] (4) unsubstituted or substituted naphthyl; wherein the substitution is mono-, di-, or tri-substitution; and wherein the substituents are selected from the group consisting of halogen, C1-C3 alkyl substituted with 1, 2, or 3 halogens, C1-C3 alkoxy, C1-C3 alkoxy substituted with 1, 2, or 3 halogens, C1-C3 alkylmercapto, sulfur-containing C1-C3 heteroalkyl, hydroxyl, oxygen-containing C1-C3 heteroalkyl, aminyl, C1-C3 alkylaminyl, nitrogen-containing C1-C3 heteroalkyl, C1-C3 carboxyl, C2-C3 ester, C1-C3 amido, ureido, cyano, and ureido substituted with 0, 1, 2, or 3 halogen-substituted C1-C3 alkyl;

[0093] preferably selected from the group consisting of:

[0094] (1) substituted phenyl; wherein the substitution is mono-, di-, or tri-substitution; and wherein the substituents are selected from the group consisting of halogen, C1-C3 alkyl substituted with 1, 2, or 3 halogens, C1-C3 alkoxy, C1-C3 alkoxy substituted with 1, 2, or 3 halogens, and C1-C4 alkylaminyl; wherein, when mono-substituted, the substituent is selected from the group consisting of halogen, C2-C3 alkyl, C1-C3 alkyl substituted with 1, 2, or 3 halogens, C1-C3 alkoxy, C1-C3 alkylaminyl, C3-C8 cycloalkyl, C1-C3 alkylmercapto, sulfur-containing C1-C3 heteroalkyl, C1-C3 sulfoxide, C1-C3 sulfone, and cyano;

[0095] (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl; wherein the substitution is mono-, di-, or tri-substitution; and wherein the substituents are selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkyl substituted with 1, 2, or 3 halogens, C1-C3 alkoxy, C1-C3 alkoxy substituted with 1, 2, or 3 halogens, C1-C3 alkylaminyl, C1-C3 alkylmercapto, sulfur-containing C1-C3 heteroalkyl, C1-C3 sulfoxide, C1-C3 sulfone, and cyano;

[0096] if when selected from substituted phenyl and is mono-substituted, the substituent is preferably selected from the group consisting of halogen, C1-C3 alkoxy, and cyano;

[0097] like When the substituent is selected from a substituted phenyl group and is disubstituted, the substituent is preferably selected from halogen, C1-C3 alkoxy, and cyano groups;

[0098] like When the substituted phenyl group is selected and is trisubstituted, the substituent is preferably selected from halogen, C1-C3 alkoxy, C1-C3 alkyl mercapto, and cyano.

[0099] In some embodiments, R1 is preferably selected from hydroxyl groups;

[0100] R2 is preferably selected from the following groups:

[0101] (1) A substituted phenyl group; wherein the substitution is mono-, di-, tri-, or tetra-substituted, and the substituent is selected from halogens, C1-C5 alkyl groups substituted with 1-3 halogens, C1-C3 alkoxy groups, C1-C3 alkoxy groups substituted with 1, 2, or 3 halogens, C1-C3 alkyl groups, sulfur-containing C1-C3 heteroalkyl groups, and C1-C3 amide groups;

[0102] (2) A substituted pyridyl group; wherein the pyridyl group is selected from 2-pyridyl, 3-pyridyl and 4-pyridyl; wherein the substitution is mono-, di- or tri-substituted, and the substituent is selected from halogen, C1-C3 alkyl group substituted with 1, 2 or 3 halogens, C1-C3 alkoxy group, C1-C3 alkoxy group substituted with 1, 2 or 3 halogens and C1-C3 amide group;

[0103] (3) Unsubstituted or substituted biphenyl; wherein the substitution is mono-, di-, or tri-substituted; the substituent is selected from halogens, C1-C3 alkyl groups substituted with 1, 2, or 3 halogens, C1-C3 alkoxy groups, C1-C3 alkoxy groups substituted with 1, 2, or 3 halogens, and C1-C3 amide groups;

[0104] (4) Unsubstituted or substituted naphthyl; wherein the substitution is mono-, di-, or tri-substituted; wherein the substituent is selected from halogen, C1-C3 alkyl substituted with 1, 2, or 3 halogens, C1-C3 alkoxy, C1-C3 alkoxy substituted with 1, 2, or 3 halogens, and C1-C3 amide.

[0105] The groups are preferably selected from the following:

[0106] (1) A substituted phenyl group; wherein the substitution is divided into mono-, di- or tri-substituted; the substituent is selected from halogen, cyano, C1-C6 alkyl mercapto and C1-C3 alkyl group substituted by 1, 2 or 3 halogens, wherein the substituent is selected from halogen and cyano when mono-substituted;

[0107] (2) Unsubstituted or substituted pyridinyl; wherein the pyridinyl is selected from 2-pyridinyl, 3-pyridinyl and 4-pyridinyl; wherein the substitution is mono-, di- or tri-substituted; and the substituent is halogen.

[0108] In some embodiments, n1 is 0 or 1 ;

[0109] R1 is selected from the group consisting of hydrogen, hydroxyl, amine, thiol, C1-C6 alkoxy, C1-C6 alkylamine, C1-C6 alkylthiol, halogen, C2-C6 ester, C2-C6 ester substituted with hydroxyl, C2-C6 ester substituted with amine, and carboxyl; 2-6 C2-C6 ester substituted with hydroxyl, C2-C6 ester substituted with amine, and carboxyl;

[0110] R2 is selected from the group consisting of:

[0111] (1) unsubstituted or substituted phenyl; wherein the substitution is mono-, di-, tri-, or tetra-substitution with substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkyl substituted with 1, 2, or 3 halogens, C1-C6 alkoxy, C1-C6 alkoxy substituted with 1, 2, or 3 halogens, C1-C6 heteroalkyl containing sulfur, C1-C6 alkylthiol, C1-C6 sulfoxide, C1-C6 sulfone, hydroxyl, cyano, nitro, ureido, C1-C6 heteroalkyl containing oxygen, amine, C1-C6 heteroalkyl containing nitrogen, C1-C6 alkylamine, C1-C6 carboxyl, C2-C6 ester, and ureido substituted with 0, 1, 2, or 3 halogens substituted C1-C6 alkyl;

[0112] (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein the substitution is mono-, di-, or tri-substitution with substituents selected from the group consisting of halogen, C1-C6 alkyl, cyano, nitro, C1-C6 alkyl substituted with 1, 2, or 3 halogens, C1-C6 alkoxy, C1-C6 alkoxy substituted with 1, 2, or 3 halogens, C1-C3 heteroalkyl containing sulfur, C1-C6 alkylthiol, C1-C6 sulfoxide, C1-C6 sulfone, hydroxyl, C1-C6 heteroalkyl containing oxygen, amine, C1-C6 heteroalkyl containing nitrogen, C1-C6 alkylamine, C1-C6 carboxyl, C2-C6 ester, C1-C6 amide, and ureido substituted with 0, 1, 2, or 3 halogens substituted C1-C6 alkyl;

[0113] (3) unsubstituted or substituted biphenyl; wherein the substitution is mono-, di-, tri-, tetra- to octa-substitution; substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkyl substituted with 1, 2, or 3 halogens, C1-C6 alkoxy, C1-C6 alkoxy substituted with 1, 2, or 3 halogens, C1-C6 alkylthiol, C1-C6 sulfoxide, C1-C6 sulfone, hydroxyl, C1-C6 heteroalkyl containing oxygen, amine, C1-C6 heteroalkyl containing nitrogen, C1-C6 alkylamine, C1-C6 carboxyl, C2-C6 ester, C1-C6 amide, and ureido substituted with 0, 1, 2, or 3 halogens substituted C1-C6 alkyl;

[0114] (4) unsubstituted or substituted naphthyl; wherein the substitution is mono-, di- or tri- substitution; wherein the substituents are selected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6alkyl substituted with 1, 2 or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2 or 3 halogen, C1-C6alkylmercapto, C1-C6sulfoxide, C1-C6sulfone, hydroxy, oxygen-containing C1-C6heteroalkyl, aminyl, nitrogen-containing C1-C6heteroalkyl, C1-C6alkylamino, C1-C6carboxyl, C2-C6ester, C1-C6amide, and ureido substituted with 0, 1, 2 or 3 halogen substituted C1-C6alkyl;

[0115] (5) C1-C6alkyl substituted with a carbonyl group, wherein the carbonyl group is -(C=O)R3, wherein R3is selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1-3 halogen, hydroxy, oxygen-containing C1-C6heteroalkyl, aminyl, and C1-C6alkylamino;

[0116] selected from the group consisting of:

[0117] (1) substituted phenyl; wherein the substitution is mono-, di- or tri- substitution; wherein the substituents are selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2 or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2 or 3 halogen, C1-C6alkylamino, C3-C8cycloalkyl, C1-C6alkylmercapto, C1-C6sulfoxide, C1-C6sulfone, and cyano; wherein the aminyl group can be substituted with 0-3 halogen substituted C1-C6alkyl;

[0118] (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl; wherein the substitution is mono-, di- or tri- substitution; wherein the substituents are selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2 or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2 or 3 halogen, C1-C6alkylamino, C1-C6alkylmercapto, C1-C6sulfoxide, C1-C6sulfone, and cyano; wherein the sulfur-containing C1-C6heteroalkyl group contains 1 S heteroatom which can replace a C atom in the alkyl chain at a position allowed by normal valence and the S atom is not directly attached to the group being substituted;

[0119] wherein the oxygen-containing C1-C6heteroalkyl group contains 1 O heteroatom which can replace a C atom in the alkyl chain at a position allowed by normal valence and the O atom is not directly attached to the group being substituted;

[0120] said nitrogen-containing C1-C6heteroalkyl is a C1-C6alkyl group containing one N heteroatom, which N atom can be substituted for a C atom in the alkyl chain at a position allowed by normal valence, and the N atom is not directly attached to the group being substituted.

[0121] In some embodiments, n1 is 0 or 1 ;

[0122] R1 is selected from the group consisting of hydrogen, hydroxyl, and C2-C6 ester;

[0123] R2 is selected from the group consisting of:

[0124] (1) substituted phenyl; wherein substitution is mono-, di-, tri-, or tetra-substitution with substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1-3 halogens, C1-C6alkoxy, C1-C6alkylmercapto, cyano, C2-C6ester, and ureido substituted with C1-C6alkyl; 1- C6alkyl;

[0125] (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein substitution comprises mono-, di-, or tri-substitution with substituents selected from the group consisting of halogen, C1-C6alkyl, cyano, C1-C6alkyl substituted with 1, 2, or 3 halogens, and C2-C6ester;

[0126] (3) unsubstituted or substituted biphenyl; wherein substitution is mono-, di-, tri-, tetra- to octa-substitution; substituents are selected from the group consisting of halogen and C1-C6alkyl substituted with 1, 2, or 3 halogens;

[0127] (4) unsubstituted or substituted naphthyl; wherein substitution is mono-; wherein the substituent is C1-C6alkoxy;

[0128] (5) C1-C6alkyl substituted with a carbonyl group, wherein the carbonyl group is -(C=O)R3, wherein R3 is C1-C6alkylamino;

[0129] selected from the group consisting of:

[0130] (1) substituted phenyl; wherein substitution is mono-, di-, or tri-substitution; substituents are selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogens, cyano, C1-C6alkoxy, C1-C6alkylamino, and C1-C6alkylmercapto; wherein the amine group is C1-C6alkyl substituted;

[0131] (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl; wherein substitution is mono-, di-, or tri-substitution; substituents are halogen.

