DEZOCINE DERIVATIVE AND MEDICAL USE THEREOF

Abstract

Provided are a dezocine derivative represented by Formula I, or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof, as well as a pharmaceutical composition containing the same, preparations thereof, and medical use thereof, and the structure of Formula I is as below:

##STR00001##

Claims

1. A compound represented by Formula I, or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof, ##STR00056## wherein R.sub.1 and R.sub.2 are each independently selected from H, C.sub.1-C.sub.12 aliphatic hydrocarbyl, C.sub.6-C.sub.14 aryl, C.sub.6-C.sub.14 aryl-C.sub.1-C.sub.12 aliphatic hydrocarbyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkyl-C.sub.1-C.sub.12 aliphatic hydrocarbyl, five- to fourteen-membered heteroaryl, or five- to fourteen-membered heteroaryl-C.sub.1-C.sub.12 aliphatic hydrocarbyl, wherein the C.sub.6-C.sub.14 aryl, the C.sub.3-C.sub.8 cycloalkyl, and the five- to fourteen-membered heteroaryl are optionally substituted with one or more halogens, —OH groups, C1-C12 aliphatic hydrocarbyl groups, C.sub.1-C.sub.12 aliphatic hydrocarbyl oxyl groups, or C.sub.1-C.sub.12 aliphatic hydrocarbyl-S— groups; or wherein R.sub.1, R.sub.2 and N connected thereto together form a N-containing four- to six-membered ring, and the N-containing four- to six-membered ring is optionally substituted by one or more halogens, —OH groups, C1-C12 aliphatic hydrocarbyl groups, C.sub.1-C.sub.12 aliphatic hydrocarbyl oxyl groups, or C.sub.1-C.sub.12 aliphatic hydrocarbyl-S— groups; R.sub.3 is selected from H, C.sub.1-C.sub.12 aliphatic hydrocarbyl, C.sub.6-C.sub.14 aryl, C.sub.6-C.sub.14 aryl-C.sub.1-C.sub.12 aliphatic hydrocarbyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkyl-C.sub.1-C.sub.12 aliphatic hydrocarbyl, five- to fourteen-membered heteroaryl, or five- to fourteen-membered heteroaryl-C.sub.1-C.sub.12 aliphatic hydrocarbyl, wherein the C.sub.6-C.sub.14 aryl, the C.sub.3-C.sub.8 cycloalkyl, and the five- to fourteen-membered heteroaryl are optionally substituted by one or more halogens, C.sub.1-C.sub.12 aliphatic hydrocarbyl groups, C.sub.1-C.sub.12 aliphatic hydrocarbyl oxyl groups, or C.sub.1-C.sub.12 aliphatic hydrocarbyl-S— groups; R.sub.4 is selected from H, OH, halogen, C.sub.1-C.sub.12 aliphatic hydrocarbyl, C.sub.1-C.sub.12 aliphatic hydrocarbyl oxyl, or C.sub.1-C.sub.12 aliphatic hydrocarbyl-S—; at least one of R.sub.1, R.sub.2, or R.sub.3 is not H; A is selected from O or S; and n is selected from 0, 1 or 2.

2. The compound represented by Formula I, or the tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R.sub.1 and R.sub.2 are each independently selected from H, C.sub.1-C.sub.12 aliphatic hydrocarbyl, C.sub.6-C.sub.14 aryl-C.sub.1-C.sub.6 aliphatic hydrocarbyl, C.sub.3-C.sub.8 cycloalkyl, or C.sub.3-C.sub.8 cycloalkyl-C.sub.1-C.sub.6 aliphatic hydrocarbyl, wherein the C.sub.6-C.sub.14 aryl and the C.sub.3-C.sub.8 cycloalkyl are optionally substituted by one or more halogens, —OH groups, C.sub.1-C.sub.6 aliphatic hydrocarbyl groups, C.sub.1-C.sub.6 aliphatic hydrocarbyl oxyl groups, or C.sub.1-C.sub.6 aliphatic hydrocarbyl-S— groups; or, R.sub.1, R.sub.2 and N connected thereto together form a N-containing four- to six-membered ring; R.sub.3 is selected from H, C.sub.1-C.sub.6 aliphatic hydrocarbyl, or C.sub.6-C.sub.14 aryl-C.sub.1-C.sub.12 aliphatic hydrocarbyl, wherein the C.sub.6-C.sub.14 aryl is optionally substituted by one or more halogens, C.sub.1-C.sub.6 aliphatic hydrocarbyl groups, C.sub.1-C.sub.6 aliphatic hydrocarbyl oxyl groups, or C.sub.1-C.sub.6 aliphatic hydrocarbyl-S— groups; R.sub.4 is selected from C.sub.1-C.sub.6 aliphatic hydrocarbyl, C.sub.1-C.sub.6 aliphatic hydrocarbyl oxyl, or C.sub.1-C.sub.6 aliphatic hydrocarbyl-S—; at least one of R.sub.1, R.sub.2, or R.sub.3 is not H; A is selected from O or S; and n is selected from 1 or 2.

3. The compound represented Formula I, or the tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R.sub.1 and R.sub.2 are each independently selected from H, C.sub.1-C.sub.12 alkyl, C.sub.6-C.sub.14 aryl-C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, or C.sub.3-C.sub.8 cycloalkyl-C.sub.1-C.sub.6 alkyl, wherein the C.sub.6-C.sub.14 aryl and the C.sub.3-C.sub.8 cycloalkyl are optionally substituted by one or more halogens, C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 alkoxyl groups, or C.sub.1-C.sub.6 alkyl-S— groups; or, R.sub.1, R.sub.2 and N connected thereto together form a N-containing five-membered ring; R.sub.3 is selected from H, C.sub.1-C.sub.6 alkyl, or C.sub.6-C.sub.14 aryl-C.sub.1-C.sub.12 alkyl, wherein the C.sub.6-C.sub.14 aryl is optionally substituted by one or more halogens, C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 alkoxyl groups, or C.sub.1-C.sub.6 alkyl-S— groups; R.sub.4 is selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxyl, or C.sub.1-C.sub.6 alkyl-S—; at least one of R.sub.1, R.sub.2, or R.sub.3 is not H; A is O; and n is 1.

4. The compound represented by Formula I, or the tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein the C.sub.1-C.sub.12 aliphatic hydrocarbyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentenyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 1-ethylvinyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, or 1-hexynyl; the halogen is selected from F, Cl, Br, or I; the aryl is selected from phenyl or naphthyl; the C.sub.3-C.sub.8 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; the N-containing four- to six-membered ring is selected from ethylenimine, pyrrolidine, piperidine, piperazine, morpholine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, or pyridazine; and the pharmaceutically acceptable salt is selected from hydrochlorides.

