Amino alcohol derivative, pharmaceutical composition and application thereof

Abstract

The present invention belongs to the field of medicine, and specifically discloses an amino alcohol derivative represented by Formula I, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof. In addition, the present invention also discloses a pharmaceutical composition comprising the above substances, and a use of the substance in the preparation of a medicament for the prevention and treatment of an immune inflammatory disease, or a disease or condition associated with immunological competence such as multiple sclerosis, ALS, CIDP, systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, psoriasis, polymyositis, etc.

Claims

1. An amino alcohol derivative represented by the following Formula I′, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph, or prodrug thereof: ##STR00084## wherein R.sub.1 and R.sub.2 are the same or different, and is each independently selected from the group consisting of H, —F, —Cl, —Br, —I, —OH, —SH, —CN, —COOH, —NO.sub.2 and the following group of C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.3-20 cycloalkyl, C.sub.3-20 cycloalkoxy, 3- to 20-membered heterocyclyl, 3- to 20-membered heterocycloxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, 5- to 20-membered heteroaryl, 5- to 20-membered heteroaryloxy, H[(CH.sub.2).sub.nO].sub.m—, —NR.sub.dR.sub.e, —CONR.sub.dR.sub.e or —C(O)Y.sub.1R.sub.d, each of which is unsubstituted or optionally substituted with one or more R.sub.a; R.sub.3 is selected from the group consisting of C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-20 aryl and 5- to 20-membered heteroaryl, each of which is unsubstituted or optionally substituted with one or more R.sub.b; each R.sub.a is the same as or different from any other one and is independently selected from the group consisting of C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.3-20 cycloalkyl, —F, —Cl, —Br, —I, —OH, —NH, —SH, —CN, ═O or —COOH; (i) each R.sub.b is the same as or different from any other one and is independently selected from the group consisting of —F, —Cl, —Br, —I, —SH, —OH, —CN, —COOH and the following group of C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-20 aryl, 5- to 20-membered heteroaryl, C.sub.3-20 cycloalkoxy, 3- to 20-membered heterocycloxy, C.sub.6-20 aryloxy, 5- to 20-membered heteroaryloxy, (C.sub.3-20)cycloalkyl(C.sub.1-40)alkyl, (3- to 20-membered)heterocyclyl(C.sub.1-40)alkyl, (C.sub.6-20)aryl(C.sub.1-40)alkyl, (5- to 20-membered)heteroaryl(C.sub.1-40)alkyl, H[(CH.sub.2).sub.nO].sub.n—, —NR.sub.cR.sub.d, —C(O)NR.sub.cR.sub.d, —Y.sub.1C(O)R.sub.e and —C(O)Y.sub.1R.sub.e, each of which is unsubstituted or optionally substituted with one or more R.sub.a, or, (ii) when R.sub.3 is substituted with two or more identical or different R.sub.b, two of which losing their hydrogen atoms or other groups respectively, are taken together with the carbon atoms to which they are attached to form a ring system R.sub.s fused with R.sub.3, wherein R.sub.s is selected from the group consisting of C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-20 aryl, or 5- to 20-membered heteroaryl fused with R.sub.3; R.sub.c, R.sub.d and R.sub.e are the same or different, each of which is independently selected from the group consisting of H and the following group of C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-20 aryl, 5- to 20-membered heteroaryl or CONH.sub.2, each of which is unsubstituted or optionally substituted with one or more R.sub.a; Y.sub.1 is selected from the group consisting of a chemical bond, —O—, —S—, and the group of —NH—, C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-20 aryl, 5- to 20-membered heteroaryl, or (CH.sub.2CH.sub.2O).sub.j—, each of which is unsubstituted or optionally substituted with one or more R.sub.a; m, n and j may be the same or different, each of which is independently selected from an integer equal to or more than 1; R.sub.3 is selected from the group consisting of C.sub.3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-10 aryl and 5- to 6-membered heteroaryl, each of which is unsubstituted or optionally substituted with one or more R.sub.b; each R.sub.b is the same as or different from any other one and is independently selected from the group consisting of —F, —Cl, —Br, —I, —SH, —OH, —CN, —COOH and the following group of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-10 aryl, 5- to 6-membered heteroaryl, C.sub.3-8 cycloalkoxy, 3- to 8-membered heterocycloxy, C.sub.6-10 aryloxy, 5- to 6-membered heteroaryloxy, (C.sub.3-8)cycloalkyl(C.sub.1-6)alkyl, (3- to 8-membered)heterocyclyl(C.sub.1-6)alkyl, (C.sub.6-10)aryl(C.sub.1-6)alkyl, (5- to 6-membered)heteroaryl(C.sub.1-6)alkyl, H[(CH.sub.2).sub.nO].sub.n—, —NR.sub.cR.sub.d, —C(O)NR.sub.cR.sub.d, —Y.sub.1C(O)R.sub.e or —C(O)Y.sub.1R.sub.e, each of which is unsubstituted or optionally substituted with one or more R.sub.a; or, when R.sub.3 is substituted with two or more identical or different R.sub.b, two of which losing their hydrogen atoms or other groups respectively, are taken together with the carbon atoms to which they are attached to form a ring system R.sub.s fused with R.sub.3, wherein R.sub.s is selected from the group consisting of C.sub.3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-10 aryl, or 5- to 6-membered heteroaryl fused with R.sub.3.

2. The amino alcohol derivative, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph, or prodrug thereof according to claim 1, wherein R.sub.3 is selected from the group consisting of phenyl, pyridinyl, pyrazinyl, cyclohexyl, piperidinyl and piperazinyl.

3. The amino alcohol derivative, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph, or prodrug thereof according to claim 1, wherein the compound of Formula I′ is selected from the group consisting of the following compounds: ##STR00085##

4. The amino alcohol derivative, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph, or prodrug thereof according to claim 1, wherein R.sub.1 and R2 are the same or different, each of which is independently selected from the group consisting of H, —F, —CI, —Br, —I, —OH, —SH, —CN, —COOH, and C.sub.1-40 alkyl.

5. The amino alcohol derivative, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph, or prodrug thereof according to claim 1, wherein R.sub.3 is selected from the group consisting of phenyl, pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl.

6. The amino alcohol derivative, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph, or prodrug thereof according to claim 1, wherein each R.sub.b is the same as or different from any other one and is independently selected from the group consisting of —F, —CI, —Br, —I, —SH, —OH, —CN, —COOH and the following group of C.sub.1-6 alkyl (such as methyl, ethyl, propyl, isopropyl, t-butyl), alkoxy (methoxy, ethoxy, propoxy, i-propoxy, t-butoxy), C3-6 cycloalkyl, C.sub.3-6 cycloalkoxy, alkylcarbonylamino, C.sub.1-6 alkoxycarbonal, C.sub.1-6 a lkylcarbonyloxy, (3- to 6-membered)heterocyclyl(C.sub.1-6)alkyl, —CONH.sub.2, and —NHCOCH.sub.3, each of which is unsubstituted or optionally substituted with one or more R.sub.a.

7. The amino alcohol derivative, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph, or prodrug thereof according to claim 1, wherein each R.sub.b is the same as or different from any other one and is independently selected from the group consisting of —F, —OH, —CN, —CF.sub.3, —COOH, —CONH.sub.2, methoxy, ethoxy, propoxy, i-propoxy, —NHCOCH.sub.3, cyclopentyl, —C(O)OCH.sub.3, 1-azetidinylmethyl, 1-pyrrolidinylmethyl, and 1-piperidinylmethyl.

8. The amino alcohol derivative, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph, or prodrug thereof according to claim 1, wherein when R.sub.3 is substituted with two or more identical or different R.sub.b, two of which losing their hydrogen atoms or other groups respectively, are taken together with the carbon atoms to which they are attached to form a ring system R.sub.s fused with R.sub.3, wherein R.sub.s is a dioxol ring system fused with R.sub.3.

9. The amino alcohol derivative, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph, or prodrug thereof according to claim 1, wherein when R.sub.3 is phenyl, which is optionally substituted with R.sub.b3 at least in position 3 and R.sub.b3 is an electron withdrawing group.

10. The amino alcohol derivative, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph, or prodrug thereof according to claim 1, wherein when R.sub.3 is phenyl, which is optionally substituted with R.sub.b4 at least in position 4 and R.sub.b4 is an electron donating group.

11. The amino alcohol derivative, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph, or prodrug thereof according to claim 1, wherein R.sub.b3 is selected from the group consisting of —Cl, —Br, —I, —SH, —OH, —CN, —COOH, —CONH.sub.2, —CO—(C.sub.1-6) alkyl, —CO—(C.sub.3-6)cycloalkyl, and —CF.sub.3; or R.sub.b4 is selected from the group consisting of C.sub.1-6 alkyl optionally including methyl, ethyl, propyl, isopropyl, t-butyl, C.sub.1-6 alkoxy optionally including methoxy, ethoxy, propoxy, i-propoxy, t-butoxy, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkoxy, and C.sub.1-6 alkylcarbonylamino.

Description

DETAILED DESCRIPTION

(1) Hereinafter, the compound of formula I, preparation method and application thereof of the present invention will be described in more detail through the examples. It is understood that the following examples are merely exemplary descriptions and explanations, and should not be construed as limiting the scope of the present invention. Solutions obtained by a person skilled in the art based on the contents above mentioned of the invention are all covered in the scope of protection of the present invention.

(2) Unless otherwise indicated, the starting materials and reagents in the following examples were all commercially available products, or were prepared by the methods known in the art.

