Modified compound of andrographolide

Abstract

The present disclosure discloses a modified compound of andrographolide, and particularly discloses a compound shown in formula (I) and (II) or a pharmaceutically acceptable salt thereof. ##STR00001##

Claims

1. A compound represented by formula (I), pharmaceutically acceptable salt or tautomer thereof, ##STR00169## wherein, W is O, N(R.sub.5) or a ring ##STR00170## R.sub.5 is H, or a C.sub.1-3 alkyl optionally substituted by 1, 2 or 3 halogen, OH, NH.sub.2, COOH, NHMe or N(Me).sub.2; L.sub.1 is selected from a single bond and (CRR).sub.1-3; R.sub.1 is piperidinyl, which is optionally substituted with 1, 2, or 3 R or R; R.sub.2, R.sub.3 are each independently selected from H, or are each independently selected from the group consisting of a C.sub.1-6 alkyl, a C.sub.1-6 heteroalkyl, and a C.sub.3-6 cycloalkyl, which are optionally substituted with 1, 2, or 3 R or R; the ring A is ##STR00171## which is optionally substituted with 1, 2 or 3 R; R is independently selected from F, Cl, Br, I, OH, NH.sub.2, CN, C(O)OH, or from the group consisting of a C.sub.1-6 alkyl, a C.sub.1-6 heteroalkyl, and a -L-C.sub.3-6 cycloalkyl, which is optionally substituted with 1, 2 or 3 R; L is a single bond, O, S, C(O)NH, NH, C(O)O, C(O), C(S), S(O), S(O).sub.2; R is independently selected from halogen, CN, OH, N(CH.sub.3).sub.2, NH(CH.sub.3), NH.sub.2, CHO, C(O)OH, C(O)NH.sub.2, S(O)NH.sub.2, S(O).sub.2NH.sub.2, trihalomethyl, dihalomethyl, monohalomethyl, aminomethyl, hydroxymethyl, methyl, methoxy, formyl, methoxycarbonyl, Boc, methylsulfonyl, methylsulfinyl, ethyl, n-propyl, isopropyl, and C.sub.3-6 membered cycloalkyl; hetero refers to a heteroatom or a heteroatomic group selected from the group consisting of C(O)N(R), N(R), C(NR), S(O).sub.2N(R), S(O)N(R), O, S, O, S, C(O)O, C(O), C(S), S(O), S(O).sub.2 and N(R)C(O)N(R); in any of the above cases, the number of heteroatom or heteroatom group is independently selected from 1, 2 or 3.

2. The compound, pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein R is each independently selected from the group consisting of F, Cl, Br, I, OH, NH.sub.2, CN, Me, CF.sub.3q, Et, N(CH.sub.3).sub.2, C(O)OH, and Boc.

3. The compound, pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein R is selected from the group consisting of F, Cl, Br, I, OH, NH.sub.2, CN and C(O)OH, or is selected from the group consisting of Me, Et, OMe, OEt, ##STR00172## which is optionally substituted with 1, 2 or 3 R.

4. The compound, pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein R.sub.5 is selected from H, ##STR00173##

5. The compound, pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein L.sub.1 is selected from a single bond and a methylene.

6. The compound, pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein R.sub.1 is ##STR00174## which is optionally substituted with 1, 2 or 3 R.

7. The compound, pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein R.sub.2 and R.sub.3 are independently selected from H, or independently selected from the group consisting of Me, Et, n-propyl, ##STR00175##

8. The compound, pharmaceutically acceptable salt or tautomer thereof according to claim 1, which is selected from the group consisting of ##STR00176## wherein L.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.5, and the ring A are as defined in claim 1.

9. The compound, pharmaceutically acceptable salt or tautomer thereof according to claim 1, which is selected from the group consisting of ##STR00177## wherein L.sub.1, R.sub.1, R.sub.2, R.sub.5 and the ring A are as defined in claim 1.

10. The compound according to claim 1, which is selected from the group consisting of ##STR00178## ##STR00179## ##STR00180## ##STR00181##

11. The compound, pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein R is selected from the group consisting of F, Cl, Br, I, OH, NH.sub.2, CN, C(O)OH, Me, Et, OMe, ##STR00182##

12. The compound, pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein R.sub.1 selected from the group consisting of ##STR00183##

13. The compound, pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein R.sub.2 and R.sub.3 are independently selected from H, Me, Et, ##STR00184##

Description

DETAILED DESCRIPTION

(1) Example embodiments will now be described more fully.

Compound 297

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(2) ##STR00072## ##STR00073##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethylidene)-4-hydroxydihydrofuran-2(3H)-one

(3) (4S,E)-4-hydroxy-3-(2-((1R,5R,6R,8aS)-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylenedecahydronaphthalenemethanol-1-yl) ethylene)dihydrofuran-2(3H)-one (300.00 g, 856.04 mmol) was dissolved in dichloromethane (3.00 L), and cyclopentylcarbaldehyde (84.85 g, 864.60 mmol) and amberlyst-15 (300.00 g) were added in sequence, then stirred at 20 C. for 12 hours. The system was filtered and concentrated to give 300 g (4S,E)-3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-amethylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethylene)-4-hydroxydihydrofuran-2(3H)-one as a white solid, yield: 81.39%.

(4) .sup.1H NMR (400 MHz, CDCl3) 6.97 (d, J=6.4 Hz, 1H), 5.05 (s, 1H), 4.92 (s, 1H), 4.62 (s, 2H), 4.46 (d, J=6 Hz, 1H), 4.29-4.26 (m, 1H), 4.03 (d, J=10.8 Hz, 1H), 3.49-3.44 (m, 2H), 2.59-2.46 (m, 4H), 2.21 (s, 1H), 2.08-1.87 (m, 2H), 1.85-1.71 (m, 3H), 1.69-1.56 (m, 9H), 1.54 (s, 3H), 1.52-1.26 (m, 3H), 0.83 (s, 3H).

Step 2

(E)-3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethylidene)-furan-2 (3H)-one

(5) (4S,E)-3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethylidene)-4-hydroxydihydrofuran-2(3H)-one (200.00 g, 464.49 mmol) was dissolved in 2000 mL dichloromethane and added with acetic anhydride (490.50 g, 4.80 mol) and pyridine (392.00 g, 4.96 mol) at 0 C., then stirred at 20 C. for 17 hours. The reaction solution was concentrated under reduced pressure at 35 C., added with 6000 mL water to precipitate a precipitate, and filtered. The resulting residue was pulped with petroleum ether (500 mL*2) to give 200 g crude product of (E)-3-(2-((3R, 4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethylidene)furan-2(3H)-one.

(6) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.02 (br. s., 1H), 6.71 (t, J=6.9 Hz, 1H), 6.19 (d, J=3.0 Hz, 1H), 4.88 (s, 1H), 4.62 (d, J=5.5 Hz, 1H), 4.45 (s, 1H), 4.04 (d, J=11.3 Hz, 1H), 3.55-3.36 (m, 2H), 2.63-2.52 (m, 1H), 2.48-2.38 (m, 2H), 2.35-2.23 (m, 1H), 2.15-1.99 (m, 2H), 1.94-1.82 (m, 3H), 1.72 (br. s., 3H), 1.64-1.45 (m, 6H), 1.39 (s, 3H), 1.27 (br. s., 3H), 0.83 (s, 3H).

Step 3

2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl) acetaldehyde

(7) (E)-3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethylidene)furan-2(3H)-one (200.00 g, 484.78 mmol) was dissolved in 2000 mL tetrahydrofuran, a solution of potassium permanganate (229.83 g, 1.45 mol) dissolved in 2000 mL water was added at 0 C., followed by being stirred at 20 C. for 6 hours. 1000 mL brine was added and the layers were separated. The organic phase was concentrated under reduced pressure and the residue was dissolved in 1000 mL ethyl acetate. 9000 mL petroleum ether was added and the mixture was filtered. The filtrate was concentrated under reduced pressure to give 78 g crude product of 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde.

(8) .sup.1H NMR (400 MHz, CDCl.sub.3) 9.65 (d, J=2.0 Hz, 1H), 4.85 (s, 1H), 4.60 (d, J=6.0 Hz, 1H), 4.43 (s, 1H), 4.03 (d, J=11.0 Hz, 1H), 3.53-3.42 (m, 2H), 2.55-2.21 (m, 5H), 2.14-2.06 (m, 2H), 1.86-1.80 (m, 1H), 1.72-1.67 (m, 3H), 1.61-1.43 (m, 7H), 1.38 (s, 3H), 1.26-1.09 (m, 3H), 0.83-0.66 (m, 3H).

Step 4

2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethanol

(9) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl) acetaldehyde (70.00 g, 202.02 mmol) was dissolved in 1000 mL tetrahydrofuran, and sodium borohydride (22.93 g, 606.06 mmol) was added at 0 C., followed by stirring at 25 C. for 4 hours. The reaction was quenched by adding 500 mL water, and extracted with ethyl acetate (200 mL*5). The combined organic phases were washed with saturated sodium chloride solution (200 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After that, the resulting residue was purified by silica gel column chromatography with the eluent system PE:EA=10:1 to 2:1 to give 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethanol, (40 g, yield: 56.8%).

(10) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.87 (s, 1H), 4.61 (d, J=6 Hz, 2H), 4.03 (d, J=11.2 Hz, 1H), 3.75 (s, 1H), 3.52-3.43 (m, 3H), 2.44-2.41 (m, 2H), 2.08-1.75 (m, 3H), 1.74-1.66 (m, 7H), 1.57-1.54 (m, 6H), 1.37 (s, 4H), 1.26-1.25 (m, 3H), 0.77 (s, 3H).

Step 5

(3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin

(11) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethanol (35.00 g, 100.42 mmol) was dissolved in 500 mL dichloromethane, and carbon tetrabromide (36.63 g, 110.46 mmol) and triphenylphosphine (28.97 g, 110.46 mmol) was added at 25 C., then stirred at 25 C. for 4 hours. The reaction was quenched with 200 mL water, extracted with dichloromethane (200 mL*3), and the organic phases were combined, washed with saturated sodium chloride solution (200 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After that, the resulting residue was purified by silica gel column chromatography with the eluent system PE:EtOAc=10:1 to 5:1 to give (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3] dioxin (40 g, yield: 96.82%).

(12) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.89 (s, 1H), 4.61 (d, J=6 Hz, 1H), 4.53 (s, 1H), 4.02 (d, J=11.2 Hz, 1H), 3.55-3.52 (m, 3H), 3.46-3.29 (m, 1H), 2.42 (s, 1H), 2.08 (s, 1H), 2.04-1.84 (m, 4H), 1.84-1.81 (m, 3H), 1.72-1.70 (m, 3H), 1.59-1.54 (m, 6H), 1.38 (s, 3H), 1.26-1.22 (m, 3H), 0.78 (s, 3H).

Step 6

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(13) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3] dioxin (10.00 g, 24.31 mmol) was dissolved in 150 mL N,N-dimethylformamide, and potassium carbonate (6.72 g, 48.62 mmol) and 4-hydroxypyridine (2.31 g, 24.31 mmol) were added at 20 C., then stirred at 80 C. for 10 hours. The reaction solution was concentrated under reduced pressure, diluted with 500 mL water, and extracted with ethyl acetate (250 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (200 mL*1), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. After that, the resulting residue was purified by silica gel column chromatography with an eluent system of PE:EtOAc=5:1 to 1:1 to give 5.3 g 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl) ethoxy) pyridine 297.

(14) MS m/z (ESI): 426.6 [M+1]

(15) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.42 (d, J=5.0 Hz, 2H), 6.78 (d, J=5.3 Hz, 2H), 4.91 (s, 1H), 4.74-4.44 (m, 2H), 4.14-4.07 (m, 1H), 4.04 (d, J=11.3 Hz, 1H), 3.94-3.84 (m, 1H), 3.56-3.40 (m, 2H), 2.44 (d, J=12.8 Hz, 1H), 2.29 (dq, J=3.3, 13.2 Hz, 1H), 2.14-1.97 (m, 3H), 1.93-1.79 (m, 4H), 1.71 (dd, J=4.4, 8.7 Hz, 3H), 1.61-1.41 (m, 6H), 1.38 (s, 3H), 1.30-1.16 (m, 3H), 0.80 (s, 3H).

Compound 420

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-methoxypyridine

(16) ##STR00074##

Step 1

4-benzyloxy-2-methoxypyridine

(17) 4-Benzyloxypyridin-2-ol (40.00 g, 198.79 mmol) was dissolved in chloroform (500.00 mL), and silver carbonate (109.63 g, 397.58 mmol, 18.03 mL) and methyl iodide (282.16 g, 1.99 mol, 123.75 mL) were added successively, and then stirred at 40 C. for 12 hours. The reaction was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=30/1 to 10/1) to give 4-benzyloxy-2-methoxypyridine (a white solid, 18 g, yield: 42.06%).

(18) .sup.1H NMR (400 MHz, CDCl3) 8.00 (d, J=6 Hz, 1H), 7.43-7.36 (m, 5H), 6.58-6.56 (m, 1H), 6.29 (d, J=1.6 Hz, 1H), 5.09 (s, 2H), 3.94 (s, 3H).

Step 2

2-methoxypyridin-4-ol

(19) 4-Benzyloxy-2-methoxypyridine (1.00 g, 4.65 mmol) was dissolved in ethanol (20.00 mL), and palladium on carbon (100.00 mg, 10% purity) was added, and then stirred at 30 C. in 30 PSI hydrogen atmosphere for 3 hours. The reaction was filtered and the filtrate was concentrated to give 2-methoxypyridin-4-ol (a white solid, 450 mg, yield: 70.38%).

(20) .sup.1H NMR (400 MHz, CDCl3) 7.67 (d, J=6.4 Hz, 1H), 6.35-6.32 (m, 1H), 6.05 (d, J=2H, 1H), 3.88 (s, 3H).

Step 3

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-methoxypyridine

(21) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin (200.00 mg, 486.13 umol) was dissolved in N,N-dimethylformamide (10.00 mL), and cesium carbonate (316.78 mg, 972.26 umol) and 2-methoxypyridin-4-ol (66.91 mg, 534.74 umol) were added successively, then stirred at 70 C. for 4 hours. The reaction was quenched with 10 mL water and extracted with ethyl acetate (10 mL*3). The organic phases were combined and washed with saturated brine (10 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by preparative liquid chromatography (HCOOH) to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-methoxypyridine 420 (50 mg, yield: 14.75%).

(22) MS m/z (ESI):456.7 [M+1]

(23) .sup.1H NMR (400 MHz, CDCl3) 7.96 (d, J=6 Hz, 1H), 6.47-6.45 (m, 1H), 6.16 (d, J=2 Hz, 1H), 4.90 (s, 1H), 4.63-4.59 (m, 2H), 4.07-4.03 (m, 2H), 3.93 (s, 3H), 3.86-3.84 9 m, 1H), 3.53-3.44 (m, 2H), 2.45-2.42 (m, 1H), 2.08-2.02 (m, 1H), 1.83-1.71 (m, 3H), 1.71-1.70 (m, 4H), 1.69-1.54 (m, 10H), 1.38 (s, 3H), 1.27-1.25 (m, 3H), 0.80 (s, 3H).

Compound 321

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-pyridin-2-amine

(24) ##STR00075##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-pyridin-2-amine

(25) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (500 mg, 1.14 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by the sequential addition of 2-amino-4-hydroxypyridine (250 mg, 2.28 mmol) and potassium carbonate (314 mg, 2.28 mmol), then stirred at 60 C. for 12 hours. After the reaction was completed, the reaction solution was concentrated and separated by a column (Eluents by MeOH:DCM from 1:100 to 1:30) to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-pyridin-2-amine 321(100 mg, yield: 20%).

(26) MS m/z (ESI): 441.6[M+1]

(27) .sup.1H NMR (400 MHz, CDCl3) 7.68 (br. s., 1H), 6.29 (s., 1H), 6.06 (br. s., 1H), 5.88 (brs, 2H), 4.89 (s, 1H), 4.59-4.55 (m, 2H), 4.09-3.89 (m, 3H), 3.48-3.43 (m, 2H), 2.52-2.13 (m, 2H), 2.11-1.27 (m, 17H), 1.36 (s, 3H), 1.25-0.87 (m, 2H), 0.79 (s, 3H).

Compound 319

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-methylpyridine

(28) ##STR00076##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-methylpyridine

(29) 2-Methylpyridin-4-ol (60 mg, 0.55 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and potassium carbonate (75.5 mg, 0.55 mmol) and (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (150 mg, 0.37 mmol) were successively added to the reaction solution and stirred overnight at 60 C. The reaction solution was cooled and extracted with dichloromethane (30 mL). The organic layer was washed with water (10 mL3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated by column chromatography to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-methylpyridine 319 (80 mg, yield: 50%).

(30) MS m/z (ESI): 440.8 [M+1]

(31) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.31 (d, J=6.0 Hz, 1H), 6.67-6.64 (m, 1H), 4.91 (s, 1H), 4.63-4.60 (m, 2H), 4.10-3.88 (m, 3H), 3.53-3.45 (m, 2H), 2.54 (s, 3H), 2.46-1.56 (m, 18H), 1.55 (s, 3H), 1.39-1.27 (m, 3H), 0.81 (s, 3H).

Compound 430

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridin-2(1H)-one

(32) ##STR00077##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridin-2(1H)-one

(33) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (400.00 mg, 972.27 umol) was dissolved in anhydrous N,N-dimethylformamide (10.00 mL), and potassium carbonate (268.75 mg, 1.94 mmol) and pyridine-2,4-diol (108.02 mg, 972.27 umol) were successively added and stirred at 70 C. under nitrogen atmosphere for 12 hours. The reaction was quenched by adding 30 mL water and extracted with ethyl acetate (30.00 mL). The organic phase was washed with water (30 mL) and saturated brine (30 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica, ethyl acetate/methanol=10/1) to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridin-2(1H)-one 430 (100 mg, yield: 23.29%).

(34) MS m/z (ESI):442.2 [M+1]

(35) .sup.1H NMR (400 MHz, CDCl3) 12.46 (br. s., 1H), 7.20 (d, J=7.3 Hz, 1H), 5.95 (dd, J=1.9, 7.2 Hz, 1H), 5.80 (s, 1H), 4.88 (s, 1H), 4.60 (d, J=5.8 Hz, 1H), 4.55 (s, 1H), 4.02 (d, J=11.0 Hz, 2H), 3.86-3.75 (m, 1H), 3.58-3.36 (m, 2H), 2.42 (d, J=13.1 Hz, 1H), 2.32-2.19 (m, 1H), 2.13-2.03 (m, 1H), 2.02-1.93 (m, 2H), 1.90-1.81 (m, 2H), 1.78-1.63 (m, 5H), 1.61-1.49 (m, 4H), 1.48-1.39 (m, 2H), 1.36 (s, 3H), 1.29-1.16 (m, 3H), 0.77 (s, 3H).

Compound 357

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-1-methylpyridin-2(1H)-one

(36) ##STR00078##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-1-methylpyridin-2(1H)-one

(37) 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridin-2(1H)-one (50 mg, 0.11 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), sodium hydrogen (4.1 mg, 0.17 mmol) was added at 0 C. and stirred for 15 minutes under nitrogen atmosphere at 0 C. Methyl iodide (190 mg, 1.34 mmol) was added to the reaction solution and stirred at 30 C. for 12 hours. The reaction solution was quenched with water and extracted with dichloromethane (30 mL). The organic layer was washed with water (10 mL3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by thin layer chromatography to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-1-methylpyridin-2(1H)-one 357 (20 mg, yield: 39%).

(38) MS m/z (ESI): 478.3 [M+23]

(39) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.11 (d, J=7.2 Hz, 1H), 5.88-5.84 (m, 2H), 4.87 (s, 1H), 4.61-4.54 (m, 2H), 4.04-3.42 (m, 8H), 2.43-1.54 (m, 18H), 1.52 (s, 3H), 1.37-1.24 (m, 3H), 0.77 (s, 3H).

Compound 339

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) piperidin-3-amine

(40) ##STR00079##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) piperidin-3-amine

(41) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (100 mg, 0.24 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by the addition of 3-amino-4-hydroxypyridine (32.12 mg, 0.29 mmol) and potassium carbonate (67.19 mg, 0.49 mmol), then stirred at 60 C. overnight. After the reaction was completed, the reaction solution was diluted with water and then extracted with dichloromethane. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and separated by a preparative plate (Develop: EtOAc:MeOH=10:1) to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) piperidin-3-amine 339 (30 mg, yield: 28.01%).

(42) MS m/z (ESI): 441.2 [M+1]

(43) .sup.1H NMR (400 MHz, CDCl3) 8.16 (s, 1H), 8.00 (s, 1H), 6.76 (s, 1H), 4.91 (s, 1H), 4.61-4.59 (m, 2H), 4.18 (s, 1H), 4.04-4.01 (m, 2H), 3.55-3.48 (m, 2H), 2.44 (d, J=12.0 Hz, 1H), 2.33-2.23 (m, 1H), 2.08-1.43 (m, 16H), 1.37 (s, 3H), 1.25-1.15 (m, 3H), 0.79 (s, 3H).

Compound 344

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-3-fluoropyridine

(44) ##STR00080##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-3-fluoropyridine

(45) 3-Fluoropyridin-4-ol (33 mg, 0.29 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and potassium carbonate (67.2 mg, 0.49 mmol) and (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (100 mg, 0.24 mmol) were successively added to the reaction mixture and stirred at 60 C. overnight. The reaction solution was cooled and extracted with dichloromethane (30 mL). The organic layer was washed with water (10 mL3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated on a thin layer chromatography plate to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-3-fluoropyridine 344 (55 mg, yield: 51.0%).

(46) MS m/z (ESI): 460.3 [M+1]

(47) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.37 (s, 3H), 8.29 (s, 3H), 6.86 (s, 3H), 4.90 (s, 1H), 4.61-3.95 (m, 5H), 3.51-3.43 (m, 2H), 2.45-1.53 (m, 18H), 1.51 (s, 3H), 1.37-1.25 (m, 3H), 0.879 (s, 3H).

Compound 310

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-pyridine

(48) ##STR00081##

Step 1

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-pyridine

(49) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (150 mg, 0.365 mmol) was dissolved in 10 mL anhydrous dimethyl sulfoxide, and 3-hydroxypyridine (52 mg, 0.547 mmol) and potassium hydroxide (30.6 mg, 0.547 mmol) were added successively and stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was diluted with water and then extracted with dichloromethane. The resulting organic phase was washed with anhydrous sodium sulfate, concentrated, and separated by a column (Eluents:PE:EtOAc=2:1) to give 3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-pyridine 310 (50 mg, yield: 32.26%).

(50) MS m/z (ESI): 426.7 [M+1]

(51) .sup.1H NMR (400 MHz, CDCl3) 8.29 (s, 1H), 8.21 (s, 1H), 7.25-7.20 (m, 2H), 4.89 (s, 1H), 4.60-4.59 (m, 2H), 4.10-4.09 (m, 1H), 4.03 (d, J=11.2 Hz, 1H), 3.89-3.83 (m, 1H), 3.51-3.43 (m, 2H), 2.43 (d, J=12.8 Hz, 1H), 2.33-2.25 (m, 1H), 2.09-1.53 (m, 19H), 1.37 (s, 3H), 1.26-1.18 (m, 3H), 0.77 (s, 3H).