[0132] In some embodiments, n1 is 0 or 1 ;

[0133] R1is selected from the group consisting of hydrogen, hydroxyl, and C2-C6 ester;

[0134] R2is selected from the group consisting of:

[0135] (1) substituted phenyl; wherein the substitution is mono-, di-, tri-, or tetra-substitution with substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1-3 halogens, C1-C6alkoxy, and C1-C6alkylthio; 1- C6alkyl substituted ureido;

[0136] (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein the substitution is mono-, di-, or tri-substitution with substituents selected from the group consisting of halogen and cyano;

[0137] (3) unsubstituted or substituted biphenyl; wherein the substitution comprises mono-, di-, tri-, tetra- to octa-substitution; the substituents are halogen;

[0138] (4) naphthyl;

[0139] substituted phenyl; wherein the substitution is mono-, di-, or tri-substitution; the substituents are selected from the group consisting of halogen, cyano, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogens, C1-C6alkoxy, and C1-C6alkylthio.

[0140] In some embodiments, n1 is 0 or 1;

[0141] R1is hydroxyl;

[0142] R2is selected from the group consisting of:

[0143] (1) substituted phenyl; wherein the substitution is mono-, di-, tri-, or tetra-substitution with substituents selected from the group consisting of halogen, cyano, C1-C6alkyl, C1-C6alkyl substituted with 1-3 halogens, and C1-C6alkoxy;

[0144] (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein the substitution is mono-, di-, or tri-substitution with substituents selected from halogen;

[0145] (3) unsubstituted or substituted naphthyl; wherein the substitution is mono-substitution with substituents selected from C1-C6alkoxy;

[0146] substituted phenyl; wherein the substitution is mono-, di-, or tri-substitution; the substituents are selected from the group consisting of halogen and C1-C6alkoxy.

[0147] In some embodiments, n1 is 0 or 1;

[0148] R1is hydroxyl;

[0149] R2is selected from the group consisting of:

[0150] (1) substituted phenyl; wherein the substitution is mono-, di- or tri-substitution with substituents selected from the group consisting of halogen, cyano, C1-C6alkyl, C1-C6alkyl substituted with 1-3 halogens, C1-C6alkylmercapto and C1-C6alkoxy;

[0151] (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from 2-pyridyl, 3-pyridyl or 4-pyridyl; wherein the substitution is mono-substitution with substituents selected from halogen;

[0152] (3) unsubstituted or substituted biphenyl; wherein the substitution is mono-substitution with substituents selected from halogen;

[0153] (4) unsubstituted or substituted naphthyl; wherein the substitution is mono-substitution with substituents selected from C1-C6alkoxy;

[0154] substituted phenyl; wherein the substitution is mono-, di- or tri-substitution with substituents selected from the group consisting of halogen, cyano and C1-C6alkoxy.

[0155] In some embodiments, R2is

[0156] In some embodiments, R1is hydrogen, -OH or

[0157] In some embodiments,

[0158] In some embodiments, the compound of Formula I is any one of the following:

[0159] In some embodiments, the opioid receptor agonist is used in vivo in a mammalian organism; it can also be used in vitro, mainly for experimental purposes, for example, as a standard or control to provide a comparison, or as a kit according to the methods conventional in the art.

[0160] In some embodiments, the opioid receptor agonist is used in vitro.

[0161] ​The present application also provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use as a medicament.

[0162] The present application also provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use as an analgesic.

[0163] The present application also provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with an opioid receptor.

[0164] The present application also provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with an opioid receptor.

[0165] The disease associated with an opioid receptor is preferably pain.

[0166] The opioid receptor is preferably a mu-opioid receptor.

[0167] The present application also provides a method of treating pain, comprising administering to a subject in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I.

[0168] The present application provides a compound of Formula I and pharmaceutically acceptable salts thereof, other than:

[0169] The present application also provides a pharmaceutical composition comprising (i) a compound of Formula I or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

[0170] Definitions of Terms

[0171] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The definitions provided herein do not limit the meaning of such terms.

[0172] In the present application, the term "pharmaceutically acceptable salt" refers to a salt of a compound prepared from a relatively non-toxic, pharmaceutically acceptable acid or base. Base addition salts can be prepared when an acidic functional group is present in the compound. Such salts can be obtained by contacting the neutral form of such compounds in pure solution or in a suitable inert solvent with a sufficient amount of the pharmaceutically acceptable base. Acid addition salts can be prepared when a basic functional group is present in the compound. Such salts can be obtained by contacting the neutral form of such compounds in pure solution or in a suitable inert solvent with a sufficient amount of the pharmaceutically acceptable acid. When a compound contains both a relatively acidic functional group and a relatively basic functional group, it can be converted into either a base addition salt or an acid addition salt.

[0173] In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0174] In the present application, the term "hydroxy" means -OH.

[0175] In the present application, the term "amine" means -NH2.

[0176] In the present application, the term "mercapto" means -SH.

[0177] In the present application, the term "alkyl" means a saturated straight chain or branched chain monovalent hydrocarbon radical having a certain number of carbon atoms. C 1–6 Alkyl means an alkyl group having 1-6 (e.g. 1, 2, 3, 4, 5, 6) carbon atoms, including C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, s-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0178] In the present application, the term "cycloalkyl" means C3-C8 cycloalkyl, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane.

[0179] In the present application, the term "cycloalkane" means C3-C8 cycloalkane, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane.

[0180] In the present application, the term "alkoxy" means -O-alkyl, wherein alkyl is alkyl as defined above.

[0181] In the present application, the term "C X-C Y Ester group" means -O-CO-alkyl or -CO-O-alkyl, wherein alkyl is alkyl as defined above, wherein X and Y represent the total number of carbon atoms, for example CO-O-CH3 is a C2 ester group.

[0182] In the present application, the term "C X -C Y Carboxyl group" means "-alkyl-COOH", wherein alkyl is alkyl as defined above, wherein X and Y represent the total number of carbon atoms, for example -CH2COOH is a C2 carboxyl group.

[0183] In the present application, the term "C X -C Y Sulfoxide group" means -SO-alkyl, wherein alkyl is alkyl as defined above.

[0184] In the present application, the term "C X -C Y Sulfone group" means -SO2-alkyl, wherein alkyl is alkyl as defined above.

[0185] In the present application, the term "C X -C Y Aminoalkyl" means an amino substituted alkyl group "-NH-alkyl" or "-N-(alkyl)2", alkyl being alkyl as defined above.

[0186] In the present application, the term "C X -C Y Alkylamino" means an amino substituted alkyl group "-NH-alkyl" or "-N-(alkyl)2", alkyl being alkyl as defined above.

[0187] In the present application, the term "C X -C Y Amido" means -NH-CO-alkyl, -N(alkyl)-CO-alkyl, -CO-NH-alkyl or -CO-N-(alkyl)2, wherein alkyl is alkyl as defined above.

[0188] In the present application, the term "alkylthio" means -S-alkyl, wherein alkyl is alkyl as defined above.

[0189] In the present application, the term "sulfur-containing C1-C6 heteroalkyl" means "-R4-S-R5", wherein R4 is selected from alkyl and R5 is selected from alkyl or hydrogen, alkyl being alkyl as defined above.

[0190] In the present application, the term "oxygen-containing C1-C6 heteroalkyl" means "-R4-O-R5", wherein R4 is selected from alkyl and R5 is selected from alkyl or hydrogen, alkyl being alkyl as defined above.

[0191] In the present application, the term "nitrogen-containing C1-C6 heteroalkyl" means "-R4-N-R5", wherein R4 is selected from alkyl and R5 is selected from alkyl or hydrogen, and alkyl is as defined above.

[0192] In the present application, the term "ureido" means NH-CO-NH2.

[0193] In the present application, the term "C6-C 18 "Aryl" means an aromatic carbocyclic ring which does not contain any heteroatoms, and can be phenyl, naphthyl or biphenyl.

[0194] In the present application, the term "C3-C 18 "Heteroaryl" means a monocyclic or polycyclic aromatic heterocycle, and at least one heteroatom is present in the ring, which can contain 1, 2, 3 or 4; the heteroatom is selected from one, two or three of N, O and S, for example furanyl, pyranyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl or tetrazolyl.

[0195] In the present application, the term "C4-C8 aliphatic heterocycle" means a group formed by a heterocyclic compound without aromatic characteristics, the heteroatom is independently selected from one or more of N, O, S and P (for example, the heteroatom is independently selected from N and / or O), the number of heteroatoms is 1, 2, 3 or 4 (for example, the number of heteroatoms is 1 or 2), for example piperidine, piperazine, dioxane or morpholine.

[0196] In general, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced by a particular substituent. Further, when the group is substituted with more than one of the mentioned substituents, the substituents are independent of each other, i.e. the more than one substituents can be different or the same. Unless explicitly indicated otherwise, a substituent group can be substituted at each substitutable position of the substituted group. When more than one position in the given structure can be substituted with one or more substituents selected from a particular group of substituents, then those substituents can be the same or different at each position.

[0197] When an enumerated substituent does not specify through which atom of the chemical structure it is attached to the compound included but not specifically mentioned in the general formula, such substituent can be bonded through any of its atoms. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0198] When an enumerated group does not explicitly indicate that it has a substituent, then such group means unsubstituted. For example, when "C 1-6 "Alkyl" means "C1-C6 alkyl" unless otherwise specified.1-6 "unsubstituted C1-C6alkyl" or "unsubstituted C1-C6alkyl". 1-6 "unsubstituted C1-C6alkyl".

[0199] Further, it should be noted that the description "independently" as employed in the present application is to be interpreted broadly, unless explicitly stated otherwise, and means that each individual described can be the same or different specific group independently of the others. In more detail, the description "independently" can mean that the specific options expressed by the same symbols in different groups do not influence each other, or that the specific options expressed by the same symbols in the same group do not influence each other.

[0200] The term "treatment" as used herein refers to therapeutic treatment. With respect to a particular condition, treatment refers to: (1) relieving the disease or condition, or one or more of the biological manifestations thereof, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more of the biological manifestations of the condition, (3) ameliorating one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment, or (4) slowing the development of the condition or one or more of the biological manifestations thereof.

[0201] The term "therapeutically effective amount" as used herein refers to the amount of a compound that, when administered to a patient, is sufficient to effect treatment or prevention of the diseases or conditions described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted by one of ordinary skill in the art as needed. Amounts in ranges exceeding this range can also be used depending on the dosage form and the severity of the disease.