5. The compound represented by Formula I, or the tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein a structure of Formula I comprises a structure of Formula II below: ##STR00057##

6. The compound represented by Formula I, or the tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein the compound represented by Formula I comprises the following structures: ##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062##

7. A preparation method of the compound represented by Formula I, or the tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, the preparation method being selected from the following synthesis schemes: ##STR00063## the scheme 1 comprising: compound M-1 reacting with an aldehyde R.sub.aCHO to obtain an intermediate T-1; and obtaining the compound represented by Formula I through a reduction of the intermediate T-1, wherein in the scheme 1, R.sub.1, R.sub.2, R.sub.3, R.sub.4, A, and n are those as defined in the Formula I, except that at least one of R.sub.1 or R.sub.2 is not H; R.sub.aCHO is an aldehyde compound corresponding to substitutes R.sub.1 and R.sub.2 to be introduced in the target compound represented by Formula I, and allows a mono-substitution or di-substitution reaction with N, wherein when neither of R.sub.1 nor R.sub.2 is H, a disubstituted product is obtained correspondingly; and when one of R.sub.1 and R.sub.2 is H, a monosubstituted product is obtained correspondingly; ##STR00064## the scheme 2 comprising: compound M-2 reacting with an aldehyde R.sub.bCHO to obtain an intermediate T-2; and obtaining the compound represented by Formula I through a reduction of the intermediate T-2, wherein in the scheme 2, R.sub.1, R.sub.2, R.sub.3, R.sub.4, A, and n are those as defined in the Formula I, except that neither R.sub.1 nor R.sub.2 is H; R.sub.bCHO is an aldehyde compound corresponding to R.sub.2 to be introduced in the target compound represented by Formula I; ##STR00065## the scheme 3 comprising: compound M-3 reacting with compound X(CH.sub.2).sub.mX to obtain a compound represented by Formula I-1, wherein in the scheme 3, R.sub.3, R.sub.4, A, and n are those as defined in the Formula I, m is from 3 to 5; and X is F, Cl, Br, or I; ##STR00066## the scheme 4 comprising: compound M-4 reacting with HX to obtain a compound represented by Formula I-2, wherein in the scheme 4, R.sub.1, R.sub.2, R.sub.3, R.sub.4, A, and n are those as defined in the Formula I, except that R.sub.3 is not H; and X is F, Cl, Br, or I; and ##STR00067## the scheme 5 comprising: compound M-5 reacting with an amino-protecting agent to obtain an amino-protected intermediate T-3; T-3 reacting with R.sub.3X to obtain an intermediate T-4; and obtaining the compound represented by Formula I by completely deprotecting T-4, or obtaining a N-methylated product of the compound represented by Formula I from T-4 in presence of a reducing agent B, wherein in the scheme 5, R.sub.3, R.sub.4, A, and n are those as defined in the Formula I, except that R.sub.3 is not H; X is F, Cl, Br, or I; and G is an amino-protecting agent.

8. A pharmaceutical composition, comprising: the compound represented by Formula I, or the tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1; and optionally, a second therapeutic agent, wherein the second therapeutic agent comprises MOR antagonists such as naloxone, naltrexone, tramadol, and samidorphan.

9. Use of the compound represented by Formula I, or the tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 in manufacture of a medicament for treating opioid receptor-related disorders, wherein the disorders comprise pain, hyperalgesia, and cardiovascular and cerebrovascular diseases; further, the disorders are pain, such as neuropathic pain or nociceptive pain; specific types of the pain comprise, but are not limited to, acute pain, chronic pain, postoperative pain, neuralgia-caused pain such as postherpetic neuralgia-caused pain or trigeminal neuralgia-caused pain, diabetic neuropathy-caused pain, toothache, arthritis- or osteoarthritis-associated pain, and pain associated with cancer or treatment thereof.

10. Use of the compound represented by Formula I, or the tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 in manufacture of a medicament for treating depression-related diseases and symptoms, wherein the depression-related diseases and symptoms comprise acute stress disorder, low mood adjustment disorder, Asperger's syndrome, attention deficit, bipolar disorder, borderline personality disorder, circulatory disorders, depression such as major depressive disorder (MDD) and treatment-resistant depression (TRD), dysthymic disorder, hyperactivity disorder, impulse control disorder, mixed mania, obsessive-compulsive personality disorder (OCD), paranoia, post-traumatic stress disorder, seasonal affective disorder, self-harm separation, sleep disorders, substance-induced emotional disorders.

Description

DESCRIPTION OF EMBODIMENTS

[0095] The preparation methods of the present disclosure will be further described in detail below in conjunction with specific examples. It should be understood that the following examples are only illustrative to explain the present disclosure, and should not be construed as limiting the scope of protection of the present disclosure. The techniques achieved by the above content of the present disclosure are all included within the scope of the present disclosure to be protected. The experimental methods used in the following examples are conventional methods unless otherwise specified. Reagents, materials and the like used in the following examples without special instructions can be obtained from commercial channels.

Example 1: Preparation of Compound 1

[0096] ##STR00015##

[0097] O-methyl dezocine (1-1, 0.732 mmol) was dissolved in 5 ml methanol, then a HCHO solution (0.805 mmol), NaBH.sub.3CN (1.464 mmol) and acetic acid (0.2 ml) were sequentially added, and the mixture reacted at room temperature overnight. After the completion of massive reaction of the raw materials was monitored by TLC, ammonia water was added dropwise until pH=9. The solution was diluted with 30 ml ethyl acetate and separated, the aqueous phase was washed with ethyl acetate (30 ml), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and subjected to column chromatography (DCM/MeOH=200:1) to obtain the target compound 1 (light yellow oily liquid, 120 mg, 60%).

[0098] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.01 (d, J=8.4 Hz, 1H), 6.77 (d, J=2.5 Hz, 1H), 6.70 (dd, J=8.4, 2.7 Hz, 1H), 3.80 (d, J=0.6 Hz, 3H), 3.05 (dd, J=16.5, 7.0 Hz, 1H), 2.69 (dd, J=10.7, 5.6 Hz, 2H), 2.60-2.32 (m, 4H), 1.97 (t, J=13.3 Hz, 1H), 1.77-1.34 (m, 11H), 1.10-0.73 (m, 3H). Ms(m/z): 274.2 [M+H].

[0099] Example 2 to Example 10: Target compounds 2 to 10 were obtained by referring to the synthesis method of compound 1.