Compound 443

5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-pyridin-3-ol

(52) ##STR00082##

Step 1

5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-pyridin-3-ol

(53) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin (500.00 mg, 1.22 mmol) was dissolved in N,N-dimethylformamide (10.00 mL), followed by the successive addition of potassium carbonate (337.23 mg, 2.44 mmol) and pyridine-3,5-diol (149.10 mg, 1.34 mmol), then stirred at 80 C. for 12 hours. The reaction was quenched by adding 10 mL water and then extracted with ethyl acetate (20.00 mL*3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography to give 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-pyridin-3-ol 443 (28 mg, yield: 5.15%).

(54) MS m/z (ESI): 442.2[M+1]

(55) .sup.1H NMR (400 MHz, CDCl3) 7.95 (s, 1H), 7.75 (s, 1H), 6.88 (s, 1H), 4.89 (s, 1H), 4.62-4.56 (m, 2H), 4.08-4.02 (m, 4H), 3.86 (d, J=6 Hz, 1H), 3.51-3.43 (m, 2H), 2.41 (s, 1H), 2.07 (s, 1H), 2.01-1.83 (m, 3H), 1.83-1.71 (m, 4H), 1.57-1.50 (m, 4H) 1.69-1.67 (m, 3H), 1.57-1.52 (m, 5H), 1.37-1.25 (m, 3H), 0.79 (s, 3H).

Compound 442

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-5-methoxypyridine

(56) ##STR00083##

Step 1

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-5-methoxypyridine

(57) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin (1.00 g, 2.43 mmol) was dissolved in N,N-dimethylformamide (10.00 mL), followed by successive addition of potassium carbonate (671.70 mg, 4.86 mmol) and 5-methoxypyridin-3-ol (334.47 mg, 2.67 mmol), then stirred at 80 C. for 12 hours. The reaction was quenched by adding 10 mL water and then extracted with ethyl acetate (20.00 mL*3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=10/1 to 2/1) to give 3-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-5-methoxypyridine 442 (700 mg, yield: 63.37%).

(58) MS m/z (ESI): 456.6[M+1]

(59) .sup.1H NMR (400 MHz, CDCl3) 7.91 (d, J=8 Hz, 2H), 6.69 (t, J=4.4 Hz, 1H), 4.89 (s, 1H), 4.59 (t, J=6 Hz, 2H), 4.08-4.02 (m, 2H), 3.84 (s, 4H), 3.51-3.43 (m, 2H), 2.44-2.40 (m, 2H), 2.05-2.01 (m, 3H), 1.88-1.83 (m, 4H), 1.60 (s, 3H), 1.55-1.35 (m, 6H), 1.45-1.27 (m, 3H) 1.26-1.21 (m, 3H), 0.79 (s, 3H).

Compound 317

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) pyridine

(60) ##STR00084##

Step 1

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) pyridine

(61) Pyridin-2-ol (45.1 mg, 0.47 mmol) was dissolved in anhydrous N,N dimethylformamide (5 mL), followed by successive addition of potassium carbonate (75.6 mg, 0.54 mmol) and (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin (150 mg, 0.37 mmol), then stirred at 80 C. overnight. The reaction solution was cooled and extracted with dichloromethane (30 mL). The organic layer was washed with water (10 mL3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give 40 mg 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) pyridine 317.

(62) MS m/z (ESI): 426.1 [M+1]

(63) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.14 (d, J=2.4 Hz, 1H), 7.58-7.54 (m, 1H), 6.86-6.83 (m, 1H), 6.72 (d, J=8.4 Hz, 1H), 4.88 (s, 1H), 4.69 (s, 1H), 4.61 (d, J=6.0 Hz, 1H), 4.40-4.02 (m, 3H), 3.52-3.42 (m, 2H), 2.43-1.51 (m, 18H), 1.37 (s, 3H), 1.25-1.21 (m, 3H), 0.78 (s, 3H).

Compound 351

4-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)methyl)pyridine

(64) ##STR00085##

Step 1

4-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)methyl)pyridine

(65) Sodium hydrogen (14.6 mg, 0.36 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), added with pyridine-4-benzyl alcohol (26.5 mg, 0.24 mmol) at 0 C., and stirred under nitrogen atmosphere at 0 C. for 15 minutes. (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (100 mg, 0.24 mmol) was added to the reaction mixture and stirred at 25 C. for 2 hours. The reaction solution was cooled and extracted with dichloromethane (30 mL). The organic layer was washed with water (10 mL3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated on a thin layer chromatography plate to give 4-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)methyl)pyridine 351 (60 mg, yield: 56%).

(66) MS m/z (ESI): 440.2 [M+1]

(67) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.60 (d, J=4.0 Hz, 1H), 7.27 (d, J=5.6 Hz, 1H), 4.83 (s, 1H), 4.61-4.49 (m, 4H), 4.02 (d, J=11.2 Hz, 1H), 3.57-3.37 (m, 4H), 2.42-1.54 (m, 18H), 1.52 (s, 3H), 1.36-1.23 (m, 3H), 0.79 (s, 3H).

Compound 289

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-methyl-1H-pyrazole

(68) ##STR00086##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-methyl-1H-pyrazole

(69) 1-Methyl-1H-imidazol-4-ol (28.61 mg, 0.292 mmol) was dissolved in 5 mL N,N-dimethylformamide, and added with sodium hydride (11.67 mg, 0.486 mmol) at 0 C., then stirred at 0 C. for 15 minutes. (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (100 mg, 0.243 mmol) was added at 0 C., then stirred at 0 C. for 12 hours. The reaction was quenched with 10 mL water and extracted with dichloromethane (25 mL*3), the organic phases were combined, washed with saturated sodium chloride solution (25 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After that, the resulting residue was purified by thin layer chromatography to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-methyl-1H-pyrazole 289 (20 mg, yield: 19.2%).

(70) MS m/z (ESI): 429.5[M+1]

(71) .sup.1H NMR (400 MHz, CDCl.sub.3) (s, 1H), 7.00 (s, 1H), 4.86 (s, 1H), 4.61-4.56 (m, 2H), 4.02 (d, J=11.6 Hz, 1H), 3.93-3.80 (m, 1H), 3.72 (s, 3H), 3.71-3.70 (m, 1H), 3.50-3.42 (m, 2H), 2.43-2.20 (m, 2H), 2.15-1.50 (m, 16H), 1.36 (s, 3H), 1.24-1.20 (m, 3H), 0.77 (s, 3H).

Compound 422

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid

(72) ##STR00087##

Step 1

Methyl 4-hydroxybenzoate

(73) 4-Hydroxybenzoic acid (2.00 g, 14.48 mmol) was dissolved in 20 mL methanol, and sulfuric acid (184.00 mg, 1.88 mmol) was added at room temperature, and then stirred at 70 C. for 48 hours. The reaction solution was added with 200 mL aqueous sodium bicarbonate solution (4M) and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give methyl 4-hydroxybenzoate (a white solid, 1.6 g, crude product).

(74) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.97 (d, J=8.5 Hz, 2H), 6.92 (d, J=8.5 Hz, 2H), 6.73 (br. s., 1H), 3.93 (s, 3H).

Step 2

Methyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoate

(75) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (300.00 mg, 729.20 umol) was dissolved in 5 mL N,N-dimethylformamide, and cesium carbonate (700.88 mg, 2.15 mmol) and methyl 4-hydroxybenzoate (122.00 mg, 802.12 umol) were successively added at room temperature, and then stirred at 80 C. for 8 hours. 50 mL water was added and the mixture was extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give methyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoate (a bright yellow oil, 250 mg, crude product).

(76) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.95 (d, J=9.0 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.87 (s, 1H), 4.63-4.50 (m, 2H), 4.15-4.00 (m, 2H), 3.86 (s, 3H), 3.86-3.82 (m, 1H), 3.48 (dd, J=4.8, 12.5 Hz, 1H), 3.42 (d, J=11.3 Hz, 1H), 2.41 (d, J=13.1 Hz, 1H), 2.26 (dq, J=3.3, 13.2 Hz, 1H), 2.05-1.42 (m, 16H), 1.35 (s, 3H), 1.27-1.15 (m, 3H), 0.78 (s, 3H).

Step 3

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid

(77) Methyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoate (250.00 mg, 517.97 umol) was dissolved in 5 mL methanol, 5 mL water and potassium hydroxide (290.63 mg, 5.18 mmol) were successively added at room temperature, and then stirred at 80 C. for 8 hours. 100 mL water was added and the mixture was extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid 422 (210 mg, yield: 84.61%).

(78) MS m/z (ESI): 467.3 [M1]

(79) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.66 (br. s., 2H), 6.43 (br. s., 2H), 4.89 (br. s., 1H), 4.60 (d, J=9.3 Hz, 2H), 4.03 (d, J=10.8 Hz, 1H), 3.91 (d, J=19.1 Hz, 1H), 3.67 (br. s., 1H), 3.46 (d, J=9.8 Hz, 2H), 2.43-1.56 (m, 18H), 1.38 (br. s., 3H), 1.30-1.10 (m, 3H), 0.93-0.72 (m, 3H).

Compound 423

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid

(80) ##STR00088##

Step 1

Methyl 3-hydroxybenzoate

(81) 3-Hydroxybenzoic acid (2.00 g, 14.48 mmol) was dissolved in 20 mL of methanol, and sulfuric acid (184.63 mg, 1.88 mmol) was added at room temperature, and then stirred at 70 C. for 48 hours. 200 mL of aqueous sodium bicarbonate solution (4M) was added, and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give methyl 3-hydroxybenzoate as a white solid (2 g, crude product).

(82) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.65-7.52 (m, 2H), 7.30 (t, J=7.9 Hz, 1H), 7.11 (dd, J=1.9, 8.2 Hz, 1H), 6.04 (br. s., 1H), 3.92 (s, 3H).

Step 2

Methyl 3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoate

(83) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (300.00 mg, 729.20 umol) was dissolved in 5 mL N,N-dimethylformamide, and cesium carbonate (700.88 mg, 2.15 mmol) and methyl 3-hydroxybenzoate (122.00 mg, 802.12 umol) were successively added at room temperature, and then stirred at 80 C. for 8 hours. 50 mL water was added and the mixture was extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give methyl 3-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoate (a bright yellow oil, 250 mg, crude product).

(84) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.70-7.58 (m, 1H), 7.57-7.47 (m, 1H), 7.38-7.29 (m, 1H), 7.07 (dd, J=2.0, 8.0 Hz, 1H), 4.89 (s, 1H), 4.66-4.45 (m, 2H), 4.15-4.00 (m, 2H), 3.95-3.89 (m, 3H), 3.89-3.82 (m, 1H), 3.51 (dd, J=4.9, 12.7 Hz, 1H), 3.45 (d, J=11.3 Hz, 1H), 2.43 (d, J=13.3 Hz, 1H), 2.35-2.23 (m, 1H), 2.10-1.42 (m, 16H), 1.40-1.35 (m, 3H), 1.32-1.18 (m, 3H), 0.80 (s, 3H).

Step 3

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid

(85) Methyl 3-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoate (250.00 mg, 517.97 umol) was dissolved in 5 mL methanol, 5 mL water and potassium hydroxide (290.64 mg, 5.18 mmol) were successively added at room temperature, and then stirred at 80 C. for 8 hours. 100 mL water was added and the mixture was extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid 423 (196 mg, yield: 80.75%).

(86) MS m/z (ESI): 469.3 [M+1]

(87) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.29 (s, 2H), 6.89 (br. s., 1H), 6.73 (br. s., 1H), 4.77 (br. s., 1H), 4.60 (d, J=5.3 Hz, 1H), 4.48 (br. s., 1H), 4.00 (d, J=11.0 Hz, 1H), 3.81 (br. s., 1H), 3.62 (br. s., 1H), 3.42 (d, J=9.5 Hz, 2H), 2.24-1.48 (m, 18H), 1.34 (br. s., 3H), 1.26-1.01 (m, 3H), 0.72 (br. s., 3H).

Compound 407

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid

(88) ##STR00089##

Step 1

Ethyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoate

(89) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (400.00 mg, 972.27 umol) was dissolved in acetonitrile (10.00 mL), and potassium carbonate (134.38 mg, 972.27 umol) and ethyl 2-hydroxybenzoate (193.87 mg, 1.17 mmol) were successively added, and then stirred under nitrogen atmosphere at 75 C. for 12 hours. The reaction was quenched with 30 mL water and then extracted with ethyl acetate (30 mL). The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=8/1) to give ethyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoate (a yellow oil, 200 mg, yield: 41.42%).

(90) .sup.1H NMR (400 MHz, CDCl3) 7.74 (dd, J=1.5, 7.8 Hz, 1H), 7.44-7.36 (m, 1H), 6.95 (t, J=7.5 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 4.86 (s, 1H), 4.67-4.56 (m, 2H), 4.36 (q, J=7.0 Hz, 2H), 4.19-4.09 (m, 1H), 4.03 (d, J=11.3 Hz, 1H), 3.92-3.79 (m, 1H), 3.55-3.37 (m, 2H), 2.41 (d, J=13.3 Hz, 1H), 2.27 (dq, J=3.1, 13.2 Hz, 1H), 2.14-2.02 (m, 2H), 2.01-1.84 (m, 4H), 1.83-1.75 (m, 1H), 1.73-1.63 (m, 3H), 1.62-1.57 (m, 1H), 1.55-1.43 (m, 4H), 1.42-1.32 (m, 7H), 1.28-1.19 (m, 3H), 0.78 (s, 3H).

Step 2

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid

(91) Ethyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoate (200.00 mg, 402.67 umol) was dissolved in tetrahydrofuran (2.00 mL), and potassium hydroxide (45.19 mg, 805.35 umol) and water (1.00 mL) were added successively, and then stirred at 75 C. under nitrogen atmosphere for 12 hours. The system was adjusted to neutrality with hydrochloric acid solution (1M). The organic phase was removed by rotary evaporation under reduced pressure, and the aqueous phase was separated by preparative liquid chromatography (HCOOH) to give 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid 407 (29 mg, yield: 15.37%).

(92) MS m/z (ESI): 491.3 [M+23]

(93) .sup.1H NMR (400 MHz, CDCl3) 8.24-8.13 (m, 1H), 7.60-7.48 (m, 1H), 7.13 (t, J=7.5 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 4.92 (s, 1H), 4.65-4.51 (m, 2H), 4.41-4.26 (m, 1H), 4.20-4.10 (m, 1H), 4.02 (d, J=11.3 Hz, 1H), 3.56-3.35 (m, 2H), 2.44 (d, J=12.0 Hz, 1H), 2.34-2.20 (m, 1H), 2.18-2.04 (m, 2H), 2.04-1.93 (m, 2H), 1.91-1.78 (m, 3H), 1.77-1.61 (m, 3H), 1.60-1.39 (m, 6H), 1.36 (s, 3H), 1.28-1.12 (m, 3H), 0.80 (s, 3H).

Compound 409

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-5-fluorobenzoic acid

(94) ##STR00090##

Step 1

Methyl 5-fluoro-2-hydroxybenzoate

(95) 5-Fluoro-2-hydroxybenzoic acid (2.50 g, 16.01 mmol) was dissolved in methanol (25.00 mL), added with sulfuric acid (78.51 mg, 800.50 umol), and then stirred at 70 C. for 12 hours under nitrogen atmosphere. After the reaction mixture was concentrated, the residue was dissolved in ethyl acetate (20.00 mL). The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give methyl 5-fluoro-2-hydroxybenzoate (a yellow oil, 2.0 g, crude product).

(96) .sup.1H NMR (400 MHz, CDCl3) 10.51 (s, 1H), 7.49 (dd, J=3.1, 8.7 Hz, 1H), 7.24-7.10 (m, 1H), 6.94 (dd, J=4.5, 9.0 Hz, 1H), 3.95 (s, 3H).

Step 2

Methyl 2-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-5-fluorobenzoate

(97) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (400.00 mg, 972.27 umol) was dissolved in acetonitrile (10.00 mL), and potassium carbonate (268.75 mg, 1.94 mmol) and ethyl 5-fluoro-2-hydroxybenzoate (330.84 mg, 1.94 mmol) were successively added, and then stirred under nitrogen atmosphere at 75 C. for 12 hours. The reaction was quenched with 30 mL water and then extracted with ethyl acetate (30 mL). The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=8/1) to give methyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-5-fluorobenzoate (a yellow oil, 300 mg, yield: 61.63%).

(98) .sup.1H NMR (400 MHz, CDCl3) 7.50 (dd, J=3.1, 8.7 Hz, 1H), 7.14 (ddd, J=3.1, 7.7, 9.0 Hz, 1H), 6.87 (dd, J=4.3, 9.3 Hz, 1H), 4.88 (s, 1H), 4.68-4.55 (m, 2H), 4.20-4.00 (m, 2H), 3.96-3.79 (m, 4H), 3.57-3.38 (m, 2H), 2.44 (d, J=12.8 Hz, 1H), 2.29 (dq, J=3.0, 13.2 Hz, 1H), 2.14-2.05 (m, 2H), 2.01 (t, J=12.7 Hz, 1H), 1.97-1.86 (m, 3H), 1.86-1.79 (m, 1H), 1.71 (td, J=4.4, 8.8 Hz, 3H), 1.61-1.50 (m, 4H), 1.49-1.42 (m, 2H), 1.39 (s, 3H), 1.31-1.24 (m, 3H), 0.81 (s, 3H).

Step 3

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-5-fluorobenzoic acid

(99) Methyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-5-fluorobenzoate (300.00 mg, 599.23 umol) was dissolved in methanol (2.00 mL), and potassium hydroxide (67.25 mg, 1.20 mmol) and water (1.00 mL) were added successively, and then stirred at 75 C. under nitrogen atmosphere for 12 hours. The system was adjusted to neutrality with hydrochloric acid solution (1M). The organic phase was removed by rotary evaporation under reduced pressure, and the aqueous phase was separated by preparative liquid chromatography to give 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-5-fluorobenzoic acid 409 (205 mg, yield: 70.30%).

(100) MS m/z (ESI): 509.3 [M+23]

(101) .sup.1H NMR (400 MHz, CDCl3) 7.84 (dd, J=3.3, 8.8 Hz, 1H), 7.26-7.17 (m, 1H), 6.95 (dd, J=3.8, 9.3 Hz, 1H), 4.92 (s, 1H), 4.65-4.49 (m, 2H), 4.37-4.25 (m, 1H), 4.16-4.06 (m, 1H), 4.01 (d, J=11.0 Hz, 1H), 3.54-3.37 (m, 2H), 2.44 (d, J=12.0 Hz, 1H), 2.26 (dq, J=2.8, 13.1 Hz, 1H), 2.16-2.02 (m, 2H), 2.02-1.91 (m, 2H), 1.90-1.77 (m, 3H), 1.74-1.63 (m, 3H), 1.59-1.40 (m, 6H), 1.35 (s, 3H), 1.28-1.12 (m, 3H), 0.79 (s, 3H).

Compound 441

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-4-fluorobenzoic acid

(102) ##STR00091## ##STR00092##

Step 1

Methyl 4-fluoro-2-hydroxybenzoate

(103) 4-Fluoro-2-hydroxybenzoic acid (5.00 g, 32.03 mmol) was dissolved in methanol (50.00 mL), added with sulfuric acid (920.00 mg, 9.38 mmol, 500.00 uL), and then stirred at 70 C. for 15 hours. The reaction mixture was concentrated and diluted with water (50.00 mL), and the system was adjusted to pH=9 with saturated sodium bicarbonate solution. The system was extracted with ethyl acetate (30.00 mL*3). The organic phase was washed with saturated brine (30.00 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give methyl 4-fluoro-2-hydroxybenzoate (a white solid, 2.2 g, yield: 40.37%).

(104) .sup.1H NMR (400 MHz, CDCl3) 10.81 (d, J=1.0 Hz, 1H), 7.85 (dd, J=6.9, 8.9 Hz, 1H), 6.92-6.74 (m, 2H), 3.88 (s, 3H).

Step 2

Methyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-4-fluorobenzoate

(105) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (200.00 mg, 486.13 umol) was dissolved in N,N-dimethylformamide (3.00 mL), and potassium carbonate (134.38 mg, 972.26 umol) and methyl 4-fluoro-2-hydroxybenzoate (90.98 mg, 534.74 umol) were successively added, and then stirred at 70 C. for 15 hours. The reaction was quenched with 20 mL water and then extracted with ethyl acetate (20.00 mL*3). The organic phase was washed with saturated brine (25 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=100/0 to 10/1) to give methyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-4-fluorobenzoate (a colorless oil, 240 mg, yield: 65.74%).

(106) .sup.1H NMR (400 MHz, CDCl3) 7.84 (dd, J=7.0, 8.5 Hz, 1H), 6.71-6.55 (m, 2H), 4.88 (s, 1H), 4.65-4.56 (m, 2H), 4.14-4.00 (m, 2H), 3.92-3.80 (m, 4H), 3.54-3.40 (m, 2H), 2.43 (d, J=12.8 Hz, 1H), 2.28 (dq, J=3.1, 13.3 Hz, 1H), 2.15-1.88 (m, 6H), 1.84-1.77 (m, 1H), 1.74-1.66 (m, 3H), 1.58-1.42 (m, 6H), 1.37 (s, 3H), 1.29-1.23 (m, 3H), 0.80 (s, 3H).

Step 3

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-4-fluorobenzoic acid

(107) Methyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-4-fluorobenzoate (240.00 mg, 179.39 umol) was dissolved in methanol (3.00 mL), and potassium hydroxide (161.39 mg, 2.88 mmol) and water (3.00 mL) were added successively, and then stirred at 70 C. for 24 hours. The reaction solution was diluted with 20 mL water, washed with 20 mL tert-butyl methyl ether, and the aqueous phase was adjusted to pH=4 with hydrochloric acid solution (1M). The system was extracted with ethyl acetate (30 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-4-fluorobenzoic acid 441 (73.6 mg, yield: 31.36%).

(108) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.70 (t, J=7.8 Hz, 1H), 6.92 (d, J=10.3 Hz, 1H), 6.84-6.68 (m, 1H), 4.84 (br. s., 1H), 4.65 (d, J=5.5 Hz, 1H), 4.58 (br. s., 1H), 4.11 (br. s., 1H), 3.94 (d, J=11.3 Hz, 1H), 3.83 (d, J=5.3 Hz, 1H), 3.61-3.45 (m, 2H), 2.43-2.11 (m, 3H), 2.10-1.84 (m, 4H), 1.76 (d, J=14.6 Hz, 3H), 1.63-1.32 (m, 8H), 1.29-1.11 (m, 6H), 0.71 (s, 3H).

Compound 448

4-chloro-2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid

(109) ##STR00093## ##STR00094##

Step 1

Methyl 4-chloro-2-hydroxybenzoate

(110) 4-Chloro-2-hydroxybenzoic acid (5.00 g, 28.97 mmol) was dissolved in methanol (50.00 mL), sulfuric acid (4.26 g, 43.46 mmol, 2.32 mL) was added, and then stirred at 80 C. for 12 hours. The reaction was quenched with 30 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL*3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 4-chloro-2-hydroxybenzoate (a white solid, 4.0 g, yield: 74.00%).

