Cannabidiol derivatives, preparation method thereof and use thereof

Abstract

Cannabidiol derivatives and medical use thereof, in particular to compounds represented by general formula (I), or stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or cocrystals thereof, wherein the definitions of the substituents in general formula (I) are the same as those in the description. ##STR00001##

Claims

1. A compound represented by general formula (I), or stereoisomer, solvate, metabolite, pharmaceutically acceptable salt or cocrystal thereof: ##STR00064## wherein: X is selected from the group consisting of hydrogen, hydroxyl, C.sub.1-6 alkyl and halogen; Y is selected from the group consisting of hydrogen, carboxylic acid, C.sub.1-6 alkyl and halogen; r is selected from the group consisting of 0, 1, 2 and 3; n is selected from the group consisting of 0, 1 and 2; R.sub.0 is selected from the group consisting of methyl, C.sub.3-8 carbocyclic group, CH.sub.2OH, C(O)OC.sub.1-6 alkyl, C(O)NR.sup.b1R.sup.b2 and carboxyl; R.sub.1 is selected from the group consisting of C.sub.1-6 alkyl optionally further substituted with 0 to 3 halogen atoms; R.sub.2 is ##STR00065## R.sub.a is selected from the group consisting of H and C.sub.1-6 alkyl; R.sub.b and R.sub.c are each independently selected from the group consisting of H, C.sub.1-6 alkyl, amino acid side chain, C.sub.1-6 alkylene-C.sub.3-12 carbocyclic ring and C.sub.1-6 alkylene-C.sub.3-12 heterocyclic ring; wherein, the C.sub.3-12 heterocyclic ring contains 1 to 4 heteroatoms selected from the group consisting of N, O and S; the C.sub.1-6 alkylene, the C.sub.1-6 alkyl, the C.sub.3-12 carbocyclic ring or the C.sub.3-12 heterocyclic ring is optionally substituted with 0 to 3 substituents selected from the group consisting of hydroxyl, carboxyl, halogen, cyano, O, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, NR.sup.b1R.sup.b2, C(O)OC.sub.1-6 alkyl, C(O)NR.sup.b1R.sup.b2, C.sub.3-12 cycloalkyl, C.sub.3-12 heterocylcloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl; and as substituents, the C.sub.1-6 alkyl, the C.sub.1-6 heteroalkyl, the C.sub.2-6 alkenyl or the C.sub.2-6 alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, carboxyl, cyano, halogen, OR.sup.b1, NR.sup.b1R.sup.b2, C.sub.3-12 cycloalkyl, C.sub.3-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl; when the amino acid side chain contains hydroxyl, mercapto or carboxyl, the hydroxyl, the mercapto or the carboxyl is optionally esterified; R.sup.b1 and R.sup.b2 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, C(O)R.sup.b3 and C(O)NR.sup.b4R.sup.b5, wherein the C.sub.1-6 alkyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, C.sub.3-12 cycloalkyl and C.sub.3-12 heterocycloalkyl; R.sup.b3 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 alkoxy and C.sub.6-12 aryl; R.sup.b4 and R.sup.b5 are each independently selected from the group consisting of H and C.sub.1-6 alkyl; or R.sup.b4 and R.sup.b5 together with N atom form a 3 to 12 membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; or, R.sup.b and R.sup.c together with the atom to which they are attached form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, wherein the 3 to 6 membered carbocyclic ring or the 3 to 6 membered heterocyclic ring is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxyl, carboxyl and amino, wherein the 3 to 6 membered heterocyclic ring contains 1 to 4 heteroatoms selected from the group consisting of N, O and S; R.sup.d is selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclic ring, 3 to 10 membered heterocyclic ring, C.sub.1-6 alkylene-C.sub.3-10 carbocyclic ring, C.sub.1-6 alkylene-3 to 10 membered carbocyclic ring, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-10 carbocyclic ring, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-3 to 10 membered heterocyclic ring and C.sub.1-6 alkylene-OC.sub.1-4 alkyl, wherein the C.sub.1-6 alkylene, the C.sub.2-6 alkenyl, the C.sub.2-6 alkynyl, the C.sub.1-6 alkyl, the C.sub.3-10 carbocyclic ring or the 3 to 10 membered heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, hydroxyl, carboxyl, amino, 1-cyclopropyl ethyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OC(O)OR.sub.d1 and OC(O)OR.sub.d2, wherein the 3 to 10 membered heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of N, O and S; R.sub.d1 and R.sub.d2 are each independently selected from the group consisting of C.sub.1-4 alkyl, C.sub.3-10 carbocyclic ring and 3 to 10 membered heterocyclic ring, wherein the C.sub.1-4 alkyl, the C.sub.3-10 carbocyclic ring or the 3 to 10 membered heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, hydroxyl, carboxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-10 carbocyclic ring and 3 to 10 membered heterocyclic ring, wherein the 3 to 10 membered heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of N, O and S; R.sub.3 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-8 carbocyclic group and C.sub.2-6 alkenyl, wherein the C.sub.1-6 alkyl, the C.sub.2-6 alkenyl or the C.sub.3-8 carbocyclic group is optionally further substituted with 0 to 3 substituents selected from the group consisting of halogen, C.sub.3-8 carbocyclic group and hydroxyl and C.sub.1-6 alkyl; R.sub.4 is selected from the group consisting of H, hydroxyl, C.sub.1-6 alkoxy, C(O)OR.sub.d1, C(O)R.sub.d1, C(O)C(NH.sub.2)R and ##STR00066## wherein the amino in C(O)CH(NH.sub.2)R optionally forms a polypeptide chain with an amino acid; R is selected from the group consisting of amino acid side chain; when the amino acid side chain contains hydroxyl, mercapto and carboxyl, the hydroxyl, the mercapto or the carboxyl is optionally esterified; R.sub.5 is selected from the group consisting of C.sub.1-12 alkyl, C.sub.1-12 heteroalkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 carbocyclic group, C.sub.3-12 heterocyclic group, C.sub.1-6 alkylene-C.sub.3-12 carbocyclic group, C.sub.1-6 alkylene-C.sub.3-12 heterocyclic group, NR.sup.b1R.sup.b2, C.sub.1-6 alkylene-C(O) OC.sub.1-6 alkyl and C.sub.1-6 alkylene-C(O)NR.sup.b1R.sup.b2, wherein the C.sub.1-12 alkyl, the C.sub.1-12 heteroalkyl, the C.sub.2-12 alkenyl, the C.sub.2-12 alkynyl, the C.sub.1-6 alkylene, the C.sub.3-12 carbocyclic group or the C.sub.3-12 heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, carboxyl, halogen, cyano, O, C.sub.1-6 alkyl, NR.sup.b1R.sup.b2, C.sub.3-12 carbocyclic group, C.sub.3-12 heterocyclic group, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C(O) OC.sub.1-6 alkyl, C(O) C.sub.1-6 alkyl, C(O)NR.sup.b1R.sup.b2, S(O) C.sub.1-6 alkyl and S(O).sub.2C.sub.1-6 alkyl, wherein as substituents, the C.sub.1-6 alkyl, the C.sub.3-12 carbocyclic group or the C.sub.3-12 heterocyclic group is further substituted with one or more substituents selected from the group consisting of O, hydroxyl, carboxyl, halogen, cyano, C(O)OC.sub.1-6 alkyl and C(O)C.sub.1-6 alkyl; is a single bond or a double bond; and; the general formula (I) is optionally substituted with one or more D atoms.