[0202] The above-mentioned preferred conditions can be combined in any way, without departing from the general knowledge of a person skilled in the art, to give further preferred embodiments of the present application.

[0203] The reagents and starting materials used in the present application are commercially available.

[0204] The positive progress effect of the present application is that:

[0205] The present application provides the use of an azacycloalkane compound and a salt thereof as a medicine. The present application provides an opioid receptor agonist having no side effects of constipation and intestinal function disorder and no addiction, which can be used as an analgesic drug. DETAILED DESCRIPTION

[0206] The present application is further illustrated by the following examples, which are not intended to limit the application in any way. The experimental procedures in the following examples, for which no specific conditions are indicated, are in accordance with standard procedures and conditions, or are chosen according to the manufacturer's instructions.

[0207] Preparation of compounds:

[0208] All non-aqueous reactions were carried out using oven-dried glassware under a dry argon atmosphere. Thin layer chromatography on glass plates coated with Merck silica gel 60 was used to monitor the progress of reactions. Flash column chromatography was performed on Merck silica gel. Compound mass spectra were recorded using a Shimadzu LCMS-2050 liquid chromatograph mass spectrometer. NMR spectra were recorded at ambient temperature using a Bruker Avance 400-600 spectrometer. Chemical shifts of1Hare reported in parts per million (δ) relative to external tetramethylsilane and referenced to the signal of residual protons in the deuterated solvent.

[0209] Different synthetic routes were applied in the preparation of the compounds of the present application. The compounds of formula (I) can be synthesized by the following synthetic methods.

[0210] Scheme 1:

[0211] Intermediates I and II were reacted to give intermediates III in the presence of a strong base (such as n-butyllithium, etc.) in an ether solvent (such as diethyl ether, tetrahydrofuran, etc.) at low temperature. The reaction can be carried out under normal pressure, usually at -78 °C for several hours.

[0212] Scheme 2:

[0213] Intermediates III were reacted to give intermediates IV in the presence of an acid (such as hydrochloric acid, trifluoroacetic acid, etc.) in ethyl acetate. The reaction can be carried out under normal pressure, usually at room temperature for several tens of minutes to several hours.

[0214] Scheme 3:

[0215] Intermediates IV and V were reacted to give product A in the presence of a reducing agent (such as sodium cyanoborohydride, etc.) in an alcohol solvent (such as methanol, etc.). The reaction can be carried out under normal pressure, usually at 0 °C to room temperature for several hours to several tens of hours.

[0216] Scheme 4:

[0217] Intermediates VI and VII were reacted to give intermediates VIII in the presence of a strong base (such as potassium hexamethyldisilazide, etc.) in a suitable solvent (such as toluene, tetrahydrofuran, etc.). The reaction can be carried out under normal pressure. The reaction is usually carried out at 0 °C to room temperature for several hours to several tens of hours.

[0218] Detailed implementation process:

[0219] Preparation of intermediate compound 3-(3,4-difluorophenyl)azetidin-3-ol (3):

[0220] Preparation of 3-(3,4-difluorophenyl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (2)

[0221] To a solution of 4-bromo-1,2-difluorobenzene (1) (5.0 g, 25.91 mmol) in Et2O (30 mL), n-butyllithium (10.36 mL, 25.91 mmol) was added at -78 °C. And 3-oxoazetidine-1-carboxylic acid tert-butyl ester (3.55 g, 20.73 mmol) was added at -78 °C, stirred for 2 h, then the reaction mixture was quenched with saturated NH4Cl solution, extracted with EA (100 mL x 3). The organic layer was washed with brine (100 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound 2 as colorless oil (2.40 g, 8.41 mmol, 32.5%).

[0222] ESI-MS calc: 285.12, MS found: 284.0 [M-H] - .

[0223] Preparation of 3-(3,4-difluorophenyl)azetidin-3-ol (3)

[0224] To 3-(3,4-difluorophenyl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (2.40 g, 8.41 mmol) was added 1,4-dioxane solution of hydrochloric acid (20 mL), stirred at room temperature for 2 h. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography (0.1% ammonia water-acetonitrile, 30%-70%) to give the title compound 3 as colorless oil (1.00 g, 5.40 mmol, yield 64.2%).

[0225] ESI-MS calc: 185.07, MS found: 186.1 [M+H] + .

[0226] Preparation of intermediate compound 3-(5-chloropyridin-2-yl)azetidine-3-carboxylic acid methyl ester dihydrochloride (6)

[0227] Preparation of 1-(tert-butyl) 3-methyl-3-(pyridin-2-yl)azetidine-1,3-dicarboxylate (5)

[0228] Into a round bottom flask was placed 1-(tert-butyl) 3-methylazetidine-1,3- dicarboxylate (20.0 g, 92.92 mmol) and 5-chloro-2-fluoropyridine (12.2 g, 92.92 mmol) and toluene (200 mL) was added. After the mixture was cooled to 0 °C, KHMDS (93.0 mL, 92.92 mmol) was added. After slowly recovering to room temperature, the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction was quenched with saturated NH4Cl and extracted with EA (300 mL x 3). After the organic phase was combined, it was washed with saturated brine (500 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure. After the residue was purified by silica gel column chromatography (PE / EA = 10:1) and preparative HPLC (10 mmol NH4HCO3 aqueous solution-acetonitrile), the title compound 5 was obtained as a white solid (5.0 g, 15.30 mmol, 16.7%).

[0229] ESI-MS calcd: 326.10, MS found: 326.9 [M+H] + .

[0230] Preparation of 3-(5-chloropyridin-2-yl)azetidine-3-carboxylic acid methyl ester dihydrochloride (6)

[0231] Into a round bottom flask was placed 3-(3,4-difluorophenyl)-3-hydroxyazetidine-1- carboxylic acid tert-butyl ester (2.40 g, 8.41 mmol) in hydrochloric acid 1,4-dioxane solution (20 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (0.1% ammonia water-acetonitrile, 30%-70%) to obtain the title compound 6 as a colorless oil (1.00 g, 5.40 mmol, yield 64.2%).

[0232] ESI-MS calcd: 185.07, MS found: 186.1 [M+H] + .

[0233] Preparation of intermediate compound 11

[0234] Preparation of 3-(2,6-difluorophenyl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (8)

[0235] Into a round bottom flask was placed 2-bromo-1,3-difluorobenzene (15.0 g, 77.72 mmol), Et20 (200 mL) was added and the mixture was cooled to -78 °C, then to the mixture was added n-butyllithium (16.63 g, 97.15 mmol). After the mixture was stirred at -78 °C for 1 h, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (4.95 g, 77.72 mmol) in Et20 (100 mL) was added dropwise. After the reaction was completed, the mixture was quenched with saturated NH4CI and extracted with EA (100 mL x 3). The organic phase was combined and washed with saturated brine (300 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound 8 as a yellow oil (13.0 g, 45.57 mmol, 58.6% yield).

[0236] ESI-MS calculated: 285.12, MS measured: 571.2 [2M+H] + .

[0237] Preparation of tert-butyl 3-(2,6-difluorophenyl)-3-hydroxyazetidine-1-carboxylate (9)

[0238] To a mixture of tert-butyl 3-(2,6-difluorophenyl)-3-hydroxyazetidine-1-carboxylate (13.0 g, 45.57 mmol) and THF (150 mL) was added Burgess reagent (32.5 g, 136.7 mmol) and the reaction was allowed to proceed for real time. The resulting mixture was stirred at 70 °C under nitrogen atmosphere for 2 h. The reaction mixture was dried and concentrated under reduced pressure to give a yellow oil (13 g).

[0239] Preparation of tert-butyl 3-(2,6-difluorophenyl)azetidine-1-carboxylate (10)

[0240] To a solution of tert-butyl 3-(2,6-difluorophenyl)azetidine-1(2H)-carboxylate (13 g, 48.64 mmol) in MeOH (200 mL) was added 10% wt Pd / C (1.3 g). The mixture was stirred in a thermostatic chamber under hydrogen atmosphere for 16 h. After the reaction was completed, the mixture was filtered through celite and the filter cake was washed with MeOH. The filtrates were combined and concentrated under reduced pressure. The residue was purified by preparative HPLC (10 mmol aqueous NH4HCO3-acetonitrile) to give the title compound 10 as a yellow solid (1.0 g, 3.71 mmol, 7.6%).

[0241] ESI-MS calculated: 269.12, MS measured: 214.0 [M+H-56] + .

[0242] Preparation of 3-(2,6-difluorophenyl)azetidine (11)

[0243] To a solution of 7-bromo-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydroquinoline-3- carboxylic acid (1.0 g, 3.71 mmol) in 1,4-dioxane (10 mL) was added hydrochloric acid 1,4-dioxane (10 mL) dropwise at room temperature. After half an hour of reaction at room temperature, the pH of the reaction mixture was adjusted to 9 with saturated NaHC03. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and then by preparative HPLC (10 mmol NH4HC03aqueous solution-acetonitrile) to give the title compound 11 as a white solid (231.64 mg, 1.37 mmol, 36.87% yield). ESI-MS calculated value: 169.07, MS detected value: 169.8 [M+H] + .

[0244] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.48 - 7.36 (m, 1H), 7.13 (t, J = 8.4 Hz, 2H), 4.45 - 4.31 (m, 1H), 4.27 - 4.09 (m, 4H).

[0245] Preparation of intermediate compound 14

[0246] Preparation of 3-(4-chlorophenyl)-3-hydroxyazetidine-l-carboxylic acid tert-butyl ester (13)

[0247] Dissolve 3-oxoazetidine-l-carboxylic acid tert-butyl ester (5.13 g, 30 mmol) in THF (50 ml), replace with nitrogen, and cool the mixture in an ice water mixture at 0 °C for 15 minutes. Then, add 4-chlorophenyl magnesium bromide (1 N, 30 ml) dropwise to the mixture. Slowly raise the temperature of the mixture to room temperature in an ice bath, and allow the mixture to react at room temperature overnight. After the reaction is complete, quench the reaction by adding saturated NH4CI to the reaction system in an ice bath. Extract the mixture with EA (30 mL x 3), wash the organic phase with saturated brine, combine the organic phases, dry with Na2S04, filter, and distill under reduced pressure. Purify the residue by silica gel column chromatography to obtain the title compound as a white solid (7.41 g, 26.17 mmol, 87.2%). ESI-MS calculated value: 283.10, MS detected value: 284.0 [M+H] + .

[0248] Preparation of 3-(4-chlorophenyl)azetidin-3-ol (14)

[0249] Dissolve 3-(4-chlorophenyl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (2.83 g, 10 mmol) in MeOH (20 mL), then add HCl / EA (4 N, 20 mL) inwards, stir at 40 °C for 2 h, after the reaction is completed, the mixture is concentrated under reduced pressure to obtain the crude 3-(4-chlorophenyl)azetidin-3-ol which can be directly used in the subsequent reaction.

[0250] ESI-MS calculated value: 183.05, MS detected value: 184.0 [M+H] + .