(111) .sup.1H NMR (400 MHz, CDCl3) 10.86 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.00 (s, 1H), 6.88-6.85 (m, 1H), 3.95 (s, 3H).

Step 2

Methyl 4-chloro-2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoate

(112) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin (200.00 mg, 486.13 umol) was dissolved in N,N-dimethylformamide (10.00 mL), and potassium carbonate (134.38 mg, 972.26 umol) and methyl 4-chloro-2-hydroxybenzoate (117.92 mg, 631.97 umol) were added successively, then stirred at 80 C. for 12 hours. The reaction solution was filtered and concentrated, and the residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=10/1 to 1/1) to give methyl 4-chloro-2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydrometh ylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoate (a white solid, 350 mg, yield: 69.62%).

(113) .sup.1H NMR (400 MHz, CDCl3) 7.73 (d, J=8.4 Hz, 1H), 6.95-6.89 (m, 2H), 4.88 (s, 1H), 4.61 (t, J=6 Hz, 2H), 4.11-3.88 (m, 2H), 3.85 (s, 3H), 3.52-3.42 (m, 3H), 2.44-2.40 (m, 2H), 2.08-1.69 (m, 9H), 1.52-1.37 (m, 7H), 1.25-1.21 (m, 3H), 0.76 (s, 3H).

Step 3

4-chloro-2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid

(114) Methyl 4-chloro-2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoate (150.00 mg, 290.08 umol) was dissolved in tetrahydrofuran (12.00 mL), and lithium hydroxide monohydrate (60.86 mg, 1.45 mmol) and water (4.00 mL) were added successively, followed by stirring at 35 C. for 12 hours. The tetrahydrofuran was removed by rotary evaporation under reduced pressure, and the system was adjusted to pH=3 with a hydrochloric acid solution (1 M) and then extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by preparative liquid chromatography (HCOOH) to give 4-chloro-2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid 448 (20 mg, yield: 13.29%).

(115) .sup.1H NMR (400 MHz, CDCl3) 8.11 (d, J=8.4 Hz, 1H), 7.13-7.10 (m, 1H), 6.99 (d, J=3.2 Hz, 1H), 4.94 (s, 1H), 4.59 (t, J=6 Hz, 2H), 4.14-4.01 (m, 3H), 3.51-3.42 (m, 2H), 2.45 (d, J=11.6 Hz, 1H), 2.12-1.69 (m, 11H), 1.57-1.52 (m, 6H), 1.51 (s, 3H), 1.37-1.25 (m, 3H), 0.81 (s, 3H).

Compound 447

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-4-methylbenzoic acid

(116) ##STR00095## ##STR00096##

Step 1

Methyl 2-hydroxy-4-methylbenzoate

(117) 2-hydroxy-4-methylbenzoic acid (5.00 g, 32.86 mmol) was dissolved in methanol (50.00 mL), added with sulfuric acid (4.83 g, 49.29 mmol, 2.63 mL), and then stirred at 80 C. for 12 hours. The reaction was quenched with 50 mL saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 2-hydroxy-4-methylbenzoate (a white solid, 4.5 g, yield: 82.41%).

(118) .sup.1H NMR (400 MHz, CDCl3) 10.78 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 6.79 (s, 1H), 6.69 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 2.35 (s, 3H).

Step 2

Methyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-4-methylbenzoate

(119) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin (200.00 mg, 486.13 umol) was dissolved in N,N-dimethylformamide (10.00 mL), and potassium carbonate (134.38 mg, 972.26 umol) and methyl 2-hydroxy-4-methylbenzoate (105.01 mg, 631.97 umol) were added successively, then stirred at 80 C. for 12 hours. The reaction solution was filtered and concentrated, and the residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=10/1 to 1/1) to give methyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-4-methylbenzoate (a white solid, 300 mg, yield: 62.12%).

(120) .sup.1H NMR (400 MHz, CDCl3) 7.69 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 6.70 (s, 1H), 4.87 (s, 1H), 4.61 (d, J=4.8 Hz, 2H), 4.12-4.02 (m, 2H), 3.85 (s, 4H), 3.52-3.42 (m, 2H), 2.43-2.08 (m, 5H), 1.95-1.68 (m, 9H), 1.56-1.52 (m, 4H), 1.43 (s, 3H), 1.37-1.25 (3H), 0.79 (s, 3H).

Step 3

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-4-methylbenzoic acid

(121) Methyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-4-methylbenzoate (150.00 mg, 302.01 umol) was dissolved in tetrahydrofuran (12.00 mL), and lithium hydroxide monohydrate (63.36 mg, 1.51 mmol) and water (4.00 mL) were added successively, followed by stirring at 35 C. for 12 hours. The tetrahydrofuran was removed by rotary evaporation under reduced pressure, and the system was adjusted to pH=3 with a hydrochloric acid solution (1 M) and then extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, filtered and concentrated to give 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-4-methylbenzoic acid 447 (50 mg, yield: 32.93%).

(122) MS m/z (ESI):483.4[M+1]

(123) .sup.1H NMR (400 MHz, CDCl3) 8.07 (d, J=8 Hz, 1H), 6.95 (d, J=8 Hz, 1H), 6.80 (s, 1H), 4.95 (s, 1H), 4.61 (d, J=6 Hz, 2H), 4.32 (s, 1H), 4.13-4.03 (m, 2H), 3.53-3.44 (m, 2H), 2.48-2.00 (m, 5H), 1.86-1.70 (m, 11H), 1.59-1.54 (m, 5H), 1.38 (s, 3H), 1.26-1.22 (m, 3H), 0.83 (s, 3H).

Compound 397

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)nicotinic acid

(124) ##STR00097##

Step 1

Methyl 4-hydroxynicotinate

(125) 4-Hydroxynicotinic acid (5.00 g, 35.94 mmol) was dissolved in methanol (50.00 mL), added with sulfuric acid (18M, 100.00 uL), and then stirred at 70 C. under nitrogen atmosphere for 12 hours. After the reaction mixture was concentrated, the residue was dissolved in dichloromethane (50.00 mL) and the system was adjusted to pH=8 with saturated sodium bicarbonate solution. A white solid was slowly precipitated and filtered to give methyl 4-hydroxynicotinate (a white solid, 3.0 g, crude product).

(126) .sup.1H NMR (400 MHz, CDCl3) 8.27 (s, 1H), 7.67 (d, J=6.8 Hz, 1H), 6.21 (d, J=7.0 Hz, 1H), 3.69 (s, 3H).

Step 2

Methyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) nicotinate

(127) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin (300.00 mg, 729.20 umol) was dissolved in N,N-dimethylformamide (5.00 mL), and potassium carbonate (201.57 mg, 1.46 mmol) and methyl 4-hydroxynicotate (223.34 mg, 1.46 mmol) were added successively and then stirred at 70 C. for 12 hours under nitrogen atmosphere. The reaction was quenched by adding 30 mL water and then extracted with ethyl acetate (30.00 mL). The organic phase was successively washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=1/1) to give methyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) nicotinate (a yellow oil, 200 mg, yield: 56.71%).

(128) .sup.1H NMR (400 MHz, CDCl3) 8.89 (s, 1H), 8.51 (d, J=6.0 Hz, 1H), 6.80 (d, J=5.8 Hz, 1H), 4.88 (s, 1H), 4.66-4.50 (m, 2H), 4.24-4.14 (m, 1H), 4.03 (d, J=11.3 Hz, 1H), 3.98-3.85 (m, 4H), 3.54-3.39 (m, 2H), 2.42 (d, J=12.3 Hz, 1H), 2.27 (dq, J=3.0, 13.2 Hz, 1H), 2.16-2.04 (m, 2H), 1.95-1.87 (m, 3H), 1.83-1.76 (m, 1H), 1.72-1.67 (m, 3H), 1.54 (td, J=7.4, 19.3 Hz, 4H), 1.49-1.38 (m, 3H), 1.36 (s, 3H), 1.30-1.24 (m, 3H), 0.79 (s, 3H).

Step 3

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)nicotinic acid

(129) Methyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) nicotinate (200.00 mg, 413.53 umol) was dissolved in tetrahydrofuran (2.00 mL), and potassium hydroxide (46.41 mg, 827.06 umol) and water (1.00 mL) were added successively, and then stirred at room temperature under nitrogen atmosphere for 12 hours. The system was adjusted to neutrality with hydrochloric acid solution (1M). The organic phase was removed by rotary evaporation under reduced pressure, and the aqueous phase was separated by preparative liquid chromatography (HCOOH) to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)nicotinic acid 397 (54 mg, yield: 26.75%).

(130) MS m/z (ESI):470.2 [M+1]

(131) .sup.1H NMR (400 MHz, CDCl3) 9.15 (s, 1H), 8.64 (d, J=5.8 Hz, 1H), 6.91 (d, J=6.0 Hz, 1H), 4.92 (s, 1H), 4.65-4.53 (m, 2H), 4.33 (dt, J=4.5, 7.9 Hz, 1H), 4.18-4.06 (m, 1H), 4.02 (d, J=11.3 Hz, 1H), 3.52-3.38 (m, 2H), 2.44 (d, J=12.0 Hz, 1H), 2.34-2.21 (m, 1H), 2.20-2.10 (m, 1H), 2.10-2.03 (m, 1H), 2.02-1.92 (m, 2H), 1.92-1.76 (m, 3H), 1.75-1.62 (m, 3H), 1.60-1.47 (m, 4H), 1.43 (dd, J=6.8, 12.3 Hz, 2H), 1.35 (s, 3H), 1.28-1.15 (m, 3H), 0.80 (s, 3H).

Compound 410

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)picolinic acid

(132) ##STR00098##

Step 1

Methyl 4-hydroxypicolinate

(133) 4-Hydroxypicolinic acid (2.50 g, 17.97 mmol) was dissolved in methanol (25.00 mL), added with sulfuric acid (88.13 mg, 898.50 umol), and then stirred at 70 C. under nitrogen atmosphere for 12 hours. After the reaction mixture was concentrated, the residue was dissolved in dichloromethane (50.00 mL) and the system was adjusted to pH=8 with saturated sodium bicarbonate solution. A white solid was slowly precipitated and filtered to give methyl 4-hydroxypicolinate (a white solid, 1.5 g, crude product).

(134) .sup.1H NMR (400 MHz, CDCl3) 7.72 (d, J=6.8 Hz, 1H), 6.80 (br. s., 1H), 6.35 (d, J=5.0 Hz, 1H), 3.38 (s, 3H).

Step 2

Methyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) picolinate

(135) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin (400.00 mg, 972.27 umol) was dissolved in acetonitrile (10.00 mL), and potassium carbonate (268.75 mg, 1.94 mmol) and methyl 4-hydroxypicolinate (297.79 mg, 1.94 mmol) were added successively and then stirred at 70 C. for 12 hours under nitrogen atmosphere. The reaction was quenched by adding 30 mL water and then extracted with ethyl acetate (30.00 mL). The organic phase was successively washed with water and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=4/1) to give methyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) picolinate (a yellow oil, 200 mg, yield: 42.53%).

(136) .sup.1H NMR (400 MHz, CDCl3) 8.51 (d, J=5.5 Hz, 1H), 7.62 (d, J=2.3 Hz, 1H), 6.92 (dd, J=2.5, 5.8 Hz, 1H), 4.89 (s, 1H), 4.67-4.53 (m, 2H), 4.22-4.13 (m, 1H), 4.06-3.98 (m, 4H), 3.97-3.88 (m, 1H), 3.56-3.39 (m, 2H), 2.43 (d, J=12.8 Hz, 1H), 2.27 (dq, J=3.1, 13.3 Hz, 1H), 2.07 (d, J=3.0 Hz, 1H), 2.02-1.94 (m, 1H), 1.92-1.77 (m, 4H), 1.73-1.65 (m, 3H), 1.63 (s, 1H), 1.54 (dd, J=7.2, 11.7 Hz, 3H), 1.50-1.40 (m, 3H), 1.37 (s, 3H), 1.28-1.22 (m, 3H), 0.79 (s, 3H).

Step 3

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)picolinic acid

(137) Methyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) picolinate (200.00 mg, 413.53 umol) was dissolved in methanol (2.00 mL), and potassium hydroxide (46.41 mg, 827.06 umol) and water (1.00 mL) were added successively, and then stirred at room temperature under nitrogen atmosphere for 12 hours. The system was adjusted to neutrality with hydrochloric acid solution (1M). The organic phase was removed by rotary evaporation under reduced pressure, and the aqueous phase was separated by preparative liquid chromatography (HCOOH) to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)picolinic acid 410 (75 mg, yield: 38.62%).

(138) MS m/z (ESI):470.3 [M+1]

(139) .sup.1H NMR (400 MHz, CDCl3) 8.87 (d, J=6.0 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.14 (d, J=4.0 Hz, 1H), 4.91 (s, 1H), 4.66-4.50 (m, 2H), 4.31 (br. s., 1H), 4.18-4.06 (m, 1H), 4.02 (d, J=11.0 Hz, 1H), 3.57-3.38 (m, 2H), 2.43 (d, J=13.1 Hz, 1H), 2.34-2.20 (m, 1H), 2.15-2.02 (m, 2H), 2.01-1.90 (m, 2H), 1.90-1.77 (m, 3H), 1.75-1.63 (m, 3H), 1.61-1.40 (m, 6H), 1.37 (s, 3H), 1.30-1.11 (m, 3H), 0.79 (s, 3H).

Compound 415

(140) ##STR00099##

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)isonicotinic acid

Step 1

Ethyl 3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)isonicotinate

(141) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin (400.00 mg, 972.27 umol) was dissolved in acetonitrile (10.00 mL), and potassium carbonate (268.75 mg, 1.94 mmol) and ethyl 3-hydroxyisopicolinate (243.79 mg, 1.94 mmol) were added successively and then stirred at 70 C. for 12 hours under nitrogen atmosphere. The reaction was quenched by adding 30 mL water and then extracted with ethyl acetate (30.00 mL). The organic phase was successively washed with water and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=4/1) to give ethyl 3-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)isonicotinate (a yellow oil, 200 mg, yield: 41.33%).

(142) .sup.1H NMR (400 MHz, CDCl3) 8.36 (s, 1H), 8.29 (d, J=4.8 Hz, 1H), 7.53 (d, J=4.8 Hz, 1H), 4.88 (s, 1H), 4.64-4.55 (m, 2H), 4.39 (q, J=7.0 Hz, 2H), 4.28-4.20 (m, 1H), 4.06-3.94 (m, 2H), 3.55-3.39 (m, 2H), 2.42 (d, J=12.8 Hz, 1H), 2.27 (dq, J=3.1, 13.3 Hz, 1H), 2.15-2.05 (m, 2H), 2.01-1.94 (m, 1H), 1.93-1.85 (m, 3H), 1.83-1.76 (m, 1H), 1.74-1.64 (m, 3H), 1.61-1.49 (m, 4H), 1.47-1.39 (m, 5H), 1.36 (s, 3H), 1.25-1.16 (m, 3H), 0.79 (s, 3H).

Step 2

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)isonicotinic acid

(143) Ethyl 3-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)isonicotinate (200.00 mg, 401.88 umol) was dissolved in methanol (2.00 mL), and potassium hydroxide (45.10 mg, 803.76 umol) and water (1.00 mL) were added successively, and then stirred at room temperature under nitrogen atmosphere for 12 hours. The system was adjusted to neutrality with hydrochloric acid solution (1M). The organic phase was removed by rotary evaporation under reduced pressure, and the aqueous phase was separated by preparative liquid chromatography (HCOOH) to give 3-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)isonicotinic acid 415 (75 mg, yield: 37.99%).

(144) MS m/z (ESI): 470.2 [M+1]

(145) .sup.1H NMR (400 MHz, CDCl3) 8.60-8.33 (m, 2H), 7.86 (br. s., 1H), 4.91 (br. s., 1H), 4.58 (br. s., 2H), 4.42 (br. s., 1H), 4.21 (br. s., 1H), 4.00 (d, J=10.0 Hz, 1H), 3.49-3.36 (m, 2H), 2.43 (d, J=11.8 Hz, 1H), 2.30-2.16 (m, 1H), 2.06 (d, J=6.3 Hz, 1H), 1.97 (br. s., 2H), 1.83 (br. s., 3H), 1.68 (br. s., 4H), 1.53 (d, J=12.5 Hz, 4H), 1.44-1.38 (m, 2H), 1.35 (br. s., 3H), 1.22 (br. s., 3H), 0.78 (br. s., 3H).

Compound 406

5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)nicotinic acid

(146) ##STR00100##

Step 1

Methyl 5-hydroxynicotinate

(147) 5-Hydroxynicotinic acid (2.50 g, 17.97 mmol) was dissolved in methanol (20.00 mL), added with sulfuric acid (18M, 47.90 uL), and then stirred at 70 C. under nitrogen atmosphere for 12 hours. After the reaction mixture was concentrated, the residue was dissolved in dichloromethane (50.00 mL) and the system was adjusted to pH=8 with saturated sodium bicarbonate solution. A white solid was slowly precipitated and filtered to give methyl 5-hydroxynicotinate (a white solid, 1.5 g, crude product).

(148) .sup.1H NMR (400 MHz, CDCl3) 8.25 (s, 1H), 8.13 (d, J=1.8 Hz, 1H), 7.38 (br. s., 1H), 3.17 (s, 3H).

Step 2

Methyl 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) nicotinate

(149) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin (300.00 mg, 972.27 umol) was dissolved in acetonitrile (10.00 mL), and potassium carbonate (268.75 mg, 1.94 mmol) and methyl 5-hydroxynicotate (297.79 mg, 1.94 mmol) were added successively and then stirred at 70 C. for 12 hours under nitrogen atmosphere. The reaction was quenched by adding 30 mL water and then extracted with ethyl acetate (30.00 mL). The organic phase was successively washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=4/1) to give methyl 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) nicotinate (a yellow oil, 200 mg, yield: 21.27%).

(150) .sup.1H NMR (400 MHz, CDCl3) 8.79 (s, 1H), 8.43 (d, J=2.5 Hz, 1H), 7.71 (br. s., 1H), 4.89 (s, 1H), 4.67-4.52 (m, 2H), 4.12 (s, 1H), 4.03 (d, J=11.0 Hz, 1H), 3.98-3.86 (m, 4H), 3.58-3.34 (m, 2H), 2.43 (d, J=13.1 Hz, 1H), 2.27 (q, J=13.1 Hz, 1H), 2.13-2.07 (m, 1H), 2.04-1.94 (m, 2H), 1.93-1.78 (m, 4H), 1.71 (br. s., 3H), 1.61-1.40 (m, 6H), 1.37 (s, 3H), 1.26-1.16 (m, 3H), 0.79 (s, 3H).

Step 3

5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)nicotinic acid

(151) Methyl 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) nicotinate (200.00 mg, 413.53 umol) was dissolved in tetrahydrofuran (2.00 mL), and potassium hydroxide (46.41 mg, 827.06 umol) and water (1.00 mL) were added successively, and then stirred at room temperature under nitrogen atmosphere for 12 hours. The system was adjusted to neutrality with hydrochloric acid solution (1M). The organic phase was removed by rotary evaporation under reduced pressure, and the aqueous phase was separated by preparative liquid chromatography (HCOOH) to give 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)nicotinic acid 406 (38 mg, yield: 19.57%).

(152) MS m/z (ESI):470.3 [M+1]

(153) .sup.1H NMR (400 MHz, CDCl3) 8.92 (s, 1H), 8.53 (d, J=2.5 Hz, 1H), 7.88 (br. s., 1H), 4.90 (s, 1H), 4.67-4.53 (m, 2H), 4.17 (br. s., 1H), 4.04 (d, J=11.3 Hz, 1H), 4.00-3.88 (m, 1H), 3.61-3.39 (m, 2H), 2.43 (d, J=13.3 Hz, 1H), 2.35-2.20 (m, 1H), 2.14-2.03 (m, 2H), 2.02-1.95 (m, 1H), 1.94-1.86 (m, 3H), 1.84-1.78 (m, 1H), 1.76-1.63 (m, 3H), 1.60-1.40 (m, 6H), 1.38 (s, 3H), 1.32-1.17 (m, 3H), 0.80 (s, 3H).

Compound 436

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)nicotinic acid

(154) ##STR00101##

Step 1

Methyl 2-hydroxynicotinate

(155) 2-Hydroxynicotinic acid (2.50 g, 17.97 mmol) was dissolved in methanol (20.00 mL), added with sulfuric acid (18M, 47.90 uL), and then stirred at 70 C. under nitrogen atmosphere for 12 hours. After the reaction mixture was concentrated, the residue was dissolved in dichloromethane (50.00 mL) and the system was adjusted to pH=8 with saturated sodium bicarbonate solution. A white solid was slowly precipitated and filtered to give methyl 2-hydroxynicotinate (a white solid, 1.5 g, yield: 54.51%).

(156) .sup.1H NMR (400 MHz, CDCl3) 8.27 (dd, J=2.0, 7.0 Hz, 1H), 7.78 (dd, J=2.0, 6.0 Hz, 1H), 6.41 (t, J=6.8 Hz, 1H), 3.90 (s, 3H).

Step 2

Methyl 2-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) nicotinate

(157) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin (400.00 mg, 972.27 umol) was dissolved in acetonitrile (10.00 mL), and potassium carbonate (268.75 mg, 1.94 mmol) and methyl 2-hydroxynicotate (148.89 mg, 972.27 umol) were added successively and then stirred at 70 C. for 2 hours under nitrogen atmosphere. The reaction was quenched by adding 30 mL water and then extracted with ethyl acetate (30.00 mL). The organic phase was successively washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica, dichloromethane/ethyl acetate=4/1) to give methyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) nicotinate (a yellow oil, 100 mg, yield: 21.27%).

(158) .sup.1H NMR (400 MHz, CDCl3) 8.27 (d, J=3.0 Hz, 1H), 8.14 (d, J=7.3 Hz, 1H), 6.91 (dd, J=5.0, 7.3 Hz, 1H), 4.88 (s, 1H), 4.72 (s, 1H), 4.61 (d, J=5.8 Hz, 1H), 4.58-4.46 (m, 1H), 4.28-4.16 (m, 1H), 4.04 (d, J=11.3 Hz, 1H), 3.90 (s, 3H), 3.59-3.33 (m, 2H), 2.42 (d, J=12.5 Hz, 1H), 2.34-2.18 (m, 1H), 2.08 (br. s., 1H), 2.01 (d, J=15.6 Hz, 2H), 1.95-1.84 (m, 3H), 1.82-1.76 (m, 1H), 1.70 (br. s., 3H), 1.56-1.41 (m, 6H), 1.37 (s, 3H), 1.25 (d, J=6.0 Hz, 3H), 0.78 (s, 3H).

Step 3

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)nicotinic acid

(159) Methyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) nicotinate (100.00 mg, 206.77 umol) was dissolved in methane (2.00 mL), and potassium hydroxide (23.20 mg, 413.53 umol) and water (1.00 mL) were added successively, and then stirred at room temperature under nitrogen atmosphere for 12 hours. The system was adjusted to neutrality with hydrochloric acid solution (1M). The organic phase was removed by rotary evaporation under reduced pressure, and the aqueous phase was separated by preparative liquid chromatography (HCOOH) to give 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)nicotinic acid 436 (9.6 mg, yield: 9.89%).