2. The compound, or stereoisomer, solvate, pharmaceutically acceptable salt or cocrystal thereof according to claim 1, wherein the compound is represented by general formula (II): ##STR00067## wherein, R.sub.0 is selected from the group consisting of methyl and CH.sub.2OH; R.sub.1 is C.sub.1-6 alkyl; R.sub.2 is ##STR00068## R.sub.a is H; R.sub.b and R.sub.c are each independently selected from the group consisting of H and amino acid side chain; and when the amino acid side chain contains hydroxyl, mercapto or carboxyl, the hydroxyl, the mercapto or the carboxyl is optionally esterified; R.sub.d is selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-10 carbocyclic ring and 3 to 10 membered heterocyclic ring, wherein the C.sub.1-6 alkyl, the C.sub.3-10 carbocyclic ring or the 3 to 10 membered heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, hydroxyl, carboxyl, amino, 1-cyclopropylethyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OC(O)OR.sub.d1 and OC(O)R.sub.d2, and the 3 to 10 membered heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of N, O and S; R.sub.d1 and R.sub.d2 are each independently C.sub.1-4 alkyl; and, the general formula (II) is optionally substituted with one or more D atoms.

3. The compound, or stereoisomer, solvate, pharmaceutically acceptable salt or cocrystal thereof according to claim 2, wherein the compound is represented by general formula (III): ##STR00069## wherein, R.sub.1 is C.sub.1-6 alkyl; R.sub.2 is ##STR00070## R.sub.d is selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-10 carbocyclic ring and 3 to 10 membered heterocyclic ring, wherein the C.sub.1-6 alkyl, the C.sub.3-10 carbocyclic ring or the 3 to 10 membered heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, hydroxyl, carboxyl, amino, 1-cyclopropylethyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OC(O)OR.sub.d1 and OC(O)R.sub.d2, and the 3 to 10 membered heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of N, O and S; R.sub.d1 and R.sub.d2 are each independently C.sub.1-4 alkyl; and, the general formula (III) is optionally substituted with one or more D atoms.

4. The compound, or stereoisomer, solvate, pharmaceutically acceptable salt or cocrystals thereof according to claim 1, wherein the compound has one of the following structures: ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078##

5. A pharmaceutical composition comprising: (1) the compound, or stereoisomer, solvate, pharmaceutically acceptable salt or cocrystal thereof according to claim 4, (2) optional one or more other active ingredients; and (3) a pharmaceutically acceptable carrier and/or excipient.

6. The pharmaceutical composition according to claim 5, wherein, the other active ingredient is one or more selected from the group consisting of ginkgolide, antineoplastic agent, anticoagulant, antiepileptic agent, antidepressant, anxiolytic, hypnotic, analgesic and anesthetic, or stereoisomer, solvate, metabolite, pharmaceutically acceptable salt or cocrystal of the other active ingredient.

7. The pharmaceutical composition according to claim 6, wherein the ginkgolide is one, two or more selected from the group consisting of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide D, ginkgolide J, ginkgolide M, ginkgolide K, ginkgolide L, ginkgolide N, ginkgolide P, ginkgolide Q and bilobalide or combinations thereof in any ratio.