(3) The conditions for LC-MS analysis in the synthesis process are as follows:

(4) Instrument: Agilent LCMS1260/MSD6120;

(5) Chromatographic column: Agilent SB-C18, 2.1*50 mm, 1.8 μm, SN: USWEY07289;

(6) Mobile phase: A: H.sub.2O (0.1% FA) 90%, B: acetonitrile 10%, 0.400 ml/min, 45.00° C.

(7) Schedule

(8) TABLE-US-00002 Time Function Parameters 2.24 Changing solvent Solvent components A: 0.0% B: 100.0% components 3.00 Changing solvent Solvent components A: 0.0% B: 100.0% components 3.01 Changing flow Flow rate: 0.5 ml/min rate 3.01 Changing solvent Solvent components A: 90.0% B: 10.0% components 5.00 Changing solvent Solvent components A: 90.0% B: 10.0% components 5.01 Changing flow Flow rate: 0.4 ml/min rate 5.01 Changing solvent Solvent components A: 90.0% B: 10.0%. components

(9) Instrument Parameters:

(10) Ionization Mode: API-ES

(11) Polarity: Positive

(12) Collision-induced dissociations ascending order: Disabled

(13) Percentage of cycle time: 50.00%.

Preparation Example 1

(14) ##STR00021##

(15) Synthesis of Intermediate 2

(16) 100 g (465 mmol) of compound 1 was dissolved in 500 ml of dichloromethane, cooled to 0° C. in ice-salt bath, and added dropwise with 120 g (930 mmol) of oxalyl chloride. After the dropping was finished, the mixture obtained was heated at reflux and reacted for 2 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated to dryness, and dichloromethane was added and evaporated to dryness again to afford 112 g of intermediate, as a yellow liquid which was used directly in the next step. 210 g (1410 mmol) of aluminum chloride was suspended in 400 ml of dichloromethane, cooled to −10° C. to −5° C., and then added dropwise with a solution of 112 g of the above intermediate in 100 ml of dichloromethane. After the dropping was finished, ethylene gas was introduced into the reaction system for about 2 h keeping the temperature of −10° C. to −5° C. After TLC showed that the reaction was completed, the reaction solution was poured into ice-water mixture and extracted with dichloromethane. The organic phases were combined, washed twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried, and evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=5/1, v/v) to give a product (85 g) as an orange-red liquid. Yield: 81.7%. LC-MS: 225, 227 [M+1].sup.+, t.sub.R=2.153 min.

(17) Synthesis of Intermediate 3

(18) Under the protection of nitrogen, 25.5 g (113 mmol) of intermediate 2 was dissolved in 20 ml of dichloromethane, added with 1.78 g (5.6 mmol) of zinc iodide, and added dropwise with 20.7 ml (167 mmol) of trimethylsilyl cyanide under cooling in a water bath. The resulting mixture was stirred and reacted for 3 h at room temperature. The reaction was monitored by TLC. After the reaction was completed, a solution (80 ml, 20%) of ammonia in methanol was added and stirred for 3 days at room temperature. The reaction was stopped and the reaction solution was evaporated to dryness. A solution (100 ml, 11%) of hydrogen chloride in methanol was added to the residual. The mixture was stirred for 30 min, then added with 400 ml of methyl tert-butyl ether, stirred for 30 minutes again and filtered to give a product (27.9 g) as a light yellowish-white solid. Yield: 85.5%. LC-MS: 251, 253 [M+1].sup.+, t.sub.R=1.731 min.

(19) Synthesis of Intermediate 4

(20) 30 g (102 mmol) of intermediate 3 was suspended in 150 ml of sulphuric acid (50%, v:v), heated to 150° C. and reacted for 3 h. After HPLC showed that the reaction was completed, the mixture obtained was cooled to room temperature, placed in a refrigerator at 4° C. overnight and filtered. The filter cake was washed with concentrated hydrochloric acid and pumped to dryness in a dryer to give a product (32 g), as a light brown solid. Yield: 100%. LC-MS: 270, 272 [M+1].sup.+, t.sub.R=1.382 min.

(21) Synthesis of Intermediate 5

(22) 12.1 g (102 mmol) of thionyl chloride was added to 200 ml of methanol at 0° C., stirred for 1 h, then added with 25 g (34 mmol) of intermediate 4, heated at reflux and reacted for 15 h. The reaction was monitored by HPLC. After the reaction was completed, the reaction solution was evaporated to dryness and adjusted pH to 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and evaporated to dryness to give a product (9 g) as a reddish brown oily substance. Yield: 91.1%. LC-MS: 284,286 [M+1].sup.+, t.sub.R=1.507 min.

Preparation of Intermediate 6: (2-amino-7-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)methanol

(23) 4.8 g (126 mmol) of lithium aluminium hydride was suspended in 200 ml of tetrahydrofuran, cooled to −10° C., added dropwise with a solution of 18 g (63 mmol) of intermediate 5 in 100 ml of tetrahydrofuran and then reacted for 30 min at −10° C. The reaction was monitored by TLC. After the reaction was completed, 4.8 ml of water, 14.4 ml of sodium hydroxide solution (10%) and 24 ml of water were added sequentially to the reaction system. The mixture was stirred for 20 min, then added with 70 g of anhydrous sodium sulfate, stirred for 30 minutes and allowed to stand overnight. The resulting mixture was filtered, dried and evaporated to dryness to give a product (17 g) as a black oily substance. Yield: 100%. LC-MS: 256, 258 [M+1].sup.+, t.sub.R=1.143 min.

Preparation of Intermediate 7-1: (S)-(2-amino-7-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)methanol

(24) The racemic mixture of intermediate 6 was separated by recrystallization process with D-tartaric acid many times until specific rotation of the product no longer increased to give chiral intermediate 7-1. Specific Rotation [α].sub.D.sup.20=27 (C=1, MeOH). LC-MS: 256,258 [M+1].sup.+, t.sub.R=1.143 min.

(25) Synthesis of Intermediate 8-1

(26) 17 g (66 mmol) of intermediate 7-1 and 7.75 g (73 mmol) of benzaldehyde were dissolved in 200 ml of dichloromethane, added with 6 g (99.6 mmol) of acetic acid, stirred for 1 hour, added with 21.1 g (99.6 mmol) of sodium triacetoxyborohyride in batches in an ice-salt bath, and then reacted for 2 h at room temperature. The reaction was monitored by TLC. After the reaction was completed, the reaction system was adjusted to pH 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=10/1, v/v) to give a product (15.6 g) as a black oily substance. Yield: 73%. LC-MS: 346, 348 [M+1].sup.+, t.sub.R=1.821 min.

(27) Synthesis of Intermediate 8-2

(28) 15.6 g (45 mmol) of intermediate 8-1 was dissolved in 120 ml of 2,2-dimethoxypropane, added with 1 g (5.8 mmol) of p-toluenesulfonic acid monohydrate and 10 g of molecular sieve, heated to 135° C. under confinement and reacted for 16 h. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was filtered, evaporated to dryness, added with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phases were combined, dried and evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=30/1, v/v) to give a product (13 g) as a faint yellow solid. Yield: 75.1%. LC-MS: 386, 388 [M+1].sup.+, t.sub.R=3.352 min.

(29) Synthesis of Intermediate 9-1

(30) 14 g (36 mmol) of intermediate 8-2 was dissolved in 100 ml of tetrahydrofuran, cooled to −78° C. under the protection of nitrogen and added dropwise with 17 ml (43.5 mmol) of n-butyllithium. The resulting mixture was stirred for 30 min at −78° C., then introduced with carbon dioxide gas for 30 minutes and naturally warmed to room temperature. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was adjusted to pH 5-6 with acetic acid and evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=30/1, v/v) to give a product (9.1 g) as a yellowish-white solid. Yield: 71.9%. LC-MS: 352 [M+1].sup.+, t.sub.R=2.415 min.

(31) Synthesis of Intermediate 17

(32) ##STR00022##

(33) 0.8 g (4.7 mmol) of material 16, 2.6 g (18.8 mmol) of potassium carbonate and 1.8 ml (18.8 mmol) of 2-bromopropane were suspended in 8 ml of DMF and reacted at 100° C. for 1 h. The reaction was monitored by TLC (PE/EA=3:1). After the reaction was completed, 30 ml of saturated sodium bicarbonate solution and 30 ml of ethyl acetate were added to the resulting mixture, which was stirred, allowed to stand, and separated. The organic phase was washed with 2×30 ml of water, dried and evaporated to dryness to give a crude product, as a brown liquid (0.94 g). Yield: 93.7%.

(34) Synthesis of Intermediate 19

(35) ##STR00023##

(36) Under the protection of nitrogen, 0.94 g (4.4 mmol) of intermediate 17 was suspended in 3.2 g (52.9 mmol, 85%) of hydrazine hydrate, and reacted at 85° C. for 500 min. The reaction was monitored by TLC (PE/EA=1:1+Et.sub.3N). After the reaction was completed, the resulting mixture was cooled to room temperature, filtered, washed with water, and pumped to dryness to give a white solid (0.86 g). Yield: 91.7%. LC-MS: 213 [M+1].sup.+, t.sub.R=2.441 min.