[0251] A series of derivatives can be obtained by replacing similar raw materials in the same preparation route described above.

[0252] The present application is further illustrated by the following examples, which illustrate some of the several preferred embodiments of the present application. These examples are provided merely as representative embodiments and should not be construed as limiting the scope of the present application in any way.

[0253] Example 1: 3-(3,4-difluorophenyl)-1-(4-fluorobenzyl)azetidin-3-ol

[0254] Dissolve 3-(3,4-difluorophenyl)azetidin-3-ol (3) (1.00 g, 5.40 mmol) and 4-fluorobenzaldehyde (0.80 g, 6.48 mmol) in a round-bottom flask, add DCE (10 mL), stir the mixture at room temperature for 1 h, then add sodium triacetoxyborohydride (2.29 g, 10.80 mmol). After the mixture is stirred at room temperature for 16 h, quench the reaction mixture with H2O (20 mL), then extract with DCM (30 mL x 3). Wash the organic phase with saturated brine (30 mL), dry over Na2SO4, filter, and concentrate under reduced pressure. Subject the residue to preparative HPLC (0.1% ammonia water-acetonitrile) to obtain Example 1 as a white solid (107.58 mg, 0.37 mmol, 6.8%). ESI-MS calculated value: 293.10, MS detected value: 294 [M+H] + .

[0255] 1 H NMR (400 MHz, DMSO-d6) δ 7.68 - 7.48 (m, 2H), 7.46 - 7.30 (m, 3H), 7.15 (t, J = 8.8 Hz, 2H), 6.14 (s, 1H), 3.69 (s, 2H), 3.50 (d, J = 7.9 Hz, 2H), 3.32 (d, J = 8.0 Hz, 2H).

[0256] Example 2: 3-(5-chloropyridin-2-yl)-1-(3-(trifluoromethyl)benzyl)azetidine-3- carboxylate

[0257] Intermediate 6 (50.0 mg, 0.17 mmol) was placed in a round bottom flask followed by MeOH (3 mL) at room temperature. To the mixture was added 3-(trifluoromethyl)benzaldehyde (34.0 mg, 0.19 mmol). After the mixture was stirred at room temperature for one hour, NaCNBH3(15.6 mg, 0.24 mmol) was added followed by stirring at room temperature overnight. After the reaction was completed, the reaction was quenched with saturated NaHCO3and extracted with ethyl acetate (10 mL x 3), and the organic phase was washed with saturated brine. The organic phase was washed with saturated brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give Example 2 as a colorless oil (45 mg, 0.12 mmol, 68.9%). ESI-MS calc. 384.09, MS obs. 385 [M+H] + .

[0258] 1 H NMR (600 MHz, DMSO-d6) δ 8.59 (dd, J = 2.6, 0.7 Hz, 1H), 7.97 (dd, J = 8.5, 2.6 Hz, 1H), 7.65 - 7.51 (m, 5H), 3.79 (d, J = 7.4 Hz, 2H), 3.71 (s, 2H), 3.68 - 3.63 (m, 5H).

[0259] Example 3: 3-(2,6-difluorophenyl)-1-(3-(trifluoromethyl)benzyl)azetidine

[0260] Intermediate 11 (60.0 mg, 0.35 mmol) was placed in a round bottom flask followed by MeOH (3 mL) and 3-(trifluoromethyl)benzaldehyde (74.1 mg, 0.42 mmol) at room temperature. After the mixture was stirred at room temperature for one hour, NaCNBH3(33.0 mg, 0.53 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with saturated NaHCO3and extracted with ethyl acetate (10 mL x 3), and the organic phase was washed with saturated brine. The organic phase was washed with saturated brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give Example 3 as a colorless oil (77 mg, 0.23 mmol, 65.7%). ESI-MS calc. 327.10, MS obs. 328 [M+H] + .

[0261] 1 H NMR (600 MHz, DMSO-d6) δ 7.65-7.52 (m, 4H), 7.35-7.28 (m, 1H), 7.08-7.02 (m, 2H), 3.89-3.82 (m, 1H), 3.77 (t, J = 7.1 Hz, 2H), 3.68 (s, 2H), 3.20 (t, J = 7.7 Hz, 2H).

[0262] Example 4: 3-(4-chlorophenyl)-1-(naphthalen-2-ylmethyl)azetidin-3-ol

[0263] Into a round bottom flask, 3-(4-chlorophenyl)azetidin-3-ol 14 (2.50 g, 10 mmol) was dissolved in DMF (15 mL) and Na2CO3 (2.65 g, 25 mmol) was added under stirring. After 10 min, the reaction was cooled to 0 °C and 2-bromomethylnaphthalene (2.2 g, 10 mmol) was added, then slowly warmed to room temperature and stirred overnight. After the reaction was completed, water was added to quench and washed with EA (30 mL x 3), the organic phase was combined and washed with saturated brine, then the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give Example 4 as a white solid (750 mg, 2.32 mmol, 23.5%).

[0264] ESI-MS Calcd: 323.11, MS Found: 324 [M+H] + .

[0265] 1 H NMR (600 MHz, DMSO-d6) δ 7.65-7.52 (m, 4H), 7.35-7.28 (m, 1H), 7.08-7.02 (m, 2H), 3.89-3.82 (m, 1H), 3.77 (t, J = 7.1 Hz, 2H), 3.68 (s, 2H), 3.20 (t, J = 7.7 Hz, 2H).

[0266] Example 5: 3-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)benzyl)azetidin-3-ol

[0267] Referring to the preparation process in Examples 1-4, the similar starting materials were replaced to obtain the target structure as follows:

[0268] ESI-MS Calcd: 323.11, MS Found: 324 [M+H] + .

[0269] 1 H NMR (400 MHz, DMSO-d6) δ 7.74 - 7.51 (m, 6 H), 7.47 - 7.37 (m, 2 H), 6.07 (s, 1 H), 3.81 (s, 2 H), 3.56 - 3.47 (m, 2 H), 3.39-3.35 (m, 2 H).

[0270] Example 6: 3-(4-chlorophenyl)-1-(3-(trifluoromethyl)benzyl)azetidin-3-ol

[0271] Referring to the preparation process in Examples 1-4, the target structure is obtained by replacing similar raw materials as follows:

[0272] ESI-MS calculated value: 341.08, MS detected value: 342 [M+H] + .

[0273] 1 H NMR (400 MHz, DMSO-d6) δ 7.74 - 7.51 (m, 6 H), 7.47 - 7.37 (m, 2 H), 6.07 (s, 1 H), 3.81 (s, 2 H), 3.56 - 3.47 (m, 2 H), 3.39-3.35 (m, 2 H).

[0274] According to the similar method, the present application also synthesized a series of compounds with the structure as shown below:

[0275] Biological evaluation

[0276] In vitro evaluation

[0277] MOR agonist cAMP test experiment

[0278] The compounds of the present application can activate mu-opioid receptor (MOR). The activated MOR can modulate the level of cAMP in the cell, which enters the nucleus and binds to the CRE region of the reporter gene Luciferase, initiating the expression of the reporter gene. The reaction of Luciferase with its substrate can emit fluorescence, which reflects the agonistic activity of the compound by measuring the fluorescence signal.

[0279] Experimental Methods

[0280] The agonistic activity of the example compounds to affect the change of downstream cAMP level was tested by the following method.

[0281] Materials and Reagents

[0282] HTRF cAMP Gi kit (Perkin Elmer, 62AM9PEB; the kit contains 1X stimulation buffer, Eu-Cryptate and Anti-cAMP-d2-antibody). IBMX (Sigma, I5879). Forskolin (Sigma, E7384).

[0283] Experimental Operation Steps

[0284] Prepare the detection buffer: 1X stimulation buffer, 500 mM IBMX, ddH2O.

[0285] Compound preparation: dissolve the compound with DMSO to prepare a stock solution with a final concentration of 10 mM, and dilute the compound with 1X stimulation buffer to prepare 6 concentration gradients, with an initial concentration of 0.08 mM and a final concentration of 0.4 nM. Dilute the Forskolin with 1X stimulation buffer (the final concentration is 40 mM).

[0286] Preparation of standard curve: dilute the standard cAMP with the detection buffer in 4-fold gradient, a total of 8 concentration points, the highest concentration is 800 nM, and add 10 mL per well according to the layout of the microplate.

[0287] Cell plating: thaw the frozen cells, centrifuge at 1000 rpm for 5 min, discard the supernatant, wash the cells twice with HBSS buffer, resuspend the cells with 1X stimulation buffer, adjust the cell density to 5.0 X 10 5 cells / mL, add 5 mL per well to the 96-well plate, and place the cell plate in a 37°C incubator for 60 min.

[0288] Detection reagent preparation: dilute Eu-Cryptate and Anti-cAMP-d2-antibody to 1X with detection buffer, add 10 μL detection reagent to each well according to the layout of the microplate, shake for 20 s, and place the cell plate in a 25℃ incubator for 60 min; read the plate on the BMG PHERAstar.

[0289] Result analysis

[0290] The Libreoffice software was used to calculate the percentage of activity, and the formula %Effect = 100X (Sample Raw Value-Low Control Average) / (High Control Average-Low Control Average) was used for agonists. The GraphPad Prism 5 data analysis software was used, and the Dose-response-Stimulation-log[agonist] vs. response-Variable slope mode was selected for agonists for fitting analysis, and the EC 50 values of each test sample were obtained.

[0291] The change in downstream cAMP level affected by the MOR agonism of the compound of the application was determined by the above test, and the experimental results showed that the series of compounds exhibited strong MOR agonism effect, and the EC 50 values of the typical representative examples measured are shown in Table 1.

[0292] Table 1: EC 50 and Emax

[0293] Note: 10 μM > EC 50 ≥ 0.2 μM is +, 0.2 μM > EC 50 ≥ 0.02 μM is ++, 0.02 μM > EC 50 ≥ 0.001 μM is +++

[0294] In vivo evaluation

[0295] Experiment 1: evaluation of the animal in vivo analgesic effect of the test product

[0296] 1 animal

[0297] C57BL / 6 mice (SPF level animals provided by Beijing Vantoll Life Science and Technology Co., Ltd.), male, 18-22 g;

[0298] 2. Grouping

[0299] Mice were acclimated for 1 week after purchase. Mice were placed on the hot plate apparatus (55.0 ± 0.5 °C) and the latency to respond to the thermal stimulus (pain threshold) was determined. Mice with a pain threshold of 5-30 s were used for the test. All mice were randomly divided into 11 groups of 8 animals each according to the baseline pain threshold.

[0300] Each group of mice was given either the vehicle (10% DMSO + 10% Solutol HS-15 + 80% saline) or the compound. The dosing schedule is detailed in Table 2.

[0301] Table 2. Grouping and dosing schedule

[0302] 3. Index detection:

[0303] Each group of mice was tested up to 120 min after dosing. Mice were placed on the hot plate apparatus (55.0 ± 0.5 °C) and the latency to respond to the thermal stimulus (pain threshold) was determined. The time taken for the mouse to show a pain threshold of licking or lifting the hind paw was recorded and the maximum possible effect percentage %MPE was calculated.