Description

SPECIFIC EMBODIMENTS

(1) The following examples will illustrate the technical solution of the present application in detail, and the scope of the present application includes, but is not limited to these examples.

(2) The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shift () was given in units of 10.sup.6 (ppm). The NMR test was conducted by using nuclear magnetic instrument (Bruker Avance III 400 and Bruker Avance 300), and the solvent for the test was deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated chloroform (CDCl.sub.3), deuterated methanol (CD.sub.3OD), and the internal standard was tetramethylsilane (TMS).

(3) MS test was conducted on Agilent 6120B (ESI) and Agilent 6120B (APCI).

(4) HPLC test was conducted on Agilent 1260DAD high pressure liquid chromatograph (zorbax sb-C18 1004.6 mm, 3.5 m).

(5) HSGF254 silica gel plate from Yantai Huanghai or Qingdao GF254 silica gel plate was used for thin layer chromatography (TLC), and the size of the silica gel plate for thin layer chromatography (TLC) was 0.15 mm to 0.20 mm, and the size of the silica gel plate for thin layer chromatography separation and purification products was 0.4 mm to 0.5 mm.

(6) Silica gel of 200-300 mesh by Yantai Huanghai was generally used as a carrier of the column chromatography.

(7) The known starting materials in the present application can be synthesized by using the methods known in the field, or can be purchased from Titan Technology company, Annaiji Chemical company, Shanghai DEMO Medical Tech Co., Ltd, Chengdu Kelong Chemical company, Shaoyuan Chemical Technology company, Bailingwei Technology company, etc.

(8) Nitrogen atmosphere means that the reaction flask was connected with a nitrogen balloon with a volume of about 1 L.

(9) Hydrogen atmosphere means that the reaction flask was connected with a hydrogen balloon with a volume of about 1 L.

(10) Hydrogenation reaction was usually vacuumized, filled with hydrogen, and repeated for 3 times.

(11) Unless otherwise stated in Examples, the reaction was carried out in nitrogen atmosphere.

(12) Unless otherwise stated in Examples, the solution was an aqueous solution.

(13) Unless otherwise stated in Examples, the reaction temperature was room temperature, and the most suitable reaction temperature for room temperature was 20 C.-30 C.

(14) DCM: dichloromethane;

(15) EA: ethyl acetate;

(16) HCl: hydrochloric acid;

(17) THF: tetrahydrofuran;

(18) DMF: N,N-dimethyl formamide;

(19) PE: petroleum ether;

(20) TLC: thin layer chromatography;

(21) SFC: supercritical fluid chromatography;

(22) NCS: N-chlorosuccinimide;

(23) Pd(dppf)Cl.sub.2: [1,1-bis (diphenylphosphine) ferrocene]palladium dichloride.

EXAMPLES

(24) The technical solution of the present application will be illustrated by the following examples in detail; and the scope of the present application comprises but is not limited to the examples.

Example 1

Isopropyl((ethoxycarbonyl)(((1R,2R)-6-hydroxy-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate (Compound 1)

(25) ##STR00019##

(26) Ethyl (dichlorophosphoryl) formate (0.31 g, 1.6 mmol) was dissolved in dichloromethane (1 ml) in a dry round-bottom flask, triethylamine (0.25 mL, 1.1 eq) was added thereto at 60 C., and then the solution of isopropyl L-alaninate hydrochloride (0.16 g, 0.95 mmol, 0.6 eq) in dichloromethane was added dropwise thereto. The thus obtained mixture was stirred for 1.5 hours at 60 C. (1R, 2R)-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2,6-diol (0.78 g, 1.6 mmol, 1 eq) and triethylamine (0.5 mL, 2.2 eq) were successively added into the reaction solution, then the reaction solution was slowly heated to room temperature, and stirred overnight. The reaction was monitored by LC-MS until the reaction was completed. Saturated solution of ammonium chloride was added at 0 C., and then the thus obtained mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate and dried using rotary evaporator, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10:11:10) to give the isomer 1-1 (113 mg, with a yield of 33.5%, yellow oil) and isomer 1-2 (64 mg, with a yield of 19.3%, yellow oil) of the titled compound 1, isopropyl ((ethoxycarbonyl)(((1R,2R)-6-hydroxy-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate.

Isomer 1-1

(27) .sup.1H NMR (300 MHz, Chloroform-d) 6.78 (s, 1H), 6.49 (s, 1H), 6.04 (s, 1H), 5.54 (s, 1H), 5.07-4.99 (m, 1H), 4.66 (s, 1H), 4.21 (s, 1H), 4.31-4.08 (m, 3H), 3.84-3.77 (m, 2H), 2.49-2.44 (m, 3H), 2.19-2.11 (m, 1H), 2.04-1.55 (m, 10H), 1.39-1.21 (m, 16H), 0.87 (t, 3H).

(28) .sup.31P NMR (121 MHz, Chloroform-d): 2.98.

(29) LC-MS m/z (ESI)=564.19 [M+1].

Isomer 1-2

(30) .sup.1H NMR (300 MHz, Chloroform-d) 6.68 (s, 1H), 6.47 (s, 1H), 6.12 (s, 1H), 5.55 (s, 1H), 5.02-4.94 (m, 1H), 4.52 (s, 1H), 4.35 (s, 1H), 4.28-4.04 (m, 3H), 3.87-3.72 (m, 2H), 2.45-2.40 (m, 3H), 2.19-2.08 (m, 1H), 1.79-1.46 (m, 10H), 1.39-1.21 (m, 16H), 0.84 (t, 3H).