(160) MS m/z (ESI):470.3 [M+1]

(161) .sup.1H NMR (400 MHz, CDCl3) 8.47 (dd, J=1.8, 7.5 Hz, 1H), 8.36 (dd, J=1.9, 4.9 Hz, 1H), 7.12 (dd, J=5.0, 7.5 Hz, 1H), 4.93 (s, 1H), 4.79-4.66 (m, 2H), 4.60 (d, J=5.8 Hz, 1H), 4.51-4.38 (m, 1H), 4.02 (d, J=11.3 Hz, 1H), 3.54-3.39 (m, 2H), 2.44 (d, J=11.8 Hz, 1H), 2.32-2.18 (m, 1H), 2.13-2.04 (m, 2H), 2.03-1.93 (m, 2H), 1.88 (d, J=13.1 Hz, 1H), 1.84-1.76 (m, 2H), 1.69 (td, J=4.5, 8.8 Hz, 4H), 1.61-1.59 (m, 1H), 1.51 (d, J=6.8 Hz, 2H), 1.43 (dd, J=7.0, 12.0 Hz, 2H), 1.37 (s, 3H), 1.27-1.12 (m, 3H), 0.79 (s, 3H).

Compound 431

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-picolinic acid

(162) ##STR00102##

Step 1

Methyl 3-hydroxy-2-picolinate

(163) 3-Hydroxypyridin-2-carboxylic acid (2.50 g, 17.97 mmol) was dissolved in methanol (20.00 mL), added with sulfuric acid (18M, 47.90 uL) at room temperature, and then stirred at 70 C. for 12 hours. After the reaction mixture was concentrated, the residue was dissolved in dichloromethane (50.00 mL) and the system was adjusted to pH=8 with saturated sodium bicarbonate solution. A white solid was precipitated out, and the filter cake was dried to give methyl 3-hydroxy-2-picolinate (a white solid, 1.5 g, yield: 54.51%).

(164) .sup.1H NMR (400 MHz, CDCl.sub.3) 10.63 (s, 1H), 8.27 (dd, J=1.3, 4.3 Hz, 1H), 7.49-7.40 (m, 1H), 7.40-7.31 (m, 1H), 4.05 (s, 3H).

Step 2

Methyl 3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-picolinate

(165) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin 432c (400.00 mg, 972.27 umol) was dissolved in acetonitrile (10.00 mL), and potassium carbonate (403.13 mg, 2.92 mmol) and methyl 3-hydroxy-2-picolinate (297.79 mg, 1.94 mmol) were added successively at room temperature and then stirred at 70 C. for 12 hours. The reaction was quenched by adding 30 mL water and then extracted with ethyl acetate (30.00 mL). The organic phases were combined and successively washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by gel column chromatography (elution system: PE/EtOAc=1:2) to give methyl 3-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-picolinate (a yellow oil, 120 mg, yield: 25.52%).

(166) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.25 (d, J=3.8 Hz, 1H), 7.38-7.34 (m, 1H), 7.31-7.24 (m, 1H), 4.88 (s, 1H), 4.65-4.56 (m, 2H), 4.19-4.14 (m, 1H), 4.03 (d, J=11.3 Hz, 1H), 3.97 (s, 3H), 3.90 (dt, J=5.5, 8.4 Hz, 1H), 3.54-3.40 (m, 2H), 2.42 (d, J=13.1 Hz, 1H), 2.28 (dq, J=3.0, 13.2 Hz, 1H), 2.14-2.06 (m, 2H), 2.03-1.94 (m, 1H), 1.92 (d, J=2.8 Hz, 1H), 1.89-1.86 (m, 1H), 1.84-1.76 (m, 2H), 1.75-1.65 (m, 3H), 1.62-1.49 (m, 4H), 1.45 (dd, J=6.9, 12.2 Hz, 2H), 1.37 (s, 3H), 1.29-1.24 (m, 3H), 0.79 (s, 3H).

Step 3

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-picolinic acid

(167) Methyl 3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-picolinate (100.00 mg, 206.77 umol) was dissolved in 1 mL tetrahydrofuran and 1 mL water, and potassium hydroxide (23.20 mg, 413.54 umol) was added, followed by stirring at room temperature for 12 hours. The system was adjusted to pH=7 with diluted hydrochloric acid solution (1M), and extracted with ethyl acetate (10 mL*2). The organic phases were combined, successively washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-picolinic acid 431 (37 mg, yield: 36.20%).

(168) MS m/z (ESI): 492.3 [M+23]

(169) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11 (br. s., 1H), 7.46 (d, J=5.8 Hz, 1H), 7.38 (br. s., 1H), 4.83 (br. s., 1H), 4.65 (d, J=5.3 Hz, 1H), 4.58 (br. s., 1H), 4.11 (br. s., 1H), 3.93 (d, J=11.0 Hz, 1H), 3.84 (d, J=6.3 Hz, 1H), 3.30 (br. s., 2H), 2.39-2.17 (m, 2H), 2.01-1.84 (m, 4H), 1.74 (d, J=10.0 Hz, 3H), 1.55 (d, J=10.5 Hz, 2H), 1.51-1.36 (m, 7H), 1.24 (br. s., 3H), 1.21-1.11 (m, 3H), 0.70 (s, 3H).

Compound 432

5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-picolinic acid

(170) ##STR00103##

Step 1

Methyl 5-hydroxy-2-picolinate

(171) 5-Hydroxypyridin-2-carboxylic acid (2.50 g, 17.97 mmol) was dissolved in methanol (20.00 mL), added with sulfuric acid (18M, 47.90 uL) at room temperature, and then stirred at 70 C. for 12 hours. After the reaction mixture was concentrated, the residue was dissolved in dichloromethane (50.00 mL) and the system was adjusted to pH=8 with saturated sodium bicarbonate solution. A white solid was precipitated out, and the filter cake was dried to give methyl 5-hydroxy-2-picolinate (a white solid, 1.5 g, yield: 54.51%).

(172) .sup.1H NMR (400 MHz, CDCl.sub.3) 10.82 (br. s., 1H), 8.20 (d, J=2.5 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.25 (dd, J=2.8, 8.5 Hz, 1H), 3.80 (s, 3H).

Step 2

Methyl 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-picolinate

(173) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin (400.00 mg, 972.27 umol) was dissolved in acetonitrile (10.00 mL), and potassium carbonate (268.75 mg, 1.94 mmol) and methyl 5-hydroxy-2-picolinate (148.89 mg, 972.27 umol) were added successively at room temperature and then stirred at 70 C. for 12 hours. The reaction was quenched by adding 30 mL water and then extracted with ethyl acetate (30.00 mL). The organic phases were combined and successively washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by gel column chromatography (elution system: PE/EtOAc=1:3) to give methyl 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-picolinate (a yellow solid, 250 mg, yield: 53.17%).

(174) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.35 (d, J=2.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.21 (dd, J=2.9, 8.7 Hz, 1H), 4.90 (s, 1H), 4.63-4.53 (m, 2H), 4.19-4.13 (m, 1H), 4.03 (d, J=11.3 Hz, 1H), 3.98 (s, 3H), 3.96-3.90 (m, 1H), 3.54-3.38 (m, 2H), 2.43 (d, J=13.1 Hz, 1H), 2.32-2.22 (m, 1H), 2.13-2.07 (m, 1H), 2.03-1.95 (m, 1H), 1.92-1.78 (m, 4H), 1.74-1.65 (m, 3H), 1.60-1.58 (m, 1H), 1.56-1.48 (m, 4H), 1.44 (dd, J=7.2, 12.2 Hz, 2H), 1.37 (s, 3H), 1.28-1.23 (m, 3H), 0.80 (s, 3H).

Step 3

5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-picolinic acid

(175) Methyl 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-picolinate (100.00 mg, 206.77 umol) was dissolved in 1 mL tetrahydrofuran and 1 mL water, and potassium hydroxide 30.16 mg, 537.58 umol) was added, followed by stirring at room temperature for 12 hours. The system was adjusted to pH=7 with diluted hydrochloric acid solution (1M), and extracted with ethyl acetate (10 mL*2). The organic phases were combined, successively washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-picolinic acid 432 (73 mg, yield: 56.50%).

(176) MS m/z (ESI): 470.7 [M+1]

(177) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.24 (br. s., 1H), 8.14 (br. s., 1H), 7.35-7.28 (m, 1H), 4.89 (br. s., 1H), 4.62-4.56 (m, 2H), 4.15 (br. s., 1H), 4.02 (d, J=11.0 Hz, 1H), 3.96 (br. s., 1H), 3.53-3.47 (m, 1H), 3.44 (d, J=11.3 Hz, 1H), 2.42 (d, J=12.0 Hz, 1H), 2.32-2.21 (m, 1H), 2.11-2.04 (m, 2H), 2.01-1.94 (m, 1H), 1.91-1.80 (m, 4H), 1.69-1.64 (m, 2H), 1.58-1.51 (m, 4H), 1.48-1.41 (m, 3H), 1.37 (s, 3H), 1.25 (br. s., 3H), 0.79 (br. s., 3H).

Compound 428

2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-carbonylpyridin-1(2H)-yl)acetic acid

(178) ##STR00104## ##STR00105##

Step 1

Ethyl 2-(4-(benzyloxy)-2-carbonylpyridin-1 (2H)-yl)acetate

(179) 4-Benzyloxypyridin-2-ol (5.00 g, 24.85 mmol) in tetrahydrofuran (100.00 mL), and added with sodium hydrogen (1.99 g, 49.70 mmol, 60% purity) at 0 C., then stirred at 0 C. for 0.5 hours. Ethyl 2-bromoacetate (6.22 g, 37.28 mmol, 4.12 mL) was added to the reaction solution, followed by stirring at room temperature for 12 hours. The reaction was quenched with 20 mL water and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 2-(4-(benzyloxy)-2-carbonylpyridin-1 (2H)yl) ethyl acetate (a white solid, 5 g, yield: 70.02%).

(180) .sup.1H NMR (400 MHz, CDCl3) 7.42-7.35 (m, 5H), 7.11 (d, J=8 Hz, 1H), 6.03-6.01 (m, 2H), 5.01 (s, 2H), 4.60 (s, 2H), 4.26-4.22 (m, 2H), 1.33-1.27 (m, 6H).

Step 2

Ethyl 2-(4-hydroxy-2-carbonylpyridin-1(2H)-yl) acetate

(181) Ethyl 2-(4-(benzyloxy)-2-carbonylpyridin-1(2H)-yl) acetate (1.00 g, 3.48 mmol) was dissolved in ethanol (20.00 mL) and palladium on carbon (100.00 mg, 10% purity) was added, then stirred at 30 C. for 3 hours under 30 PSI of hydrogen atmosphere. The reaction was filtered and the filtrate was concentrated to give ethyl 2-(4-hydroxy-2-carbonylpyridin-1(2H))-yl)acetate (a white solid, 450 mg, yield: 65.58%).

(182) .sup.1H NMR (400 MHz, CDCl3) 7.47 (d, J=7.6 Hz, 1H), 6.09-6.06 (m, 1H), 5.83 (s, 1H), 4.66 (s, 2H), 4.21-4.19 (m, 2H), 1.30-1.26 (m, 5H).

Step 3

Ethyl 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-carbonylpyridin-1(2H)-yl) acetate

(183) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin (500.00 mg, 1.22 mmol) was dissolved in N,N-dimethylformamide (20.00 mL), and cesium carbonate (791.96 mg, 2.43 mmol) and ethyl 2-(4-hydroxy-2-carbonylpyridin-1(2H)-yl)acetate (250.00 mg, 1.27 mmol) were successively added, and then stirred at 70 C. for 12 hours. The reaction was quenched with 10 mL water and extracted with dichloromethane (10 mL*3). The combined organic phases were washed with saturated brine (10 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=10/1 to 2/1) to give ethyl 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-carbonylpyridin-1(2H)-yl) acetate (a yellow solid, 280 mg, yield: 36.24%).

(184) .sup.1H NMR (400 MHz, CDCl3) 7.05 (d, J=7.6 Hz, 1H), 5.94-5.91 (m, 1H), 5.83 (d, J=2.4 Hz, 1H), 4.88 (s, 1H), 4.61-4.54 (m, 5H), 4.24-4.22 (m, 2H), 4.04-4.01 (m, 2H), 3.81-3.79 (m, 1H), 3.45-3.42 (m, 2H), 2.06-1.69 (m, 12H), 1.59-1.36 (m, 13H), 1.28-1.24 (m, 9H), 0.78 (s, 3H).

Step 4

2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-carbonylpyridin-1(2H)-yl)acetic acid

(185) Ethyl 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-carbonylpyridin-1(2H)-yl) acetate (100.00 mg, 189.51 umol) was dissolved in tetrahydrofuran (6.00 mL), and lithium hydroxide monohydrate (39.76 mg, 947.55 umol) and water (2.00 mL) were successively added, followed by stirring at 40 C. for 12 hours. The tetrahydrofuran was removed by rotary evaporation under reduced pressure, the system was adjusted to pH=3 with a hydrochloric acid solution (1M), the reaction solution was extracted with ethyl acetate (30 mL*3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to give 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-2-carbonylpyridin-1(2H)-yl)acetic acid 428 (46 mg, yield: 36.25%).

(186) MS m/z (ESI): 500.3 [M+1]

(187) .sup.1H NMR (400 MHz, CDCl3) 7.15 (d, J=7.6 Hz, 1H), 8.06-8.03 (m, 1H), 5.93 (d, J=2 Hz, 1H), 4.88 (s, 1H), 4.61-4.53 (m, 4H), 4.03-3.82 (m, 3H), 3.51-3.42 (m, 2H), 2.27-2.25 (m, 2H), 1.98-1.67 (m, 18H), 1.53 (s, 3H), 1.52-1.25 (m, 4H), 0.78 (s, 3H).

Compound 417

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine-3,5-dicarboxylic acid

(188) ##STR00106##

Step 1

Dimethyl 4-hydroxypyridine-3,5-dicarboxylate

(189) Dimethyl 3-oxoglutarate (2.00 g, 11.48 mmol) was dissolved in methanol (20.00 mL) and sodium methoxide (639.00 mg, 11.82 mmol) and 1,3,5-triazine (903.22 mg, 11.14 mmol) were added successively, and then stirred for 10 minutes at room temperature and 30 minutes at 70 C. The system was adjusted to neutrality with concentrated hydrochloric acid, then allowed to stand for 2 hours, filtered, and the filter cake was washed successively with water (3*100 mL), methanol (3*50 mL) and petroleum ether (3*50 mL) to give dimethyl 4-hydroxypyridine-3,5-dicarboxylate (a light yellow solid, 1.45 g, crude product).

(190) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.05 (br. s., 1H), 8.20 (br. s., 2H), 3.70 (br. s., 6H).

Step 2

Dimethyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine-3,5-dicarboxylate

(191) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin (200.00 mg, 486.13 umol) was dissolved in N,N-dimethylformamide (10.00 mL), and cesium carbonate (316.78 mg, 972.26 umol) and dimethyl 4-hydroxypyridine-3,5-dicarboxylate 417b (123.19 mg, 583.36 umol) were added successively, then stirred at 80 C. for 8 hours. The system was filtered and the filtrate was separated by preparative liquid chromatography to give dimethyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine-3,5-dicarboxylate (a white solid, 40 mg, yield: 15.19%).

(192) .sup.1H NMR (400 MHz, CDCl3) 8.97 (s, 2H), 4.84 (s, 1H), 4.67-4.56 (m, 2H), 4.19-4.11 (m, 1H), 4.06-3.97 (m, 3H), 3.92 (s, 6H), 3.49-3.38 (m, 3H), 2.40 (d, J=13.3 Hz, 1H), 2.24 (t, J=13.1 Hz, 1H), 2.07-1.70 (m, 14H), 1.35 (br. s., 3H), 1.24 (br. s., 3H), 0.77 (s, 3H).

Step 3

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine-3,5-dicarboxylic acid

(193) Dimethyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine-3,5-dicarboxylate (35.00 mg, 64.61 umol) was dissolved in tetrahydrofuran (5.00 mL), and sodium hydroxide (2.58 mg, 64.61 umol) and water (5.00 mL) were successively added, followed by stirring at room temperature for 1 hour. Ethyl acetate (5.00 mL) was added to the system, and the organic phase was separated from the aqueous phase. The aqueous phase was separated by preparative liquid chromatography to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine-3,5-dicarboxylic acid 417 (25 mg, yield: 71.49%).

(194) MS m/z (ESI):514.2 [M+1]

(195) .sup.1H NMR (400 MHz, MeOD) 8.66 (s, 2H), 4.70 (d, J=5.5 Hz, 1H), 4.59 (s, 1H), 4.47 (d, J=6.8 Hz, 1H), 4.26-4.16 (m, 1H), 4.09 (d, J=11.0 Hz, 1H), 3.51 (dd, J=4.9, 12.4 Hz, 1H), 3.41 (d, J=11.3 Hz, 1H), 3.37 (br. s., 1H), 2.43-2.29 (m, 2H), 2.12-1.95 (m, 4H), 1.91-1.77 (m, 3H), 1.71-1.43 (m, 9H), 1.35 (s, 3H), 1.33-1.15 (m, 3H), 0.80 (s, 3H).

Compound 349

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)cyanopyridine

(196) ##STR00107##

Step 2

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)cyanopyridine

(197) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethanol (150 mg, 0.43 mmol) was dissolved in anhydrous N,N-dimethylformamide (15 mL), and sodium hydrogen (15.5 mg, 0.65 mmol) was added at 0 C. After stirring at 0 C. for 15 minutes, 4-chloro-3-cyanopyridine (71.6 mg, 0.52 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction solution was quenched with water, extracted with dichloromethane, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated on a thin layer chromatography plate to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)cyanopyridine 349 (75 mg, yield: 38.7%).

(198) MS m/z (ESI): 451.2 [M+1]

(199) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.68 (s, 1H), 8.59 (d, J=5.6 HZ, 1H), 6.84 (d, J=6.0 HZ, 1H),4.91 (s, 1H), 4.61-4.00 (m, 5H), 3.53-3.43 (m, 2H), 2.45-1.52 (m, 18H), 1.51 (s, 3H), 1.37-1.25 (m, 3H), 0.80 (s, 3H).

Compound 312

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyrimidine

(200) ##STR00108##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyrimidine

(201) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethanol (200 mg, 0.57 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydrogen (48.2 mg, 2.01 mmol) was added at 0 C. and stirred for 15 minutes at 0 C. 2-chloropyrimidine hydrochloride 312b (173 mg, 1.15 mmol) was added to the reaction and stirred at room temperature overnight. The reaction solution was quenched with water (5 mL), extracted with dichloromethane (30 mL), the organic layer was washed with water (10 mL3), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and separated through a thin layer chromatographic plate to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyrimidine 312 (150 mg, yield: 61.3%).

(202) MS m/z (ESI): 427.2 [M+1]

(203) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.75 (s, 1H), 8.41 (d, J=5.6 Hz, 1H), 6.71 (d, J=6.0 Hz, 1H), 4.90 (s, 1H), 4.67 (s, 1H), 4.60 (d, J=6.0 Hz, 1H), 4.50-4.01 (m, 4H), 3.50-3.43 (m, 2H), 2.44-1.52 (m, 18H), 1.37 (s, 3H), 1.25-1.19 (m, 3H), 0.78 (s, 3H).

Compound 453

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)thiophene-3-carboxylic acid

(204) ##STR00109## ##STR00110##

Step 1

Methyl 4-hydroxythiophene-3-carboxylate

(205) Methyl 4-oxytetrahydrothiophene-3-carboxylate (1.00 g, 6.24 mmol) was dissolved in methanol (20.00 mL), and hydrogen peroxide (2.83 g, 24.96 mmol, 2.40 mL, 30% purity) was added dropwise under nitrogen atmosphere at 70 C., and then stirred at 70 C. for 2 hours. The reaction was quenched with 20 mL saturated sodium sulfite solution at 0 C. and the system was adjusted to pH=6-7 with hydrochloric acid solution (1M). The system was concentrated and the residue was dissolved in dichloromethane/methanol=5/1 (30 mL), filtered and concentrated to give methyl 4-hydroxythiophene-3-carboxylate (0.6 g, crude product).

(206) .sup.1H NMR (400 MHz, CDCl3) 8.73 (br. s., 1H), 7.90 (d, J=3.5 Hz, 1H), 6.40 (d, J=3.5 Hz, 1H), 3.93 (s, 3H).

Step 2

Methyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)thiophene-3-carboxylate

(207) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene-1H-naphthop[2,1-d][1,3]dioxin (500.00 mg, 1.22 mmol) was dissolved in N,N-dimethylformamide (5.00 mL), and cesium carbonate (795.00 mg, 2.44 mmol) and methyl 4-hydroxythiophene-3-carboxylate (289.45 mg, 1.83 mmol) were added successively, and then stirred at 80 C. for 12 hours. The reaction solution was filtered and concentrated, and the residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=5/1) to give methyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)thiophene-3-carboxylate (a white solid, 100 mg, yield: 13.98%).

(208) .sup.1H NMR (400 MHz, CDCl3) 8.00 (d, J=3.5 Hz, 1H), 6.21 (d, J=3.8 Hz, 1H), 4.87 (s, 1H), 4.65-4.59 (m, 2H), 4.13-4.01 (m, 2H), 3.89-3.68 (m, 4H), 3.53-3.43 (m, 2H), 2.42 (d, J=13.1 Hz, 1H), 2.33-2.22 (m, 1H), 2.16-1.81 (m, 7H), 1.70 (dd, J=4.1, 8.7 Hz, 3H), 1.56-1.40 (m, 6H), 1.37 (s, 3H), 1.27-1.21 (m, 3H), 0.82-0.76 (m, 3H).

Step 3

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)thiophene-3-carboxylic acid

(209) Methyl 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)thiophene-3-carboxylate (100.00 mg, 204.63 umol) was dissolved in methanol (2.00 mL) and potassium hydroxide (68.89 mg, 1.23 mmol) and water (2.00 mL) were added successively, then stirred at 70 C. for 24 hours. The system was adjusted to pH=5-6 with hydrochloric acid solution (1M) and then extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)thiophene-3-carboxylic acid 453 (66.1 mg, yield: 64.84%).

(210) MS m/z (ESI):475.3[M+1]

(211) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.97 (br. s., 1H), 6.54 (d, J=3.5 Hz, 1H), 4.84 (s, 1H), 4.65 (d, J=5.3 Hz, 1H), 4.60 (s, 1H), 4.01-3.90 (m, 2H), 3.79-3.69 (m, 1H), 3.61-3.49 (m, 2H), 2.38-2.21 (m, 3H), 1.98-1.84 (m, 4H), 1.81-1.70 (m, 3H), 1.57-1.40 (m, 8H), 1.25-1.17 (m, 6H), 0.75-0.68 (m, 3H).