(37) Synthesis of Intermediate 21

(38) ##STR00024##

(39) 0.9 g (2.56 mmol) of intermediate 9-1 was dissolved in 36 ml of dichloromethane, added with 0.015 ml (cat.) of N,N-dimethylformamide and cooled to 0° C. 0.65 ml (7.68 mmol) of oxalyl chloride was added dropwise to the mixture, then naturally warmed to room temperature and reacted for 1 h. After the reaction was completed, the reaction solution was concentrated and added with 16 ml of dichloromethane, as a stock solution. 0.82 g (3.84 mmol) of compound 19 and 1.1 ml (7.68 mmol) of triethylamine were dissolved in 16 ml of dichloromethane, cooled to 0° C., added dropwise with the solution of acyl chloride in dichloromethane obtained above, then naturally warmed to room temperature and reacted overnight. The reaction was monitored by TLC (PE/EA=3:1+AcOH). After the reaction was completed, 40 ml of saturated sodium bicarbonate solution was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1, v/v) to give a product (1.2 g) as a yellow solid. Yield: 84.8%. LC-MS: 546 [M+1].sup.+, t.sub.R=4.125 min.

(40) Synthesis of Intermediate 22

(41) ##STR00025##

(42) 1.2 g (2.16 mmol) of intermediate 21 and 1 ml (6.49 mmol) of triethylamine were dissolved in 24 ml of acetonitrile, cooled to 0° C., added with 0.62 g (3.24 mmol) of 4-toluene sulfonyl chloride, and stirred overnight at room temperature. The reaction was monitored by TLC (PE/EA=1:1). After the reaction was completed, water was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=10/1, v/v) to give a product (0.7 g) as a white solid. Yield: 61.4%. LC-MS: 528 [M+1].sup.+, t.sub.R=5.226 min.

(43) Synthesis of Intermediate 23

(44) ##STR00026##

(45) 0.7 g (1.33 mmol) of intermediate 22 was dissolved in 3.7 ml of hydrochloric acid (1 M) and 21 ml of methanol, and reacted for 120 min at 80° C. The reaction was monitored by TLC (PE/EA=1:1+Et.sub.3N). After the reaction was completed, the resulting mixture was concentrated by rotary evaporation, added with 20 ml of saturated sodium bicarbonate solution and 20 ml of dichloromethane, and separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/2+1% Et.sub.3N, v/v) to give a product (0.6 g) as a white solid. Yield: 94.0%.

Example 1 (S)-(2-amino-7-(5-(3-fluoro-4-isopropoxyphenyl)-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)methanol

(46) ##STR00027##

(47) 0.6 g (1.24 mmol) of intermediate 23 was dissolved in 13 ml of methanol, added with 0.01 ml of concentrated hydrochloric acid, purged with nitrogen to remove air, followed by the addition of 0.122 g (20% m/m) of palladium 10% on carbon, purged with hydrogen, and reacted for 240 min at 95° C. The reaction was monitored by TLC (DCM:MeOH=10:1). After the reaction was completed, the resulting mixture was filtered, and the filter cake was washed with plenty of methanol. The filtrate was concentrated by rotary evaporation, added with 30 ml of saturated sodium bicarbonate solution and 30 ml of dichloromethane, stirred, allowed to stand and separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried, filtered and rotary evaporated to give a crude product, which was purified with silica gel column (eluent: DCM:MeOH=10/1+1% Et.sub.3N, V/V) to give the target compound of Example 1 as a white solid (0.3 g). Yield: 61.89%. LC-MS: 398 [M+1].sup.+, t.sub.R=3.090 min. A corresponding hydrogenchloride salt was obtained by mixing the solid with a solution of hydrogen chloride in methanol under stirring.

Preparation Example 2

(48) Synthesis of Intermediate 27

(49) ##STR00028##

(50) 2.0 g (12 mmol) of intermediate 26 was dissolved in 20 ml of methanol, cooled to 0° C., added dropwise with 2.6 ml (36 mmol) of thionyl chloride, warmed to room temperature, stirred and reacted overnight. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution, and rotary evaporated to dryness to remove methanol. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a product (1.9 g) as a white solid. Yield: 81.67%.

(51) Synthesis of Intermediate 28

(52) ##STR00029##

(53) Under the protection of nitrogen, 1.911 g (9.8 mmol) of intermediate 27 was dissolved in 7 g (118.7 mmol, 85%) of hydrazine hydrate, heated to 85° C. and reacted for 7 h. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was cooled to room temperature, filtered and pumped to dryness to give a white solid (1.728 g). Yield: 81.67%.

(54) Synthesis of Intermediate 29

(55) ##STR00030##

(56) 1.0 g (2.84 mmol) of intermediate 9-1 was dissolved in 40 ml of dichloromethane, added with 5 drops of N,N-dimethylformamide and cooled to 0° C. 0.72 ml (8.52 mmol) of oxalyl chloride was added dropwise to the mixture, then naturally warmed to room temperature and reacted for 1 hour. After the reaction was completed, the reaction solution was concentrated and added with 30 ml of dichloromethane, as a stock solution. 0.823 g (8.52 mmol) of compound 28 and 1.19 ml (8.52 mmol) of triethylamine were dissolved in 30 ml of dichloromethane and cooled to 0° C. The solution of acyl chloride in dichloromethane obtained above was added dropwise to the mixture, then naturally warmed to room temperature and reacted overnight. The reaction was monitored by TLC (PE/EA=3:1+AcOH). After the reaction was completed, 500 ml of saturated sodium bicarbonate solution was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1, v/v) to give a product (1.3 g) as a yellow solid. Yield: 89.08%. LC-MS: 514 [M+1].sup.+, t.sub.R=8.349 min.

(57) Synthesis of Intermediate 30

(58) ##STR00031##

(59) 1.3 g (2.53 mmol) of intermediate 29 and 1.06 ml (7.60 mmol) of triethylamine were dissolved in 30 ml of acetonitrile, cooled to 0° C., added with 0.73 g (3.80 mmol) of 4-toluene sulfonyl chloride, and stirred overnight at room temperature. The reaction was monitored by TLC (PE/EA=1:1). After the reaction was completed, water was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1, v/v) to give a product (1.2 g) as a yellow solid. Yield: 95.65%.

(60) Synthesis of Intermediate 31

(61) ##STR00032##

(62) 1.2 g (2.42 mmol) of intermediate 30 was dissolved in 5.2 ml of hydrochloric acid (1 M) and 30 ml of methanol, and reacted for 30 min at 80° C. The reaction was monitored by TLC (PE/EA=1:1+Et.sub.3N). After the reaction was completed, the resulting mixture was concentrated by rotary evaporation, added with 30 ml of saturated sodium bicarbonate solution and 30 ml of dichloromethane, and separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1+1% Et.sub.3N, v/v) to give a product (0.7 g) as a yellow solid. Yield: 63.64%.

Example 2 (S)-(2-amino-7-(5-(3-fluoro-4-isopropoxyphenyl)-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)methanol

(63) ##STR00033##

(64) 0.7 g (1.54 mmol) of intermediate 31 was dissolved in 30 ml of methanol, added with 4 drops of concentrated hydrochloric acid, purged with nitrogen to remove air, followed by the addition of 0.14 g (20% m/m) of palladium 10% on carbon, purged with hydrogen, and reacted for 5 h at 95° C. The reaction was monitored by TLC (DCM:MeOH=10:1). After the reaction was completed, the resulting mixture was filtered, and the filter cake was washed with plenty of methanol. The filtrate was concentrated by rotary evaporation, added with 30 ml of saturated sodium bicarbonate solution and 30 ml of ethyl acetate, stirred, allowed to stand and separated into layers. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, filtered and rotary evaporated to give a crude product, which was purified with silica gel column (eluent: DCM:MeOH=10/1, V/V) to give the target compound of Example 2 as a faint yellow solid (0.514 g). Yield: 91.35%. LC-MS: 366 [M+1].sup.+, t.sub.R=2.64 min. A corresponding hydrogenchloride salt was obtained by mixing the solid with a solution of hydrogen chloride in methanol under stirring. .sup.1H NMR (400 MHz, DMSO) δ 8.31 (s, 3H), 7.89 (d, J=6.8 Hz, 2H), 7.77-7.68 (m, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 6.18 (s, 2H), 3.17 (s, 2H), 3.08 (s, 2H), 3.02-2.81 (m, 3H), 2.11-1.90 (m, 2H).

Preparation Example 3

(65) Synthesis of Intermediate 35

(66) ##STR00034##

(67) Under the protection of nitrogen, 5.5 g (23.8 mmol) of intermediate 34 and 2.3 g (26.1 mmol) of cuprous cyanide were suspended in 30 ml of N-methylpyrrolidone, and reacted at 200° C. for 5 h. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was added with 60 ml of water and 60 ml of ethyl acetate, stirred for 30 min, and filtered. The filter cake was washed with ethyl acetate and the mother liquor was extracted with ethyl acetate. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: ethyl acetate/petroleum ether=1/1, v/v) to give a product (3.6 g) as a yellow oily substance. Yield: 85.3%. LC-MS: 178 [M+1].sup.+, t.sub.R=3.251 min.

(68) Synthesis of Intermediate 36

(69) ##STR00035##

(70) 3.6 g (20.3 mmol) of intermediate 35, 9.9 g (81.3 mmol) of 2-bromopropane and 11.2 g (81.3 mmol) of potassium carbonate were suspended in 36 ml of N,N-dimethylformamide, and reacted at 90° C. for 2 h. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was added with 30 ml of water and 30 ml of ethyl acetate, and separated into layers. The organic phase was washed with water for 3 times, dried and rotary evaporated to dryness to give a crude product (2.6 g) as a yellow oily substance. Yield: 58.1%.