(31) .sup.31P NMR (121 MHz, Chloroform-d): 3.47.

(32) LC-MS m/z (ESI)=564.20 [M+1].

Example 2

Ethyl((ethoxycarbonyl)(((1R,2R)-6-hydroxy-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate (Compound 2)

(33) ##STR00020##

(34) Compound 2 was synthesized and separated by the same method as that of compound 1 to obtain isomer 2-1 (68 mg, with a yield of 8.1%, yellow oil) and isomer 2-2 (77 mg, with a yield of 6.7%, yellow oil) of the titled compound.

Isomer 2-1

(35) .sup.1H NMR (300 MHz, Chloroform-d) 6.78 (s, 1H), 6.49 (s, 1H), 6.04 (s, 1H), 5.54 (s, 1H), 4.65 (s, 1H), 4.42 (s, 1H), 4.22-4.15 (m, 4H), 3.87-3.84 (m, 1H), 3.79-3.72 (m, 1H), 2.49-2.44 (m, 3H), 2.23-2.04 (m, 2H), 1.82-1.52 (m, 10H), 1.41-1.24 (m, 13H), 0.87 (t, 3H).

(36) .sup.31P NMR (121 MHz, Chloroform-d): 2.98.

(37) LC-MS m/z (ESI)=550.22 [M+1].

Isomer 2-2

(38) .sup.1H NMR (300 MHz, Chloroform-d) 6.69 (s, 1H), 6.49 (s, 1H), 6.09 (s, 1H), 5.58 (s, 1H), 4.55 (s, 1H), 4.36 (s, 1H), 4.31-4.10 (m, 4H), 3.87-3.84 (m, 1H), 3.77-3.70 (m, 1H), 2.47-2.42 (m, 3H), 2.20-2.04 (m, 2H), 1.82-1.51 (m, 10H), 1.32-1.22 (m, 13H), 0.86 (t, 3H).

(39) .sup.31P NMR (121 MHz, Chloroform-d): 3.49.

(40) LC-MS m/z (ESI)=550.20 [M+1].

Example 3

Benzyl((ethoxycarbonyl)(((1R,2R)-6-hydroxy-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate (Compound 3)

(41) ##STR00021##

(42) Compound 3 was synthesized and separated by the same method as that of compound 1 to obtain isomer 3-1 (66 mg, with a yield of 5.7%, yellow oil) and isomer 3-2 (76 mg, with a yield of 6.3%, yellow oil) of titled compound 3.

Isomer 3-1

(43) .sup.1H NMR (300 MHz, Chloroform-d) 7.39-7.29 (m, 5H), 6.78 (s, 1H), 6.49 (s, 1H), 6.04 (s, 1H), 5.53 (s, 1H), 5.21-5.11 (m, 2H), 4.63 (s, 1H), 4.41 (s, 1H), 4.33-4.10 (m, 3H), 3.87-3.74 (m, 2H), 2.46 (t, 3H), 2.22-2.04 (m, 2H), 1.83-1.20 (m, 20H), 0.86 (t, 3H).

(44) .sup.31P NMR (121 MHz, Chloroform-d): 3.05.

(45) LC-MS m/z (ESI)=612.45 [M+1].

Isomer 3-2

(46) .sup.1H NMR (300 MHz, Chloroform-d) 7.39-7.29 (m, 5H), 6.70 (s, 1H), 6.49 (s, 1H), 6.09 (s, 1H), 5.55 (s, 1H), 5.18-5.09 (m, 2H), 4.54 (s, 1H), 4.36 (s, 1H), 4.27-4.20 (m, 3H), 3.87-3.71 (m, 2H), 2.45 (t, 3H), 2.26-2.10 (m, 2H), 1.83-1.18 (m, 20H), 0.86 (t, 3H).

(47) .sup.31P NMR (121 MHz, Chloroform-d): 3.61.

(48) LC-MS m/z (ESI)=612.53 [M+1].

Example 4

Ethyl((((1R,2R)-6-hydroxy-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)-L-alaninate (Compound 4)

(49) ##STR00022##

(50) Compound 4 was synthesized and separated by the same method as that of compound 1 to obtain isomer 4-1 (85 mg, with a yield of 7.9%, yellow oil) and isomer 4-2 (129 mg, with a yield of 12%, yellow oil) of titled compound 4.

Isomer 4-1

(51) .sup.1H NMR (300 MHz, Chloroform-d) 6.78 (s, 1H), 6.48 (s, 1H), 6.04 (s, 1H), 5.54 (s, 1H), 5.19-5.13 (m, 1H), 4.65 (s, 1H), 4.42 (s, 1H), 4.22-4.14 (m, 4H), 3.87-3.84 (m, 1H), 3.78-3.71 (m, 1H), 2.48-2.43 (m, 3H), 2.22-2.10 (m, 2H), 1.81-1.49 (m, 10H), 1.40-1.1.23 (m, 15H), 0.87 (t, 3H).

(52) .sup.31P NMR (121 MHz, Chloroform-d): 2.86.

(53) LC-MS m/z (ESI)=564.28 [M+1].