Compound 445

4-cyano-2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid

(212) ##STR00111##

Step 1

4-cyano-2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid

(213) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenepentahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethanol (500.00 mg, 1.43 mmol) was dissolved in N,N-dimethylformamide (20.00 mL) and sodium hydrogen (150.00 mg, 3.75 mmol, 60% purity) was added at 0 C., then stirred at 0 C. for 2 hours. 4-Cyano-2-fluoro-benzoic acid (309.32 mg, 1.87 mmol) was then added at 0 C. and stirred at 95 C. for 10 hours. The reaction was quenched with 100 mL of saturated brine, diluted with 50 mL of dichloromethane, and extracted with 90 mL (30 mL*3) of dichloromethane. The organic phase was washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica, dichloromethane/methanol=40/1) to give an initial product. The initial product was separated by preparative liquid chromatography to give 4-cyano-2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)benzoic acid 445 (30 mg, yield: 4.25%).

(214) MS m/z (ESI): 494.2[M+1]

(215) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.55 (d, J=7.5 Hz, 1H), 7.46 (br. s., 1H), 7.38 (d, J=7.5 Hz, 1H), 4.86 (s, 1H), 4.67 (d, J=5.5 Hz, 1H), 4.59 (br. s., 1H), 4.14 (br. s., 1H), 3.96 (d, J=11.0 Hz, 1H), 3.88 (d, J=6.5 Hz, 1H), 3.40 (d, J=12.5 Hz, 2H), 2.42-2.20 (m, 3H), 1.94 (d, J=10.0 Hz, 4H), 1.83-1.69 (m, 3H), 1.62-1.39 (m, 8H), 1.30-1.09 (m, 6H), 0.73 (s, 3H).

Compound 452

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-6-fluoro-benzoic acid

(216) ##STR00112##

Step 1

Methyl 2-fluoro-6-hydroxybenzoate

(217) 2-fluoro-6-hydroxybenzoic acid (1.00 g, 6.41 mmol) was dissolved in methanol (10.00 mL), added with sulfuric acid (1.26 g, 12.82 mmol, 683.36 uL), and then stirred at 80 C. for 12 hours. The reaction was quenched with 20 mL saturated sodium bicarbonate solution and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 0.5 g methyl 2-fluoro-6-hydroxybenzoate. Yield: 45.85%.

(218) .sup.1H NMR (400 MHz, CDCl3) 11.24 (s, 1H), 7.42-7.36 (m, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.65-6.6 (m, 1H).

Step 2

Methyl 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-6-fluoro-benzoate

(219) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin (300.00 mg, 729.18 umol) was dissolved in N,N-dimethylformamide (10.00 mL) and potassium carbonate (201.56 mg, 1.46 mmol) and methyl 2-fluoro-6-hydroxybenzoate (148.88 mg, 875.02 umol) were added successively, then stirred at 80 C. for 12 hours. The reaction solution was filtered and concentrated, and the residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=10/1 to 5/1) to give 120 mg methyl 2-(2-((3R,4aR,6aS, 7R, 10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin7-yl)ethoxy)-6-fluoro-benzoate as a white solid. Yield: 32.87%.

(220) .sup.1H NMR (400 MHz, CDCl3) 7.27 (d, J=6.8 Hz, 1H), 6.72-6.63 (m, 2H), 4.86 (s, 1H), 4.61-4.57 (m, 2H), 4.10-4.01 (m, 2H), 3.92 (s, 3H), 3.84 (s, 1H), 3.50-3.42 (m, 2H), 2.42-2.39 (m, 2H), 1.99-1.70 (m, 10H), 1.56 (s, 3H), 1.42-1.36 (m, 5H), 1.37 (s, 3H), 1.24-1.20 (m, 4H), 0.88-0.84 (m, 3H), 0.77 (s, 3H).

Step 3

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-6-fluoro-benzoic acid

(221) Methyl 2-(2-((3R,4aR,6aS, 7R, 10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin7-yl)ethoxy)-6-fluoro-benzoate (120 mg, 239.68 umol) was dissolved in methanol (6.00 mL), and potassium hydroxide (67.25 mg, 1.20 mmol) and water (3.00 mL) were added successively, then stirred at 40 C. for 12 hours. Methanol was removed by rotary evaporation under reduced pressure, and the system was adjusted to Ph=3 with a hydrochloric acid solution (1M) and then extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 60 mg 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-6-fluoro-benzoic acid 452. Yield: 46.30%.

(222) MS m/z (ESI):487.4[M+1]

(223) .sup.1H NMR (400 MHz, CDCl3) 7.41-7.35 (m, 1H), 6.81-6.71 (m, 2H), 4.89 (s, 1H), 4.59 (d, J=5.6 Hz, 2H), 4.23-4.21 (m, 1H), 4.02 (d, J=11.6 Hz, 2H), 3.50-3.41 (m, 2H), 2.44-2.09 (m, 2H), 2.07-1.54 (m, 16H), 1.50 (s, 3H), 1.42-1.24 (m, 3H), 0.79 (s, 3H).

Compound 454

5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyrimidine-2-carboxylic acid

(224) ##STR00113##

Step 1

Methyl 5-hydroxypyrimidine-2-carboxylate

(225) 5-hydroxypyrimidine-2-carbonitrile (200.00 mg, 1.65 mmol) was dissolved in methanol (5.00 mL), and methanolic hydrochloride (20.00 mmol, 3.00 mL, 4.0M) was added, and then stirred at 70 C. for 12 hours. The reaction was quenched with 20 mL saturated sodium bicarbonate solution and extracted with ethyl acetate (20 mL*3). The system was concentrated to give 0.18 g methyl 5-hydroxypyrimidine-2-carboxylate as a white solid. Yield: 70.78%.

(226) .sup.1H NMR (400 MHz, CDCl3) 8.50 (d, J=4.8 Hz, 2H), 3.84 (s, 3H).

Step 2

Methyl 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyrimidine-2-carboxylate

(227) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin (200.00 mg, 486.12 umol) was dissolved in N,N-dimethylformamide (5.00 mL), and potassium carbonate (134.37 mg, 972.24 umol) and methyl 5-hydroxypyrimidine-2-carboxylate (74.92 mg, 486.12 umol) were added successively, and then stirred at 80 C. for 4 hours. The reaction solution was filtered and concentrated, and the residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=10/1 to 2/1) to give 120 mg methyl 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) pyrimidine-2-carboxylate. Yield: 50.94%.

(228) .sup.1H NMR (400 MHz, CDCl3) 8.49 (s, 2H), 4.92 (s, 1H), 4.61-4.58 (m, 2H), 4.23 (s, 1H), 4.05-4.01 (m, 4H), 3.51-3.43 (m, 2H), 2.45-2.42 (m, 2H), 2.08-1.68 (m, 10H), 1.55-1.25 (m, 11H), 0.80 (s, 3H).

Step 3

5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyrimidine-2-carboxylic acid

(229) Methyl 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) pyrimidine-2-carboxylate (120.00 mg, 247.61 umol) was dissolved in tetrahydrofuran (6.00 mL), and lithium hydroxide monohydrate (51.95 mg, 1.24 mmol) and water (2.00 mL) were added successively, then stirred at 80 C. for 12 hours. The tetrahydrofuran was removed by rotary evaporation under reduced pressure, and the system was adjusted to Ph=3 with a hydrochloric acid solution (1M) and then extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 80 mg 5-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyrimidine-2-carboxylic acid 454. Yield: 65.22%.

(230) MS m/z (ESI):471.3[M+1]

(231) .sup.1H NMR (400 MHz, CDCl3) 8.51 (s, 2H), 4.92 (s, 1H), 4.61-4.58 (m, 2H), 4.23 (s, 1H), 4.05-4.01 (m, 2H), 3.51-3.43 (m, 2H), 2.45-2.42 (m, 2H), 2.08-1.68 (m, 10H), 1.55-1.25 (m, 11H), 0.80 (s, 3H).

Compound 385

(1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-(pyridin-4-oxy)ethyl) decahydronaphthalene-2-ol

(232) ##STR00114##

Step 1

(1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-(pyridin-4-oxy)ethyl) decahydronaphthalene-2-ol

(233) 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine (150.00 mg, 352.44 umol) was dissolved in methanol (2.00 mL), followed by successive addition of L-camphorsulfonic acid (245.62 mg, 1.06 mmol)) and water (2.00 mL), then stirred at 70 C. for 12 hours. The system was adjusted to neutrality with saturated sodium bicarbonate solution and filtered. The filtrate was separated by preparative liquid chromatography (HCOOH) to give (1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-(pyridin-4-oxy)ethyl) decahydronaphthalene-2-ol 385 (2.5 mg, yield: 0.97%).

(234) MS m/z (ESI): 345.9 [M+1]

(235) .sup.1H NMR (400 MHz, CDCl3) 8.41 (d, J=6.0 Hz, 2H), 6.78 (d, J=6.0 Hz, 2H), 4.89 (s, 1H), 4.56 (s, 1H), 4.19 (d, J=11.0 Hz, 1H), 4.13-4.03 (m, 1H), 3.93-3.81 (m, 1H), 3.51 (dd, J=4.8, 10.3 Hz, 1H), 3.33 (d, J=11.3 Hz, 1H), 2.43 (d, J=13.3 Hz, 1H), 2.07-1.91 (m, 2H), 1.89-1.79 (m, 6H), 1.31-1.20 (m, 6H), 0.67 (s, 3H).

Compound 402

4-(2-((4aR,6aS,7R,10bR)-3,3,6a, 10b-tetramethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(236) ##STR00115##

Step 1

4-(2-((4aR,6aS,7R,10bR)-3,3,6a, 10b-tetramethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(237) (1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-(pyridin-4-oxy)ethyl) decahydronaphthalene-2-ol (50.00 mg, 144.73 umol) was dissolved in dichloromethane (10.00 mL), and 2,2-dimethoxypropane (15.07 mg, 144.73 umol) and pyridinium 4-toluenesulfonate (254.59 mg, 1.01 mmol) were successively added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated. The residue was separated by preparative liquid chromatography to give 4-(2-((4aR,6aS,7R,10bR)-3,3,6a,10b-tetramethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine 402 (5 mg, yield: 7.44%).

(238) MS m/z (ESI): 386.2 [M+1]

(239) .sup.1H NMR (400 MHz, CDCl3) 8.39 (d, J=5.6 Hz, 2H), 6.76 (d, J=5.6 Hz, 2H), 4.89 (s, 1H), 4.59 (s, 1H), 4.09-4.07 (m, 1H), 3.96 (d, J=11.6 Hz, 1H), 3.86 (s, 1H), 3.51 (t, J=4.8 Hz, 1H), 3.17 (d, J=11.6 Hz, 1H), 2.40 (s, 1H), 2.02-1.72 (m, 7H), 1.42 (s, 3H), 1.37-1.29 (m, 4H), 1.26 (s, 3H), 1.20 (s, 3H), 0.95 (s, 3H).

Compound 416

4-(2-((4aR,6aS,7R, 10bR)-6a, 10b-dimethyl-8-dihydromethylenedecahydro-1.SUP.1.H-spiro[cyclopentyl-1,3-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(240) ##STR00116##

Step 1

4-(2-((4aR,6aS,7R, 10bR)-6a, 10b-dimethyl-8-dihydromethylenedecahydro-1H-spiro[cyclopentyl-1,3-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(241) (1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-(pyridin-4-oxy)ethyl) decahydronaphthalene-2-ol (200.00 mg, 578.92 umol) was dissolved in dichloromethane (10.00 mL), and 1,1-dimethylcyclopentane (150.73 mg, 1.16 mmol) and pyridinium 4-toluenesulfonate (72.74 mg, 289.46 umol) were successively added, followed by stirring at 40 C. for 15 hours. The reaction was quenched with 50 mL saturated sodium bicarbonate solution, exacted with dichloromethane (50 mL*3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by preparative liquid chromatography to give 4-(2-((4aR, 6aS,7R, 10bR)-6a, 10b-dimethyl-8-dihydromethylenedecahydro-1H-spiro[cyclopentyl-1,3-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine 416 (40.2 mg, yield: 16.07%).

(242) MS m/z (ESI): 412.3 [M+1]

(243) .sup.1H NMR (400 MHz, CDCl3) 8.43 (br. s., 2H), 6.79 (d, J=5.3 Hz, 2H), 4.92 (s, 1H), 4.61 (s, 1H), 4.16-4.08 (m, 1H), 4.04 (d, J=11.5 Hz, 1H), 3.93-3.85 (m, 1H), 3.49 (dd, J=4.0, 11.0 Hz, 1H), 3.26 (d, J=11.3 Hz, 1H), 2.45 (d, J=12.0 Hz, 1H), 2.11-1.61 (m, 16H), 1.38-1.18 (m, 6H), 0.93-0.83 (m, 3H).

Compound 400

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopropyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(244) ##STR00117##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopropyl-6a, 10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(245) (1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-(pyridin-4-oxy)ethyl))decahydronaphthalene-2-ol (100.00 mg, 289.46 umol) was dissolved in dichloromethane (10.00 mL), and cyclopropylcarboxaldehyde (22.32 mg, 318.41 umol) and amberlyst-15 (100.00 mg) were added sequentially, then stirred under nitrogen atmosphere at room temperature for 12 hours. The reaction was quenched by the addition of 10 mL water and extracted with dichloromethane DCM (10 mL*3). The combined organic phases were washed with saturated brine (10 mL*1), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by preparative liquid chromatography to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopropyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine 400 (5 mg, yield: 4.00%).

(246) MS m/z (ESI): 398.2 [M+1]

(247) .sup.1H NMR (400 MHz, CDCl3) 8.42 (d, J=5.6 Hz, 2H), 6.78 (d, J=5.6 Hz, 2H), 4.91 (s, 1H), 4.60 (s, 1H), 4.38 (d, J=4.8 Hz, 1H), 4.11-4.03 (m, 2H), 3.89 (d, J=6 Hz, 1H), 3.56-3.45 (m, 2H), 2.47 (s, 1H), 2.43 (s, 1H), 2.04 (s, 1H), 1.92-1.87 (m, 4H), 1.73 (s, 2H), 1.40 (s, 3H), 1.27 (s, 3H), 1.13 (d, J=5.6 Hz, 1H), 0.79 (s, 3H), 0.54 (d, J=5.2 Hz, 2H), 0.53-0.43 (m, 2H).

Compound 411

4-(2-((3R,4aR,6aS,7R,10bR)-3-isopropyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(248) ##STR00118##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-isopropyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(249) (1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-(pyridin-4-oxy)ethyl))decahydronaphthalene-2-ol (100.00 mg, 289.46 umol) was dissolved in 1,2-dichloroethane (2.00 mL), and isobutyraldehyde (208.73 mg, 2.89 mmol) and AMBERLYST 15 HYDROGEN FORM (100.00 mg) were added successively, then stirred at 60 C. for 15 hours. The reaction solution was filtered, concentrated, and separated by a preparative liquid chromatography to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-isopropyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine 411 (8 mg, yield: 6.26%).

(250) MS m/z (ESI): 400.3 [M+1]

(251) .sup.1H NMR (400 MHz, CDCl3) 8.47-8.35 (m, 2H), 6.82-6.72 (m, 2H), 4.90 (s, 1H), 4.63-4.50 (m, 2H), 4.17-3.82 (m, 3H), 3.57-3.38 (m, 2H), 2.44 (d, J=12.0 Hz, 1H), 2.35-2.20 (m, 1H), 2.02-1.71 (m, 8H), 1.38-1.33 (m, 3H), 1.29-1.11 (m, 3H), 0.99-0.89 (m, 6H), 0.88-0.77 (m, 3H).

Compound 412

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclobutyl-6a,10b-dimethyl-8-dihydro methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(252) ##STR00119##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclobutyl-6a,10b-dimethyl-8-dihydro methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(253) (1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-(pyridin-4-oxy)ethyl))decahydronaphthalene-2-ol (100.00 mg, 289.46 umol) was dissolved in 1,2-dichloroethane (2.00 mL), and cyclobutylcarboxaldehyde (243.49 mg, 2.89 mmol) and AMBERLYST 15 HYDROGEN FORM (100.00 mg) were added sequentially, then stirred at 60 C. for 15 hours. The reaction was filtered and concentrated and separated by preparative liquid chromatography to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclobutyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine 412 (4 mg, yield: 3.23%).

(254) MS m/z (ESI): 412.3[M+1]

(255) .sup.1H NMR (400 MHz, CDCl3) 8.41 (d, J=6.0 Hz, 2H), 6.77 (d, J=6.3 Hz, 2H), 4.90 (s, 1H), 4.76 (d, J=5.5 Hz, 1H), 4.60 (s, 1H), 4.15-4.00 (m, 2H), 3.93-3.83 (m, 1H), 3.56-3.41 (m, 2H), 2.57-2.39 (m, 2H), 2.37-2.22 (m, 1H), 2.05-1.81 (m, 12H), 1.72 (td, J=4.5, 8.7 Hz, 1H), 1.38-1.34 (m, 3H), 1.30-1.17 (m, 3H), 0.81 (s, 3H).

Compound 429

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclohexyl-6a,10b-dimethyl-8-dihydro methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(256) ##STR00120##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclohexyl-6a,10b-dimethyl-8-dihydro methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(257) (1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-(pyridin-4-oxy)ethyl))decahydronaphthalene-2-ol (200.00 mg, 578.92 umol) was dissolved in 1,2-dichloroethane (20.00 mL), and cyclohexylcarboxaldehyde (64.94 mg, 578.92 umol, 69.83 uL) and pyridinium 4-toluenesulfonate (72.74 mg, 289.46 umol) were added sequentially, then stirred at 80 C. for 12 hours. The reaction was quenched by the addition of 5 mL water and extracted with dichloromethane (10 mL*3). The combined organic phases were washed with saturated brine (10 mL*1), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by preparative liquid chromatography to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclohexyl-6a,10b-dimethyl-8-dihydromethylenedeca hydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine 429 (40 mg, yield: 7.86%).

(258) MS m/z (ESI): 440.3 [M+1]

(259) .sup.1H NMR (400 MHz, CDCl3) 8.39 (d, J=6 Hz, 2H), 6.76 (d, J=6 Hz, 2H), 4.89 (s, 1H), 4.58-4.54 (m, 2H), 4.09-3.87 (m, 3H), 3.50-3.42 (m, 2H), 2.44-2.28 (m, 2H), 2.02-1.87 (m, 2H), 1.83-1.71 (m, 11H), 1.35 (s, 3H), 1.25-1.09 (m, 8H), 0.79 (s, 3H).

Compound 446

4-(2-((3R,4aR,6aS,7R,10bR)-6a,10b-dimethyl-8-dihydromethylene-3-(tetrahydro-2H-pyran-4-yl)decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(260) ##STR00121##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-6a,10b-dimethyl-8-dihydromethylene-3-(tetrahydro-2H-pyran-4-yl)decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine

(261) (1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylen e-5-(2-(pyridin-4-oxy)ethyl)decahydronaphthalene-2-ol (400.00 mg, 1.16 mmol) was dissolved in dichloromethane (20.00 mL), and tetrahydro-2H-pyran-4-carbaldehyde (1.32 g, 11.60 mmol) and amberlyst-15 (400.00 mg, 1.16 mmol) were added successively, and then stirred at 45 C. for 20 hours. The system was separated by preparative liquid chromatography to give 4-(2-((3R,4aR,6aS,7R,10bR)-6a,10b-dimethyl-8-dihydromethylene-3-(tetrahydro-2H-pyran-4-yl)decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)pyridine 446 (6.4 mg, yield: 1.24%).

(262) MS m/z (ESI): 442.8 [M+1]

(263) .sup.1H NMR (400 MHz, CDCl3) 8.42 (d, J=3.5 Hz, 2H), 6.80 (d, J=5.0 Hz, 2H), 4.90 (br. s., 1H), 4.66-4.48 (m, 2H), 4.16-3.85 (m, 5H), 3.56-3.32 (m, 4H), 2.44 (d, J=12.0 Hz, 1H), 2.32-2.19 (m, 2H), 2.13-2.00 (m, 3H), 1.91-1.82 (m, 3H), 1.65 (d, J=11.5 Hz, 3H), 1.45 (dd, J=5.8, 11.8 Hz, 2H), 1.35 (s, 3H), 1.28-1.17 (m, 3H), 0.79 (s, 3H).

Compound 405

Methyl 3-((3R,4aR,6aS,7R,10bR)-6a,10b-dimethyl-8-dihydromethylenedecahydro-7-(2-pyridin-4-oxy)ethyl) 1H-naphtho[2,1-d][1,3]dioxin-3-yl)propanoate

(264) ##STR00122##

Step 1

Methyl 3-((3R,4aR,6aS,7R,10bR)-6a,10b-dimethyl-8-dihydromethylenedecahydro-7-(2-pyridin-4-oxy)ethyl) 1H-naphtho[2,1-d][1,3]dioxin-3-yl)propanoate

(265) (1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-(pyridin-4-oxy)ethyl))decahydronaphthalene-2-ol (80.00 mg, 231.57 umol) was dissolved in N,N-dimethylformamide (1.00 mL), and methyl 4,4-dimethoxybutyrate (160.00 mg, 986.49 umol) and 4-methylbenzenesulfonic acid (39.88 mg, 231.57 umol) were added successively, then stirred under microwave conditions at 80 C. for 2 hours. The reaction solution was concentrated and the residue was separated by preparative liquid chromatography to give methyl 3-((3R,4aR,6aS,7R,10bR)-6a,10b-dimethyl-8-dihydromethylenedecahydro-7-(2-pyridin-4-oxy)ethyl)1H-naphtho[2,1-d][1,3]dioxin-3-yl)propanoate 405 (29 mg, yield: 27.78%).

(266) MS m/z (ESI): 445.2 [M+1]

(267) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.33 (d, J=6.0 Hz, 2H), 6.89 (d, J=6.0 Hz, 2H), 4.89-4.80 (m, 2H), 4.59 (s, 1H), 4.13-4.01 (m, 1H), 3.97-3.81 (m, 2H), 3.56 (s, 3H), 3.40 (dd, J=4.5, 12.3 Hz, 2H), 2.33 (t, J=7.5 Hz, 3H), 2.28-2.16 (m, 1H), 2.00-1.87 (m, 2H), 1.84-1.66 (m, 6H), 1.50 (dd, J=4.3, 9.0 Hz, 1H), 1.25 (br. s., 1H), 1.22 (s, 3H), 1.20-1.09 (m, 2H), 0.70 (s, 3H).

Compound 408

3-((3R,4aR,6aS,7R,10bR)-6a,10b-dimethyl-8-dihydromethylenedecahydro-7-(2-pyridin-4-oxy)ethyl) 1H-naphtho[2,1-d][1,3]dioxin-3-yl)propanoic acid

(268) ##STR00123##

Step 1

3-((3R,4aR,6aS,7R,10bR)-6a,10b-dimethyl-8-dihydromethylenedecahydro-7-(2-pyridin-4-oxy)ethyl) 1H-naphtho[2,1-d][1,3]dioxin-3-yl)propanoic acid

(269) Methyl 3-((3R,4aR,6aS,7R,10bR)-6a,10b-dimethyl-8-dihydromethylenedecahydro-7-(2-pyridin-4-oxy)ethyl)-1H-naphtho[2,1-d][1,3]dioxoin-3-yl)propanoate (25.00 mg, 56.36 umol) was dissolved in tetrahydrofuran (1.00 mL), and sodium hydroxide (6.76 mg, 169.08 umol) and water (1.00 mL) were added successively, then stirred at room temperature for 1 hour. Ethyl acetate (5.00 mL) was added to the system, and the organic phase and the aqueous phase were separated. The aqueous phase was separated by preparative liquid chromatography to give 3-((3R,4aR,6aS,7R,10bR)-6a,10b-dimethyl-8-dihydromethylenedecahydro-7-(2-pyridin-4-oxy)ethyl) 1H-naphtho[2,1-d][1,3]dioxin-3-yl)propanoic acid 408 (20 mg, yield: 82.36%).