[0304] Table 3. Thermal paw withdrawal latency

[0305] Table 4. Maximum possible effect percentage MPE

[0306] 4. Results:

[0307] The analgesic effect of the test product on acute pain in mice was observed during the test period. No significant tolerance symptoms to the thermal stimulus were observed in the normal group. The example group showed a significant analgesic effect within 60 min after dosing. Each test product group showed a strong analgesic effect, with an effective analgesic time of up to 4 hours. Each example group showed a significant analgesic effect to the thermal stimulus within 60 min after dosing, and a good analgesic effect was still observed at 120 min after dosing (“normal group” refers to the vehicle control group of G1).

[0308] Experiment 2: Evaluation of the addictive properties of the test product (mouse forced withdrawal test - jumping)

[0309] 1. Animals

[0310] C57BL / 6 mice (SPF level animals, provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.), male, 18-22 g;

[0311] 2. Grouping

[0312] Mice were acclimated for 1 week after purchase. All mice were trained in the mine field test equipment for 30 min before grouping. All mice were randomly divided into 8 groups of 8 animals each according to the baseline pain threshold.

[0313] Each group of mice was given vehicle (10% DMSO + 10% Solutol HS-15 + 80% normal saline) or compound, and positive control was morphine, an agonist of opioid receptors. The dose was increased from 10 mg / kg on the first day to 50 mg / kg daily. The experiment was completed by a third party institution with the qualification of morphine use. The administration details are shown in Table 5.

[0314] Table 5 Grouping and administration scheme

[0315] 3. Index detection:

[0316] After the last administration for 2 h, the mice were intraperitoneally injected with the drug naloxone (5 mg / kg). Within 30 min after the administration of naloxone, the general signs such as the number of jumps and spontaneous activity were observed by the mine field experiment. The mice were observed and the activity state was recorded for 30 min, and the results are shown in Table 6.

[0317] Table 6 Results of the mine field experiment

[0318] 4. Results:

[0319] During the test period, no abnormal withdrawal symptoms occurred in the normal group, and the positive control group (G8) showed obvious withdrawal jump reaction after the administration of naloxone, and the spontaneous activity decreased. The example groups did not induce significant withdrawal jump reaction after the administration of naloxone, and the spontaneous activity had no significant difference with the normal group, indicating that the continuous administration of the test substance did not form physical dependence effect (“normal group” refers to the vehicle control group of G1).

[0320] Experiment 3: Evaluation of the effect of the test product on the side effect of constipation

[0321] 1 Animal

[0322] C57BL / 6 mice (SPF level animals, provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.), male, 18-22 g;

[0323] 2. Grouping

[0324] The mice were adaptively fed for 1 week after purchase. All mice were randomly divided into 9 groups according to the body weight, 16 animals in each group.

[0325] Each group of mice was administered with solvent (10% DMSO + 10% Solutol HS-15 + 80% normal saline) or the corresponding compound, wherein the constipation model group was modeled using loperamide hydrochloride, a laxative, which was used in this experiment as a modeling agent for the constipation animal index. The positive control was DAMGO (CAS: 78123-71-4), a selective MOR receptor agonist. The grouping and administration are shown in Table 7.

[0326] Table 7 Grouping and administration scheme

[0327] 3. Index detection:

[0328] 3.1 Body weight was recorded during the experiment, and the body weight change is shown in Table 8.

[0329] Table 8 Body weight data table (unit: g)

[0330] Results: During the experiment, the body weight of the G1 solvent group animals increased steadily, the body weight of the G2 constipation model group decreased significantly, the body weight of the G3 to G8 example groups decreased slightly, and the body weight of the G9 positive control group decreased slightly.

[0331] 3.2 Small intestine propulsion experiment detection of mice

[0332] The first 8 mice in each group were each given 0.2 mL of ink half an hour after the last administration of the drug. Half an hour later, the animals were sacrificed, the mouse abdominal cavity was opened with surgical scissors, and the intestinal tube starting from the pylorus and ending at the ileocecal junction was selected, placed flat on the table, and its length was measured, resulting in the value of "total length of intestinal tube";

[0333] The ink propulsion length in the intestinal tube from the pylorus was measured with a ruler, resulting in the value of "ink propulsion length", both values were expressed in cm; after obtaining the values, the intestinal propulsion rate was calculated, the calculation formula was: intestinal propulsion rate (%) = ink propulsion length (cm) / total length of intestinal tube (cm) * 100%, and the specific results are shown in Table 9.

[0334] Table 9 Small intestine propulsion rate data table

[0335] Results: The small intestine propulsion rate results, compared with the G1 solvent group, the small intestine propulsion rate of the G2 constipation model group was significantly reduced, the small intestine propulsion rate of the G3 to G8 example groups had no obvious effect, and the small intestine propulsion rate of the G9 positive control group was significantly reduced.

[0336] 3.3 Mouse defecation experiment

[0337] The remaining 8 mice in each group were filled with ink in the stomach, and each mouse was filled with 0.2 mL of ink. The half hour after the last administration was taken as the ink administration time. The ink administration time was taken as the starting point of the defecation experiment, and the feces of each group were collected after 6 h. The number of black feces and the weight of black feces were calculated, and the specific results are shown in Table 10.

[0338] Table 10 Defecation data

[0339] Note: The feces in Table 10 refer to "black feces".

[0340] Results: Compared with the G1 solvent group, the number of defecation of the G2 constipation model group was significantly reduced, the G3 to G8 example groups had no obvious effect on the number of defecation, and the G9 positive control group had no obvious effect on the number of defecation.

[0341] Conclusion: According to the data in Tables 8-10, the small intestine propulsion rate of mice taking the compound of the present application is higher, indicating that the compound of the present application has no constipation side effects; and the defecation amount of mice taking the compound of the present application is normal, indicating that the compound of the present application will not cause intestinal function disorder.

[0342] Although the specific embodiments of the present application are described above, those skilled in the art should understand that these are only illustrative, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present application. Therefore, the scope of protection of the present application is defined by the appended claims.

Claims

1. Use of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof, as an opioid receptor agonist; ###0001### Formula I wherein, n1 is 0 or 1; R1 is selected from the group consisting of hydrogen, hydroxyl, amine, thiol, C1-C6 alkoxy, C1-C6 alkylamine, nitrogen-containing C1-C6 heteroalkyl, oxygen-containing C1-C6 heteroalkyl, sulfur-containing C1-C6 heteroalkyl, halogen, C1-C6 carboxyl, C1-C6 amide, C2-C6 ester, and C2-C6 ester substituted with 1, 2, or 3 halogens; R2 is selected from the group consisting of: Unsubstituted or substituted C6-C 18 Aryl, unsubstituted or substituted C3-C 18 Heteroaryl, carbonyl-substituted C1-C6 alkyl, unsubstituted or substituted C3-C8 cycloalkanes, and unsubstituted or substituted C4-C8 aliphatic heterocycles; wherein the substitution is mono, di, tri, or tetrasubstituted, and the substituent is selected from halogens, C1-C6 alkyl, C1-C6 alkyl substituted with 1, 2, or 3 halogens, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with 1, 2, or 3 halogens, C1-C6 alkoxy, C1-C6 alkoxy substituted with 1, 2, or 3 halogens, sulfur-containing C1-C6 heteroaryl... Alkyl, C1-C6 alkylthiol, C1-C6 alkylthiol substituted with 1, 2 or 3 halogens, C1-C6 sulfoxide, C1-C6 sulfone, hydroxyl, cyano, nitro, urea, oxygen-containing C1-C6 heteroalkyl, amino, nitrogen-containing C1-C6 heteroalkyl, C1-C6 alkylamine, C1-C6 alkylamine substituted with 1, 2 or 3 halogens, C1-C6 carboxyl, C1-C6 amide, C2-C6 ester, and urea substituted with C1-C6 alkyl substituted with 0, 1, 2 or 3 halogens; a group selected from the group consisting of unsubstituted or substituted C6-Ci8aryl and unsubstituted or substituted C3-Ci8heteroaryl; wherein the substituents are mono-, di-, tri- or tetra-substitution with substituents selected from the group consisting of halogen, Ci-C6alkyl, Ci-C6alkyl substituted with 1, 2 or 3 halogen, C3-C8cycloalkyl, C3-C8cycloalkyl substituted with 1, 2 or 3 halogen, Ci-C6alkoxy, Ci-C6alkoxy substituted with 1, 2 or 3 halogen, sulphur containing Ci-C6heteroalkyl, Ci-C6alkylmercapto, Ci-C6alkylmercapto substituted with 1, 2 or 3 halogen, Ci-C6sulphoxy, Ci-C6sulphone, hydroxy, cyano, nitro, ureido, oxygen containing Ci-C6heteroalkyl, aminyl, nitrogen containing Ci-C6heteroalkyl, Ci-C6alkylaminyl, Ci-C6alkylaminyl substituted with 1, 2 or 3 halogen, Ci-C6carboxyl, Ci-C6carboxamido, C2-C6carboxylester and ureido substituted with Ci-C6alkyl substituted with 0, 1, 2 or 3 halogen; 18 a group selected from the group consisting of unsubstituted or substituted C6-Ci8aryl and unsubstituted or substituted C3-Ci8heteroaryl; wherein the substituents are mono-, di-, tri- or tetra-substitution with substituents selected from the group consisting of halogen, Ci-C6alkyl, Ci-C6alkyl substituted with 1, 2 or 3 halogen, C3-C8cycloalkyl, C3-C8cycloalkyl substituted with 1, 2 or 3 halogen, Ci-C6alkoxy, Ci-C6alkoxy substituted with 1, 2 or 3 halogen, sulphur containing Ci-C6heteroalkyl, Ci-C6alkylmercapto, Ci-C6alkylmercapto substituted with 1, 2 or 3 halogen, Ci-C6sulphoxy, Ci-C6sulphone, hydroxy, cyano, nitro, ureido, oxygen containing Ci-C6heteroalkyl, aminyl, nitrogen containing Ci-C6heteroalkyl, Ci-C6alkylaminyl, Ci-C6alkylaminyl substituted with 1, 2 or 3 halogen, Ci-C6carboxyl, Ci-C6carboxamido, C2-C6carboxylester and ureido substituted with Ci-C6alkyl substituted with 0, 1, 2 or 3 halogen; 18 a group selected from the group consisting of unsubstituted or substituted C6-Ci8aryl and unsubstituted or substituted C3-Ci8heteroaryl; wherein the substituents are mono-, di-, tri- or tetra-substitution with substituents selected from the group consisting of halogen, Ci said sulfur-containing C1-C6 heteroalkyl is a C1-C6 alkyl chain with 1 S heteroatom that can replace a C atom in the alkyl chain at a position allowed by normal valence, and the S atom is not directly connected to the group being substituted; said oxygen-containing C1-C6 heteroalkyl is a C1-C6 alkyl chain with 1 O heteroatom that can replace a C atom in the alkyl chain at a position allowed by normal valence, and the O atom is not directly connected to the group being substituted; said nitrogen-containing C1-C6 heteroalkyl is a C1-C6 alkyl chain with 1 N heteroatom that can replace a C atom in the alkyl chain at a position allowed by normal valence, and the N atom is not directly connected to the group being substituted; said C4-C8 aliphatic heterocycle has heteroatoms independently selected from one or more of N, O, S, and P, and the number of heteroatoms is 1, 2, 3, or 4; said C3-C 18 the heteroatoms of the aromatic heterocycle are independently selected from one or more of N, O and S, the number of heteroatoms being 1, 2, 3 or 4.