Isomer 4-2

(54) .sup.1H NMR (300 MHz, Chloroform-d) 6.70 (s, 1H), 6.48 (s, 1H), 6.07 (s, 1H), 5.58 (s, 1H), 5.17-5.12 (m, 1H), 4.54 (s, 1H), 4.37 (s, 1H), 4.19-4.07 (m, 4H), 3.89-3.86 (m, 1H), 3.75-3.68 (m, 1H), 2.47-2.42 (m, 3H), 2.24-2.05 (m, 2H), 1.79-1.42 (m, 10H), 1.32-1.18 (m, 15H), 0.86 (t, 3H).

(55) .sup.31P NMR (121 MHz, Chloroform-d): 3.39.

(56) LC-MS m/z (ESI)=564.51 [M+1].

Example 5

Isopropyl 2-(((ethoxycarbonyl)(((1R,2R)-6-hydroxy-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate (Compound 5)

(57) ##STR00023##

(58) Compound 5 was synthesized and separated by the similar method as that of compound 1 to obtain isomer 5-1 (760 mg, with a yield of 4.4%, white solid) and isomer 5-2 (691 mg, with a yield of 4%, white solid) of titled compound 5.

Isomer 5-1

(59) .sup.1H NMR (300 MHz, Chloroform-d) 6.78 (s, 1H), 6.45 (s, 1H), 6.09 (s, 1H), 5.48 (s, 1H), 4.57-3.81 (m, 6H), 2.43-1.95 (m, 5H), 1.72-1.50 (m, 16H), 1.26-1.19 (m, 13H), 0.81 (t, 3H).

(60) .sup.31P NMR (121 MHz, Chloroform-d): 3.43.

(61) LC-MS m/z (ESI)=578.47 [M+1].

Isomer 5-2

(62) .sup.1H NMR (300 MHz, Chloroform-d) 6.69 (s, 1H), 6.43 (s, 1H), 6.01 (s, 1H), 5.47 (s, 1H), 5.00-4.92 (m, 1H), 4.46-3.82 (m, 6H), 2.40-1.97 (m, 5H), 1.70-1.44 (m, 16H), 1.21-1.16 (m, 13H), 0.79 (t, 3H).

(63) .sup.31P NMR (121 MHz, Chloroform-d): 3.65.

(64) LC-MS m/z (ESI)=578.65 [M+1].

Example 6

Isopropyl((((1R,2R)-6-hydroxy-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)-L-alaninate (Compound 6)

(65) ##STR00024##

(66) Compound 6 was synthesized and separated by the same method as that of compound 1 to obtain isomer 6-1 (30 mg, with a yield of 1.8%, yellow oil) and isomer 6-2 (120 mg, with a yield of 7.3%, white solid) of titled compound 6.

Isomer 6-1

(67) .sup.1H NMR (300 MHz, Chloroform-d) 6.78 (s, 1H), 6.49 (s, 1H), 6.04 (s, 1H), 5.55 (s, 1H), 5.18-5.01 (m, 2H), 4.66 (s, 1H), 4.42 (s, 1H), 4.19-4.16 (m, 1H), 3.88-3.77 (m, 2H), 2.49-2.44 (m, 3H), 2.21-2.05 (m, 2H), 1.79-1.37 (m, 10H), 1.28-1.19 (m, 19H), 0.87 (t, 3H).

(68) .sup.31P NMR (121 MHz, Chloroform-d): 2.89.

(69) LC-MS m/z (ESI)=578.05 [M+1].

Isomer 6-2

(70) .sup.1H NMR (300 MHz, Chloroform-d) 6.70 (s, 1H), 6.49 (s, 1H), 6.08 (s, 1H), 5.59 (s, 1H), 5.17-4.99 (m, 2H), 4.55 (s, 1H), 4.37 (s, 1H), 4.12-3.70 (m, 3H), 2.47-2.42 (m, 3H), 2.21-2.04 (m, 2H), 1.81-1.51 (m, 10H), 1.32-1.19 (m, 19H), 0.87 (t, 3H). .sup.31P NMR (121 MHz, Chloroform-d): 3.38.

(71) LC-MS m/z (ESI)=578.12 [M+1].

Example 7

Isopropyl 2-(((((1R,2R)-6-hydroxy-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)amino)-2-methylpropanoate (Compound 7)

(72) ##STR00025##

(73) Compound 7 was synthesized and separated by the similar method as that of compound 1 to obtain isomer 7-1 (21 mg, with a yield of 1.2%, yellow oil) and isomer 7-2 (163 mg, with a yield of 9.3%, yellow oil) of titled compound 7.

Isomer 7-1

(74) .sup.1H NMR (300 MHz, Chloroform-d) 6.81 (s, 1H), 6.46 (s, 1H), 6.04 (s, 1H), 5.53 (s, 1H), 5.18-5.09 (m, 1H), 5.07-4.99 (m, 1H), 4.62 (s, 1H), 4.40 (s, 1H), 4.19 (d, 1H), 3.86 (d, 1H), 2.47-2.42 (m, 3H), 2.21-2.03 (m, 2H), 1.81-1.21 (m, 32H), 0.85 (t, 3H).

(75) .sup.31P NMR (121 MHz, Chloroform-d): 3.36.

(76) LC-MS m/z (ESI)=592.45 [M+1].