(270) MS m/z (ESI): 430.6 [M+1]

(271) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.33 (d, J=6.0 Hz, 2H), 6.88 (d, J=6.0 Hz, 2H), 4.85 (s, 2H), 4.59 (s, 1H), 4.07 (br. s., 1H), 3.95-3.82 (m, 2H), 3.46-3.38 (m, 2H), 2.37-2.07 (m, 4H), 2.01-1.85 (m, 2H), 1.84-1.63 (m, 6H), 1.49 (d, J=10.0 Hz, 1H), 1.27-1.23 (m, 1H), 1.22 (s, 3H), 1.15 (t, J=12.4 Hz, 2H), 0.70 (s, 3H).

Compound 399

2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethanol

(272) ##STR00124##

Step 1

2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethanol

(273) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenepentahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (1.00 g, 2.89 mmol) was dissolved in tetrahydrofuran (20.00 mL), and sodium borohydride (327.99 mg, 8.67 mmol) was added to the system at 0 C. and stirred at room temperature for 18 hours. The reaction was quenched with 50 mL water and then extracted with ethyl acetate (25 mL*3). The combined organic phases were successively washed with water (25 mL*3) and saturated brine (25 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by flash silica gel column (petroleum ether/ethyl acetate=100:0 to 50:50) to give 850 mg 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethanol 399. Yield: 84.39%.

(274) MS m/z (ESI):349.2[M+1]

(275) .sup.1H NMR (400 MHz, CDCl3) 4.85 (s, 1H), 4.60 (d, J=6.02 Hz, 1H), 4.56 (s, 1H), 4.02 (d, J=11.04 Hz, 1H), 3.73 (br. s., 1H), 3.39-3.57 (m, 3H), 2.40 (d, J=13.05 Hz, 1H), 2.25 (dq, J=3.01, 13.22 Hz, 1H), 1.93-2.14 (m, 2H), 1.84-1.91 (m, 1H), 1.62-1.83 (m, 7H), 1.39-1.60 (m, 7H), 1.35 (s, 3H), 1.10-1.30 (m, 4H), 0.75 (s, 3H).

Compound 281

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)- N,N-dimethylpropan-1-amine

(276) ##STR00125##

Step 1

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)- N,N-dimethylpropan-1-amine

(277) 3-(dimethylamino)propan-1-ol (55 mg, 0.537 mmol) was dissolved in 8 mL N,N-dimethylformamide, added with sodium hydride (18 mg, 0.732 mmol) at 0 C., then stirred at 0 C. for 15 minutes. (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (200 mg, 0.488 mmol) was added at 0 C. and then stirred at 50 C. for 2 hours. The reaction was quenched with 6 mL water and extracted with dichloromethane (15 mL*2). The organic phases were combined, washed with saturated sodium chloride solution (15 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and separated by the preparative liquid chromatography to give 3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-N,N-dimethylpropan-1-amine 281 (70 mg, yield:33%).

(278) MS m/z (ESI): 434.6[M+1]

(279) .sup.1H NMR (400 MHz, MeOD) 8.50 (s, 1H), 4.68 (d, J=5.77 Hz, 1H), 4.58 (s, 1H), 4.07 (d, J=11.29 Hz, 1H), 3.36-3.52 (m, 5H), 2.92-3.00 (m, 2H), 2.69 (s, 6H), 2.30-2.47 (m, 2H), 1.45-2.07 (m, 18H), 1.32 (s, 3H), 1.16-1.30 (m, 3H), 0.78 (s, 3H).

Compound 313

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)- 1-isopropyl azetidine

(280) ##STR00126##

Step 1

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)- 1-isopropyl azetidine

(281) 3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)azetidine (150 mg, 0.37 mmol) was dissolved in dichloromethane (10 mL), and acetone 313b (108 mg, 1.86 mmol) and triethylamine (75 mg, 0.74 mmol) were added successively and stirred at room temperature for 30 minutes. Sodium borohydride (236 mg, 1.11 mmol) was added to the reaction solution and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and separated by column chromatography to give 3-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-1-isopropyl azetidine 313 (15 mg, yield: 9%).

(282) MS m/z (ESI): 446.3 [M+1]

(283) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.86 (br. s., 1H), 4.31-4.72 (m, 5H), 4.01 (d, J=11.2 Hz, 1H), 3.10-3.62 (m, 7H), 2.41 (d, J=12.4 Hz, 1H), 2.13-2.34 (m, 2H), 1.59-2.11 (m, 11H), 1.50-1.55 (m, 3H), 1.20-1.43 (m, 13H), 0.74 (s, 3H).

Compound 366

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)- 1-methylpiperidine

(284) ##STR00127##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)- 1-methylpiperidine

(285) 1-Methylpiperidin-4-ol (84 mg, 0.73 mmol) was dissolved in N,N-dimethylformamide (10 mL) and sodium hydrogen (32 mg, 1.01 mmol) was added at 0 C. and stirred at 0 C. for 15 minutes. (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (300 mg, 0.73 mmol) was added to the reaction mixture and stirred at room temperature for 12 hours. The reaction solution was added to water (5 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with water (10 mL3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by preparative liquid chromatography to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-1-methylpiperidine 366 (20 mg, yield: 6.1%).

(286) MS m/z (ESI): 446.6 [M+1]

(287) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.44-8.55 (m, 1H), 4.54-4.66 (m, 4H), 4.02-4.07 (m, 1H), 3.40-3.53 (m, 3H), 2.96-3.16 (m, 3H), 2.77-2.92 (m, 2H), 2.56-2.65 (m, 3H), 2.25-2.40 (m, 2H), 1.45-2.03 (m, 19H), 1.30 (s, 3H), 1.15-1.26 (m, 3H), 0.76 (s, 3H).

Compound 482

2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-yl)ethanol

(288) ##STR00128## ##STR00129##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine

(289) Tert-butyl 4-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-carboxylate (5.00 g, 9.40 mmol) was dissolved in 50 mL acetonitrile and added with ammonium nitrate (4.12 g, 7.52 mmol, 3.75 mL) at room temperature, then stirred at 80 C. for 12 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography using an eluent system of DCM:MeOH:NH.sub.3H.sub.2O=100:1:0.5 to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine (3.1 g, yield: 92.7%).

(290) MS m/z (ESI): 432.7[M+1]

(291) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.83 (s, 1H), 4.60 (d, J=6.0 Hz, 1H), 4.51 (s, 1H), 4.02 (d, J=10.8 Hz, 1H), 3.57-3.40 (m, 4H), 3.38-3.15 (m, 5H), 2.40 (d, J=11.5 Hz, 1H), 2.25 (q, J=3.1, 1H), 2.12-2.06 (m, 3H), 2.03-1.90 (m, 3H), 1.90-1.82 (m, 1H), 1.80-1.75 (m, 2H), 1.75-1.65 (m, 5H), 1.65-1.1.40 (m, 7H), 1.36 (s, 3H), 1.24-1.10 (m, 3H), 0.75 (s, 3H).

Step 2

Ethyl 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidin-1-yl)acetate

(292) 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine (1.00 g, 2.32 mmol) was dissolved in 20 mL tetrahydrofuran, and ethyl glyoxylate (2.12 g, 10.39 mmol) and triethylamine (744.19 mg, 7.35 mmol) were added successively at room temperature, and then stirred at room temperature for 20 minutes. Sodium borohydride (2.34 g, 11.04 mmol) was added at room temperature, followed by stirring at room temperature for 12 hours. The reaction was quenched with 100 mL water, extracted with ethyl acetate (100 mL*3), and the organic phases were combined, washed with saturated sodium chloride solution (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After that, the resulting residue was purified by silica gel column chromatography with the eluent system PE:EA=4:1 to 2:1 to give ethyl 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidin-1-yl)acetate (630 mg, yield: 52.4%).

(293) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.84 (s, 1H), 4.63-4.53 (m, 2H), 4.19 (q, J=7.2 Hz, 2H), 4.03 (d, J=11.5 Hz, 1H), 3.55-3.40 (m, 3H), 3.31-3.24 (m, 2H), 3.22 (s, 2H), 2.81 (br. s., 2H), 2.44-2.17 (m, 4H), 2.01-1.41 (m, 20H), 1.36 (s, 3H), 1.31-1.22 (m, 6H), 0.75 (s, 3H).

Step 3

2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-yl)ethanol

(294) Ethyl 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxypiperidine-1-yl)acetate (430.00 mg, 830.53 umol) was dissolved in 5 mL tetrahydrofuran, added with lithium tetrahydroaluminum (47.91 mg, 1.26 mmol) at 0 C., and then stirred at 0 C. for 0.5 hours. The reaction was quenched by dropwise adding 0.5 mL aqueous sodium hydroxide solution (2.4N) at 0 C., diluted with 15 mL ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with an eluent system DCM:MeOH=10:1 to give 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidin-1-yl)ethanol 482 (163.8 mg, yield: 41.46%).

(295) MS m/z (ESI): 476.3[M+1]

(296) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.84 (s, 1H), 4.65-4.53 (m, 2H), 4.02 (d, J=11.3 Hz, 1H), 3.67 (t, J=5.1 Hz, 2H), 3.55-3.40 (m, 3H), 3.37-3.20 (m, 2H), 2.84 (br. s., 2H), 2.62 (t, J=5.0 Hz, 2H), 2.49-1.99 (m, 5H), 1.96-1.39 (m, 19H), 1.36 (s, 3H), 1.34-1.07 (m, 4H), 0.75 (s, 3H).

Compound 483

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)- 1-(2,2,2,-trifluoroethyl)piperidine

(297) ##STR00130##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)- 1-(2,2,2,-trifluoroethyl)piperidine

(298) 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine (100 mg, 232 umol) dissolved in 8 mL acetonitrile, and triethylamine (70 mg, 696 umol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (161 mg, 696 umol) were added successively, then refluxed for 3 hours. The reaction solution was concentrated and separated through a column (eluent EA:PE from 1:20 to 1:10) to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-1-(2,2,2-trifluoroethyl)piperidine 483 (30 mg, yield: 25%).

(299) MS m/z (ESI): 514.6 [M+1]

(300) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.83 (s, 1H), 4.60 (d, J=6.0 Hz, 1H), 4.56 (s, 1H), 4.02 (d, J=11.3 Hz, 1H), 3.55-3.38 (m, 3H), 3.30-3.19 (m, 2H), 2.96 (q, J=9.79 Hz, 2H), 2.85 (m., 2H), 2.52-2.33 (m, 3H), 2.25 (dd, J1=13.30 Hz, J2=3.01 Hz, 1H), 2.19-1.90 (m, 2H), 1.90-1.62 (m, 9H), 1.56-1.39 (m, 8H), 1.36 (s, 3H), 1.28-1.06 (m, 4H), 0.75 (s, 3H).

Compound 426

2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-yl)acetic acid

(301) ##STR00131##

Step 1

2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-yl)acetic acid

(302) Ethyl 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-1-piperidine-1-yl)acetate (500.00 mg, 965.74 umol) was dissolved in 5 mL tetrahydrofuran and 2.5 mL water, and sodium hydroxide (154.52 mg, 3.86 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was added with 100 mL water, adjusted to pH 6-7 with dilute hydrochloric acid and extracted with dichloromethane (150 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-yl)acetic acid 426(420 mg, yield: 88.81%).

(303) MS m/z (ESI): 491.1 [M+2]

(304) .sup.1H NMR (400 MHz, DMSO) 4.81 (s, 1H), 4.64 (d, J=5.3 Hz, 1H), 4.52 (s, 1H), 3.92 (d, J=11.3 Hz, 1H), 3.35-3.18 (m, 4H), 3.18-3.09 (m, 2H), 2.94 (br. s., 2H), 2.66 (d, J=9.3 Hz, 2H), 2.38-2.16 (m, 2H), 1.97-1.66 (m, 8H), 1.59-1.35 (m, 12H), 1.23 (s, 4H), 1.20-1.04 (m, 3H), 0.68 (s, 3H).

Compound 463

2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-1-piperidine-1-yl)-2-methylpropanoic acid

(305) ##STR00132##

Step 1

Ethyl 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-decahydro-1H-naphtho [2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-yl)-2-methylpropanoate

(306) 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine (3.80 g, 8.80 mmol) was dissolved in N,N-dimethylformamide (160 mL), and ethyl 2-bromo-2-methylpropanoate (2.57 g, 13.20 mmol) and potassium carbonate (3.65 g, 26.40 mmol) were added successively, then stirred at 60 C. for 10 hours. The system was concentrated. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=0/100 to 5/1 and dichloromethane/methanol/ammonia 10/1/0.1) to give ethyl 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-decahydro-1H-naphtho [2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-yl)-2-methylpropanoate (a colorless oil, 2.4 g, yield: 48.82%).

(307) .sup.1H NMR (400 MHz, CDCl3) 4.82 (s, 1H), 4.64-4.51 (m, 2H), 4.23-4.13 (m, 2H), 4.01 (d, J=11.0 Hz, 1H), 3.53-3.38 (m, 3H), 3.29-3.13 (m, 2H), 2.94-2.74 (m, 2H), 2.39 (d, J=11.5 Hz, 1H), 2.24 (d, J=10.0 Hz, 2H), 2.12-2.05 (m, 1H), 1.95-1.41 (m, 20H), 1.35 (s, 3H), 1.31-1.27 (m, 6H), 1.27-1.23 (m, 3H), 1.21-1.09 (m, 3H), 0.74 (s, 3H).

Step 2

2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxyl)piperidine-1-yl)-2-methylpropanoic acid

(308) Ethyl 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-decahydro-1H-naphtho [2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-yl)-2-methylpropanoate (2.40 g, 4.40 mmol) was dissolved in ethanol (50 mL), and water (50 mL) and potassium hydroxide (2.47 g, 44.00 mmol) were added successively, and then stirred at 70 C. for 10 hours. The ethanol was removed by rotary evaporation under reduced pressure, and the system was added with diluted hydrochloric acid (44 mL, 1M) and the reaction was extracted with ethyl acetate (200 mL*3). The organic phases were washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica, dichloromethane/methanol/ammonia solution=50/1/0.1 to 20/1/0.1) to give 2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxyl)piperidine-1-yl)-2-methylpropanoic acid 463 (1.63 g, yield: 70.54%).

(309) MS m/z (ESI):540.4 [M+23]

(310) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 4.83 (s, 1H), 4.66 (d, J=5.5 Hz, 1H), 4.54 (s, 1H), 3.94 (d, J=11.5 Hz, 1H), 3.45-3.38 (m, 3H), 3.32 (d, J=11.5 Hz, 1H), 3.26-3.19 (m, 1H), 2.97 (d, J=7.5 Hz, 2H), 2.79-2.74 (m., 2H), 2.39-2.23 (m, 2H), 1.99-1.82 (m, 4H), 1.81-1.64 (m, 6H), 1.60-1.39 (m, 10H), 1.24 (s, 9H), 1.19-1.02 (m, 3H), 0.69 (s, 3H).

Compound 484

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxyl)-1-(cyclopropylsulfonyl)piperidine

(311) ##STR00133##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxyl)-1-(cyclopropylsulfonyl)piperidine

(312) 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine (150 mg, 0.349 mmol) was dissolved in 8 mL dichloromethane, and cyclopropylsulfonyl chloride (54 mg, 0.383 mmol) and triethylamine (39 mg, 0.383 mmol) were added successively, then stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated, and separated by preparative plate to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxyl)-1-(cyclopropylsulfonyl)piperidine 484 (20 mg, yield: 16.1%).

(313) MS m/z (ESI): 558.1[M+23]

(314) .sup.1H NMR (CDCl3) ppm 4.84 (s, 1H), 4.59 (d, J=6.0 Hz, 1H), 4.55 (s, 1H), 4.02 (d, J=11.2 Hz, 1H), 3.53-3.39 (m, 6H), 3.31-3.13 (m, 3H), 2.41 (d, J=11.6 Hz, 1H), 2.32-2.18 (m, 2H), 2.14-1.57 (m, 17H), 1.35 (s, 3H), 1.21-1.16 (m, 7H), 0.98-0.85 (m, 3H), 0.75 (s, 3H).

Compound 373

2-Amino-1-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-yl)acetamide

(315) ##STR00134##

Step 1

(9H-fluoren-9-yl)methyl(2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) piperidine-1-yl)-2-oxoethyl)carbamate

(316) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amine)acetic acid (379 mg, 1.27 mmol) was dissolved in N,N-dimethylformamide (20 mL), and triethylamine (0.5 mL) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (660 mg, 1.74 mmol) were added successively, and stirred at room temperature for 0.5 hours. 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine (500 mg, 1.16 mmol) was added to the reaction and stirred at room temperature for 18 hours. The reaction solution was quenched with water, extracted with dichloromethane, and the organic layer was washed with saturated brine and water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography to give (9H-fluoren-9-yl)methyl(2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-yl)-2-oxoethyl)carbamate (150 mg, yield: 18%).

Step 2

2-Amino-1-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-yl)acetamide

(317) (9H-fluoren-9-yl)methyl(2-(4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopenty 1-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy) piperidine-1-yl)-2-oxoethyl)carbamate (150 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (2.5 g, 34.2 mmol), and piperidine (500 mg, 5.87 mmol) was added at 25 C. under nitrogen atmosphere at room temperature, and stirred for 2 hours. The reaction solution was concentrated under reduced pressure and was separated by liquid chromatography to give 2-amino-1-(4-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)piperidine-1-yl)acetamide 373 (15 mg, yield: 15%).

(318) MS m/z (ESI): 489.4 [M+1]

(319) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.86 (s, 1H), 4.62 (d, J=6.0 Hz, 1H), 4.56 (s, 1H), 4.04 (d, J=11.2 Hz, 1H), 3.79-3.43 (m, 11H), 2.44-1.52 (m, 22H), 1.50 (s, 3H), 1.38-1.24 (m, 3H), 0.77 (s, 3H).

Compound 386

(1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-((1-methylpiperidine-4-yl)oxy) ethyl) decahydronaphthalene-2-ol

(320) ##STR00135##

Step 1

(1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-((1-methylpiperidine-4-yl)oxy) ethyl) decahydronaphthalene-2-ol

(321) 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethoxy)-1-methylpiperidine (300.00 mg, 673.13 umol) was dissolved in methanol (3.00 mL) and 3 mL hydrochloric acid (1M) was added to the system followed by stirring at 75 C. for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=100:0 to 85:15) to give a crude product. The crude product was separated by preparative liquid chromatography to give 23 mg (1R,2R,4aS,5R)-1-(hydroxymethyl)-1,4a-dimethyl-6-dihydromethylene-5-(2-((1-meth ylpiperidine-4-yl)oxy) ethyl) decahydronaphthalene-2-ol 386. Yield: 9.35%.

(322) MS m/z (ESI): 366.1 [M+1]

(323) .sup.1H NMR (400 MHz, CDCl3) 4.24 (d, J=11.0 Hz, 1H), 3.52-3.26 (m, 5H), 2.96-2.60 (m, 4H), 2.50-2.33 (m, 2H), 2.31 (s, 3H), 2.24-1.61 (m, 15H), 1.45-1.15 (m, 6H), 0.92 (s, 3H).

Compound 403

2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)amino)acetic acid

(324) ##STR00136##

Step 1

Methyl 2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)amino)acetate

(325) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (2.00 g, 5.77 mmol) was dissolved in tetrahydrofuran (50 mL), and methyl 2-aminoacetate (1.09 g, 8.65 mmol, HCl) and triethylamine (2.34 g, 23.08 mmol) were added successively, then stirred at 25 C. for 4 hours. Sodium borohydride (6.11 g, 28.85 mmol) was added followed by stirring at 25 C. for 8 hours. The reaction solution was diluted with 100 mL water and extracted with ethyl acetate (100 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate/ammonia water=1:1:0.01) to give methyl 2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)amino)acetate (a yellow solid, 1.8 g, yield: 74.35%).

(326) .sup.1H NMR (400 MHz, CDCl3) 4.83 (s, 1H), 4.61-4.52 (m, 2H), 4.01 (d, J=11.3 Hz, 1H), 3.72 (s, 2H), 3.50-3.41 (m, 2H), 3.40 (s, 2H), 3.08 (br. s., 3H), 2.81-2.66 (m, 1H), 2.49-2.35 (m, 2H), 2.24 (dq, J=2.9, 13.2 Hz, 1H), 2.12-2.04 (m, 1H), 1.96 (t, J=11.8 Hz, 1H), 1.89-1.83 (m, 1H), 1.80-1.74 (m, 1H), 1.72-1.65 (m, 3H), 1.65-1.60 (m, 2H), 1.60-1.49 (m, 4H), 1.47-1.37 (m, 2H), 1.34 (s, 3H), 1.23-1.07 (m, 3H), 0.74 (s, 3H).

Step 2

2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)amino)acetic acid

(327) Methyl 2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)amino)acetate (200.00 mg, 476.64 umol) was dissolved in tetrahydrofuran (2.00 mL), and potassium hydroxide (53.49 mg, 953.29 umol) and water (1.00 mL) were added successively, then stirred at 25 C. for 12 hours. The system was separated by preparative liquid chromatography to give 80 mg 2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)amino)acetic acid 403. Yield: 41.38%.

(328) MS m/z (ESI):406.3 [M+1]

(329) .sup.1H NMR (400 MHz, MeOD) 4.92 (s, 1H), 4.69 (d, J=5.8 Hz, 1H), 4.64 (s, 1H), 4.07 (d, J=11.3 Hz, 1H), 3.52-3.37 (m, 4H), 3.13-3.01 (m, 1H), 2.85-2.71 (m, 1H), 2.49-2.28 (m, 2H), 2.11-1.95 (m, 2H), 1.93-1.76 (m, 4H), 1.74 (s, 1H), 1.72-1.55 (m, 5H), 1.55-1.41 (m, 4H), 1.34 (s, 3H), 1.32-1.20 (m, 3H), 0.81 (s, 3H).

Compound 404

2,2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)azanediyl)diacetic acid

(330) ##STR00137##

Step 1

Ethyl 2,2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)(2-methoxy-2-oxoethyl)amino)acetate

(331) Methyl 2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)amino)acetate (200.00 mg, 476.64 umol) was dissolved in N,N-dimethylformamide (4 mL), and ethyl 2-bromoacetate (159.20 mg, 953.28 umol) and potassium carbonate (131.75 mg, 953.28 umol) were added successively, followed by stirring at 75 C. for 12 hours. The reaction solution was diluted with 10 mL water and extracted with ethyl acetate (10 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=10/1) to give ethyl 2,2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)(2-methoxy-2-oxoethyl)amino)acetate (a yellow oil, 100 mg, yield: 41.49%).