(71) Synthesis of Intermediate 37

(72) ##STR00036##

(73) Under the protection of nitrogen, 2.6 g (11.8 mmol) of intermediate 36 was dissolved in 5.9 g (110 mmol, 85%) of hydrazine hydrate, and reacted at 60° C. for 1 h. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was cooled to room temperature, filtered, washed with water, and pumped to dryness to give a white solid (2 g). Yield: 77.1%.

(74) Synthesis of Intermediate 38

(75) ##STR00037##

(76) 2.6 g (7.6 mmol) of intermediate 9-1 was dissolved in 120 ml of dichloromethane, added with 0.01 g (cat.) of N,N-dimethylformamide and cooled to 0° C. 2.9 g (22.8 mmol) of oxalyl chloride was added dropwise to the mixture, then naturally warmed to room temperature and reacted for 3 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated and added with 50 ml of dichloromethane, as a stock solution. 2 g (9.1 mmol) of compound 37 and 7.9 g (22.8 mmol) of triethylamine were dissolved in 50 ml of dichloromethane and cooled to 0° C. The solution of acyl chloride in dichloromethane obtained above was added dropwise to the mixture, then naturally warmed to room temperature and reacted overnight. The reaction was monitored by TLC. After the reaction was completed, 100 ml of saturated sodium bicarbonate solution was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1, v/v) to give a product (4.1 g) as a yellow solid. Yield: 97.3%.

(77) Synthesis of Intermediate 39

(78) ##STR00038##

(79) 4.1 g (7.4 mmol) of intermediate 38 and 2.2 g (22.2 mmol) of triethylamine were dissolved in 120 ml of acetonitrile, added with 2.1 g (11.1 mmol) of 4-toluene sulfonyl chloride, and stirred overnight at room temperature. The reaction was monitored by TLC. After the reaction was completed, water was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and evaporated to dryness to give a crude product (4.3 g) as a tan solid. Yield: 100%.

(80) Synthesis of Intermediate 40

(81) ##STR00039##

(82) 4.3 g (8 mmol) of intermediate 39 was dissolved in 20.1 ml of hydrochloric acid (1 M) and 120 ml of methanol, and reacted for 2 h at 80° C. The reaction was monitored by TLC. After the reaction was completed, 50 ml of saturated sodium bicarbonate solution was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1, v/v) to give a product (1.5 g) as a white solid. Yield: 37.5%.

Example 3 (S)-5-(5-(7-amino-7-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-oxadiazol-2-yl)-2-isopropoxybenzonitrile

(83) ##STR00040##

(84) 1.5 g (3.0 mmol) of intermediate 40 was dissolved in 45 ml of methanol, added with 0.5 ml of concentrated hydrochloric acid, purged with nitrogen to remove air, followed by the addition of 0.3 g (20% m/m) of palladium 10% on carbon, purged with hydrogen, and reacted for 8 h at 80° C. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was filtered, and the filter cake was washed with hot methanol. The filtrate was rotary evaporated to dryness to give a crude product (1.5 g), which was recrystallized in 15 ml of methanol, filtered and washed to give the target compound of Example 3 as a white solid (0.65 g). Yield: 54.1%. LC-MS: 405 [M+1].sup.+, t.sub.R=3.002 min. A corresponding hydrogenchloride salt was obtained by mixing the solid with a solution of hydrogen chloride in methanol under stirring. .sup.1H NMR (400 MHz, DMSO) δ 8.51 (d, J=2.2 Hz, 1H), 8.37 (dd, J=9.0, 2.2 Hz, 1H), 8.12 (s, 3H), 7.96 (d, J=6.6 Hz, 2H), 7.54 (d, J=9.2 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 5.62 (t, J=5.1 Hz, 1H), 5.01-4.87 (m, 1H), 3.47 (d, J=4.9 Hz, 2H), 3.22-2.83 (m, 5H), 2.06-1.89 (m, 2H), 1.38 (d, J=6.0 Hz, 6H).

Example 4 (S)-5-(5-(7-amino-7-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-oxadiazol-2-yl)-2-isopropoxybenzamide

(85) ##STR00041##

(86) 0.2 g (0.49 mmol) of the target compound of Example 3 was dissolved in 5 ml of dimethyl sulfoxide, added with 0.25 g (1.8 mmol) of potassium carbonate, cooled to 0° C., added dropwise with 2 ml of hydrogen peroxide solution (30%), and stirred for 2 h at room temperature. The reaction was monitored by TLC. After the reaction was completed, the resulting solution was added with 30 ml of water, stirred for 10 min, filtered, washed with water, and pumped to dryness to give a crude product. The crude product was recrystallized in 20 ml of methanol, filtered and washed to give the target compound of Example 4 as a white solid (110 mg). Yield: 53.4%. A corresponding hydrogenchloride salt was obtained by mixing the solid with a solution of hydrogen chloride in methanol under stirring. H NMR (400 MHz, DMSO) δ 8.50 (d, J=2.3 Hz, 1H), 8.26 (s, 3H), 8.19 (dd, J=8.8, 2.3 Hz, 1H), 7.90 (s, 2H), 7.79 (s, 1H), 7.65 (s, 1H), 7.40 (t, J=9.5 Hz, 2H), 6.11-5.14 (br s, 1H), 5.01-4.85 (m, 1H), 3.48 (s, 3H), 3.19-2.76 (m, 4H), 2.00 (t, J=6.4 Hz, 2H), 1.40 (d, J=6.0 Hz, 6H).

Example 5 (S)-5-(5-(7-amino-7-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-oxadiazol-2-yl)-2-hydroxybenzonitrile

(87) ##STR00042##

(88) 100 mg (0.24 mmol) of the target compound of Example 3 was dissolved in sulphuric acid (50%), and reacted for 1 h at 90° C. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was added with saturated sodium bicarbonate solution to adjust pH to 2-3, filtered, washed with water, and pumped to dryness to give the target compound of Example 5 as a white solid (35 mg). Yield: 34.3%. LC-MS: 363 [M+1].sup.+, t.sub.R=1.142 min. A corresponding hydrogenchloride salt was obtained by mixing the solid with a solution of hydrogen chloride in methanol under stirring.

Preparation Example 4

(89) Synthesis of Intermediate 46

(90) ##STR00043##

(91) 2.0 g (9.08 mmol) of material 45, 0.98 g (18.17 mmol) of sodium methoxide and a small amount of TBAB were suspended in 40 ml of THF, stirred for 30 min at room temperature, followed by the addition of 1.7 ml of methyl iodide, stirred and reacted at room temperature. The reaction was monitored by TLC (PE/EA=3:1). The reaction solution was added with methyl iodide until the material was reacted completely, then concentrated by rotary evaporation, added with 40 ml of saturated sodium bicarbonate solution and 40 ml of dichloromethane, stirred, allowed to stand and separated. The aqueous phase was extracted with 2×40 ml of dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product (2.1 g) as a yellow solid. Yield: 100%. LC-MS: 235 [M+1].sup.+, t.sub.R=4.457 min.

(92) Synthesis of Intermediate 47

(93) ##STR00044##

(94) Under the protection of nitrogen, 2.12 g (9.08 mmol) of intermediate 46 was suspended in 6.4 ml (108.96 mmol, 85%) of hydrazine hydrate, and reacted at 85° C. for 100 min. The reaction was monitored by TLC (PE/EA=1:1+Et.sub.3N). After the reaction was completed, the resulting mixture was cooled to room temperature, filtered, washed with water, and pumped to dryness to give a crude product (1.96 g), as a white solid. Yield: 92.4%. LC-MS: 235 [M+1].sup.+, t.sub.R=3.005 min.

(95) Synthesis of Intermediate 48

(96) ##STR00045##

(97) 2.9 g (8.25 mmol) of intermediate 9-1 was dissolved in 60 ml of dichloromethane, added with 0.01 g (cat.) of N,N-dimethylformamide and cooled to 0° C. 2.1 ml (24.75 mmol) of oxalyl chloride was added dropwise to the mixture, then naturally warmed to room temperature and reacted for 1 h. After the reaction was completed, the reaction solution was concentrated and added with 30 ml of dichloromethane, as a stock solution. 2.32 g (9.9 mmol) of compound 47 and 3.5 ml (24.75 mmol) of triethylamine were dissolved in 30 ml of dichloromethane and cooled to 0° C. The solution of acyl chloride in dichloromethane obtained above was added dropwise to the mixture, then naturally warmed to room temperature and reacted for 3 h. The reaction was monitored by TLC (PE/EA=1:1+AcOH). After the reaction was completed, 70 ml of saturated sodium bicarbonate solution was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1, v/v) to give a product (3.1 g) as a brown solid. Yield: 66.2%. LC-MS: 568 [M+1], t.sub.R=4.678 min.

(98) Synthesis of Intermediate 49

(99) ##STR00046##

(100) 3.1 g (5.46 mmol) of intermediate 48 and 2.3 ml (16.38 mmol) of triethylamine were dissolved in 124 ml of acetonitrile, cooled to 0° C., added with 1.56 g (8.19 mmol) of 4-toluene sulfonyl chloride, and stirred overnight at room temperature. The reaction was monitored by TLC (PE/EA=1:1). After the reaction was completed, water was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=3/1, v/v) to give a product (1.9 g) as a faint yellow solid. Yield: 63.3%. LC-MS: 550 [M+1].sup.+, t.sub.R=6.464 min.

(101) Synthesis of Intermediate 50

(102) ##STR00047##

(103) 1.0 g (1.82 mmol) of intermediate 49 was dissolved in 4.55 ml of hydrochloric acid (1 M) and 30 ml of methanol, and reacted for 100 min at 80° C. The reaction was monitored by TLC (PE/EA=1:1+Et.sub.3N). After the reaction was completed, the resulting mixture was concentrated by rotary evaporation, added with 50 ml of saturated sodium bicarbonate solution and 50 ml of dichloromethane, and separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/2+1% Et.sub.3N, v/v) to give a product (0.8 g) as a white solid. Yield: 86.32%.