2. The use according to claim 1, characterized in that, said compound of Formula I satisfies one or more of the following conditions: (1) said C1-C6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, or i-hexyl; (2) said C1-C6 alkoxy is methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentoxy, i-pentoxy, neopentoxy, n-hexoxy, n-hexoxy, or i-hexoxy; (3) said C1-C6 alkylamine is methylamine, ethylamine, n-propylamine, i-propylamine, n-butylamine, i-butylamine, s-butylamine, t-butylamine, n-pentylamine, i-pentylamine, neopentylamine, n-hexylamine, or i-hexylamine; (4) said C1-C6 alkylthiol is methylthiol, ethylthiol, n-propylthiol, i-propylthiol, n-butylthiol, i-butylthiol, s-butylthiol, t-butylthiol, n-pentylthiol, i-pentylthiol, neopentylthiol, n-hexylthiol, or i-hexylthiol; (5) said C2-C6 ester is -CO2C1-C5 alkyl or -OCOC1-C5 alkyl; preferably, the alkyl in said -CO2C1-C5 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, or i-pentyl; and / or, said -OCOC1-C5 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, or i-pentyl; (6) said halogen is fluorine, chlorine, bromine, or iodine; (7) the sulfur-containing Ci-C6heteroalkyl is -CH2-SH, -CH2CH2-SH, -CH2CH2CH2-SH, -CH2CH2CH2CH2-SH, -CH2CH2CH2CH2CH2-SH, -CH2CH2CH2CH2CH2CH2-SH, -CH2-S-CH3, -CH2CH2-S-CH3, -CH2CH2-S-CH2CH3, -CH2CH2-S-CH2CH2CH3, -CH2CH2CH2-S-CH2CH3, or -CH2CH2CH2-S-CH2CH2CH3; (8) the oxygen-containing Ci-C6heteroalkyl is -CH2-OH, -CH2CH2-OH, -CH2CH2CH2-OH, -CH2CH2CH2CH2-OH, -CH2CH2CH2CH2CH2-OH, -CH2CH2CH2CH2CH2CH2-OH, -CH2-O-CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2CH2-O-CH2CH2CH3, -CH2CH2CH2-O-CH2CH3, or -CH2CH2CH2-O-CH2CH2CH3; (9) the nitrogen-containing Ci-C6heteroalkyl is -CH2-NH2, -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH2CH2CH2CH2-NH2, -CH2CH2CH2CH2CH2-NH2, -CH2CH2CH2CH2CH2CH2-NH2, -CH2-NH-CH3, -CH2CH2-NH-CH3, -CH2-N-(CH3)2, -CH2CH2-NH-CH2CH3, -CH2CH2-N-(CH3)2, -CH2CH2-NH-CH2CH2CH3, -CH2CH2CH2-NH-CH2CH3, -CH2CH2CH2-N-(CH3)2, -CH2CH2CH2-NH-CH2CH2CH3, or -CH2CH2CH2CH2-N-(CH3)2; (10) the Ci-C6sulfoxide group is a methylsulfoxide group, an ethylsulfoxide group, an n-propylsulfoxide group, an i-propylsulfoxide group, an n-butylsulfoxide group, an i-butylsulfoxide group, a sec-butylsulfoxide group, a t-butylsulfoxide group, an n-pentylsulfoxide group, an i-pentylsulfoxide group, a neopentylsulfoxide group, an n-hexylsulfoxide group, or an i-hexylsulfoxide group; (11) the Ci-C6sulfone group is a methylsulfone group, an ethylsulfone group, an n-propylsulfone group, an i-propylsulfone group, an n-butylsulfone group, an i-butylsulfone group, a sec-butylsulfone group, a t-butylsulfone group, an n-pentylsulfone group, an i-pentylsulfone group, a neopentylsulfone group, an n-hexylsulfone group, or an i-hexylsulfone group; (12) said C1-C6carboxyl is -COOH, -CH2COOH, -CH(CH3)COOH, -CH2CH2COOH, -CH(CH3)CH2COOH, -CH2CH(CH3)COOH, -C(CH3)2COOH, -CH2CH2CH2COOH, -CH(CH3)CH2CH2COOH, -CH2CH(CH3)CH2COOH, -CH2CH2CH(CH3)COOH, -C(CH3)2CH2CH2COOH, -CH2C(CH3)2CH2COOH, -CH2CH2C(CH3)2COOH, -CH(CH3)CH(CH3)CH2COOH, -CH(CH3)CH2CH(CH3)COOH, -CH2CH(CH3)CH(CH3)COOH, -CH2CH2CH2CH2COOH, -CH(CH3)CH2CH2CH2COOH, -CH2CH(CH3)CH2CH2COOH, -CH2CH2CH(CH3)CH2COOH, -CH2CH2CH2CH(CH3)COOH, or -CH2CH2CH2CH2CH2COOH; (13) said C1-C6amide group is -CONHC1-C5alkyl, -CON(C1-C3alkyl)2, -NHCOC1-C5alkyl, or -N(C1-C2alkyl)COC1-C3alkyl; preferably, in said -CONHC1-C5alkyl, the C1-C5alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or neopentyl; and / or, in said -NHCOC1-C5alkyl, the C1-C5alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or neopentyl; and / or, in said -CON(C1-C3alkyl)2, the C1-C3alkyl is methyl, ethyl, n-propyl, or i-propyl; and / or, in said -N(C1-C2alkyl)COC1-C3alkyl, the C1-C3alkyl is methyl, ethyl, n-propyl, or i-propyl; and / or, in said -N(C1-C2alkyl)COC1-C3alkyl, the C1-C2alkyl is methyl or ethyl; (14) said C3-C8cycloalkyl is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or cyclooctane; (15) said heteroatom of said C4-C8aliphatic heterocycle is independently selected from N and / or O; (16) said C4-C8aliphatic heterocycle has 1 or 2 heteroatoms; (17) said C4-C8aliphatic heterocycle is a 3-6 membered aliphatic heterocycle; for example, piperidine, piperazine, dioxane, or morpholine; (18) said C6-Ci8-aryl can be phenyl, naphthyl or biphenyl; and 18 Aryl can be phenyl, naphthyl or biphenyl; (19) said C3-C 18 Heteroaryl is a 5-10 membered heteroaryl group, preferably a 5-6 membered heteroaryl group; for example furanyl, pyranyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl or tetrazolyl; and (20) the C3-C 18 The heteroatoms of the heteroaryl group are independently selected from one or two of N, O, and S.

3. Use according to claim 1 or 2, characterized in that, n1 is 0 or 1; and / or, R1 is selected from hydrogen, hydroxyl, and C2-C6ester, preferably, R1 is hydroxyl.