(332) .sup.1H NMR (400 MHz, CDCl3) 4.82 (s, 1H), 4.62-4.51 (m, 2H), 4.16 (q, J=7.3 Hz, 2H), 4.01 (d, J=11.0 Hz, 1H), 3.70 (s, 3H), 3.58-3.49 (m, 4H), 3.49-3.37 (m, 2H), 2.90-2.77 (m, 1H), 2.52-2.42 (m, 1H), 2.41-2.34 (m, 1H), 2.30-2.16 (m, 1H), 2.12-2.02 (m, 1H), 1.99-1.90 (m, 1H), 1.86 (d, J=13.1 Hz, 1H), 1.67 (dd, J=3.8, 8.0 Hz, 4H), 1.61 (d, J=5.8 Hz, 2H), 1.54 (dd, J=7.7, 12.4 Hz, 4H), 1.49-1.37 (m, 3H), 1.34 (s, 3H), 1.30-1.25 (m, 4H), 1.21-1.11 (m, 2H), 0.74 (s, 3H).

Step 2

2,2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)azanediyl)diacetic acid

(333) Ethyl 2,2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)(2-methoxy-2-oxoethyl)amino)acetate (100.00 mg, 197.75 umol) was dissolved in tetrahydrofuran (1.00 mL), and potassium hydroxide (22.19 mg, 395.50 umol) and water (1.00 mL) were successively added, and then stirred at 25 C. for 2 hours. The system was separated by preparative liquid chromatography to give 40 mg 2,2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)azanediyl)diacetic acid 404. Yield: 43.63%.

(334) MS m/z (ESI):464.2 [M+1]

(335) .sup.1H NMR (400 MHz, CDCl3) 4.86 (br. s., 1H), 4.66-4.52 (m, 2H), 3.97 (d, J=10.8 Hz, 1H), 3.72 (br. s., 3H), 3.43 (t, J=12.2 Hz, 2H), 3.31 (br. s., 1H), 2.95 (br. s., 1H), 2.63 (s, 1H), 2.38 (d, J=11.3 Hz, 1H), 2.23 (d, J=11.8 Hz, 1H), 2.12-2.00 (m, 1H), 1.96-1.77 (m, 4H), 1.69 (br. s., 4H), 1.58-1.38 (m, 7H), 1.35 (s, 3H), 1.19 (br. s., 3H), 0.75 (s, 3H).

Compound 284

2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)(3-(dimethylamino)propyl)amino)ethanol

(336) ##STR00138##

Step 1

Ethyl 2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)(3-(dimethylamino)propyl)amino)acetate

(337) N.sup.1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-N.sup.3,N.sup.3-dimethylpropan-1,3-diamine (1.0 g, 2.31 mmol) was dissolved in tetrahydrofuran (20 mL), and ethyl glyoxylate (354 mg, 3.47 mmol) and triethylamine (467 mg, 4.62 mmol) were successively added, followed by stirring at 15 C. for 0.5 hours. Sodium borohydride (1.47 g, 6.93 mmol) was added followed by stirring at 15 C. for 16 hours. The reaction solution was diluted with 100 mL water and extracted with dichloromethane (50 mL*5). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica, dichloromethane/ethanol=5:1) to give ethyl 2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)(3-(dimethylamino)propyl)amino)acetate (0.928 g, yield: 78%).

(338) .sup.1H NMR (400 MHz, CDCl3) 4.84 (s, 1H), 4.61 (d, J=5.6 Hz, 1H), 4.56 (s, 1H), 4.16 (q, J1=7.2 Hz, J2=14.0 Hz, 2H), 4.02 (d, J=11.2 Hz, 1H), 3.46-3.45 (m, 2H), 3.23 (s, 2H), 2.67-2.61 (m, 5H), 2.45 (s, 6H), 2.39-1.36 (m, 20H), 1.30 (s, 3H), 1.28-1.21 (m, 6H), 0.76 (s, 3H).

Step 2

2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)(3-(dimethylamino)propyl)amino)ethanol

(339) Ethyl 2-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)(3-(dimethylamino)propyl)amino)acetate (928 mg, 1.79 mmol) was dissolved in tetrahydrofuran (10.00 mL), and lithium aluminum tetrahydride (102 mg, 2.69 mmol) was added at 0 C., and then stirred at 15 C. for 0.5 h. The reaction was quenched by the addition of lmL water, then dried over anhydrous sodium sulfate, filtered and concentrated to give 629 mg 2-((2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)(3-(dimethylamino)propyl)amino)ethanol 284. Yield: 73.7%.

(340) .sup.1H NMR (400 MHz, CDCl3) 4.87 (s, 1H), 4.62 (d, J=6.4 Hz, 1H), 4.57 (s, 1H), 4.03 (d, J=11.6 Hz, 1H), 3.59 (t, J1=4.8 Hz, J=9.6 Hz, 2H), 3.47-3.43 (m, 2H), 2.60-1.54 (m, 34H), 1.37 (s, 3H), 1.22-1.61 (m, 3H), 0.77 (s, 3H).

Compound 191

3-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)amino)N,N-diethanolamine

(341) ##STR00139##

Step 1

3-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)amino)N,N-diethanolamine

(342) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-decahydro methylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde 191a (100 mg, 0.29 mmol) was dissolved in tetrahydrofuran (20 mL), followed by successive addition of N.sup.1,N.sup.1-diethanolamine (61.2 mg, 0.58 mmol) and triethylamine (58.6 mg, 0.58 mmol), and stirred at room temperature for 0.5 h. Sodium borohydride-acetic acid (184.7 mg, 0.87 mmol) was slowly added to the reaction solution, followed by stirring at room temperature for 12 hours. The reaction solution was poured into a saturated ammonium chloride solution, the organic layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-((2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)amino)N,N-diethanolamine 191 (40 mg, yield: 32%).

(343) MS m/z (ESI): 436.9 [M+1]

(344) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.44 (s, 1H), 4.91 (s, 1H), 4.60-4.58 (m, 2H), 4.01-3.94 (m, 5H), 3.43-3.18 (m, 8H), 2.05-1.64 (m, 17H), 1.34 (s, 3H), 1.24-1.19 (m, 4H), 0.65 (s, 3H)

Compound 207

N-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)isoxazol-4-amine

(345) ##STR00140##

Step 1

N-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)isoxazol-4-amine

(346) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-decahydro methylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (346.5 mg, 1.0 mmol) was dissolved in 1,2-dichloroethane (20 mL), followed by successively addition of isoxazole-4-amine (84 mg, 1.0 mmol) and acetic acid (0.2 mL), and stirred at 25 C. for 2 hours. Sodium cyanoborohydride (130 mg, 2.0 mmol) was added and stirred at 25 C. for 15 hours. The reaction solution was washed with water (10 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by preparative chromatography to give N-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)isoxazol-4-amine 201 (11 mg, yield: 5.3%).

(347) MS m/z (ESI): 415.1 [M+1]

(348) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.01 (s, 1H), 7.88 (s, 1H), 4.88 (s, 1H), 4.60-4.58 (m, 2H), 4.01 (d, J=11.6 Hz, 1H), 3.50-3.42 (m, 2H), 3.06-1.54 (m, 20H), 1.52 (s, 3H), 1.36-1.11 (m, 3H), 0.76 (s, 3H).

Compound 345

N-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-3-fluoropyridin-4-amine

(349) ##STR00141##

Step 1

N-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-3-fluoropyridin-4-amine

(350) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (150 mg, 0.43 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and 3-fluoropyridin-4-amine (73 mg, 0.65 mmol) and triethylamine (87 mg, 0.86 mmol) were successively added to the reaction solution, followed by stirring at 60 C. for 0.5 hours. Sodium borohydride-acetic acid (273 mg, 1.29 mmol) was added to the reaction solution and stirred at 60 C. for 16 hours. The reaction solution was concentrated under reduced pressure and separated by column chromatography to give N-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-3-fluoropyridin-4-amine 345 (38 mg, yield: 19.9%).

(351) MS m/z (ESI): 443.7 [M+1]

(352) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.14 (d, J=4.8 HZ, 1H), 8.09 (d, J=5.6 HZ, 1H), 6.55-6.51 (m, 1H), 4.95 (s, 1H), 4.64-4.61 (m, 2H), 4.41 (s, 1H), 4.03 (d, J=11.2 HZ, 1H), 3.52-3.10 (m, 4H), 2.49-1.54 (m, 18H), 1.53 (s, 3H), 1.38-1.25 (m, 3H), 0.79 (s, 3H).

Compound 355

(1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)oxetane-3-yl)methanol

(353) ##STR00142##

Step 1

Azetidin-3-ylmethanol hydrochloride

(354) Tert-butyl 3-(hydroxymethyl)azetidin-1-carboxylate (200 mg, 1.07 mmol) was dissolved in anhydrous methanol (10 mL), added with 4M ethyl acetate-hydrochloric acid (2.2 mL) under nitrogen atmosphere at 0 C., and stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give azetidin-3-ylmethanol hydrochloride (100 mg, crude product).

(355) .sup.1H NMR (400 MHz, MeOD) 4.15-4.01 (m, 2H), 4.00-3.97 (m, 2H), 3.68 (d, J=4.4 Hz, 2H), 3.06-3.00 (m, 1H).

Step 2

(1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)oxetane-3-yl)methanol

(356) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-methylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (150 mg, 0.43 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), followed by successively addition of azetidin-3-ylmethanol hydrochloride (70 mg, 0.56 mmol) and triethylamine (0.18 mL, 1.29 mmol), and stirred at room temperature for 0.5 h. Sodium borohydride-acetic acid (276 mg, 1.3 mmol) was added to the reaction mixture, followed by stirring at room temperature for 18 hours. The reaction solution was cooled and extracted with dichloromethane (30 mL). The organic layer was washed with water (10 mL3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by high performance liquid chromatography to give (1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)oxetane-3-yl)methanol 355 (25 mg, yield: 14%).

(357) MS m/z (ESI): 418.7 [M+1]

(358) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.92 (s, 1H), 4.61 (d, J=5.6 Hz, 1H), 4.02-3.16 (m, 11H), 2.44-1.55 (m, 20H), 1.53 (s, 3H), 1.36-1.22 (m, 3H), 0.76 (s, 3H).

Compound 196

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)oxazolidin-2-one

(359) ##STR00143##

Step 1

3-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)oxazolidin-2-one

(360) Oxazolidin-2-one (105 mg, 1.2 mmol) was dissolved in N,N-dimethylformamide (3 mL), added with sodium hydrogen (56 mg, 1.4 mmol) at 0 C. and stirred at 0 C. for 0.5 hours and at 20 C. for 0.5 hours. (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin (400 mg, 0.97 mmol) was slowly added to the reaction solution at 0 C., followed by stirring at 20 C. for 20 hours. The reaction was quenched with water and extracted with dichloromethane (50 mL3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by preparative liquid chromatography to give 3-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)oxazolidin-2-one 196 (102.5 mg, yield: 25.2%).

(361) MS m/z (ESI): 418.1 [M+1]

(362) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.88 (s, 1H), 4.60-4.57 (m, 2H), 4.30 (t, J=8.0 Hz, 2H), 3.99 (d, J=11.2 Hz, 2H), 3.59-3.40 (m, 6H), 2.42-2.39 (m, 1H), 1.78-1.51 (m, 17H), 1.49 (s, 3H), 1.34-1.11 (m, 3H), 0.74 (s, 3H).

Compound 149

N-((3 S)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxain-7-yl)ethyl)pyrrolidin-3-yl)acetamide

(363) ##STR00144##

Step 1

N-((3S)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxain-7-yl)ethyl)pyrrolidin-3-yl)acetamide

(364) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (200 mg, 0.58 mmol) was dissolved in tetrahydrofuran (10 mL) and added with (S)N-(pyrrolidin-3-yl)acetamide (113 mg, 0.87 mmol), followed by stirring at room temperature for 10 hours. Sodium cyanoborohydride (54 mg, 0.87 mmol) was added to the reaction solution and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give N-((3S)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxain-7-yl)ethyl)pyrrolidin-3-yl)acetamide 149 (106 mg, yield: 29.1%).

(365) MS m/z (ESI): 459.2 [M+1]

(366) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.50 (s, 1H), 4.92 (s, 1H), 4.89 (s, 1H), 4.58 (s, 1H), 4.00-3.40 (m, 5H), 2.90-2.79 (m, 4H), 2.43-1.84 (m, 9H), 1.69-1.55 (m, 12H), 1.35 (s, 2H), 1.23-1.20 (m, 3H), 0.76 (s, 2H).

Compound 163

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylic acid

(367) ##STR00145##

Step 1

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylic acid

(368) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (100 mg, 0.3 mmol) was dissolved in tetrahydrofuran (5 mL), and pyrrolidine-2-carboxylic acid (40 mg, 0.3 mmol) and sodium borohydride-acetic acid (245 mg, 1.1 mmol) and acetic acid (1 mL) were added successively to the reaction mixture, followed by stirring at room temperature for 12 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated by liquid chromatography to give 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylic acid 163 (20 mg, 15.5%).

(369) MS m/z (ESI): 446.0 [M+1]

(370) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.94-4.82 (m, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.97 (d, J=11.2 Hz, 1H), 3.94-3.85 (m, 1H), 3.76-3.58 (m, 1H), 3.51-3.35 (m, 2H), 3.32-3.19 (m, 1H), 3.18-3.03 (m, 1H), 3.01-2.88 (m, 1H), 2.78 (d, J=9.6 Hz, 2H), 2.46-2.14 (m, 4H), 2.02 (d, J=19.2 Hz, 5H), 1.87-1.36 (m, 12H), 1.34 (s, 2H), 1.19 (br. s., 2H), 0.74 (s, 3H).

Compound 435

(2S)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-m ethylene-decahydro-1H-naphtho) [2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylic acid

(371) ##STR00146##

Step 1

(2S)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-m ethylene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylic acid

(372) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (1.00 g, 2.89 mmol) was dissolved in tetrahydrofuran (30 mL), and (S)-pyrrolidine-2-carboxylic acid (431.95 mg, 3.75 mmol) and acetic acid (173.30 mg, 2.89 mmol, 165.05 uL) were added successively, and then stirred at 30 C. for 1 hour. Sodium borohydride-acetic acid (1.83 g, 8.66 mmol) was added followed by stirring at 30 C. for 11 hours. The system was filtered and concentrated. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=10/1 to 1/1) to give (2S)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylic acid 435 (240 mg, yield: 18.64%).

(373) MS m/z (ESI):446.1 [M+1]

(374) .sup.1H NMR (400 MHz, CDCl3) 4.89 (s, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.99-3.96 (m, 2H), 3.69 (d, J=2.8 Hz, 1H), 3.46-3.39 (m, 2H), 3.23 (s, 1H), 2.89-2.75 (m, 2H), 2.39-2.29 (m, 4H), 1.99-1.67 (m, 11H), 1.58-1.53 (m, 7H), 1.51 (s, 3H), 1.34-1.18 (m, 3H), 0.73 (s, 3H).

Compound 450

(2R)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-m ethylene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxyli c acid

(375) ##STR00147##

Step 1

(2R)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-m ethylene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxyli c acid

(376) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (1.50 g, 4.33 mmol) was dissolved in tetrahydrofuran (50 mL), and (R)-pyrrolidine-2-carboxylic acid (747.77 mg, 6.49 mmol) and acetic acid (260.03 mg, 4.33 mmol, 247.65 uL) were added successively, and then stirred at 40 C. for 1 hour. Sodium borohydride-acetic acid (2.75 g, 12.99 mmol) was added followed by stirring at 40 C. for 12 hours. The reaction was added with 20 mL saturated sodium bicarbonate and extracted with ethyl acetate (50 mL*5). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=10/1 to 1/1) to give (2R)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylic acid 450 (650 mg, yield: 33.69%).

(377) MS m/z (ESI):446.9 [M+1]

(378) .sup.1H NMR (400 MHz, CDCl3) 4.87 (s, 1H), 4.59-4.55 (m, 2H), 3.99-3.71 (m, 2H), 3.68 (d, J=2.8 Hz, 1H), 3.42-3.87 (m, 3H), 2.81-2.78 (m, 2H), 2.38-2.24 (m, 4H), 2.24-1.97 (m, 8H), 1.81-1.68 (m, 3H), 1.57-1.51 (m, 7H), 1.50 (s, 3H), 1.34-1.19 (m, 3H), 0.75 (s, 3H).

Compound 116

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)-3-methoxypyrrolidine

(379) ##STR00148##

Step 1

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methyl ene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)-3-methoxypyrrolidine

(380) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (200 mg, 0.58 mmol) was dissolved in tetrahydrofuran (10 mL), and 3-methoxypyrrolidine (88 mg, 0.87 mmol) was added, and stirred at room temperature for 10 hours. Sodium cyanoborohydride (54 mg, 0.87 mmol) was added to the reaction solution and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated by liquid chromatography to give 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)-3-methoxypyrrolidine 116 (89 mg, yield: 35.7%).

(381) MS m/z (ESI): 432.3 [M+1]

(382) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.55 (s, 1H), 4.85 (s, 1H), 4.58 (d, J=4.8 Hz, 1H), 4.01-3.96 (m, 2H), 3.47-3.39 (m, 2H), 3.28 (s, 3H), 3.78-1.51 (m, 24H), 1.49 (s, 3H), 1.33-1.19 (m, 3H), 0.74 (s, 3H).

Compound 455

(3S)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-m ethylene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylic acid

(383) ##STR00149##

Step 1

(3S)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-m ethylene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylic acid

(384) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (500.00 mg, 1.44 mmol) was dissolved in tetrahydrofuran (30 mL), and (S)-pyrrolidine-3-carboxylic acid (200.00 mg, 1.74 mmol) and acetic acid (1.05 g, 17.48 mmol, 1.00 mL) were added successively, and then stirred at 45 C. for 1 hour. Sodium borohydride-acetic acid (1.00 g, 4.72 mmol) was added followed by stirring at 45 C. for 8 hours. The system was concentrated. The residue was separated by column chromatography (silica, dichloromethane/methanol=10/1 to 6/1) to give (3 S)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylic acid 455 (257 mg, 39.97%).

(385) MS m/z (ESI):446.0 [M+1]

(386) .sup.1H NMR (400 MHz, CDCl3) 4.86 (s, 1H), 4.69-4.51 (m, 2H), 3.97 (d, J=11.3 Hz, 1H), 3.67 (d, J=18.3 Hz, 1H), 3.53 (br. s., 1H), 3.47-3.31 (m, 3H), 3.06 (br. s., 3H), 2.71 (br. s., 1H), 2.35-1.50 (m, 20H), 1.33 (s, 3H), 1.23-1.10 (m, 3H), 0.73 (s, 3H).

Compound 147

(2S)-methyl-1-(2-((4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho) [2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylate

(387) ##STR00150##

Step 1

(2S)-methyl-1-(2-((4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho) [2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylate

(388) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (200 mg, 0.58 mmol) was dissolved in tetrahydrofuran (10 mL), added with (S)-methylpyrrolidine-2-carboxylate (112 mg, 0.87 mmol) and stirred for 10 hours at room temperature. Sodium cyanoborohydride (54 mg, 0.87 mmol) was added to the reaction solution and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated by liquid chromatography to give (2 S)-methyl-1-(2-((4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2-carboxylate 147 (89 mg, yield: 33.6%).

(389) MS m/z (ESI): 460.1 [M+1]

(390) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.20 (s, 1H), 4.82 (s, 1H), 4.59-4.54 (m, 2H), 4.00 (d, J=11.2 Hz, 1H), 3.48 (s, 3H), 3.48-3.26 (m, 4H), 2.58-1.53 (m, 27H), 1.51 (s, 3H), 1.42-1.20 (m, 3H), 0.73 (s, 3H).

Compound 181

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methyl ene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)-8-methyl-2,8-diazaspiro[4,5]decane

(391) ##STR00151##

Step 1

2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methyl ene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)-8-methyl-2,8-di azaspiro[4,5]decane

(392) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-decahydro methylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (150 mg, 0.43 mmol) was dissolved in tetrahydrofuran (10 mL), and 8-methyl-2,8-diazaspiro[4.5]. decane (180.1 mg, 0.52 mmol) and sodium borohydride-acetic acid (183.8 mg, 0.88 mmol) were added successively, then stirred at room temperature for 12 hours. The reaction solution was poured into a saturated ammonium chloride solution, the organic layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure and separated by the preparative liquid chromatography to give 2-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho)[2,1-d][1,3]dioxin-7-yl)ethyl)-8-methyl-2,8-diazaspiro[4,5]decane 181 (30 mg, yield: 14.3%).

(393) MS m/z (ESI): 485.2 [M+1]

(394) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.41 (s, 1H), 4.89 (s, 1H), 4.60-4.58 (m, 2H), 4.04-4.01 (m, 2H), 3.47-2.76 (m, 11H), 2.61 (s, 3H), 2.04-1.67 (m, 22H), 1.34 (s, 2H), 1.33-1.20 (m, 3H), 0.75 (s, 3H).

Compound 361

(1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidin-3-yl)methanol

(395) ##STR00152##

Step 1

Pyrrolidine-3-methanol hydrochloride

(396) Tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (500 mg, 2.48 mmol) was dissolved in dry methanol (10 mL), added with 4M hydrochloric acid in methanol (4 mL) at 0 C. under nitrogen atmosphere, and stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure to give pyrrolidine-3-methanol hydrochloride (375 mg, crude product).

(397) .sup.1H NMR (400 MHz, MeOD) 3.66-3.57 (m, 2H), 3.41-3.13 (m, 4H), 2.59-2.57 (m, 1H), 2.18-2.14 (m, 1H), 1.88-1.84 (m, 1H).

Step 2

(1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidin-3-yl)methanol

(398) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (150 mg, 0.43 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and pyrrolidine-3-carbinol hydrochloride (77 mg, 0.56 mmol) and triethylamine (0.18 mL, 1.29 mmol) were added successively, then stirred at room temperature for 0.5 hours. Sodium borohydride-acetic acid (276 mg, 1.3 mmol) was added to the reaction mixture, followed by stirring at room temperature for 18 hours. The reaction solution was cooled and extracted with dichloromethane (30 mL). The organic layer was washed with water (10 mL3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography to give (1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidin-3-yl)methanol 361 (35 mg, yield: 19%).

(399) MS m/z (ESI): 431.7 [M+1]

(400) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.90 (s, 1H), 4.64-4.58 (m, 2H), 4.00 (d, J=11.6 Hz, 1H), 3.72-3.67 (m, 4H), 3.44-3.40 (m, 4H), 2.67-1.51 (m, 23H), 1.50 (s, 3H), 1.34-1.20 (m, 4H), 0.76 (s, 3H).

Compound 123

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)morpholine

(401) ##STR00153##

Step 1

4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)morpholine

(402) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (200 mg, 0.58 mmol) was dissolved in tetrahydrofuran (10 mL), added with morpholine (76 mg, 0.87 mmol) and stirred at room temperature for 10 hours. Sodium cyanoborohydride (54 mg, 0.87 mmol) was added to the reaction solution and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)morpholine 123 (86 mg, yield: 35.7%).