Example 6 (S)-(2-amino-7-(5-(4-methoxy-3-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)methanol

(104) ##STR00048##

(105) 0.8 g (1.57 mmol) of intermediate 50 was dissolved in 16 ml of methanol, added with 0.1 ml of concentrated hydrochloric acid, purged with nitrogen to remove air, followed by the addition of 0.16 g (20% m/m) of palladium 10% on carbon, purged with hydrogen, and reacted for 5 h at 95° C. The reaction was monitored by TLC (DCM:MeOH=10:1). After the reaction was completed, the resulting mixture was filtered, and the filter cake was washed with hot methanol. The filtrate was rotary evaporated to dryness to give a crude product, which was recrystallized in 24 ml of methanol, filtered and washed to give the target compound of Example 6 as a white solid (0.36 g). Yield: 54.67%. LC-MS: 420 [M+1].sup.+, t.sub.R=3.002 min. A corresponding hydrogenchloride salt was obtained by mixing the solid with a solution of hydrogen chloride in methanol under stirring.

Preparation Example 5

(106) Synthesis of Intermediate 54

(107) ##STR00049##

(108) Under the protection of nitrogen, 2.0 g (11.62 mmol) of material 53 was dissolved in 20 ml of methanol, added with 8.2 ml (139.44 mmol, 85%) of hydrazine hydrate, and reacted at room temperature for 1.5 h. The reaction was monitored by TLC (PE/EA=3:1). After the reaction was completed, the resulting mixture was added with 50 ml of water and stirred to precipitate out a solid, filtered, washed with water, and pumped to dryness. The aqueous phase was extracted with EA. The organic phase was dried, concentrated by rotary evaporation, and pumped to dryness to give a product (2 g), as a white solid. Yield: 100%. LC-MS: 173 [M+1].sup.+, t.sub.R=2.528 min.

(109) Synthesis of Intermediate 56

(110) ##STR00050##

(111) 1 g (2.84 mmol) of intermediate 9-1 was dissolved in 40 ml of dichloromethane, added with 0.01 g (cat.) of N,N-dimethylformamide and cooled to 0° C. 0.72 ml (8.52 mmol) of oxalyl chloride was added dropwise to the mixture, then naturally warmed to room temperature and reacted for 1 hour. After the reaction was completed, the reaction solution was concentrated and added with 20 ml of dichloromethane, as a stock solution. 0.54 g (3.13 mmol) of compound 54 and 1.2 ml (8.52 mmol) of triethylamine were dissolved in 20 ml of dichloromethane and cooled to 0° C. The solution of acyl chloride in dichloromethane obtained above was added dropwise to the mixture, then naturally warmed to room temperature and reacted overnight. The reaction was monitored by TLC (PE/EA=3:1+AcOH). After the reaction was completed, 40 ml of saturated sodium bicarbonate solution was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1, v/v) to give a product (0.7 g) as a yellow solid. Yield: 48.8%. LC-MS: 506 [M+1].sup.+, t.sub.R=4.587 min.

(112) Synthesis of Intermediate 57

(113) ##STR00051##

(114) 0.7 g (1.38 mmol) of intermediate 56 and 0.6 ml (4.14 mmol) of triethylamine were dissolved in 38 ml of acetonitrile, cooled to 0° C., added with 0.32 g (1.66 mmol) of 4-toluene sulfonyl chloride, and stirred for 5 h at room temperature. The reaction was monitored by TLC (PE/EA=1:1). After the reaction was completed, water was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=10/1, v/v) to give a product (0.43 g) as a white solid. Yield: 63.9%. LC-MS: 488[M+1].sup.+, t.sub.R=6.464 min.

(115) Synthesis of Intermediate 58

(116) ##STR00052##

(117) 0.4 g (0.82 mmol) of intermediate 57 was dissolved in 2.1 ml of hydrochloric acid (1 M) and 16 ml of methanol, and reacted for 1 h at 80° C. The reaction was monitored by TLC (PE/EA=1:1+Et.sub.3N). After the reaction was completed, 40 ml of saturated sodium bicarbonate solution was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1+1% Et.sub.3N, v/v) to give a product (0.242 g) as a white solid. Yield: 66.0%.

Example 7 (S)-(2-amino-7-(5-(3,4-difluorophenyl)-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)methanol

(118) ##STR00053##

(119) 0.24 g (0.54 mmol) of intermediate 58 was dissolved in 8 ml of methanol, added with 0.01 ml of concentrated hydrochloric acid, purged with nitrogen to remove air, followed by the addition of 0.048 g of palladium 10% on carbon, purged with hydrogen, and reacted for 5 h at 95° C. The reaction was monitored by TLC (DCM:MeOH=10:1). After the reaction was completed, the resulting mixture was filtered, and the filter cake was washed with hot methanol. The filtrate was rotary evaporated to dryness to give a crude product (1.5 g), which was purified with silica gel column (eluent: dichloromethane/methanol=10/1) to give the target compound of Example 7 as a white solid (0.18 g). Yield: 93.3%. LC-MS: 358 [M+1].sup.+, t.sub.R=3.717 min. A corresponding hydrogenchloride salt was obtained by mixing the solid with a solution of hydrogen chloride in methanol under stirring. .sup.1H NMR (400 MHz, DMSO) δ 8.30-8.16 (m, 1H), 8.09-7.96 (m, 1H), 7.87 (d, J=6.7 Hz, 2H), 7.79-7.64 (m, 1H), 7.34 (d, J=8.4 Hz, 1H), 5.38-4.14 (br, 3H), 3.74-3.16 (m, 5H), 3.05-2.65 (m, 4H), 1.91-1.60 (m, 2H).

Preparation Example 6

(120) Synthesis of Intermediate 62

(121) ##STR00054##

(122) Under the protection of nitrogen, 0.928 g (5.04 mmol) of intermediate 61 was dissolved in 3.56 g (60.48 mmol, 85%) of hydrazine hydrate, and reacted at 85° C. for 2 h. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was cooled to room temperature, filtered, and pumped to dryness to give a white solid (0.369 g). Yield: 39.68%.

(123) Synthesis of Intermediate 63

(124) ##STR00055##

(125) 0.47 g (1.34 mmol) of intermediate 9-1 was dissolved in 20 ml of dichloromethane, added with 3 drops of N,N-dimethylformamide and cooled to 0° C. 0.34 ml (4 mmol) of oxalyl chloride was added dropwise to the mixture, then naturally warmed to room temperature and reacted for 1 h. After the reaction was completed, the reaction solution was concentrated and added with 20 ml of dichloromethane, as a stock solution. 0.369 g (2 mmol) compound 62 and 0.56 ml (4 mmol) of triethylamine were dissolved in 20 ml of dichloromethane and cooled to 0° C. The solution of acyl chloride in dichloromethane obtained above was added dropwise to the mixture, then naturally warmed to room temperature and reacted overnight. The reaction was monitored by TLC (PE/EA=3:1+AcOH). After the reaction was completed, 30 ml of saturated sodium bicarbonate solution was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1, v/v) to give a product (0.302 g) as a yellow solid. Yield: 43.28%. LC-MS: 518 [M+1].sup.+, t.sub.R=5.462 min.

(126) Synthesis of Intermediate 64

(127) ##STR00056##

(128) 0.302 g (0.58 mmol) of intermediate 63 and 0.24 ml (1.74 mmol) of triethylamine were dissolved in 10 ml of acetonitrile, cooled to 0° C., added with 0.166 g (0.87 mmol) of 4-toluene sulfonyl chloride, and stirred overnight at room temperature. The reaction was monitored by TLC (PE/EA=1:1). After the reaction was completed, water was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1, v/v) to give a product (0.332 g) as a yellow solid. Yield: 100%.

(129) Synthesis of Intermediate 65

(130) ##STR00057##

(131) 0.332 g (0.58 mmol) of intermediate 64 was dissolved in 1.25 ml of hydrochloric acid (1 M) and 10 ml of methanol, and reacted for 30 min at 80° C. The reaction was monitored by TLC (PE/EA=1:1+Et.sub.3N). After the reaction was completed, the resulting mixture was concentrated by rotary evaporation, added with 10 ml of saturated sodium bicarbonate solution and 10 ml of dichloromethane, and separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1+1% Et.sub.3N, v/v) to give a product (0.214 g) as a yellow solid. Yield: 81.03%.

Example 8 (S)-(2-amino-7-(5-(3-fluoro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)methanol

(132) ##STR00058##

(133) 0.214 g (0.47 mmol) of intermediate 65 was dissolved in 10 ml of methanol, added with 2 drops of concentrated hydrochloric acid, purged with nitrogen to remove air, followed by the addition of 0.04 g (20% m/m) of palladium 10% on carbon, purged with hydrogen, and reacted for 4 h at 95° C. The reaction was monitored by TLC (DCM:MeOH=10:1). After the reaction was completed, the resulting mixture was filtered, and the filter cake was washed with plenty of methanol. The filtrate was concentrated by rotary evaporation, added with 10 ml of saturated sodium bicarbonate solution and 10 ml of ethyl acetate, stirred, allowed to stand and separated into layers. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, filtered and rotary evaporated to give a crude product, which was purified with silica gel column (eluent: DCM:MeOH=10/1, V/V) to give the target compound of Example 8 as a faint yellow solid (0.138 g). Yield: 79.49%. LC-MS: 370 [M+1].sup.+, t.sub.R=1.334 min. A corresponding hydrogenchloride salt was obtained by mixing the solid with a solution of hydrogen chloride in methanol under stirring.