Isomer 7-2

(77) .sup.1H NMR (300 MHz, Chloroform-d) 6.75 (s, 1H), 6.47 (s, 1H), 6.04 (s, 1H), 5.58 (s, 1H), 5.29-5.12 (m, 1H), 5.06-4.98 (m, 1H), 4.55 (s, 1H), 4.38 (s, 1H), 4.12 (d, 1H), 3.87 (d, 1H), 2.48-2.43 (m, 3H), 2.20-2.04 (m, 2H), 1.83-1.20 (m, 32H), 0.86 (t, 3H).

(78) .sup.31P NMR (121 MHz, Chloroform-d): 3.39.

(79) LC-MS m/z (ESI)=592.10 [M+1].

Example 8

Ethyl 2-(((ethoxycarbonyl)(((1R,2R)-6-hydroxy-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate (Compound 8)

(80) ##STR00026##

(81) Compound 8 was synthesized and separated by the similar method as that of compound 1 to obtain isomer 8-1 (180 mg, with a yield of 5%, yellow oil) and isomer 8-2 (175 mg, with a yield of 5%, yellow oil) of titled compound 8.

Isomer 8-1

(82) .sup.1H NMR (300 MHZ, Chloroform-d) 6.81 (s, 1H), 6.47 (s, 1H), 6.06 (s, 1H), 5.53 (s, 1H), 4.61 (s, 1H), 4.39 (s, 1H), 4.30-4.23 (m, 2H), 4.20-4.12 (m, 2H), 3.84 (d, 1H), 2.45 (t, 2H), 2.18 (s, 1H), 2.10-2.03 (m, 1H), 1.77 (s, 1H), 1.68-1.61 (m, 2H), 1.64 (s, 6H), 1.59-1.48 (m, 2H), 1.56 (s, 6H), 1.30-1.24 (m, 6H), 0.85 (t, 3H).

(83) .sup.31P NMR (121 MHz, Chloroform-d): 3.45.

(84) LC-MS m/z (ESI)564.40 [M+1].

Isomer 8-2

(85) .sup.1H NMR (400 MHZ, Chloroform-d) 6.74 (s, 1H), 6.47 (s, 1H), 6.07 (s, 1H), 5.56 (s, 1H), 4.54 (s, 1H), 4.36 (s, 1H), 4.32-4.24 (m, 2H), 4.21-4.02 (m, 2H), 3.84 (d, 12.0 Hz, 1H), 2.44 (t, 2H), 2.19 (s, 1H), 2.10-2.03 (m, 1H), 1.78 (s, 1H), 1.64-1.56 (m, 2H), 1.60 (s, 3H), 1.59 (s, 3H) 1.55-1.47 (m, 2H), 1.49 (s, 6H), 1.32-1.20 (m, 6H), 0.85 (t, 3H).

(86) .sup.31P NMR (121 MHz, Chloroform-d): 3.56.

(87) LC-MS m/z (ESI)=564.40 [M+1].

Example 9

Isopropyl((ethoxycarbonyl)((6-hydroxy-5-(methyl-d3)-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate (Compound 9)

(88) ##STR00027##

Step 1

3-ethoxy-6-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one 9b

(89) Under nitrogen atmosphere, 3-ethoxycyclohex-2-en-1-one 9a (10.0 g, 71.0 mmol) was added dropwise to lithium diisopropylamide (54 mL, 107.0 mmol, 2.0 N) in tetrahydrofuran (100 mL) at 70 C., and the mixture was stirred for 0.5 h after the addition was completed. Then acetone (9.2 g, 142.0 mmol) was added dropwise thereto, and the thus obtained mixture was stirred for 3 hours after the addition was completed. TLC test was used to monitor the reaction until the reaction was completed. Saturated solution of ammonium chloride (180 mL) was added dropwise to quench the reaction, and the reaction solution was separated. The aqueous phase was extracted with ethyl acetate (150 mL2). The organic phase was combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the titled compound 9b (yellow oil, 18.0 g, with a yield of 99.0%).

(90) .sup.1H NMR (400 MHz, DMSO). 5.29 (s, 1H), 4.93 (s, 1H), 3.98-3.87 (m, 2H), 2.46 (dd, J=11.2, 5.0 Hz, 1H), 2.37 (dt, J=17.4, 4.5 Hz, 1H), 2.21 (dd, J=12.1, 4.7 Hz, 1H), 2.12-2.03 (m, 1H), 1.67 (ddd, J=24.2, 12.3, 5.1 Hz, 1H), 1.27 (t, J=7.0 Hz, 3H), 0.99 (s, 3H), 0.73 (s, 3H).

(91) LC-MS m/z (ESI)=199.21 [M+1].

Step 2

4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one 9c

(92) Under nitrogen atmosphere, red aluminum (67 mL, 234.1 mmol, 3.5 N) was added dropwise to the compound 9b (17.0 g, 78.0 mmol) in tetrahydrofuran (200 mL) at 0 C., and after the addition was completed, the mixture was slowly heated to room temperature and stirred for 2 hours. TLC test was used to monitor the reaction until the reaction was completed. The thus obtained mixture was cooled to 0 C., quenched by dropwise adding saturated solution of ammonium chloride (13 mL), and filtered by suction. The aqueous phase was extracted with ethyl acetate (200 mL2). The organic phase was combined, washed with saturated brine solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrated was concentrated under vacuum to obtain crude product, then the crude product was dissolved in tetrahydrofuran (40 mL), hydrochloric acid aqueous solution (40 mL, 2 N) was added dropwise thereto and the thus obtained mixture was stirred at room temperature for 1.5 hours after the addition was completed. TLC test was used to monitor the reaction until the reaction was completed. The reaction was quenched by dropwise adding saturated solution of sodium bicarbonate. The thus obtained mixture was concentrated under vacuum, the aqueous phase was extracted with ethyl acetate (100 mL4), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether (v/v)=) to obtain the titled compound 9c (colorless oil, 5.8 g, with a yield of 48.0%).