4. Use according to claim 1 or 2, wherein R2 is selected from the following groups: (1) unsubstituted or substituted phenyl; wherein substituted is mono-, di-, tri- or tetra-substituted with substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2 or 3 halogen, C3-C8cycloalkyl, C3-C8cycloalkyl substituted with 1, 2 or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2 or 3 halogen, C1-C3heteroalkyl containing sulfur, C1-C6alkylmercapto, C1-C6alkylmercapto substituted with 1, 2 or 3 halogen, C1-C6sulfoxide, C1-C6sulfone, hydroxy, cyano, nitro, ureido, C1-C6heteroalkyl containing oxygen, aminyl, C1-C6heteroalkyl containing nitrogen, C1-C6alkylaminyl substituted with 1, 2 or 3 halogen, C1-C6alkylaminyl, C1-C6carboxyl, C1-C6amide, C2-C6ester and ureido substituted with 0, 1, 2 or 3 C1-C6alkyl substituted with halogen; (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl or 4-pyridyl; wherein substituted is mono-, di- or tri-substituted with substituents selected from the group consisting of halogen, C1-C6alkyl, cyano, nitro, C1-C6alkyl substituted with 1, 2 or 3 halogen, C3-C8cycloalkyl, C3-C8cycloalkyl substituted with 1, 2 or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2 or 3 halogen, C1-C3heteroalkyl containing sulfur, C1-C6alkylmercapto, C1-C6alkylmercapto substituted with 1, 2 or 3 halogen, C1-C6sulfoxide, C1-C6sulfone, hydroxy, C1-C6heteroalkyl containing oxygen, aminyl, C1-C6heteroalkyl containing nitrogen, C1-C6alkylaminyl substituted with 1, 2 or 3 halogen, C1-C6alkylaminyl, C1-C6carboxyl, C2-C6ester, C1-C6amide and ureido substituted with 0, 1, 2 or 3 C1-C6alkyl substituted with halogen; (3) unsubstituted or substituted biphenyl; wherein substituted is mono-, di-, tri-, tetra- to octa-substituted; substituents are selected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6alkyl substituted with 1, 2 or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2 or 3 halogen, C1-C6alkylmercapto, C1-C6alkylmercapto substituted with 1, 2 or 3 halogen, C1-C6sulfoxide, C1-C6sulfone, hydroxy, C1-C6heteroalkyl containing oxygen, aminyl, C1-C6heteroalkyl containing nitrogen, C1-C6alkylaminyl substituted with 1, 2 or 3 halogen, C1-C6alkylaminyl, C1-C6carboxyl, C2-C6ester, C1-C6amide and ureido substituted with 0, 1, 2 or 3 C1-C6alkyl substituted with halogen; (4) unsubstituted or substituted naphthyl; wherein the substitution is mono-, di- or tri- substitution; wherein the substituents are selected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6alkyl substituted with 1, 2 or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2 or 3 halogen, C1-C6alkylmercapto, C1-C6alkylmercapto substituted with 1, 2 or 3 halogen, C1-C6sulfinyl, C1-C6sulfone, hydroxy, oxygen-containing C1-C6heteroalkyl, aminyl, nitrogen-containing C1-C6heteroalkyl, C1-C6alkylaminyl, C1-C6alkylaminyl substituted with 1, 2 or 3 halogen, C1-C6carboxyl, C2-C6ester, C1-C6amido and ureido substituted with C1-C6alkyl substituted with 0, 1, 2 or 3 halogen; (5) C1-C6alkyl substituted with a carbonyl group, wherein the carbonyl group is -(C=O)R3, wherein R3is selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1-3 halogen, hydroxy, oxygen-containing C1-C6heteroalkyl, aminyl, nitrogen-containing C1-C6heteroalkyl, and C1-C6alkylaminyl; said sulfur-containing C1-C6heteroalkyl is a C1-C6alkyl group containing one S heteroatom which can replace a C atom in the alkyl chain at a position allowed by normal valence state, and the S atom is not directly attached to the group being substituted; said oxygen-containing C1-C6heteroalkyl is a C1-C6alkyl group containing one O heteroatom which can replace a C atom in the alkyl chain at a position allowed by normal valence state, and the O atom is not directly attached to the group being substituted; said nitrogen-containing C1-C6heteroalkyl is a C1-C6alkyl group containing one N heteroatom which can replace a C atom in the alkyl chain at a position allowed by normal valence state, and the N atom is not directly attached to the group being substituted; Preferably, R2is selected from the group consisting of: (1) substituted phenyl; wherein the substitution is mono-, di-, tri- or tetra-substitution, and the substituents are selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2 or 3 halogen, C1-C6alkoxy, C1-C6alkylmercapto, cyano, C2-C6ester and ureido substituted with C1-C6alkyl; (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from 2-pyridyl, 3-pyridyl or 4-pyridyl; wherein the substitution comprises mono-, di- or tri-substitution, and the substituents are selected from the group consisting of halogen, C1-C6alkyl, cyano, C1-C6alkyl substituted with 1, 2 or 3 halogen and C2-C6ester; (3) unsubstituted or substituted biphenyl; wherein the substitution is mono-, di-, tri-, tetra- to octa-substitution; and the substituents are selected from the group consisting of halogen and C1-C6alkyl substituted with 1, 2 or 3 halogen; (4) unsubstituted or substituted naphthyl; wherein the substitution is mono-; and wherein the substituent is C1-C6alkoxy; (5) C1-C6alkyl substituted with a carbonyl group, wherein the carbonyl group is -(C=O)R3, wherein R3is C1-C6alkylaminyl; More preferably, R2is selected from the group consisting of: (1) substituted phenyl; wherein the substitution is mono-, di-, tri- or tetra-substitution, and the substituents are selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2 or 3 halogen, C1-C6alkoxy, C1-C6alkylmercapto, cyano, C2-C6ester and ureido substituted with C1-C6alkyl; (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from 2-pyridyl, 3-pyridyl or 4-pyridyl; wherein the substitution comprises mono-, di- or tri-substitution, and the substituents are selected from the group consisting of halogen, C1-C6alkyl, cyano, C1-C6alkyl substituted with 1, 2 or 3 halogen and C2-C6ester; (3) unsubstituted or substituted biphenyl; wherein the substitution is mono-, di-, tri-, tetra- to octa-substitution; and the substituents are selected from the group consisting of halogen and C1-C6alkyl substituted with 1, 2 or 3 halogen; (4) unsubstituted or substituted naphthyl; wherein the substitution is mono-; and wherein the substituent is C1-C6alkoxy; (5) C1-C6alkyl substituted with a carbonyl group, wherein the carbonyl group is -(C=O)R3, wherein R3is C1-C6alkylaminyl; (1) substituted phenyl; wherein the substitution is mono-, di-, tri-, or tetra-substitution with substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogens, C1-C6alkoxy, and ureido substituted with C1-C6alkyl; (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein the substitution is mono-, di-, or tri-substitution with substituents selected from the group consisting of halogen and cyano; (3) unsubstituted or substituted biphenyl; wherein the substitution includes mono-, di-, tri-, tetra- to octa-substitution; the substituents are halogen; (4) naphthyl; More preferably, R2is selected from the group consisting of: (1) substituted phenyl; wherein the substitution is mono-, di-, tri-, or tetra-substitution with substituents selected from the group consisting of halogen, cyano, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogens, and C1-C6alkoxy; (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein the substitution is mono-substitution with substituents selected from the group consisting of halogen; (3) unsubstituted or substituted naphthyl; wherein the substitution is mono-substitution with substituents selected from the group consisting of C1-C6alkoxy; For example, R2is selected from the group consisting of: (1) substituted phenyl; wherein the substitution is mono-, di-, or tri-substitution with substituents selected from the group consisting of halogen, cyano, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogens, C1-C6alkylmercapto, and C1-C6alkoxy; (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein the substitution is mono-substitution with substituents selected from the group consisting of halogen; (3) unsubstituted or substituted biphenyl; wherein the substitution is mono-substitution; the substituents are halogen; (4) unsubstituted or substituted naphthyl; wherein the substitution is mono-substitution; the substituents are C1-C6alkoxy; and / or, selected from the group consisting of: (1) substituted phenyl; wherein the substitution is mono-, di-, or tri-substitution; the substituents are selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogens, cyano, C1-C6alkoxy, C1-C6alkylamino, C1-C6alkylmercapto, and sulfur-containing C1-C6heteroalkyl; wherein the amine group is C1-C6alkyl substituted; (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl; wherein the substitution is mono-, di-, or tri-substitution; the substituents are halogen; Preferably, is substituted phenyl; wherein the substitution is mono-, di-, or tri-substitution; the substituents are selected from the group consisting of halogen, cyano, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogens, C1-C6alkoxy, and C1-C6alkylmercapto; More preferably, is substituted phenyl; wherein the substitution is mono-, di-, or tri-substitution; the substituents are selected from the group consisting of halogen, cyano, and C1-C6alkoxy; For example, is substituted phenyl; wherein the substitution is mono-, di-, or tri-substitution; the substituents are selected from the group consisting of halogen and C1-C6alkoxy.