TABLE-US-00001 Compound No. Structural formula Spectrogram Compound 2 [00016] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.99 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 6.69 (dd, J = 8.4, 2.6 Hz, 1H), 3.79 (s, 3H), 3.04 (dd, J = 16.3, 7.1 Hz, 1H), 2.92 (s, 1H), 2.79 (s, 1H), 2.67 (d, J = 16.5 Hz, 1H), 2.56 (s, 1H), 2.49-2.32 (m, 1H), 2.00 (t, J = 13.4 Hz, 1H), 1.76-1.31 (m, 10H), 1.18-0.69 (m, 7H). Ms (m/z): 288.2 [M + H] Compound 3 [00017] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.99 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 6.68 (dd, J = 8.3, 2.6 Hz, 1H), 3.79 (s, 3H), 3.03 (dd, J = 16.3, 7.0 Hz, 1H), 2.89-2.70 (m, 2H), 2.66 (d, J = 16.3 Hz, 1H), 2.55-2.34 (m, 2H), 2.00 (t, J = 13.4 Hz, 1H), 1.77-1.43 (m, 8H), 1.38 (s, 3H), 1.14-0.74 (m, 7H). Ms (m/z): 302.2 [M + H] Compound 4 [00018] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.99 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 6.68 (dd, J = 8.4, 2.6 Hz, 1H), 3.79 (s, 3H), 3.03 (dd, J = 16.3, 6.9 Hz, 1H), 2.93-2.73 (m, 2H), 2.66 (d, J = 16.3 Hz, 1H), 2.54-2.37 (m, 2H), 1.99 (t, J = 13.5 Hz, 1H), 1.73-1.34 (m, 15H), 0.90 (dt, J = 25.0, 10.2 Hz, 6H). Ms (m/z): 316.2 [M + H] Compound 5 [00019] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.01 (dd, J = 12.3, 7.4 Hz, 1H), 6.81-6.74 (m, 1H), 6.72-6.64 (m, 1H), 3.83-3.72 (m, 3H), 3.13-2.95 (m, 1H), 2.85 (s, 1H), 2.77 (s, 1H), 2.66 (d, J = 16.2 Hz, 1H), 2.46 (dd, J = 25.8, 5.2 Hz, 2H), 1.99 (t, J = 12.5 Hz, 1H), 1.65 (s, 3H), 1.55 (s, 4H), 1.38 (d, J = 4.9 Hz, 8H), 1.07 (s, 1H), 0.93 (d, J = 5.6 Hz, 6H). Ms (m/z): 330.2 [M + H] Compound 6 [00020] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.99 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 2.6 Hz, 1H), 6.68 (dd, J = 8.4, 2.7 Hz, 1H), 3.79 (s, 3H), 3.07-2.85 (m, 2H), 2.81 (s, 1H), 2.67 (d, J = 16.6 Hz, 1H), 2.39 (s, 1H), 1.95 (d, J = 13.1 Hz, 1H), 1.75-1.37 (m, 6H), 1.36 (s, 3H), 1.14 (d, J = 6.0 Hz, 3H), 1.07-0.66 (m, 8H). Ms (m/z): 302.2 [M + H] Compound 7 [00021] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.10 (d, J = 8.3 Hz, 1H), 6.90 (s, 1H), 6.80 (d, J = 8.3 Hz, 1H), 3.89 (s, 3H), 3.12 (dt, J = 30.1, 15.1 Hz, 1H), 2.93 (d, J = 4.6 Hz, 1H), 2.86-2.57 (m, 3H), 2.51 (s, 1H), 2.16 (t, J = 13.3 Hz, 1H), 1.88-1.66 (m, 5H), 1.65-1.55 (m, 1H), 1.53 (s, 3H), 1.18 (ddd, J = 26.1, 22.0, 14.2 Hz, 3H), 1.09-0.91 (m, 2H), 0.61 (t, J = 8.4 Hz, 2H), 0.36-0.20 (m, 2H). Ms (m/z): 314.2 [M + H] Compound 8 [00022] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.29 (q, J = 7.9 Hz, 4H), 7.24- 7.17 (m, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.74 (s, 1H), 6.66 (d, J = 8.2 Hz, 1H), 3.77 (d, J = 6.7 Hz, 3H), 3.11 (dd, J = 16.7, 7.0 Hz, 1H), 2.99 (dd, J = 16.3, 6.8 Hz, 1H), 2.87 (qd, J = 13.2, 6.4 Hz, 2H), 2.81-2.72 (m, 2H), 2.62 (d, J = 16.4 Hz, 1H), 2.37 (s, 1H), 1.99-1.86 (m, 1H), 1.64 (dd, J = 14.9, 6.7 Hz, 1H), 1.59-1.48 (m, 2H), 1.43 (dd, J = 13.0, 7.6 Hz, 4H), 1.32 (d, J = 7.1 Hz, 3H), 0.83 (d, J = 12.3 Hz, 3H). Ms (m/z): 364.3 [M + H] Compound 9 [00023] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.52 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 6.76 (d, J = 8.3 Hz, 1H), 4.14 (d, J = 12.9 Hz, 1H), 3.85 (s, 3H), 3.77 (d, J = 12.9 Hz, 1H), 3.10 (dd, J = 16.4, 6.8 Hz, 1H), 2.94 (d, J = 4.7 Hz, 1H), 2.75 (d, J = 16.4 Hz, 1H), 2.59 (s, 1H), 2.10 (t, J = 13.4 Hz, 1H), 1.87-1.72 (m, 3H), 1.67 (s, 3H), 1.56 (dd, J = 14.0, 6.4 Hz, 1H), 1.45 (s, 3H), 1.16 (s, 1H), 1.08-0.86 (m, 2H). Ms (m/z): 350.3 [M + H] Compound 10 [00024] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.44-7.34 (m, 2H), 7.12 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 6.68 (d, J = 8.3 Hz, 1H), 3.79 (s, 3H), 3.12 (s, 1H), 3.01 (dd, J = 16.3, 6.7 Hz, 1H), 2.89-2.70 (m, 4H), 2.65 (d, J = 16.3 Hz, 1H), 2.38 (s, 1H), 1.91 (t, J = 13.2 Hz, 1H), 1.73-1.62 (m, 1H), 1.49 (dt, J = 29.7, 14.1 Hz, 6H), 1.33 (s, 3H), 0.94-0.81 (m, 3H). Ms (m/z): 432.2 [M + H]

Example 11: Synthesis of Compound 11

[0100] ##STR00025##

[0101] O-methyl dezocine (1-1, 0.732 mmol) was dissolved in 5 ml methanol, then a HCHO solution (7.32 mmol), NaBH.sub.3CN (1.464 mmol) and acetic acid (0.2 ml) were sequentially added, and the mixture reacted at room temperature overnight. After the completion of massive reaction of the raw materials was monitored by TLC, ammonia water was added dropwise until pH=9. The solution was diluted with 30 ml ethyl acetate and separated, the aqueous phase was washed with ethyl acetate (30 ml), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and subjected to column chromatography (DCM/MeOH=200:1) to obtain the target compound 11 (light yellow oily liquid, 155 mg, 74%).

[0102] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.96 (d, J=8.3 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 6.67 (dd, J=8.3, 2.3 Hz, 1H), 3.79 (s, 3H), 3.08 (dd, J=16.1, 6.4 Hz, 1H), 2.68-2.42 (m, 9H), 2.24 (t, J=13.6 Hz, 1H), 1.95 (t, J=12.7 Hz, 1H), 1.84-1.66 (m, 2H), 1.66-1.35 (m, 6H), 1.25 (dd, J=21.8, 11.0 Hz, 1H), 1.08 (dd, J=24.9, 12.1 Hz, 1H), 0.74 (dd, J=23.6, 11.3 Hz, 1H). Ms(m/z): 288.2 [M+H].

Example 12: Synthesis of Compound 12

[0103] ##STR00026##

[0104] O-methyl dezocine (1-1, 0.732 mmol), 1,4-diiodine (2.928 mmol), and NaHCO.sub.3(5.124 mmol) were dissolved in 20 ml acetonitrile, refluxed overnight, and filtered after the completion of the reaction of the raw material was monitored by TLC. The solvent was removed through rotary evaporation. The remained solution was diluted with 20 ml of ethyl acetate, followed by dropwise addition of ammonia water to PH=9, dilution with 30 ml of ethyl acetate, and separation. The aqueous phase was washed with ethyl acetate (30 ml), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and subjected to column chromatography (PE-PE/EA=100:1) to obtain the target compound 12 (light yellow oily liquid, 160 mg, 70%).

[0105] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.95 (d, J=8.4 Hz, 1H), 6.80 (s, 1H), 6.67 (d, J=8.2 Hz, 1H), 3.80 (s, 3H), 3.21 (s, 1H), 2.98 (d, J=16.8 Hz, 1H), 2.72 (d, J=27.3 Hz, 3H), 2.58-2.36 (m, 3H), 2.27 (t, J=12.7 Hz, 1H), 1.95 (s, 1H), 1.78 (d, J=28.0 Hz, 4H), 1.68-1.37 (m, 8H), 1.26 (s, 1H), 1.23-1.03 (m, 1H), 0.89 (s, 1H). Ms(m/z): 314.2 [M+H].