(93) .sup.1H NMR (400 MHz, DMSO) 7.19 (dt, J=10.4, 1.9 Hz, 1H), 5.93 (dd, J=10.4, 2.8 Hz, 1H), 4.58 (s, 1H), 2.44-2.38 (m, 1H), 2.38-2.29 (m, 2H), 2.08-1.96 (m, 1H), 1.62 (tdd, J=12.9, 9.4, 5.0 Hz, 1H), 0.99 (s, 3H), 0.73 (s, 3H).

(94) LC-MS m/z (ESI)=155.40 [M+1].

Step 3

4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-1-ol 9d

(95) Under nitrogen atmosphere, deuterated methyl magnesium iodide (34 mL, 33.7 mmol, 1.0 N) was added dropwise to anhydrous lithium chloride (1.4 g, 33.7 mmol) in tetrahydrofuran (20 mL) at 0 C. and the thus obtained mixture was stirred for 0.5 hour after the addition was completed. Then compound 9c (1.8 g, 11.2 mmol) in tetrahydrofuran (5 mL) was added dropwise thereto and the mixture was stirred for 0.5 hour after the addition was completed. TLC test was used to monitor the reaction until the reaction was completed. Saturated solution of ammonium chloride (20 mL) was added dropwise to quench the reaction. The aqueous phase was extracted with ethyl acetate (50 mL3) and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain a crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether (v/v)=2/1) to obtain the titled compound 9d (white solid, 1.2 g, yield: 60.0%).

(96) .sup.1H NMR (400 MHz, DMSO) 5.61 (d, J=10.4 Hz, 1H), 5.52 (d, J=10.6 Hz, 1H), 4.38 (s, 1H), 4.17 (s, 1H), 2.00 (ddd, J=10.8, 5.1, 2.4 Hz, 1H), 1.73-1.65 (m, 2H), 1.57-1.48 (m, 1H), 1.21 (dd, J=10.1, 6.8 Hz, 1H), 0.99 (s, 3H), 0.73 (s, 3H).

(97) LC-MS m/z (ESI)=174.62 [M+1].

Step 4

2-(2-hydroxypropan-2-yl)-5-(methyl-d3)-4-pentyl-1,2,3,4-tetrahydro-[1,1-biphenyl]-2,6-diol 9e

(98) 4-(2-hydroxypropyl-2-yl)-1-(methyl-d3) cyclohex-2-ene-1-ol 9d (2.37 g, 13.7 mmol), 3,5-dihydroxyamylbenzene (3.7 g, 20.6 mmol) and 4 A molecular sieve (6 g) were dissolved in 30 mL of dichloromethane, the atmosphere in the flask was replaced by nitrogen and the thus obtained mixture was stirred for 20 minutes. Then L-camphor sulfonic acid (317.8 mg, 1.37 mmol) was added thereto. The thus obtained mixture was stirred for 1 hour at room temperature. The reaction was quenched by adding 60 mL of saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate (30 mL4). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether (v/v)=) to obtain the titled compound 9e (colorless oil, 1.3 g, with a yield of 28.5%).

(99) .sup.1H NMR (400 MHz, DMSO) 9.04-8.43 (m, 2H), 6.03 (s, 2H), 4.89 (s, 1H), 3.66 (m, 2H), 2.32 (m, 3H), 2.14-2.06 (m, 1H), 2.02 (m, 1H), 1.88-1.79 (m, 1H), 1.47 (m, 2H), 1.32-1.19 (m, 5H), 0.97 (s, 3H), 0.85 (t, 3H), 0.80 (s, 3H).

(100) LC-MS m/z (ESI)=336.20 [M+1].

Step 5

5-(methyl-d3)-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2,6-diol 9f

(101) At 0 C., compound 9e (1.3 g, 3.9 mmol), Burgess reagent (1.1 g, 4.7 mmol) and tetrahydrofuran (10 mL) were successively added into the reaction flask, and the thus the obtained mixture was stirred for 3 hours under nitrogen atmosphere. TLC test was used to monitor the reaction until the reaction was completed. Ethyl acetate (50 mL) was added to the reaction solution, the thus obtained organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain a crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether (v/v)= 1/15) to obtain the titled compound 9f (colorless oil, 794 mg, with a yield of 64.0%).

(102) .sup.1H NMR (400 MHz, DMSO) 8.65 (s, 2H), 6.01 (s, 2H), 5.08 (s, 1H), 4.49 (d, 1H), 4.43-4.37 (d, 1H), 3.85-3.78 (m, 1H), 3.08-2.98 (m, 1H), 2.32-2.26 (m, 2H), 2.13-2.04 (m, 1H), 1.95-1.87 (m, 1H), 1.71-1.63 (m, 1H), 1.58 (s, 3H), 1.47 (m, 2H), 1.35-1.22 (m, 5H), 0.86 (t, 3H).

(103) LC-MS m/z (ESI)=318.20 [M+1].