5. The use according to claim 1, characterized in that, The compound of Formula I satisfies any one of Scheme 1 through Scheme 7: Scheme 1, R1is selected from the group consisting of hydroxyl and C2-C3 ester; R2is selected from the group consisting of: (1) substituted phenyl; wherein the substitution is mono-, di-, tri-, or tetra-substitution with substituents selected from the group consisting of halogen, C1-C3alkyl substituted with 1, 2, or 3 halogens, C1-C3alkoxy, C1-C3alkoxy substituted with 1, 2, or 3 halogens, C1-C3alkylmercapto, sulfur-containing C1-C3heteroalkyl, hydroxy, oxygen-containing C1-C3heteroalkyl, aminyl, nitrogen-containing C1-C3heteroalkyl, C1-C3alkylaminyl, C1-C3carboxyl, C2-C3ester, C1-C3amide, ureido, cyano, and ureido substituted with 0, 1, 2, or 3 halogen-substituted C1-C3alkyl; (2) substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl; wherein the substitution comprises mono-, di-, or tri-substitution with substituents selected from the group consisting of halogen, C1-C3alkyl substituted with 1, 2, or 3 halogens, C1-C3alkoxy, C1-C3alkoxy substituted with 1, 2, or 3 halogens, C1-C3alkylmercapto, sulfur-containing C1-C3heteroalkyl, hydroxy, oxygen-containing C1-C3heteroalkyl, aminyl, C1-C3alkylaminyl, nitrogen-containing C1-C3heteroalkyl, C1-C3carboxyl, C2-C3ester, C1-C3amide, ureido, cyano, and ureido substituted with 0, 1, 2, or 3 halogen-substituted C1-C3alkyl; (3) unsubstituted or substituted biphenyl; wherein the substitution is mono-, di-, or tri-substitution; wherein the substituents are selected from the group consisting of halogen, C1-C3alkyl substituted with 1, 2, or 3 halogens, C1-C3alkoxy, C1-C3alkoxy substituted with 1, 2, or 3 halogens, C1-C3alkylmercapto, sulfur-containing C1-C3heteroalkyl, hydroxy, oxygen-containing C1-C3heteroalkyl, aminyl, nitrogen-containing C1-C3heteroalkyl, C1-C3alkylaminyl, C1-C3carboxyl, C2-C3ester, C1-C3amide, ureido, cyano, and ureido substituted with 0, 1, 2, or 3 halogen-substituted C1-C3alkyl; (4) unsubstituted or substituted naphthyl; wherein the substitution is mono-, di-, or tri-substitution; wherein the substituents are selected from the group consisting of halogen, C1-C3alkyl substituted with 1, 2, or 3 halogens, C1-C3alkoxy, C1-C3alkoxy substituted with 1, 2, or 3 halogens, C1-C3alkylmercapto, sulfur-containing C1-C3heteroalkyl, hydroxy, oxygen-containing C1-C3heteroalkyl, aminyl, C1-C3alkylaminyl, nitrogen-containing C1-C3heteroalkyl, C1-C3carboxyl, C2-C3ester, C1-C3amide, ureido, cyano, and ureido substituted with 0, 1, 2, or 3 halogen-substituted C1-C3alkyl; a group selected from the group consisting of: (1) substituted phenyl; wherein the substitution is mono-, di- or tri-substitution; and the substituents are selected from the group consisting of halogen, C1-C3alkyl substituted with 1, 2 or 3 halogen, C1-C3alkoxy, C1-C3alkoxy substituted with 1, 2 or 3 halogen, C1-C4alkylamino, wherein, in the case of mono-substitution, the substituents are selected from the group consisting of halogen, C2-C3alkyl, C1-C3alkyl substituted with 1, 2 or 3 halogen, C1-C3alkoxy, C1-C3alkylamino, C3-C8cycloalkyl, C1-C3alkylmercapto, C1-C3heteroalkyl containing sulfur, C1-C3sulfoxide, C1-C3sulfone and cyano; (2) substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl; wherein the substitution is mono-, di- or tri-substitution; and the substituents are selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkyl substituted with 1, 2 or 3 halogen, C1-C3alkoxy, C1-C3alkoxy substituted with 1, 2 or 3 halogen, C1-C4alkylamino, C1-C3alkylmercapto, C1-C3heteroalkyl containing sulfur, C1-C3sulfoxide, C1-C3sulfone and cyano; If in the case of mono-substitution, the substituents are preferably selected from the group consisting of halogen, C1-C3alkoxy and cyano; If in the case of di-substitution, the substituents are preferably selected from the group consisting of halogen, C1-C3alkoxy and cyano; If in the case of tri-substitution, the substituents are preferably selected from the group consisting of halogen, C1-C3alkoxy, C1-C3alkylmercapto and cyano; said C1-C3heteroalkyl containing sulfur is an alkyl chain containing one S heteroatom which can replace a C atom in the alkyl chain at a position allowed by the normal valency, and the S atom is not directly connected to the group being substituted; said C1-C3heteroalkyl containing oxygen is an alkyl chain containing one O heteroatom which can replace a C atom in the alkyl chain at a position allowed by the normal valency, and the O atom is not directly connected to the group being substituted; said C1-C3heteroalkyl containing nitrogen is an alkyl chain containing one N heteroatom which can replace a C atom in the alkyl chain at a position allowed by the normal valency, and the N atom is not directly connected to the group being substituted; Scheme 2, R1is selected from the group consisting of hydroxyl; R2is selected from the group consisting of: (1) substituted phenyl; wherein the substitution is mono-, di-, tri- or tetra-substitution, and the substituents are selected from the group consisting of halogen, C1-C5alkyl substituted with 1-3 halogen, C1-C3alkoxy, C1-C3alkoxy substituted with 1, 2 or 3 halogen, C1-C3alkyl, C1-C3heteroalkyl containing sulfur and C1-C3amide; (2) substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl; wherein the substitution is mono-, di- or tri-substitution, and the substituents are selected from the group consisting of halogen, C1-C3alkyl substituted with 1, 2 or 3 halogen, C1-C3alkoxy, C1-C3alkoxy substituted with 1, 2 or 3 halogen and C1-C3amide; (3) unsubstituted or substituted biphenyl; wherein substitution is mono-, di-, or tri-substitution; and wherein the substituents are selected from the group consisting of halogen, C1-C3 alkyl substituted with 1, 2, or 3 halogens, C1-C3 alkoxy, C1-C3 alkoxy substituted with 1, 2, or 3 halogens, and C1-C3 amido; (4) unsubstituted or substituted naphthyl; wherein substitution is mono-, di-, or tri-substitution; and wherein the substituents are selected from the group consisting of halogen, C1-C3 alkyl substituted with 1, 2, or 3 halogens, C1-C3 alkoxy, C1-C3 alkoxy substituted with 1, 2, or 3 halogens, and C1-C3 amido; a group selected from the group consisting of: (1) substituted phenyl; wherein substitution is mono-, di-, or tri-substitution; and wherein the substituents are selected from the group consisting of halogen, cyano, C1-C6 alkylthio, and C1-C3 alkyl substituted with 1, 2, or 3 halogens, wherein, when mono-substituted, the substituent is selected from the group consisting of halogen and cyano; (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl; wherein substitution is mono-, di-, or tri-substitution; and wherein the substituents are halogen; Scheme 3, wherein n1 is 0 or 1; R1 is selected from hydrogen, hydroxyl, amino, mercapto, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylmercapto, halogen, C2-C6 ester group, and C groups substituted with 1-3 halogens. 2-6 Ester group, C2-C6 ester group substituted with hydroxyl group, C2-C6 ester group substituted with amino group and carboxyl group; R2 is selected from the group consisting of: (1) unsubstituted or substituted phenyl; wherein substitution is mono-, di-, tri-, or tetra-substitution, and wherein the substituents are selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkyl substituted with 1-3 halogens, C1-C6 alkoxy, C1-C6 alkoxy substituted with 1, 2, or 3 halogens, C1-C3 heteroalkyl containing sulfur, C1-C6 alkylthio, C1-C6 sulfoxide, C1-C6 sulfone, hydroxyl, cyano, nitro, ureido, C1-C6 heteroalkyl containing oxygen, amine, C1-C6 heteroalkyl containing nitrogen, C1-C6 alkylamine, C1-C6 carboxyl, C2-C6 ester, and ureido substituted with 0, 1, 2, or 3 halogens substituted C1-C6 alkyl; (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein substitution is mono-, di-, or tri-substitution, and wherein the substituents are selected from the group consisting of halogen, C1-C6 alkyl, cyano, ureido, nitro, C1-C6 alkyl substituted with 1, 2, or 3 halogens, C1-C6 alkoxy, C1-C6 alkoxy substituted with 1, 2, or 3 halogens, C1-C3 heteroalkyl containing sulfur, C1-C6 alkylthio, C1-C6 sulfoxide, C1-C6 sulfone, hydroxyl, C1-C6 heteroalkyl containing oxygen, amine, C1-C6 heteroalkyl containing nitrogen, C1-C6 alkylamine, C1-C6 carboxyl, C2-C6 ester, C1-C6 amide, and ureido substituted with 0, 1, 2, or 3 halogens substituted C1-C6 alkyl; (3) unsubstituted or substituted biphenyl; wherein substitution is mono, di, tri, tetra, penta, or octa substitution; and wherein the substituents are selected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2, or 3 halogen, C1-C6alkylmercapto, C1-C6sulfoxide, C1-C6sulfone, hydroxyl, oxygen-containing C1-C6heteroalkyl, aminyl, nitrogen-containing C1-C6heteroalkyl, C1-C6alkylaminyl, C1-C6carboxyl, C2-C6ester, C1-C6amide, and urea substituted with 0, 1, 2, or 3 C1-C6alkyl; (4) unsubstituted or substituted naphthyl; wherein substitution is mono, di, or tri substitution; and wherein the substituents are selected from the group consisting of halogen, cyano, nitro, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2, or 3 halogen, C1-C6alkylmercapto, C1-C6sulfoxide, C1-C6sulfone, hydroxyl, oxygen-containing C1-C6heteroalkyl, aminyl, nitrogen-containing C1-C6heteroalkyl, C1-C6alkylaminyl, C1-C6carboxyl, C2-C6ester, C1-C6amide, and urea substituted with 0, 1, 2, or 3 C1-C6alkyl; (5) C1-C6alkyl substituted with a carbonyl, wherein the carbonyl is -(C=O)R3, and wherein R3is selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1-3 halogen, hydroxyl, oxygen-containing C1-C6heteroalkyl, aminyl, and C1-C6alkylaminyl; selected from the group consisting of: (1) substituted phenyl; wherein substitution is mono, di, or tri substitution; and wherein the substituents are selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2, or 3 halogen, C1-C6alkylaminyl, C3-C8cycloalkyl, C1-C6alkylmercapto, C1-C6sulfoxide, C1-C6sulfone, and cyano; wherein the aminyl can be substituted with 0-3 C1-C6alkyl substituted with halogen; (2) unsubstituted or substituted pyridyl; wherein the pyridyl is selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl; wherein substitution is mono, di, or tri substitution; and wherein the substituents are selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkyl substituted with 1, 2, or 3 halogen, C1-C6alkoxy, C1-C6alkoxy substituted with 1, 2, or 3 halogen, C1-C6alkylaminyl, C1-C6alkylmercapto, C1-C6sulfoxide, C1-C6sulfone, and cyano; said sulfur-containing C1-C6heteroalkyl is an alkyl chain containing 1 S heteroatom, which S atom can replace a C atom in the alkyl chain at a position allowed by normal valence, and the S atom is not directly attached to a substituted group; said oxygen-containing C1-C6heteroalkyl is an alkyl chain containing 1 O heteroatom, which O atom can replace a C atom in the alkyl chain at a position allowed by normal valence, and the O atom is not directly attached to a substituted group; said nitrogen-containing C1-C6heteroalkyl is an alkyl group containing one N heteroatom, which N atom can be substituted for a C atom in the alkyl chain at any valence-allowed position, and the N atom is not directly attached to the group being substituted; Scheme 4, n1 is 0 or 1 ; R1 is selected from the group consisting of hydrogen, hydroxyl, and C2-C6 ester; R2 is selected from the group consisting of: (1) substituted phenyl; wherein substitution is mono, di, tri, or tetra substitution with substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkyl substituted with 1-3 halogens, C1-C6 alkoxy, C1-C6 alkylthiol, cyano, C2-C6 ester, and ureido substituted with C1-C6 alkyl; (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein substitution includes mono, di, or tri substitution with substituents selected from the group consisting of halogen, C1-C6 alkyl, cyano, C1-C6 alkyl substituted with 1, 2, or 3 halogens, and C2-C6 ester; (3) unsubstituted or substituted biphenyl; wherein substitution is mono, di, tri, tetra to octa substitution; substituents are selected from the group consisting of halogen and C1-C6 alkyl substituted with 1, 2, or 3 halogens; (4) unsubstituted or substituted naphthyl; wherein substitution is mono; wherein the substituent is C1-C6 alkoxy; (5) C1-C6 alkyl substituted with a carbonyl, wherein the carbonyl is -(C=O)R3, wherein R3 is C1-C6 alkylamino; selected from the group consisting of: (1) substituted phenyl; wherein substitution is mono, di, or tri substitution; substituents are selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkyl substituted with 1, 2, or 3 halogens, cyano, C1-C6 alkoxy, C1-C6 alkylamino, and C1-C6 alkylthiol; wherein the amine C1-C6 alkyl substitution; (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from 2-pyridyl, 3-pyridyl, and 4-pyridyl; wherein substitution is mono, di, or tri substitution; substituents are halogen; Scheme 5, n1 is 0 or 1 ; R1 is selected from the group consisting of hydrogen, hydroxyl, and C2-C6 ester; R2 is selected from the group consisting of: (1) substituted phenyl; wherein substitution is mono, di, tri, or tetra substitution with substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkyl substituted with 1-3 halogens, C1-C6 alkoxy, and ureido substituted with C1-C6 alkyl; (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein substitution is mono, di, or tri substitution with substituents selected from the group consisting of halogen and cyano; (3) unsubstituted or substituted biphenyl; wherein substitution includes mono, di, tri, tetra to octa substitution; substituents are halogen; (4) naphthyl; is substituted phenyl; wherein substitution is mono, di, or tri substitution; substituents are selected from the group consisting of halogen, cyano, C1-C6 alkyl, C1-C6 alkyl substituted with 1, 2, or 3 halogens, C1-C6 alkoxy, and C1-C6 alkylthiol; Scheme 6, n1 is 0 or 1 ; R1 is hydroxyl; R2 is selected from the group consisting of: (1) substituted phenyl; wherein substitution is mono-, di-, tri-, or tetra-substitution with substituents selected from the group consisting of halogen, cyano, C1-C6alkyl, C1-C6alkyl substituted with 1-3 halogens, and C1-C6alkoxy; (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein substitution is mono-, di-, or tri-substitution with halogen; (3) unsubstituted or substituted naphthyl; wherein substitution is mono-substitution with C1-C6alkoxy; is substituted phenyl; wherein substitution is mono-, di-, or tri-substitution; and substituents are selected from the group consisting of halogen and C1-C6alkoxy; Scheme 7, n1 is 0 or 1 ; R1 is hydroxy; R2 is selected from the group consisting of: (1) substituted phenyl; wherein substitution is mono-, di-, or tri-substitution with substituents selected from the group consisting of halogen, cyano, C1-C6alkyl, C1-C6alkyl substituted with 1-3 halogens, C1-C6alkylmercapto, and C1-C6alkoxy; (2) unsubstituted or substituted pyridyl; wherein pyridyl is selected from 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein substitution is mono-substitution with halogen; (3) unsubstituted or substituted biphenyl; wherein substitution is mono-substitution; and substituents are halogen; (4) unsubstituted or substituted naphthyl; wherein substitution is mono-substitution; and substituents are C1-C6alkoxy; is substituted phenyl; wherein substitution is mono-, di-, or tri-substitution; and substituents are selected from the group consisting of halogen, cyano, and C1-C6alkoxy.

6. The use according to claim 1, characterized in that, The compound of Formula I satisfies one or more of the following conditions: (1) R2is (2) R1is hydrogen, -OH, or and (3) For 7. The use according to claim 1, characterized in that, The compound of Formula I is any one of the following compounds:

8. Use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, or a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, for the manufacture of a medicament for the treatment of pain.

9. A compound of formula I according to any one of claims 1 to 7, which is not ###0002### and pharmaceutically acceptable salts thereof.

10. A pharmaceutical composition comprising (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof, according to claim 9; and (ii) a pharmaceutically acceptable carrier.

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