Example 13: Synthesis of Compound 13

[0106] ##STR00027##

[0107] Compound 8 (0.2 mmol) was dissolved in 5 ml methanol, then a HCHO solution (1 mmol), NaBH.sub.3CN (0.4 mmol) and acetic acid (0.2 ml) were added successively, and the mixture reacted at room temperature overnight. After the completion of massive reaction of the raw materials was monitored by TLC, ammonia water was added dropwise until pH=9. The solution was diluted with 30 ml of ethyl acetate and separated, the aqueous phase was washed with ethyl acetate (30 ml), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and subjected to column chromatography (DCM/MeOH=200:1) to obtain the target compound 13 (light yellow oily liquid, 68 mg, 90%).

[0108] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.18 (t, J=7.4 Hz, 2H), 7.08 (dd, J=12.6, 6.9 Hz, 3H), 6.85 (d, J=8.3 Hz, 1H), 6.63 (s, 1H), 6.57 (d, J=8.3 Hz, 1H), 3.66 (s, 3H), 3.08 (ddd, J=22.9, 17.1, 7.2 Hz, 2H), 2.84-2.67 (m, 4H), 2.60 (s, 3H), 2.53-2.39 (m, 2H), 2.06-1.86 (m, 2H), 1.83-1.71 (m, 1H), 1.56 (d, J=15.8 Hz, 1H), 1.51-1.41 (m, 2H), 1.37 (dd, J=14.7, 8.0 Hz, 1H), 1.29 (s, 3H), 1.06 (q, J=12.4 Hz, 1H), 0.93 (t, J=12.8 Hz, 1H), 0.65 (q, J=11.7 Hz, 1H). Ms(m/z): 378.3 [M+H].

Example 14-17: Target Compounds 14 to 17 were Obtained by Referring to the Synthetic Method of Compound 13

[0109]

TABLE-US-00002 Compound No. Structural formula Spectrogram Compound 14 [00028] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.97 (d, J = 8.5 Hz, 1H), 6.71 (dd, J = 19.6, 4.7 Hz, 2H), 3.79 (s, 3H), 3.14 (s, 1H), 2.86 (s, 2H), 2.56 (d, J = 22.2 Hz, 5H), 2.17 (s, 1H), 2.03 (d, J = 13.5 Hz, 1H), 1.90 (s, 1H), 1.57 (s, 6H), 1.44 (d, J = 10.7 Hz, 4H), 1.12 (d, J = 61.2 Hz, 2H), 0.92 (s, 3H), 0.74 (d, J = 12.3 Hz, 1H). Ms (m/z): 316.3 [M + H] Compound 15 [00029] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.95 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 2.6 Hz, 1H), 6.69-6.63 (m, 1H), 3.78 (s, 3H), 3.13 (dd, J = 16.2, 7.0 Hz, 1H), 2.88 (d, J = 12.3 Hz, 2H), 2.57 (t, J = 18.6 Hz, 6H), 2.20-1.94 (m, 2H), 1.95- 1.82 (m, 1H), 1.76-1.28 (m, 13H), 1.19-1.07 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H), 0.73 (dd, J = 25.5, 11.4 Hz, 1H). Ms (m/z): 316.3 [M + H] Compound 16 [00030] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.97 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.68 (dd, J = 8.3, 2.5 Hz, 1H), 3.79 (s, 3H), 3.14 (dd, J = 16.2, 6.9 Hz, 1H), 2.97-2.80 (m, 2H), 2.65-2.48 (m, 6H), 2.10 (dt, J = 39.7, 13.7 Hz, 2H), 1.95-1.82 (m, 1H), 1.69 (d, J = 15.8 Hz, 1H), 1.63- 1.52 (m, 3H), 1.48 (dd, J = 14.5, 7.4 Hz, 2H), 1.43- 1.37 (m, 3H), 1.37-1.26 (m, 4H), 1.19 (dd, J = 23.7, 12.7 Hz, 1H), 1.02 (dd, J = 25.1, 12.8 Hz, 1H), 0.92 (t, J = 7.0 Hz, 3H), 0.75 (dd, J = 25.4, 11.6 Hz, 1H). Ms (m/z): 344.3 [M + H] Compound 17 [00031] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.53 (d, J = 7.3 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.3, 2.2 Hz, 1H), 4.35 (d, J = 13.6 Hz, 1H), 3.86 (d, J = 5.5 Hz, 3H), 3.82 (d, J = 13.7 Hz, 1H), 3.25 (dd, J = 16.1, 6.9 Hz, 1H), 3.10 (d, J = 3.5 Hz, 1H), 2.71 (d, J = 15.9 Hz, 2H), 2.54 (s, 3H), 2.42-2.26 (m, 1H), 2.18 (t, J = 13.5 Hz, 1H), 2.09-1.94 (m, 1H), 1.84 (dd, J = 15.5, 3.7 Hz, 1H), 1.66 (d, J = 6.9 Hz, 2H), 1.62 (s, 1H), 1.60 (d, J = 8.0 Hz, 3H), 1.36 (d, J = 9.6 Hz, 1H), 1.18 (dq, J = 38.9, 13.0 Hz, 2H). Ms (m/z): 364.3 [M + H]

Example 18: Synthesis of Compound 18

[0110] ##STR00032##

[0111] Compound 1 (0.09 mmol) was dissolved in a 40% HBr aqueous solution (2 ml), heated to react under reflux conditions for 8 hours until the complete conversion of the raw material. Most of the HBr was removed through rotary evaporation. The remained solution was diluted with 10 ml of ethyl acetate, adjusted to PH=9 with ammonia water in an ice bath, and separated. The aqueous phase was washed with EA (10 ml), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and subjected to column chromatography (DCM/MeOH=200:1) to obtain the target compound 18 (light yellow oily liquid, 20 mg, 85%).

[0112] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.93 (d, J=8.0 Hz, 1H), 6.75-6.61 (m, 2H), 5.22 (s, 1H), 3.04 (dd, J=16.7, 6.7 Hz, 1H), 2.88 (s, 1H), 2.69 (d, J=22.1 Hz, 4H), 2.52 (s, 1H), 2.12-1.90 (m, 2H), 1.74 (s, 3H), 1.63-1.37 (m, 7H), 1.15 (d, J=10.1 Hz, 1H), 0.87 (s, 2H). Ms(m/z): 260.2 [M+H].