Step 6

Isopropyl((ethoxycarbonyl)((6-hydroxy-5-(methyl-d3)-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate (Compound 9)

(104) The titled compound 9 (69 mg, with a yield of 23%, yellow oil) was prepared by the same method as that of compound 1.

(105) LC-MS m/z (ESI)=567.39 [M+1].

(106) The following intermediates were synthesized according to the method indicated in the table.

(107) TABLE-US-00001 No. Preparation method Structural formula Intermediate 10 Intermediate 10 was prepared with reference to Org. Lett., 2000, 2, 3301-330. Intermediate 11 Intermediate 11 was prepared with refererence to WO2011006099. Intermediate 12 Intermediate 12 was prepared with refererence to Org. Lett., 2000, 2, 3301-330 and WO2011006099. 0 Intermediate 13 Intermediate 13 was prepared with refererence to WO2011006099. Intermediate 14 Intermediate 14 was prepared with refererence to Org. Lett., 2000, 2, 3301-330 and WO2011006099. Intermediate 15 Intermediate 15 was prepared with refererence to Org. Lett., 2000, 2, 3301-330. Intermediate 16 Intermediate 16 was prepared with reference to WO2011006099. Intermediate 17 Intermediate 17 was prepared with refererence to WO2011006099. Intermediate 18 Intermediate 18 was prepared with reference to WO2011006099. Intermediate 19 Intermediate 19 was prepared with reference to WO2011006099. Intermediate 20 Intermediate 20 was prepared with reference to WO2011006099. Intermediate 21 Intermediate 21 was prepared with reference to WO2011006099. Intermediate 22 Intermediate 22 was prepared with refererence to Org. Lett., 2008, 10, 2195-2198. 0 Intermediate 23 Intermediate 23 was prepared with refererence to Org. Lett., 2008, 10, 2195-2198 and WO2019033164. Intermediate 24 Intermediate 24 was prepared with reference to WO2017008136. Intermediate 25 Intermediate 25 was prepared with reference to WO2017008136. Intermediate 26 Intermediate 26 was prepared with reference to WO2017008136. Intermediate 27 Intermediate 27 was prepared with reference to Org. Lett., 2008, 10, 2195-2198 and WO2017008136.

(108) The following compounds were prepared using the same method as that of compound 1.

(109) TABLE-US-00002 No. Structural formula [M + H]+ Compound 10 580.34 Compound 11 567.39 Compound 12 583.37 Compound 13 569.29 Compound 14 0 585.38 Compound 15 582.30 Compound 16 575.41 Compound 17 566.35 Compound 18 578.44 Compound 19 566.28 Compound 20 566.33 Compound 21 608.32 Compound 22 560.22 Compound 23 604.26 Compound 24 0 566.37 Compound 25 584.30 Compound 26 582.28 Compound 27 562.32

Pharmacokinetics in Rats

(110) Healthy adult SD rats (n=3 per group) were fasted overnight (free access to water), and then were administrated the drugs by intragastric administration (i.g.) (50 mg/kg). 0.1 mL of blood was collected from jugular plexus of the rats at 30 minute, 1 hour and 8 hour after administration. All blood samples were anticoagulated with K.sub.2EDTA, then centrifuged at 3500 rpm at 5 C. for 10 minutes to separate plasma, and stored at 20 C. for test. Parent drug concentration in plasma was determined by LC/MS/MS method.

(111) Using the above method, the blood drug concentrations (ng/mL) of the parent drugs of the compounds at each time point in the rats were measured, the results are as follows:

(112) TABLE-US-00003 No. Administration dose Parent drug 30 min 1 h 8 h Compound 1 50 mg/kg CBD 1408 1754 151.7 Compound 3 50 mg/kg CBD 1376 1604 145.9 Compound 5 50 mg/kg CBD 1388 1653 160.8 Compound 9 50 mg/kg 9f 1577 1993 260.5 Compound 10 50 mg/kg Intermediate 10 1409 1846 164.9 Compound 11 50 mg/kg Intermediate 11 1570 1982 248.3 Compound 12 50 mg/kg Intermediate 12 1593 2027 271.1 Compound 13 50 mg/kg Intermediate 13 1568 1981 260.9 Compound 14 50 mg/kg Intermediate 14 1674 2070 264.6 Compound 18 50 mg/kg Intermediate 18 1775 2280 299.1 Compound 22 50 mg/kg Intermediate 22 1401 1682 143.0 Compound 24 50 mg/kg Intermediate 24 1383 1691 170.2 Compound 25 50 mg/kg Intermediate 25 1566 1940 242.2 Compound 26 50 mg/kg Intermediate 26 1559 1969 268.3 Compound 27 50 mg/kg Intermediate 27 1402 1675 144.9

(113) Experiment results showed that the parent drugs can respectively be detected in plasma after intragastric administration of the compounds of the present application, which indicates that the compounds of the present application can be absorbed orally, the compounds can be quickly converted into the parent drugs in vivo, and they show better oral bioavailability than the parent drugs.

(114) Although the specific embodiments are described in detail in the description of the present application, those skilled in the art should realize that the above embodiments are exemplary and cannot be understood as limitations to the present application. If those skilled in the art make improvements and modifications to the present application without departing from the principle of the present application, the technical solutions obtained by these improvements and modifications shall also fall within the protection scope of the claims of the present application.