Preparation Example 7

(134) Synthesis of Intermediate 69

(135) ##STR00059##

(136) 1.0 g (5.6 mmol) of intermediate 68 was dissolved in 10 ml of N,N-dimethylformamide, added with 2.34 ml (16.8 mmol) of triethylamine, cooled to 0° C., then added with 2.51 g (6.16 mmol) of N,N,N′,N′-tetramethyl-o-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, and stirred for 30 min. The resulting solution was added dropwise to a solution of 2.8 g (56 mmol) of hydrazine hydrate in 10 ml of N,N-dimethylformamide and reacted overnight. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was rotary evaporated to dryness, added with 10 ml of saturated sodium bicarbonate solution and 10 ml of dichloromethane, and separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: DCM/MeOH=10/1, v/v) to give a product (0.24 g) as a white solid. Yield: 22.18%. LC-MS: 194 [M+1].sup.+, t.sub.R=1.435 min.

(137) Synthesis of Intermediate 70

(138) ##STR00060##

(139) 2.1 g (5.97 mmol) of intermediate 9-1 was dissolved in 80 ml of dichloromethane, added with 10 drops of N,N-dimethylformamide and cooled to 0° C. 1.52 ml (17.92 mmol) of oxalyl chloride was added dropwise to the mixture, then naturally warmed to room temperature and reacted for 1 h. After the reaction was completed, the reaction solution was concentrated and added with 80 ml of dichloromethane, as a stock solution. 1.732 g (8.96 mmol) compound 69 and 2.5 ml (17.92 mmol) of triethylamine were dissolved in 80 ml of dichloromethane and cooled to 0° C. The solution of acyl chloride in dichloromethane obtained above was added dropwise to the mixture, then naturally warmed to room temperature and reacted overnight. The reaction was monitored by TLC (PE/EA=3:1+AcOH). After the reaction was completed, 120 ml of saturated sodium bicarbonate solution was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1, v/v) to give a product (2.0 g) as a yellow solid. Yield: 63.16%. LC-MS: 527 [M+1].sup.+, t.sub.R=2.457 min.

(140) Synthesis of Intermediate 71

(141) ##STR00061##

(142) 2.0 g (3.8 mmol) of intermediate 70 and 1.59 ml (11.4 mmol) of triethylamine were dissolved in 50 ml of acetonitrile, cooled to 0° C., added with 1.087 g (5.7 mmol) of 4-toluene sulfonyl chloride, and stirred overnight at room temperature. The reaction was monitored by TLC (PE/EA=1:1). After the reaction was completed, water was added to the resulting mixture, which was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=5/1, v/v) to give a product (2.2 g) as a yellow solid. Yield: 100%.

(143) Synthesis of Intermediate 72

(144) ##STR00062##

(145) 2.2 g (3.8 mmol) of intermediate 71 was dissolved in 8.17 ml of hydrochloric acid (1 M) and 50 ml of methanol, and reacted for 30 min at 80° C. The reaction was monitored by TLC (PE/EA=1:1+Et.sub.3N). After the reaction was completed, the resulting mixture was concentrated by rotary evaporation, added with 50 ml of saturated sodium bicarbonate solution and 50 ml of dichloromethane, and separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1+1% Et.sub.3N, v/v) to give a product (0.8 g) as a yellow solid. Yield: 45.0%.

Example 9 (S)—N-(4-(5-(7-amino-7-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)acetamide

(146) ##STR00063##

(147) 0.8 g (1.71 mmol) of intermediate 72 was dissolved in 30 ml of methanol, added with 5 drops of concentrated hydrochloric acid, purged with nitrogen to remove air, followed by the addition of 0.16 g (20% m/m) of palladium 10% on carbon, purged with hydrogen, and reacted for 4 h at 95° C. The reaction was monitored by TLC (DCM:MeOH=10:1). After the reaction was completed, the resulting mixture was filtered, and the filter cake was washed with plenty of methanol. The filtrate was concentrated by rotary evaporation, added with 30 ml of saturated sodium bicarbonate solution and 30 ml of ethyl acetate, stirred, allowed to stand and separated into layers. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, filtered and rotary evaporated to give a crude product, which was purified with silica gel column (eluent: DCM:MeOH=10/1, V/V) to give the target compound of Example 9 as a faint yellow solid (0.326 g). Yield: 50.38%. LC-MS: 379 [M+1].sup.+, t.sub.R=1.103 min. A corresponding hydrogenchloride salt was obtained by mixing the solid with a solution of hydrogen chloride in methanol under stirring.

Preparation Example 8

(148) Synthesis of Intermediate 76

(149) ##STR00064##

(150) 1.0 g (4.54 mmol) of material 75, 1.9 g (13.62 mmol) of potassium carbonate and 2.6 ml (27.00 mmol) of benzyl chloride were suspended in 40 ml of acetone, heated at reflux and reacted overnight. The reaction was monitored by TLC (PE/EA=3:1). After the material 75 was reacted completely, the reaction solution was concentrated by rotary evaporation, added with 40 ml of saturated sodium bicarbonate solution and 40 ml of dichloromethane, stirred, allowed to stand and separated into layers. The aqueous phase was extracted with 40 ml of dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=20/1, v/v) to give a product (1.4 g) as a white solid. Yield: 100%.

(151) Synthesis of Intermediate 77

(152) ##STR00065##

(153) Under the protection of nitrogen, 1.4 g (4.54 mmol) of intermediate 76 was suspended in 40 ml of methanol and 6.4 ml (108.96 mmol, 85%) of hydrazine hydrate, and reacted at 85° C. for 180 min. The reaction was monitored by TLC (PE/EA=1:1+Et.sub.3N). After the reaction was completed, the resulting mixture was concentrated by rotary evaporation, cooled to room temperature, added with 20 ml of water and stirred to precipitate out a solid, filtered, washed with water, and pumped to dryness to give a product (1.4 g), as a white solid. Yield: 100%. LC-MS: 311 [M+1].sup.+, t.sub.R=1.799 min.

(154) Synthesis of Intermediate 78

(155) ##STR00066##

(156) 1.36 g (3.87 mmol) of intermediate 9-1 was dissolved in 27 ml of dichloromethane, added with 0.01 g (cat.) of N,N-dimethylformamide and cooled to 0° C. 1.0 ml (11.61 mmol) of oxalyl chloride was added dropwise to the mixture, then naturally warmed to room temperature and reacted for 1 h. After the reaction was completed, the reaction solution was concentrated and added with 30 ml of dichloromethane, as a stock solution. 1.2 g (3.87 mmol) of intermediate 77 and 1.62 ml (11.61 mmol) of triethylamine were dissolved in 30 ml of dichloromethane and cooled to 0° C. The solution of acyl chloride in dichloromethane obtained above was added dropwise to the mixture, then naturally warmed to room temperature and reacted overnight. The reaction was monitored by TLC (PE/EA=3:1+AcOH). After the reaction was completed, 60 ml of saturated sodium bicarbonate solution was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=2/1, v/v) to give a product (1.4 g) as a yellow solid. Yield: 56.2%. LC-MS: 644 [M+1].sup.+, t.sub.R=2.396 min.

(157) Synthesis of Intermediate 79

(158) ##STR00067##

(159) 1.4 g (2.17 mmol) of intermediate 78 and 1.0 ml (6.51 mmol) of triethylamine were dissolved in 56 ml of acetonitrile, cooled to 0° C., added with 0.5 g (2.61 mmol) of 4-toluene sulfonyl chloride, and stirred overnight at room temperature. The reaction was monitored by TLC (PE/EA=1:1). After the reaction was completed, water was added to the resulting mixture, which was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=3/1, v/v) to give a product (0.6 g) as a faint yellow solid. Yield: 44.2%.

(160) Synthesis of Intermediate 80

(161) ##STR00068##

(162) 0.6 g (0.95 mmol) of intermediate 79 was dissolved in 2.4 ml of hydrochloric acid (1 M) and 30 ml of methanol, and reacted for 120 min at 80° C. to precipitate out a solid. The reaction was monitored by TLC (PE/EA=1:1+Et.sub.3N). After the reaction was completed, the resulting mixture was filtrated under vacuum. The mother liquor was concentrated by rotary evaporation, added with 30 ml of saturated sodium bicarbonate solution and 30 ml of dichloromethane, and separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/2+1% Et.sub.3N, v/v) to give a product (0.426 g) as a white solid. Yield: 76.57%.

Example 10 (S)-4-(5-(7-amino-7-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethyl)phenol

(163) ##STR00069##

(164) 0.426 g (0.727 mmol) of intermediate 80 was dissolved in 16 ml of methanol, added with 0.01 ml of concentrated hydrochloric acid, purged with nitrogen to remove air, followed by the addition of 0.09 g of palladium 10% on carbon, purged with hydrogen, and reacted overnight at 95° C. The reaction was monitored by TLC (DCM:MeOH=10:1). After the reaction was completed, the resulting mixture was filtered, and the filter cake was washed with hot methanol. The filtrate was concentrated by rotary evaporation, added with 1% sodium hydrate solution to adjust pH to 9-10. The aqueous phase was extracted with dichloromethane, added with hydrochloric acid (1 M) to adjust pH 5.8-6.2 to precipitate out a white solid, stirred for 30 min at room temperature, and then filtered under vacuum to give the target compound of Example 10 (25 mg) as a white solid, which is prone to oxidative degradation and stored at low temperature under the protection of nitrogen. Yield: 8.5%. LC-MS: 406 [M+1].sup.+, t.sub.R=1.328 min. A corresponding hydrogenchloride salt was obtained by mixing the solid with a solution of hydrogen chloride in methanol under stirring.