Example 19-34: Target Compounds 19 to 34 were Obtained by Referring to the Synthetic Method of Compound 18

[0113]

TABLE-US-00003 Compound No. Structural formula Spectrogram Compound 19 [00033] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.93 (d, J = 8.2 Hz, 1H), 6.70 (s, 1H), 6.61 (d, J = 7.9 Hz, 1H), 3.23 (s, 1H), 3.03 (dd, J = 16.4, 6.6 Hz, 2H), 2.83 (s, 1H), 2.63 (dd, J = 25.0, 13.6 Hz, 2H), 2.43 (s, 1H), 2.12-1.87 (m, 1H), 1.75-1.35 (m, 9H), 1.16 (dd, J = 21.7, 14.9 Hz, 5H), 0.86 (s, 2H). Ms (m/z): 274.2 [M + H] Compound 20 [00034] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.92 (d, J = 8.2 Hz, 1H), 6.70 (s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 3.76 (s, 1H), 3.02 (dd, J = 16.4, 6.9 Hz, 1H), 2.88- 2.73 (m, 2H), 2.65 (d, J = 16.5 Hz, 1H), 2.58- 2.39 (m, 2H), 2.07-1.92 (m, 1H), 1.75-1.45 (m, 8H), 1.37 (s, 3H), 1.27 (td, J = 7.0, 3.2 Hz, 1H), 1.15-0.73 (m, 6H). Ms (m/z): 288.2 [M + H] Compound 21 [00035] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.93 (d, J = 8.2 Hz, 1H), 6.70 (s, 1H), 6.62 (d, J = 8.1 Hz, 1H), 3.42 (s, 1H), 3.02 (dd, J = 16.5, 6.8 Hz, 1H), 2.90- 2.74 (m, 2H), 2.65 (d, J = 16.5 Hz, 1H), 2.57- 2.38 (m, 2H), 2.08-1.89 (m, 1H), 1.73-1.18 (m, 15H), 1.10-0.78 (m, 6H). Ms (m/z): 302.2 [M + H] Compound 22 [00036] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.93 (d, J = 8.1 Hz, 1H), 6.70 (s, 1H), 6.61 (d, J = 8.0 Hz, 1H), 4.13 (q, J = 7.0 Hz, 1H), 3.26 (s, 1H), 3.02 (dd, J = 16.3, 6.8 Hz, 1H), 2.95-2.81 (m, 1H), 2.78 (d, J = 4.1 Hz, 1H), 2.65 (d, J = 16.4 Hz, 1H), 2.52 (t, J = 12.3 Hz, 1H), 2.43 (s, 1H), 2.05 (s, 1H), 1.98 (t, J = 13.4 Hz, 1H), 1.65 (s, 3H), 1.55 (s, 4H), 1.36 (s, 7H), 1.26 (d, J = 3.1 Hz, 1H), 1.05 (d, J = 8.5 Hz, 1H), 0.90 (s, 4H). Ms (m/z): 316.2 [M + H] Compound 23 [00037] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.92 (d, J = 8.2 Hz, 1H), 6.71 (s, 1H), 6.62 (d, J = 8.0 Hz, 1H), 3.44-2.92 (m, 4H), 2.84 (d, J = 4.5 Hz, 1H), 2.65 (d, J = 16.4 Hz, 1H), 2.39 (s, 1H), 1.95 (t, J = 13.4 Hz, 1H), 1.74-1.42 (m, 6H), 1.35 (s, 3H), 1.27 (d, J = 10.4 Hz, 1H), 1.15 (d, J = 6.1 Hz, 3H), 1.03-0.74 (m, 6H). Ms (m/z): 288.2 [M + H] Compound 24 [00038] .sup.1H NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 9.01 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 10.3 Hz, 2H), 4.43 (s, 1H), 4.07 (d, J = 7.9 Hz, 2H), 4.03-3.94 (m, 1H), 3.81-3.71 (m, 1H), 3.09-2.90 (m, 2H), 2.56 (d, J = 16.9 Hz, 1H), 2.38 (s, 1H), 1.89-1.77 (m, 1H), 1.72 (d, J = 16.1 Hz, 2H), 1.43 (d, J = 21.9 Hz, 2H), 1.38 (s, 3H), 1.31 (d, J = 15.8 Hz, 3H), 1.10 (d, J = 6.5 Hz, 2H), 0.67 (dd, J = 38.9, 11.4 Hz, 2H). Ms (m/z): 300.2 [M + H] Compound 25 [00039] .sup.1H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 7.23 (d, J = 6.2 Hz, 4H), 7.14 (s, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.52 (s, 1H), 6.44 (d, J = 7.3 Hz, 1H), 2.97 (s, 1H), 2.79 (dd, J = 31.7, 16.4 Hz, 3H), 2.64 (s, 2H), 2.45 (s, 1H), 2.25 (s, 1H), 1.81 (t, J = 12.7 Hz, 1H), 1.52-1.26 (m, 8H), 1.17 (s, 3H), 0.69 (s, 2H). Ms (m/z): 350.2 [M + H] Compound 26 [00040] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.35 (d, J = 7.3 Hz, 2H), 7.25 (t, J = 7.3 Hz, 2H), 7.18 (d, J = 7.3 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.61 (s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 4.05 (q, J = 7.1 Hz, 1H), 3.99 (d, J = 12.9 Hz, 1H), 3.61 (d, J = 12.9 Hz, 1H), 3.27 (s, 1H), 2.92 (dd, J = 16.4, 6.6 Hz, 1H), 2.77 (d, J = 4.3 Hz, 1H), 2.57 (d, J = 16.4 Hz, 1H), 2.42 (s, 1H), 1.98 (s, 2H), 1.91 (t, J = 13.5 Hz, 1H), 1.58 (dt, J = 29.0, 21.5 Hz, 5H), 1.43- 1.31 (m, 1H), 1.24 (s, 3H), 0.98 (s, 1H). Ms (m/z): 336.2 [M + H] Compound 27 [00041] .sup.1H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 7.54 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.51 (s, 1H), 6.43 (d, J = 8.0 Hz, 1H), 2.95 (s, 1H), 2.81 (s, 1H), 2.74 (s, 2H), 2.62 (s, 2H), 2.46 (s, 1H), 2.23 (s, 1H), 1.80 (t, J = 12.6 Hz, 1H), 1.43 (s, 4H), 1.29 (d, J = 22.5 Hz, 4H), 1.23 (s, 1H), 1.16 (s, 3H), 0.69 (s, 1H). Ms (m/z): 418.2 [M + H] Compound 28 [00042] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.91 (d, J = 8.2 Hz, 1H), 6.74-6.49 (m, 2H), 5.16 (s, 1H), 3.09 (dd, J = 16.1, 6.6 Hz, 1H), 2.72-2.51 (m, 9H), 2.29-2.16 (m, 1H), 1.96 (t, J = 13.4 Hz, 1H), 1.88-1.69 (m, 2H), 1.64-1.40 (m, 6H), 1.32- 1.01 (m, 2H), 0.77 (dd, J = 23.3, 11.2 Hz, 1H). Ms (m/z): 274.2 [M + H] Compound 29 [00043] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.88 (d, J = 8.1 Hz, 1H), 6.73 (s, 1H), 6.58 (dd, J = 8.1, 1.9 Hz, 1H), 2.95 (dd, J = 15.7, 4.8 Hz, 1H), 2.70 (d, J = 26.2 Hz, 3H), 2.61-2.35 (m, 3H), 2.25 (t, J = 13.0 Hz, 1H), 1.86-1.34 (m, 13H), 1.29-1.22 (m, 1H), 1.11 (dd, J = 25.7, 12.2 Hz, 1H), 0.89 (d, J = 5.7 Hz, 1H). Ms (m/z): 300.2 [M + H] Compound 30 [00044] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.20 (t, J = 7.2 Hz, 2H), 7.15-7.07 (m, 3H), 6.81 (d, J = 8.2 Hz, 1H), 6.58 (s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 5.35- 3.29 (m, 1H), 3.08 (ddd, J = 22.5, 16.2, 7.0 Hz, 2H), 2.88-2.67 (m, 4H), 2.62 (s, 3H), 2.54- 2.39 (m, 2H), 1.97 (dt, J = 28.1, 13.6 Hz, 2H), 1.84-1.72 (m, 1H), 1.54 (d, J = 16.2 Hz, 1H), 1.51-1.43 (m, 2H), 1.41-1.32 (m, 1H), 1.28 (s, 3H), 1.07 (dd, J = 23.9, 12.6 Hz, 1H), 0.93 (q, J = 12.5 Hz, 1H), 0.75-0.60 (m, 1H). Ms (m/z): 364.2 [M + H] Compound 31 [00045] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.90 (d, J = 8.2 Hz, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 3.12 (s, 1H), 2.89 (s, 2H), 2.56 (d, J = 27.4 Hz, 4H), 2.19 (d, J = 19.1 Hz, 1H), 2.05-1.84 (m, 3H), 1.64 (d, J = 27.6 Hz, 11H), 1.25 (s, 2H), 0.92 (s, 3H), 0.82- 0.65 (m, 1H). Ms (m/z): 302.3 [M + H] Compound 32 [00046] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.90 (d, J = 8.3 Hz, 1H), 6.67 (s, 1H), 6.59 (d, J = 8.2 Hz, 1H), 3.12 (dd, J = 16.0, 6.8 Hz, 1H), 2.87 (d, J = 13.2 Hz, 2H), 2.68-2.51 (m, 6H), 2.20-1.96 (m, 3H), 1.99-1.81 (m, 2H), 1.58 (dd, J = 25.3, 14.3 Hz, 4H), 1.50-1.27 (m, 8H), 1.20-1.13 (m, 1H), 1.03 (s, 1H), 0.93 (dd, J = 8.1, 6.4 Hz, 3H), 0.82-0.66 (m, 1H). Ms (m/z): 316.3 [M + H] Compound 33 [00047] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.90 (d, J = 8.0 Hz, 1H), 6.69 (s, 1H), 6.61 (d, J = 8.0 Hz, 1H), 3.12 (dd, J = 15.9, 6.3 Hz, 1H), 2.87 (d, J = 13.4 Hz, 2H), 2.59 (s, 3H), 2.55 (d, J = 11.9 Hz, 3H), 2.09 (dt, J = 35.1, 13.4 Hz, 2H), 1.94-1.81 (m, 1H), 1.65 (d, J = 15.7 Hz, 1H), 1.56 (d, J = 9.4 Hz, 3H), 1.48 (dd, J = 13.5, 7.5 Hz, 2H), 1.38 (s, 3H), 1.36-1.25 (m, 5H), 1.22-1.11 (m, 1H), 1.10-0.99 (m, 1H), 0.92 (t, J = 6.2 Hz, 3H), 0.77 (q, J = 12.2 Hz, 1H). Ms (m/z): 330.3 [M + H] Compound 34 [00048] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.48 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.28 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 2.5 Hz, 1H), 6.64 (dd, J = 8.2, 2.5 Hz, 1H), 4.30 (d, J = 13.6 Hz, 1H), 3.77 (d, J = 13.7 Hz, 1H), 3.18 (dd, J = 16.2, 7.0 Hz, 1H), 3.04 (d, J = 3.7 Hz, 1H), 2.64 (d, J = 15.9 Hz, 2H), 2.50 (s, 3H), 2.29- 2.17 (m, 1H), 2.11 (dd, J = 18.5, 8.9 Hz, 1H), 2.00-1.89 (m, 1H), 1.74 (d, J = 15.4 Hz, 1H), 1.58 (dd, J = 17.2, 5.7 Hz, 3H), 1.51 (s, 3H), 1.30 (d, J = 8.3 Hz, 2H), 1.21-1.02 (m, 2H). Ms (m/z): 350.2 [M + H]

Example 35: Synthesis of Compound 35

[0114] ##STR00049##

[0115] Step 1: Synthesis of Compound 35-2

[0116] Dezocine (4.08 mmol) was dissolved in 10 ml of dichloromethane, DIPEA (12.24 mmol) was added, (Boc).sub.2O (4.50 mmol) dissolved in 5 ml of dichloromethane was added dropwise under an ice bath, followed by heating to room temperature to react overnight. The reaction solution was diluted with 50 ml dichloromethane, washed with 2N HCl (20 ml×2), washed with brine (10 ml), dried over anhydrous sodium sulfate, and subjected to column chromatography (PE/EA=100:1) to obtain compound 35-2 (light yellow oily liquid, 1.12 g, yield 80%).

[0117] Step 2: Synthesis of Compound 35-3

[0118] Compound 35-2 (1 mmol) was dissolved in 10 ml acetone, then potassium carbonate (1.2 mmol) and halogenated alkanes (1.1 mmol) were added, followed by refluxing overnight, cooling to room temperature, drying through rotary evaporation, and subjecting to column chromatography to obtain compound 35-3 (light yellow oily liquid, 316 mg, 80%).

[0119] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.99 (d, J=8.2 Hz, 1H), 6.73 (dd, J=28.4, 8.0 Hz, 2H), 4.95 (d, J=9.9 Hz, 1H), 4.04 (ddt, J=13.7, 11.2, 5.8 Hz, 3H), 3.18 (dd, J=16.2, 6.6 Hz, 1H), 2.62 (d, J=16.3 Hz, 1H), 2.31 (s, 1H), 1.89-1.21 (m, 25H), 0.95 (d, J=51.2 Hz, 3H). Ms(m/z): 396.2 [M+Na]

[0120] Step 3: Synthesis of Compound 35

[0121] Compound 35-3 (0.28 mmol) was dissolved in 5 ml DCM, TFA (1 ml) was added dropwise to react for 10 minutes, followed by removing TFA through rotary evaporation, dilution with 20 ml of EA, dropwise addition of ammonia to pH=9, and separation. The aqueous was washed with EA (20 ml×2), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain target compound 35 (light yellow oily liquid, 70 mg, 91%).

[0122] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.99 (d, J=8.3 Hz, 1H), 6.77 (d, J=2.1 Hz, 1H), 6.74-6.61 (m, 1H), 4.01 (dt, J=11.3, 5.7 Hz, 2H), 3.37-3.00 (m, 2H), 2.66 (d, J=16.6 Hz, 1H), 2.31 (s, 1H), 2.11-1.90 (m, 1H), 1.75 (s, 3H), 1.67-1.31 (m, 9H), 1.08 (s, 1H), 0.91-0.67 (m, 2H). Ms(m/z): 274.2 [M+H].

[0123] Compound 36-3 was obtained by referring to the synthesis method of compound 35-3.