Preparation Example 9

(165) Synthesis of Intermediate 84

(166) ##STR00070##

(167) 1.0 ml (14.4 mmol) of thionyl chloride was added to 20 ml of methanol at low temperature, stirred and reacted for 1 h in an ice-water bath, followed by the addition of 1.0 g of material 83 to the reaction vessel, naturally warmed, then heated to 55° C., stirred and reacted for 1 h. The reaction was monitored by TLC (PE/EA=3:1+AcOH). After the material 83 was reacted completely, the reaction solution was concentrated by rotary evaporation, added with 20 ml of saturated sodium bicarbonate solution and 20 ml of ethyl acetate, stirred, allowed to stand and separated into layers. The aqueous phase was extracted with 40 ml of ethyl acetate twice. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product (0.7 g), as an oily substance. Yield: 65.7%.

(168) Synthesis of Intermediate 85

(169) ##STR00071##

(170) Under the protection of nitrogen, 0.7 g (3.2 mmol) of intermediate 84 was suspended in 7 ml of methanol and 1.9 ml (32 mmol, 85%) of hydrazine hydrate, and reacted at room temperature overnight. The reaction was monitored by TLC (PE/EA=3:1). After the reaction was completed, the resulting mixture was added with 20 ml of water and 20 ml of DCM, stirred, separated and extracted with DCM twice. The organic phases were combined, dried, filtered, concentrated under reduced pressure and pumped to dryness to give a white solid (0.7 g). Yield: 100%. LC-MS: 223 [M+1].sup.+, t.sub.R=1.879 min.

(171) Synthesis of Intermediate 86

(172) ##STR00072##

(173) 1.0 g (3.1 mmol) of intermediate 9-1 was dissolved in 40 ml of dichloromethane, added with 0.01 g (cat.) of N,N-dimethylformamide and cooled to 0° C. 0.8 ml (9.3 mmol) of oxalyl chloride was added dropwise to the mixture, then naturally warmed to room temperature and reacted for 1 h. After the reaction was completed, the reaction solution was concentrated and added with 20 ml of dichloromethane, as a stock solution. 0.7 g (3.87 mmol) intermediate 85 and 1.3 ml (9.3 mmol) of triethylamine were dissolved in 20 ml of dichloromethane and cooled to 0° C. The solution of acyl chloride in dichloromethane obtained above was added dropwise to the mixture, then naturally warmed to room temperature and reacted overnight. The reaction was monitored by TLC (PE/EA=3:1+AcOH). After the reaction was completed, 40 ml of saturated sodium bicarbonate solution was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product (1.5 g). Yield: 87.1%.

(174) Synthesis of Intermediate 87

(175) ##STR00073##

(176) 1.5 g (3.1 mmol) of intermediate 86 and 1.3 ml (9.3 mmol) of triethylamine were dissolved in 60 ml of acetonitrile, cooled to 0° C., added with 0.88 g (4.65 mmol) of 4-toluene sulfonyl chloride, and stirred overnight at room temperature. The reaction was monitored by TLC (PE/EA=1:1). After the reaction was completed, water was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=3/1, v/v) to give a product (1.3 g) as a faint yellow solid. Yield: 78.0%. LC-MS: 538 [M+1].sup.+, t.sub.R=3.251 min.

(177) Synthesis of Intermediate 88

(178) ##STR00074##

(179) 1.3 g (2.4 mmol) of intermediate 87 was dissolved in 6 ml of hydrochloric acid (1 M) and 40 ml of methanol, and reacted for 3 h at 80° C. The reaction was monitored by TLC (PE/EA=1:1+Et.sub.3N). After the reaction was completed, the resulting mixture was concentrated under reduced pressure, added with sodium hydrate solution (10%) and saturated sodium bicarbonate solution to adjust pH about 8, and extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1+1% Et.sub.3N, v/v) to give a product (0.6 g) as a white solid. Yield: 50.2%.

Example 11 (S)-(2-amino-7-(5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)methanol

(180) ##STR00075##

(181) 0.6 g (1.2 mmol) of intermediate 88 was dissolved in 20 ml of methanol, added with 0.01 ml of concentrated hydrochloric acid, purged with nitrogen to remove air, followed by the addition of 0.12 g (20% m/m) of 10% wet palladium on carbon, purged with hydrogen, and reacted for 6 h at 85° C. The reaction was monitored by TLC (DCM:MeOH=10:1). After the reaction was completed, the resulting mixture was filtered while hot, and the filter cake was washed with hot methanol. The filtrate was concentrated by rotary evaporation, added with 6 ml of methanol and a solution (1 ml, 10%) of hydrogen chloride in methanol, warmed to reflux, stirred for 30 min, then naturally cooled to room temperature, and filtered under vacuum to give a white solid (0.1 g). The filtrate was rotary evaporated to dryness and the processes above-mentioned were repeated to give a white solid (0.076 g). The two white solids obtained were combined to give the target compound of Example 11 (0.176 g, hydrogenchloride salt). Yield: 33.0%. LC-MS: 408 [M+1].sup.+, t.sub.R=1.936 min.

Preparation Example 10

(182) Synthesis of Intermediate 92

(183) ##STR00076##

(184) 1.7 ml (23.1 mmol) of thionyl chloride was added to 40 ml of methanol at low temperature, stirred and reacted for 1 h in an ice-water bath, followed by the addition of 2.0 g of material 91, naturally warmed, then heated to 80° C., stirred and reacted for 1 h. The reaction was monitored by TLC (PE/EA=3:1+AcOH). After the material 91 was reacted completely, the reaction solution was concentrated by rotary evaporation, added with 20 ml of saturated sodium bicarbonate solution and 20 ml of ethyl acetate, stirred, allowed to stand and separated into layers. The aqueous phase was extracted with 40 ml of ethyl acetate twice. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product (1.5 g), as an oily substance. Yield: 71.6%.

(185) Synthesis of Intermediate 93

(186) ##STR00077##

(187) Under the protection of nitrogen, 1.5 g (5.5 mmol) of intermediate 92 was suspended in 30 ml of methanol and 3.2 ml (55 mmol, 85%) of hydrazine hydrate, and reacted at room temperature overnight. The reaction was monitored by TLC (PE/EA=3:1). After the reaction was completed, the resulting mixture was added with 20 ml of water and 20 ml of DCM, stirred, separated and extracted with DCM twice. The organic phases were combined, dried, filtered, concentrated under reduced pressure and pumped to dryness to give a white solid (1.5 g). Yield: 100%. LC-MS: 273 [M+1].sup.+, t.sub.R=2.034 min.

(188) Synthesis of Intermediate 94

(189) ##STR00078##

(190) 1.7 g (5 mmol) of intermediate 9-1 was dissolved in 68 ml of dichloromethane, added with 0.02 g (cat.) of N,N-dimethylformamide and cooled to 0° C. 1.3 ml (15 mmol) of oxalyl chloride was added dropwise to the mixture, then naturally warmed to room temperature and reacted for 1 hour. After the reaction was completed, the reaction solution was concentrated and added with 34 ml of dichloromethane, as a stock solution. 1.5 g (5.5 mmol) intermediate 93 and 2.1 ml (15 mmol) of triethylamine were dissolved in 40 ml of dichloromethane and cooled to 0° C. The solution of acyl chloride in dichloromethane obtained above was added dropwise to the mixture, then naturally warmed to room temperature and reacted overnight. The reaction was monitored by TLC (PE/EA=3:1+AcOH). After the reaction was completed, 40 ml of saturated sodium bicarbonate solution was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product (3.0 g). Yield: 100%.

(191) Synthesis of Intermediate 95

(192) ##STR00079##

(193) 3.0 g (5 mmol) of crude intermediate 94 and 2.1 ml (15 mmol) of triethylamine were dissolved in 120 ml of acetonitrile, cooled to 0° C., added with 1.1 g (6 mmol) of 4-toluene sulfonyl chloride, and stirred overnight at room temperature. The reaction was monitored by TLC (PE/EA=1:1). After the reaction was completed, water was added and the resulting mixture was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=10/1, v/v) to give a product (1.3 g) as a bubble-shaped solid. Yield: 44.2%. LC-MS: 588.5 [M+1].sup.+, t.sub.R=3.300 min.

(194) Synthesis of Intermediate 96

(195) ##STR00080##

(196) 1.3 g (2.2 mmol) of intermediate 95 was dissolved in 5.5 ml of hydrochloric acid (1 M) and 50 ml of methanol, and reacted for 2 h at 90° C. The reaction was monitored by TLC (PE/EA=1:1+Et.sub.3N). After the reaction was completed, the resulting mixture was concentrated under reduced pressure, added with sodium hydrate solution (10%) and saturated sodium bicarbonate solution to adjust pH about 8, and extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1+1% Et.sub.3N, v/v) to give a product (0.6 g) as a white solid. Yield: 49.8%.

Example 12 (S)-(2-amino-7-(5-(3,5-bis(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)methanol

(197) ##STR00081##

(198) 0.6 g (1.1 mmol) of intermediate 96 was dissolved in 34 ml of methanol, added with 0.01 ml of concentrated hydrochloric acid, purged with nitrogen to remove air, followed by the addition of 0.12 g (20% m/m) of 10% wet palladium on carbon, purged with hydrogen, and reacted for 6 h at 90° C. The reaction was monitored by TLC (DCM:MeOH=10:1). After the reaction was completed, the resulting mixture was filtered while hot, and the filter cake was washed with hot methanol. The filtrate was concentrated by rotary evaporation to give a crude product as a white solid. The crude product was purified with silica gel column (eluent: dichloromethane/methanol=5/1, v/v), then dissolved in 20 ml of DCM (containing a small amount of methanol) and 20 ml of water, stirred and separated. The aqueous phase was extracted with DCM. The DCM phases were combined, dried, and filtered. The filtrate was added with an appropriate amount of solution of hydrogen chloride in methanol, rotary evaporated to dryness, and pumped to dryness under reduced pressure to give the target compound of Example 12 (0.126 g, hydrogenchloride salt). Yield: 33%. Purity: 96.1%. LC-MS: 458 [M+1].sup.+, t.sub.R=1.961 min.

Example 13 (S)-(2-amino-7-(5-(3,4-diethoxyphenyl)-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)methanol

(199) ##STR00082##

(200) The chiral compound of the present example was obtained by using the chiral intermediate 7-1 as a starting material in a manner similar to the preparation method of example 20 in WO2013181840. LC-MS: 410.2 [M+1].sup.+, t.sub.R=1.757 min. H NMR (400 MHz, DMSO) δ 7.90-7.77 (m, 2H), 7.68 (dd, J=8.4, 1.9 Hz, 1H), 7.59 (d, J=1.9 Hz, 1H), 7.33 (d, J=7.9 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 4.98 (br s, 1H), 4.14 (p, J=6.8 Hz, 5H), 3.29 (s, 2H), 3.04-2.60 (m, 5H), 1.88-1.59 (m, 2H), 1.43-1.30 (m, 6H). A hydrogenchloride salt was obtained by processing the chiral compound with a small amount of solution of hydrogen chloride in methanol.

Example 14 (S)-(2-amino-7-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)methanol

(201) ##STR00083##

(202) The chiral compound of the present example was obtained by using the chiral intermediate 7-1 as a starting material in a manner similar to the preparation method of example 11 in WO2013181840. A hydrogenchloride salt was obtained by processing the chiral compound with a small amount of solution of hydrogen chloride in methanol. LC-MS: 448.5 [M+1].sup.+, t.sub.R=3.183 min. H NMR (400 MHz, DMSO) δ 8.43-8.31 (m, 1H), 8.27 (s, 1H), 8.13 (s, 3H), 7.94 (d, J=5.5 Hz, 2H), 7.56 (d, J=9.0 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 5.61 (t, J=5.1 Hz, 1H), 5.03-4.87 (m, 1H), 3.47 (d, J=5.0 Hz, 2H), 3.17-2.79 (m, 4H), 2.07-1.86 (m, 2H), 1.35 (d, J=6.0 Hz, 6H).

(203) Biological Activity Assays

(204) The compounds of the invention were detected for biological activity hereinafter:

Example 15 Effects of Amino Alcohol Compounds on the Expression of CD4, CD8 and CD19 on Peripheral Blood Cell in Mice

(205) 1. Test Materials:

(206) Mice (C57 BL/6, 8 weeks)

(207) FITC Rat Anti-Mouse CD8a: BD, Cat. #553030.

(208) PE Rat Anti-Mouse CD4: BD, Cat. #557308.

(209) APC Rat Anti-Mouse CD19: BD, Cat. #561738.

(210) The compounds used in the test were prepared by the chemical department of Beijing Forelandpharma Co. Ltd.

(211) 2. Test Method:

(212) Routs of administration: intragastric administration, once a day, and continuous administration for four days.

(213) After the administration, supraorbital venous blood was collected from the mouse, added to an EP tube (1.5 ml) containing an anticoagulant, and kept on the ice. The resulting mixture was transferred to a test tube, centrifuged at 4° C. and 1200 rpm/min for 5 min, removed with the supernatant liquid, added with a lysate, processed with cell lysis on the ice for 5 min, then pre-dyed, added with diluted antibody, and incubated away from light for 30 min. After the incubation, the resulting mixture was washed, removed with the supernatant liquid, added with stationary liquid, and kept in a refrigerator at 4° C. away from light for the test of flow cytometry.

(214) 3. Test Results

(215) TABLE-US-00003 TABLE 1 Effects of Amino Alcohol Compounds on the Expression of CD4, CD8 and CD19 on Peripheral Blood Cell in Mice Num- Exam- CD4 (%) CD8 (%) CD19 (%) ber ple 1 mg/kg 5 mg/kg 1 mg/kg 5 mg/kg 1 mg/kg 5 mg/kg 1 vehicle 25.7 14.5 47.5 2 13 23.4 11.6 12.7 9.4 56.8 53.8 3 1 10.9 1.2 10.0 1.8 39.0 17.5 4 2 23.1 16.4 13.0 8.6 44.8 35.2 5 3 22.1 7.2 11.9 6.1 39.3 24.7 6 6 17.8 8.7 17.0 5.7 34.0 29.1 7 4 27.1 27.0 14.5 12.3 47.1 43.6 8 7 26.5 13.4 14.5 9.2 45.2 40.6 9 8 33.4 30.0 16.6 16.0 36.8 41.7 10 9 33.1 31.9 17.3 17.0 42.5 44.3 11 5 31.5 27.1 16.8 14.7 44.3 43.8 12 10 31.1 27.7 15.3 14.0 44.3 35.7 13 11 23.5 20.5 14.9 13.8 52.1 54.0 14 12 15.2 2.8 9.6 3.4 53.2 38.1

Example 16 β-arrestin Testing Experiments (PathHunter β-Arrestin Testing System)

(216) Test Method

(217) 1. PathHunter β-arrestin testing system was used to detect the biological activity of the compounds.

(218) 2. β-arrestin engineering cells were cultured on 386-well culture plates and placed in an incubator at 37° C.

(219) 3. The sample to be tested was diluted with reaction solution in 5-fold dilution.

(220) 4. The diluted sample to be tested was added to the engineering cells and the reaction was induced and observed.

(221) 5. The chemiluminescence signal produced in the test may be detected by multifunctional enzyme marker (PerkinElmer Envision™).

(222) Test Analysis and Results

(223) 6. The data obtained was analyzed using the data analysis software of CBIS (ChemInnovation, CA) to achieve EC.sub.50, and the test results are shown in Table 2.

(224) TABLE-US-00004 TABLE 2 Biological Activity of the Compounds in Example 3 and Example 13 β-arrestin Test EC.sub.50 (nM) Compound S1P1 S1P2 S1P3 S1P4 S1P 25.2 26.4 26.3 189.7 Example 13 21.6 >100,000 613 >100,000 Example 3 4.56 >100,000 2114 >100,000

Example 17 Test of Fluorescence Detection (FLIPR Assay)

(225) Test Method and Results

(226) The sample to be tested was dissolved in DMSO and diluted with detection buffer solution in 3-fold dilution. A reagent and a positive control were diluted in the same way.

(227) The reactions of the agonist, the reagent and the positive control were detected by a device of FLIPRTETRA with a total detection time of 180 s to estimate the ability to activate GPCR (S1P5) of each compound. The results are shown in Table 3.

(228) TABLE-US-00005 TABLE 3 Biological Activity of the Compounds in Example 3 and Example 13 FLIPR Test EC.sub.50 (nM) Compound S1P5 S1P 23 Example 13 >10,000 Example 3 250

Example 18

(229) Test Method

(230) 1. HEK293 engineering cells stably expressed with hERG potassium channel were used to test the compounds.

(231) 2. Patch Clamp Detection

(232) The cells were separated by TrypLE™ Express before the test. 3×10.sup.3 of cells were spread on a cover plate, cultured in 24-well plate and tested 18 hours later. The signals produced by voltage stimulation of potassium currents in cells were recorded by electrophysiological techniques.

(233) Data Analysis and Results

(234) First of all, currents after the action of drug of each concentration and blank control were standardized separately

(235) $\left(\frac{\mathrm{Peak}\mathrm{tail}\mathrm{current}\mathrm{compound}}{\mathrm{Peak}\mathrm{tail}\mathrm{current}\mathrm{vehicle}}\right),$
and then the corresponding inhibition ratio of each concentration was calculated

(236) $\left(1\text{-}\frac{\mathrm{Peak}\mathrm{tail}\mathrm{current}\mathrm{compound}}{\mathrm{Peak}\mathrm{tail}\mathrm{current}\mathrm{vehicle}}\right).$
The average and the standard error were calculated for each concentration, and 50% inhibiting concentration of each compound was calculated according to the following equation:

(237) $\mathrm{inhibition}=\frac{1}{1+{\left(\frac{\mathrm{IC}50}{C}\right)}^h}$

(238) The dose-dependent effect was obtained through nonlinear fitting with the equation above. C refers to drug concentration, IC50 refers to 50% inhibiting concentration and h refers to hill coefficient. The curve fitting and the calculation of IC50 were processed by IGOR software. The results are shown in Table 4.

(239) TABLE-US-00006 TABLE 4 HERG Test of Example 13 and Example 14 hERG Test Compound IC.sub.50 (μM) Example 13 1.2 Example 14 0.87 Example 3 7.8

(240) The embodiments of the present invention have been described above. However, the present invention is not limited to the embodiments above mentioned. Any modification, equivalent substitution and improvement, etc., which are made within the spirit and principle of the invention, should fall within the scope of the invention.