TABLE-US-00004 Compound No. Structural formula Spectrogram Compound 36-3 [00050] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.44 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.3 Hz, 2H), 7.33 (d, J = 7.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.84-6.73 (m, 2H), 5.04 (d, J = 3.0 Hz, 2H), 4.94 (d, J = 10.0 Hz, 1H), 4.09 (dd, J = 10.2, 4.9 Hz, 1H), 3.18 (dd, J = 16.4, 6.8 Hz, 1H), 2.62 (d, J = 16.4 Hz, 1H), 2.31 (s, 1H), 1.89-1.53 (m, 5H), 1.46 (d, J = 20.9 Hz, 9H), 1.36- 1.20 (m, 5H), 0.99 (s, 3H). Ms (m/z): 458.2 [M + Na]

Example 36: Compound 36 was Obtained by Referring to the Synthesis Method of Compound 35

[0124]

TABLE-US-00005 Compound No. Structural formula Spectrogram Compound 36 [00051] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.55-7.27 (m, 5H), 7.00 (d, J = 8.3 Hz, 1H), 6.88-6.72 (m, 2H), 5.04 (s, 2H), 3.21- 2.91 (m, 2H), 2.65 (d, J = 16.6 Hz, 1H), 2.22 (s, 1H), 1.99 (dd, J = 28.0, 14.3 Hz, 1H), 1.80-1.32 (m, 11H), 1.09- 0.57 (m, 3H). Ms (m/z): 336.2 [M + H]

Example 37: Synthesis of Compound 37

[0125] ##STR00052##

[0126] Compound 35 (0.28 mmol) was dissolved in 5 ml THF, a solution of LiAlH.sub.4 in tetrahydrofuran (1M, 4 eq) was added dropwise under an ice bath, followed by heating to 60° C. to react overnight. Then, the reaction solution was cooled in an ice bath, water (10 ml) was added dropwise, 1N NaOH solution (10 ml) was added, diluted with 30 ml of EA, and separation. The aqueous phase was washed with EA (30 ml), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain target compound 37 (light yellow oily liquid, 56 mg, 69%).

[0127] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.86 (d, J=8.3 Hz, 1H), 6.63 (s, 1H), 6.55 (d, J=8.3 Hz, 1H), 4.04-3.74 (m, 2H), 2.91 (dd, J=16.5, 6.9 Hz, 1H), 2.64-2.48 (m, 2H), 2.45-2.32 (m, 4H), 1.82 (t, J=13.4 Hz, 1H), 1.66-1.18 (m, 13H), 1.02-0.54 (m, 3H). Ms(m/z): 288.2 [M+H].

Example 38: Compound 38 was Obtained by Referring to the Synthesis Method of Compound 37

[0128]

TABLE-US-00006 Compound No. Structural formula Spectrogram Compound 38 [00053] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.49-7.20 (m, 6H), 6.81- 6.57 (m, 2H), 5.14-4.85 (m, 2H), 3.00 (dd, J = 16.5, 7.0 Hz, 1H), 2.74-2.40 (m, 7H), 1.91 (t, J = 13.4 Hz, 2H), 1.71- 1.12 (m, 15H), 1.17-0.63 (m, 3H). Ms (m/z): 350.2 [M + H]

Example 39: Synthesis of Compound 39

[0129] ##STR00054##

[0130] Compound 38 (0.3 mmol) was dissolved in 5 ml methanol, then benzaldehyde (3 mmol), NaBH.sub.3CN (1.5 mmol) and acetic acid (0.2 ml) were added sequentially, and the mixture reacted at room temperature overnight. After the completion of massive reaction of the raw materials was monitored by TLC, ammonia water was added dropwise until pH=9. The solution was diluted with 30 ml of ethyl acetate and separated, the aqueous phase was washed with ethyl acetate (30 ml), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and subjected to column chromatography (PE/EA=200:1) to obtain the target compound 39 (light yellow oily liquid, 89 mg, 70%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.35 (dd, J=37.1, 31.4 Hz, 10H), 6.98 (s, 1H), 6.82 (s, 1H), 6.75 (s, 1H), 5.02 (s, 2H), 4.08 (d, J=11.7 Hz, 1H), 3.69 (d, J=12.5 Hz, 1H), 3.01 (d, J=15.9 Hz, 1H), 2.86 (s, 1H), 2.67 (d, J=16.9 Hz, 1H), 2.50 (s, 1H), 2.00 (s, 1H), 1.62 (d, J=43.5 Hz, 6H), 1.38 (d, J=33.2 Hz, 5H), 1.07 (s, 1H), 0.86 (d, J=33.1 Hz, 2H). Ms(m/z): 426.3 [M+H].

Example 40: Synthesis of Compound 40

[0131] ##STR00055##

[0132] Compound 39 (0.15 mmol) was dissolved in 5 ml methanol, then a HCHO solution (1 mmol), NaBH.sub.3CN (0.5 mmol) and acetic acid (0.2 ml) were added sequentially, and the mixture reacted at room temperature overnight. After the completion of massive reaction of the raw materials was monitored by TLC, ammonia water was added dropwise until pH=9. The solution was diluted with 30 ml ethyl acetate and separated, the aqueous phase was washed with ethyl acetate (30 ml), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and subjected to column chromatography (PE/EA=200:1) to obtain the target compound 40 (light yellow oily liquid, 40 mg, 60%).

[0133] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.57-7.26 (m, 10H), 6.98 (d, J=8.2 Hz, 1H), 6.86 6.62 (m, 2H), 5.14-4.91 (m, 2H), 4.27 (s, 1H), 3.77 (s, 1H), 3.09 (d, J=52.7 Hz, 2H), 2.64 (d, J=17.1 Hz, 2H), 2.47 (s, 2H), 2.23 (t, J=13.7 Hz, 1H), 2.07 (d, J=13.1 Hz, 1H), 1.97 (s, 1H), 1.73 (s, 1H), 1.51 (d, J=14.9 Hz, 6H), 1.26 (s, 1H), 1.13 (s, 1H), 1.05-0.72 (m, 2H). Ms(m/z): 440.3 [M+H]

Example 41: In Vitro Activity Assay

[0134] 1. Purpose

[0135] Through the radioisotope ligand competitive binding assay, IC50 of the compound was used as an indicator to evaluate the affinity of the compound to κ and δ opioid receptors.

[0136] 2. Experimental Materials

[0137] (1) Reagents [0138] The cell membrane was extracted from stably transfected cells constructed by WuXi AppTec, Shanghai. [0139] 3H-diprenophrine (PerkinElmer, Cat: NET1121250UC, Lot: 2143599) [0140] 3H-DAMGO (PerkinElmer, Cat: NET902250UC, Lot: 2139100) [0141] 3H-DADLE (PerkinElmer, Cat: NET648250UC, Lot: 2060549) [0142] Tris base (Sigma, Cat: T6066-1KG), prepare 1M stock and adjust pH to 7.4. [0143] 0.5M EDTA (Invitrogen, Cat: 15575-038) [0144] 1M MgCl2 (Sigma, Cat: M1028-100 ml) [0145] PEI (Poly ethyleneimine) (Sigma, Cat: P3143) [0146] Microscint 20 cocktail (PerkinElmer, Cat: 6013329) [0147] Naltrindole (Sigma, Cat; N115) [0148] (±)trans-U-50488 (Sigma, Cat: D8040) [0149] DAMGO (Sigma, Cat: E7384)

[0150] (2) Experiment buffer and wash buffer

TABLE-US-00007 Target Experiment buffer Plate washing buffer Op-delta 50 mM Tris-HCl pH 7.4, 50 mM Tris-HCl pH 7.4, 10 mM MgCl2, 1 mM stored at 4° C. EDTA Op-kappa 50 mM Tris-HCl pH 7.4 Op-mu 50 mM Tris-HCl pH 7.4, 5 mM MgCl.sub.2

[0151] (3) Consumables and instruments [0152] GF/C filter plate, Perkin Elmer (Cat #6005174) [0153] 96-well plate, Agilent (Cat #5042-1385) [0154] Plate sealing film, Perkin Elmer (Cat #6005250) [0155] MicroBeta2 (PerkinElmer) [0156] Cell harvest C961961, (Perkin Elmer)

[0157] 3. Method steps

[0158] 1) Cell membrane and radioisotope preparation

TABLE-US-00008 Cell membrane Final protein radioisotope concentration concentration Target (μg/well) Radioisotope (nM) DOR 6.7 [3H]-DADLE 0.5 MOR 20 [3H]DAMGO 0.5 KOR 6.7 [3H]Diprenorphine 0.3

[0159] 2) Compound preparation

TABLE-US-00009 Initial Final Initial compound Final concentration concentration Concentration concentration in compound of positive of positive of non-specific compound plate concentration compound compound binding well Target (mM) (nM) (mM) (nM) compound DOR 2 10000 0.02 100 Naltrindole (1 μM) MOR 2 10000 0.2 1000 Naltrindole (1 μM) KOR 2 10000 0.2 1000 Trans-U-50488 (5 μM)

[0160] 3) Experimental steps

[0161] (1) 1 μL of the test compounds, negative control (i.e., DMSO) and positive control (i.e., non-specific binding well compound), after being prepared, were respectively transferred to a 96-well plate;

[0162] (2) 99 μL of the prepared opioid receptor membrane protein was added to each well of the 96-well plate containing 1 μL of the compound;

[0163] (3) 100 μL of 2× corresponding radioisotope ligand was added to each well;

[0164] (4) The plate was placed on a shake and incubated at room temperature for 1 hour;

[0165] (5) Each well of the GF/C plate was soaked with 50 μL of 0.3% PEI for at least half an hour in advance;

[0166] (6) After the incubation was finished, the GF/C plate was washed with plate washing buffer once by using Harvest. Then, the cell membranes in the 96-well plate were collected onto the GF/C plate using Harvest, and the GF/C plate was washed four times with the plate washing buffer, each time about 250 μL;

[0167] (7) The GF/C plate was placed in an oven at 50° C. for 1 hour;

[0168] (8) The bottom of the GF/C plate was sealed with a plate sealing film, 50 μL of Microscint-20 scintillation fluid was added to each well, and then the plate was sealed with a transparent sealing film for microplate;

[0169] (9) The radioactive signal value CPM was read using MicroBeta2;

[0170] (10) The data was analyzed with Prism 5. The percentage inhibition rate was calculated with the calculation formula: % Inh=(1-Background subtracted Assay value/Background subtracted HC value)*100.

[0171] The following table illustrates the IC.sub.50 values of the tested compounds against μ, κ and δ opioid receptors.

TABLE-US-00010 TABLE 41 IC.sub.50 values of compounds for μ, κ and δ opioid receptors Test samples μ IC.sub.50 κ IC.sub.50 δ IC.sub.50 Hydrochloride of C D E compound 1 Hydrochloride of C D E compound 2 Hydrochloride of B C E compound 3 Hydrochloride of B D D compound 4 Hydrochloride of C D E compound 5 Hydrochloride of D D E compound 6 Hydrochloride of C C E compound 7 Hydrochloride of B E E compound 8 Hydrochloride of C C D compound 9 Hydrochloride of C D E compound 10 Hydrochloride of C E E compound 11 Hydrochloride of D E E compound 12 Hydrochloride of C E E compound 13 Hydrochloride of C D E compound 14 Hydrochloride of C D E compound 15 Hydrochloride of C E E compound 16 Hydrochloride of C E E compound 17 Hydrochloride of B C D compound 18 Hydrochloride of A B D compound 19 Hydrochloride of A B C compound 20 Hydrochloride of A B B compound 21 Hydrochloride of A B B compound 22 Hydrochloride of B C D compound 23 Hydrochloride of B C D compound 24 Hydrochloride of A C C compound 25 Hydrochloride of A A A compound 26 Hydrochloride of B B C compound 27 Hydrochloride of A C D compound 28 Hydrochloride of B D D compound 29 Hydrochloride of A B B compound 30 Hydrochloride of A C B compound 31 Hydrochloride of A B B compound 32 Hydrochloride of A C C compound 33 Hydrochloride of A A B compound 34 Hydrochloride of C E E compound 35 Hydrochloride of B D D compound 36 Hydrochloride of D D E compound 37 Hydrochloride of B D D compound 38 Hydrochloride of A C C compound 39 Hydrochloride of A A B compound 40 A: <10 nM; 10 nM < B < 100 nM; 100 nM < C < 1 μM; 1 μM < D < 10 μM; E: >10 μM

[0172] The in vitro activity assays substantiate that the compounds of the present disclosure have IC50 values≤10 μM for μ, κ and δ opioid receptors, respectively. The more preferred compounds of the present disclosure have IC50 values≤1 μM for μ, κ and δ opioid receptors, respectively. The further preferred compounds of the present disclosure have IC50 values≤100 nM for μ, κ and δ opioid receptors, respectively.

[0173] The in vitro activity assay also indicated that compounds 19-22, 25, 26, 28, 30-34, 39 and 40, and particularly, compounds 21, 22, 25, 26, 30, 33-34 and 40, are compounds of the present disclosure with higher activity. Among these compounds, the IC.sub.50 values for at least one of the and δ opioid receptors can reach Grade A, more preferably, the IC.sub.50 values for at least two of the opioid receptors can reach Grade A, and most preferably, the IC.sub.50 values for all of the three opioid receptors can reach A grade.

[0174] The most preferred compounds of the present disclosure have IC50 values≤10 nM for μ, κ, and δ opioid receptors, respectively; meanwhile, the compounds of the present disclosure have selectivity for μ, κ, and δ opioid receptors, and more preferably, the compounds of the present disclosure have better selectivity for the μ opioid receptor. For example, the preferred compounds 4, 8, 10, 11, 13-17, 28, 29, 35, 36 and 38 of the present disclosure have selectivity for the μ opioid receptor. Among them, the selectivity of compounds 4, 8, 29, 36 and 38 is more preferred.

Example 42. In Vivo Pharmacodynamic Investigation

[0175] A mode of pain induced by heat radiation in mice and a mode of pain induced by hot plate in mice were used to evaluate the analgesic intensity of the test compounds. The results in Table 42 show that compound 26 has the strongest analgesic effect in the four mouse models of pain, followed by compound 22, all of which are stronger than dezocine.

TABLE-US-00011 TABLE 42 Light and heat-induced pain Hot plate-induced pain ED.sub.50 ED.sub.95 ED.sub.50 ED.sub.95 (mg/kg) (mg/kg) (mg/kg) (mg/kg) Test substance Male Female Male Female Male Female Hydrochloride of 0.12 0.068 0.18 0.083 0.15 — compound 21 Hydrochloride of 0.74 1.15 1.18 2.88 — — compound 25 Hydrochloride of 0.017 0.025 0.021 0.043 0.045 — compound 26 Hydrochloride of 0.13 0.18 0.26 0.26 0.3 — compound 22

Example 43. Pharmacokinetic Investigation of Intravenous Administration in Mice and Rats

[0176] Male mice were injected intravenously with the compound of the present disclosure, and the concentration of the unchanged compound in plasma and the concentration of the metabolite of dezocine hydrochloride were measured after the administration.

[0177] The results prove that dezocine hydrochloride has a faster clearance rate in mouse plasma, with a T.sub.1/2 of 0.903 h. Compounds 21, 22, 25, and 26 can be cleared slower than the dezocine hydrochloride in mouse plasma, with T.sub.1/2 of 1.27 h, 1.24 h, 1.65 h, 1.35 h, respectively.

[0178] The embodiments of the present disclosure are described above. However, the present disclosure is not limited to the above-mentioned embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present disclosure should be included in the protection scope of the present disclosure.