(403) MS m/z (ESI): 418.2 [M+1]

(404) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.51 (s, 2H), 4.88 (s, 2H), 4.59-4.51 (m, 3H), 4.15 (d, J=11.2 Hz, 1H), 3.99 (d, J=11.2 Hz, 1H), 3.71-3.69 (m, 4H), 3.48-3.29 (m, 3H), 2.95-1.77 (m, 15H), 1.34 (s, 3H), 1.24-1.20 (m, 7H), 0.75 (s, 3H), 0.64 (s, 3H).

Compound 433

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methyl ene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-4-methylpiperazine

(405) ##STR00154##

Step 1

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methyl ene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-4-methylpiperazine

(406) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (3.00 g, 8.66 mmol) was dissolved in tetrahydrofuran (20 mL), and 1-methylpiperazine (4.34 g, 43.30 mmol, 4.82 mL) and triethylamine (4.38 g, 43.29 mmol, 6.00 mL) were added successively, and then stirred at 25 C. for 4 hours. Sodium borohydride-acetic acid (5.50 g, 25.97 mmol) was added and stirred at 25 C. for 8 hours. The reaction solution was diluted with 20 mL water and extracted with ethyl acetate (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica, dichloromethane/methanol=50/1 to 10/1) to give 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-4-methylpiperazine 433 (1 g, yield: 26.81%).

(407) MS m/z (ESI):431.4 [M+1]

(408) .sup.1H NMR (400 MHz, CDCl3) 4.83 (s, 1H), 4.64-4.51 (m, 2H), 4.01 (d, J=11.3 Hz, 1H), 3.54-3.33 (m, 2H), 2.71-2.33 (m, 9H), 2.29 (s, 3H), 2.26-2.15 (m, 2H), 2.12-2.02 (m, 2H), 1.98-1.84 (m, 2H), 1.80-1.62 (m, 5H), 1.60-1.38 (m, 8H), 1.34 (s, 3H), 1.25-1.06 (m, 3H), 0.74 (s, 3H).

Compound 160

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methyl ene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-4-(pyrrolidin-1-yl)piperidine

(409) ##STR00155##

Step 1

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methyl ene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-4-(pyrrolidin-1-yl)piperidine

(410) 2-((4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (300 mg, 0.87 mmol) was dissolved in tetrahydrofuran (10 mL), added with 4-(pyrrolidin-1-yl)piperidine (200 mg, 1.30 mmol) and stirred for 10 hours at room temperature. Sodium cyanoborohydride (426 mg, 1.74 mmol) was added to the reaction solution and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-4-(pyrrolidin-1-yl)piperidine 160 (59 mg, yield: 12.2%).

(411) MS m/z (ESI): 485.2 [M+1]

(412) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.40 (s, 1H), 4.86 (s, 1H), 4.59-4.56 (m, 1H), 4.15-3.98 (m, 1H), 3.48-3.10 (m, 10H), 2.48-1.55 (m, 29H), 1.34 (s, 3H), 1.23-1.15 (m, 4H), 0.75 (s, 3H).

Compound 150

1-(2-((4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-N,N-diethylpiperidin-4-amine

(413) ##STR00156##

Step 1

1-(2-((4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-N,N-diethylpiperidin-4-amine

(414) 2-((4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (200 mg, 0.58 mmol) was dissolved in tetrahydrofuran (10 mL), added with N,N-diethylpiperidin-4-amine (136 mg, 0.87 mmol), and stirred at room temperature for 10 hours. Sodium cyanoborohydride (54 mg, 0.87 mmol) was added to the reaction solution and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1-(2-((4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-N,N-diethylpiperidin-4-amine 150 (106 mg, yield: 37.8%).

(415) MS m/z (ESI): 487.2 [M+1]

(416) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.44 (s, 1H), 4.86 (s, 1H), 4.59-4.56 (m, 2H), 4.00 (d, J=11.6 Hz, 1H), 3.45-2.96 (m, 9H), 2.40-1.51 (m, 27H), 1.37-1.20 (m, 14H), 0.75 (s, 3H).

Compound 451

(2R)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-m ethylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidine-2-carboxylic acid

(417) ##STR00157##

Step 1

(2R)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-m ethylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidine-2-carb oxylic acid

(418) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (500.00 mg, 1.44 mmol) was dissolved in tetrahydrofuran (20 mL), and piperidine-2-carboxylic acid (280.00 mg, 2.17 mmol) and acetic acid (1.05 g, 17.48 mmol, 1.00 mL) were added successively and stirred at 45 C. for 1 hour. Sodium borohydride-acetic acid (915.58 mg, 4.32 mmol) was added followed by stirring at 45 C. for 8 hours. The reaction solution was diluted with 150 mL water and extracted with ethyl acetate (50 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica, dichloromethane/methanol 20/1) to give (2R)-1-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidine-2-carboxylic acid 451 (83 mg, yield: 12.54%).

(419) MS m/z (ESI):460.4 [M+1]

(420) .sup.1H NMR (400 MHz, CDCl3) 4.84 (s, 1H), 4.59 (d, J=5.5 Hz, 1H), 4.53 (br. s., 1H), 3.98 (d, J=11.5 Hz, 1H), 3.63 (d, J=9.5 Hz, 1H), 3.49-3.32 (m, 4H), 2.94-2.68 (m, 2H), 2.42-2.17 (m, 3H), 2.14-1.39 (m, 21H), 1.34 (s, 3H), 1.27-1.11 (m, 3H), 0.74 (s, 3H).

Compound 002

(1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidin-4-yl)methanol

(421) ##STR00158##

Step 1

(1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidin-4-yl)methanol

(422) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (2.0 g, 5.8 mmol) was dissolved in tetrahydrofuran (30 mL), and piperidin-4-ylmethanol (1.0 g, 8.7 mmol) and triethylamine (1.17 g, 11.6 mmol) were added successively, then stirred at 20 C. for 2 hours. Sodium borohydride-acetic acid (3.69 g, 17.4 mmol) was added followed by stirring at 20 C. for 24 hours. The reaction solution was diluted with 20 mL water and extracted with dichloromethane (50 mL*5). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica, dichloromethane/methanol=10/1) to give (1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidin-4-yl)methanol 002 (2 g, yield: 77.8%).

(423) MS m/z (ESI):446.9 [M+1]

(424) .sup.1H NMR (400 MHz, CDCl3) 4.86 (s, 1H), 4.60-4.58 (m, 2H), 4.01 (d, J=10.8 Hz, 1H), 3.53-3.40 (m, 4H), 3.38-3.25 (m, 2H), 2.75-2.60 (m, 1H), 2.41-2.38 (m, 2H), 2.23-2.10 (m, 3H), 2.10-1.50 (m, 22H), 1.35 (s, 3H), 1.20-1.10 (m, 3H), 0.75 (s, 3H).

Compound 256

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methyl ene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidin-4-carboxylic acid

(425) ##STR00159##

Step 1

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methyl ene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidin-4-carboxylic acid

(426) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (150 mg, 0.43 mmol) was dissolved in methanol (10 mL), and piperidine-4-carboxylic acid (280 mg, 2.17 mmol) and three drops of acetic acid were added successively to the reaction solution and stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (75 mg, 1.29 mmol) was added to the reaction solution and stirred at room temperature for 17 hours. The reaction solution was added to water (20 mL), extracted with dichloromethane (20 mL8), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by preparative liquid chromatography to give 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidin-4-carboxylic acid 256 911 mg, yield: 5.5%).

(427) MS m/z (ESI): 460.1 [M+1]

(428) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.89 (s, 1H), 4.62-4.60 (m, 1H), 4.01 (d, J=11.2 Hz, 1H), 3.49-3.42 (m, 3H), 2.98-1.36 (m, 26H), 1.22 (m, 3H), 0.77 (s, 3H).

Compound 456

(3R)-4-(2-((3R,4aR,6aS,7R,10bR))-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)morpholine-3-carboxylic acid

(429) ##STR00160##

Step 1

(3R)-4-(2-((3R,4aR,6aS,7R,10bR))-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)morpholine-3-carboxylic acid

(430) 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (250.00 mg, 721.50 umol) was dissolved in tetrahydrofuran (20 mL), and (3R)-morpholine-3-carboxylic acid (100.29 mg, 764.79 umol) and acetic acid (525.00 mg, 8.74 mmol, 500.00 uL) were added successively, then stirred at 45 C. for 1 hour. Sodium borohydride-acetic acid (500.00 mg, 2.36 mmol) was added and stirred at 45 C. for 8 hours. The system was concentrated. The residue was separated by column chromatography (silica, dichloromethane/methanol=20/1 to 10/1) to give (3R)-4-(2-((3R,4aR,6aS,7R,10bR))-3-cyclopentyl-6a,10b-dimethyl-8-methylene-deca hydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)morpholine-3-carboxylic acid 456 (84 mg, yield: 25.22%).

(431) MS m/z (ESI):462.1 [M+1]

(432) .sup.1H NMR (400 MHz, MeOD) 4.88-4.83 (m, 1H), 4.76 (s, 1H), 4.70 (d, J=5.5 Hz, 1H), 4.16 (d, J=10.5 Hz, 1H), 4.08 (d, J=11.3 Hz, 1H), 4.01 (d, J=12.3 Hz, 1H), 3.78 (t, J=11.4 Hz, 1H), 3.69 (t, J=10.9 Hz, 1H), 3.55-3.42 (m, 3H), 3.02 (t, J=9.8 Hz, 1H), 2.75 (br. s., 1H), 2.49-2.30 (m, 2H), 2.24-1.38 (m, 18H), 1.35 (s, 3H), 1.31-1.21 (m, 3H), 0.84 (s, 3H).

Compound 457

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid

(433) ##STR00161##

Step 1

Methyl 6-oxo-1,6-dihydropyridine-3-carboxylate

(434) 6-Oxo-1,6-dihydropyridine-3-carboxylic acid (1.00 g, 7.19 mmol) was dissolved in methanol (20.00 mL) and added with sulfuric acid (1.11 g, 11.29 mmol, 601.72 uL), then stirred at 70 C. for 10 hours. The reaction was quenched with 40 mL saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 6-oxo-1,6-dihydropyridine-3-carboxylate (0.8 g, crude product).

(435) .sup.1H NMR (400 MHz, CDCl3) 13.17 (br. s., 1H), 8.21 (d, J=2.5 Hz, 1H), 8.01 (dd, J=2.5, 9.5 Hz, 1H), 6.58 (d, J=9.5 Hz, 1H), 3.87 (s, 3H).

Step 2

Methyl 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

(436) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin (700.00 mg, 1.70 mmol) was dissolved in N,N-dimethylformamide (20.00 mL), cesium carbonate (1.66 g, 5.10 mmol) and methyl 6-oxo-1,6-dihydropyridine-3-carboxylate (299.39 mg, 1.95 mmol) were added successively, then stirred at 80 C. for 10 hours. The reaction solution was filtered and concentrated, and the residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=100/0 to 2/1) to give methyl 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (a colorless oil, 450 mg, crude product).

(437) .sup.1H NMR (400 MHz, CDCl3) 8.06 (d, J=2.5 Hz, 1H), 7.81 (dd, J=2.3, 9.3 Hz, 1H), 6.49 (d, J=9.5 Hz, 1H), 4.94 (s, 1H), 4.79 (s, 1H), 4.55 (d, J=6.0 Hz, 1H), 4.20-4.11 (m, 1H), 3.97 (d, J=11.0 Hz, 1H), 3.84 (s, 3H), 3.66 (ddd, J=6.8, 8.8, 12.5 Hz, 1H), 3.46-3.35 (m, 2H), 2.42 (d, J=13.6 Hz, 1H), 2.19 (dq, J=2.8, 13.1 Hz, 1H), 2.05-1.44 (m, 16H), 1.34-1.29 (m, 3H), 1.24-1.06 (m, 3H), 0.72 (s, 3H).

Step 3

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid

(438) Methyl 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (450.00 mg, 930.44 umol) was dissolved in methanol (10.00 mL), and potassium hydroxide (300.00 mg, 5.35 mmol) and water (10.00 mL) were added successively, followed by stirring at 70 C. for 8 hours. The system was adjusted to pH=5-6 with hydrochloric acid solution (1M) and then extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid 457 (260 mg, yield: 55.1%).

(439) MS m/z (ESI):470.3[M+1]

(440) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.08 (br. s., 1H), 7.82 (d, J=9.5 Hz, 1H), 6.23 (d, J=9.0 Hz, 1H), 4.91 (d, J=11.0 Hz, 2H), 4.62 (d, J=5.0 Hz, 1H), 4.13-4.00 (m, 1H), 3.91 (d, J=11.0 Hz, 1H), 3.56 (d, J=12.0 Hz, 1H), 3.31 (d, J=11.5 Hz, 2H), 2.40-2.18 (m, 2H), 1.98-1.39 (m, 16H), 1.23 (s, 3H), 1.17-1.02 (m, 3H), 0.66 (s, 3H).

Compound 458

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-1H-pyrazole-4-carboxylic acid

(441) ##STR00162##

Step 1

Ethyl 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-1H-pyrazole-4-carboxylate

(442) (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a,10b-dimeth yl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin (500.00 mg, 1.22 mmol) was dissolved in N,N-dimethylformamide (10.00 mL), followed by successive addition of potassium carbonate (337.23 mg, 2.44 mmol) and ethyl 1H-pyrazole-4-carboxylate (222.26 mg, 1.59 mmol), then stirred at 80 C. for 4 hours. The reaction solution was filtered and concentrated, and the residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=10/1 to 2/1) to give ethyl 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-1H-pyrazole-4-carboxylate (a white solid, 300 mg, yield: 52.25%).

(443) .sup.1H NMR (400 MHz, CDCl3) 7.93 (s, 1H), 7.84 (s, 1H), 4.97 (s, 1H), 4.66 (s, 1H), 4.60 (d, J=6 Hz, 1H), 4.34-4.29 (m, 3H), 4.03-4.00 (m, 2H), 3.46-3.42 (m, 2H), 2.21 (s, 1H), 2.06-1.65 (m, 7H), 1.56-1.51 (m, 9H), 1.50-1.35 (m, 11H), 1.18-0.83 (m, 3H), 0.78 (s, 3H).

Step 2

1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-1H-pyrazole-4-carboxylic acid

(444) Ethyl 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-1H-pyrazole-4-carboxylate (200.00 mg, 424.95 umol) was dissolved in tetrahydrofuran (9.00 mL), and lithium hydroxide monohydrate (89.15 mg, 2.12 mmol) and water (3.00 mL) were added, followed by stirring at 40 C. for 12 hours. The tetrahydrofuran was removed by rotary evaporation under reduced pressure, and the system was adjusted to pH=3 with a hydrochloric acid solution (1M) and then extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-dihydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-1H-pyrazole-4-carboxylic acid 458 (100 mg, yield: 52.11%).

(445) MS m/z (ESI):443.2[M+1]

(446) .sup.1H NMR (400 MHz, CDCl3) 7.96 (s, 1H), 7.86 (s, 1H), 4.95 (s, 1H), 4.64 (s, 1H), 4.58 (d, J=5.6 Hz, 1H), 4.25 (s, 1H), 4.01-3.98 (m, 2H), 3.46-3.40 (m, 2H), 2.42 (s, 1H), 2.20-1.65 (m, 7H), 1.56-1.51 (m, 9H), 1.50-1.35 (m, 11H), 1.18-0.83 (m, 3H), 0.78 (s, 3H).

Compound 130

(1-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidin-4-yl)methanol

(447) ##STR00163##

Step 1

(4S,E)-3-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethylene)-4-hydroxydihydrofuran-2(3H)-one

(448) (4S,E)-4-hydroxy-3-(2-((1R,5R,6R,8aS)-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylenedecahydronaphthalen-1-yl)ethylene)dihydrofuran-2(3H)-one (30 g, 85.7 mmol) was dissolved in dichloromethane (100 mL), and 3,4-difluoro benzaldehyde (12.5 g, 85.7 mol) and Macroporous resin-15 (30 g) were added successively. The mixture was stirred at room temperature until the reaction of the starting material was completed. The reaction solution was filtered, the filter cake was washed with dichloromethane, the filtrates were combined and concentrated under reduced pressure to give (4S,E)-3-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethylene)-4-hydroxydihydrofuran-2(3H)-one (28.3 g, crude product, yield: 69.7%).

Step 2

2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde

(449) (4S,E)-3-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-di methyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethylene)-4-hydroxydihydrofuran-2(3H)-one (10 g, 21.1 mmol) was dissolved in dichloromethane (150 mL) and pyridine (5 mL), added with zinc dust (1.37 g, 21.1 mmol) at 78 C., and introduced with ozone at this temperature, followed by stirring for 5 minutes. The remaining ozone gas was discharged with nitrogen. After the temperature was gradually raised to room temperature, the zinc powder was removed by filtration. The filtrate was concentrated under reduced pressure and separated by column chromatography to give 2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (1.2 g, yield: 14.5%).

Step 3

(1-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidin-4-yl)methanol

(450) 2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (200 mg, 0.51 mmol) was dissolved in tetrahydrofuran (10 mL), added with piperidine-4-methanol (88 mg, 0.77 mmol) and stirred at room temperature for 10 hours. Sodium cyanoborohydride (63 mg, 1.02 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated by liquid chromatography to give (1-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidin-4-yl)methanol 130 (82 mg, yield: 32.8%).

(451) MS m/z (ESI): 490.3 [M+1]

(452) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.25-7.09 (m, 3H), 5.70 (s, 1H), 4.85 (s, 1H), 4.61 (s, 1H), 4.23 (d, J=11.2 Hz, 1H), 3.67-3.49 (m, 4H), 2.99-2.94 (m, 2H), 2.47-1.60 (m, 19H), 1.43 (s, 3H), 1.31-1.18 (m, 5H), 0.80 (s, 3H).

Compound 214

1-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a, 10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2,5-dione

(453) ##STR00164##

Step 1

2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a, 10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethanol

(454) 2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a, 10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (10.0 g, 25.6 mmol) was dissolved in 150 mL tetrahydrofuran, and added with sodium borohydride (2.91 g, 76.8 mmol) at 0 C. The reaction was stirred at 25 C. for 3 hours, quenched with 100 mL water, and the mixture solution was extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL*1), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethanol (7 g, crude product).

Step 2

(3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-(3,4-difluorophenyl)-6a, 10 b-dimethyl-8-methylenedecahydrogen-1H-naphtho[2,1-d][1,3]dioxin

(455) 2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethanol (1.0 g, 2.5 mmol) and carbon tetrabromide (1.7 g, 5.1 mmol) were dissolved in dichloromethane (15 mL), added with triphenylphosphine (1.3 g, 5.1 mmol) at 0 C. and stirred at room temperature for 18 hours. The reaction solution was added with water (30 mL) and extracted with dichloromethane (80 mL). The organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography to give (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydrogen-1H-naphtho[2,1-d][1,3]dioxin (1.02 g, yield: 87.9%).

(456) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.35-7.20 (m, 1H), 7.20-7.13 (m, 2H), 5.72 (s, 1H), 4.90 (s, 1H), 4.54 (s, 1H), 4.24 (d, J=11.6 Hz, 1H), 3.67-3.55 (m, 3H), 3.31-3.29 (m, 1H), 2.43-1.82 (m, 9H), 1.45 (s, 3H), 1.32-1.27 (m, 3H), 0.82 (s, 3H).

Step 3

1-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2, l-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2,5-dione

(457) Sodium hydrogen (22 mg, 0.55 mmol) was dissolved in N,N-dimethylformamide (10 mL), and pyrrolidine-2,5-dione (36 mg, 0.37 mmol) was added at 0 C. and stirred at 0 C. for 10 minutes. (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (200 mg, 0.44 mmol) was added to the reaction mixture and stirred at room temperature for 18 hours. The reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated on a thin layer chromatography plate to give 1-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)pyrrolidine-2,5-dione 214 (92 mg, yield: 53.1%).

(458) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.38-7.33 (m, 1H), 7.21-7.12 (m, 2H), 5.72 (s, 1H), 4.97 (s, 1H), 4.86 (s, 1H), 4.25 (d, J=11.6 Hz, 1H), 3.76-3.41 (m, 4H), 2.72 (s, 4H), 2.45-1.83 (m, 6H), 1.83 (s, 3H), 1.75 (s, 3H), 1.69-1.25 (m, 3H), 0.80 (s, 3H).

Compound 212

3-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-1-methyltetrahydroimidazol-2-one

(459) ##STR00165##

Step 1

1-(2-Chloroethyl)-3-methylurea

(460) 1-Chloro-2-isocyanatoethane (5.0 g, 47.4 mmol) was dissolved in dry tetrahydrofuran (200 mL), and slowly added with 2M methylamine tetrahydrofuran solution (23.7 mL) at 0 C., and stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure to give 1-(2-chloroethyl)-3-methylurea (6.2 g, yield: 95.8%).

(461) .sup.1H NMR (400 MHz, DMSO) 6.17 (brs, 1H), 5.91 (brs, 1H), 3.55 (t, J=6.0 Hz, 2H), 3.31 (s, 1H), 3.28 (t, J=6.0 Hz, 1H), 2.53 (d, J=4.8 Hz, 3H).

Step 2

1-methyltetrahydroimidazol-2-one

(462) 1-(2-Chloroethyl)-3-methylurea (2.0 g, 14.64 mmol) was dissolved in dry tetrahydrofuran (100 mL) and sodium hydrogen (1.4 g, 35.14 mmol) was added in portions at 0 C. Upon the completion of addition, the reaction was stirred at room temperature overnight. The reaction solution was quenched with water (1 mL), concentrated under reduced pressure and passed through column chromatography to give 1-methyltetrahydroimidazol-2-one (1.3 g, yield: 89%).

(463) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.83 (brs, 1H), 3.42 (t, J=2.4 Hz, 4H), 2.78 (s, 3H).

Step 3

3-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-1-methyltetrahydroimidazol-2-one

(464) 1-methyltetrahydroimidazol-2-one (26 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (1 mL) and sodium hydrogen (13 mg, 0.33 mmol) was slowly added at 0 C., and stirred at 0 C. for 0.5 hours, then stirred at room temperature for 0.5 hours. (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin (100 mg, 0.22 mmol) was added to the reaction mixture at 0 C. and stirred at 20 C. for 20 hours. The reaction solution was extracted with ethyl acetate (50 mL3), and the organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated on a thin layer chromatography plate to give 3-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-decahydromethylene-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)-1-methyltetrahydroimidazol-2-one 212 (19 mg, yield: 18.3%).

(465) MS m/z (ESI): 475.2 [M+1]

(466) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.37-7.32 (m, 1H), 7.20-7.13 (m, 2H), 5.72 (s, 1H), 4.91 (s, 1H), 4.68 (s, 1H), 4.24 (d, J=11.6 Hz, 1H), 3.65-3.12 (m, 8H), 2.79 (s, 3H), 2.42-1.76 (m, 6H), 1.66 (s, 2H), 1.44 (s, 3H), 1.29-1.23 (m, 3H), 0.81 (s, 3H).

Compound 215

3-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a, 10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)oxazolidine-2,4-dione

(467) ##STR00166##

Step 1

Oxazolidine-2,4-dione

(468) 2-Hydroxyacetamide (2.0 g, 26.6 mmol) and potassium tert-butoxide (3.0 g, 26.6 mmol) were dissolved in dry methanol (50 mL), added with diethyl carbonate (3.8 g, 31.9 mmol) and stirred at reflux for 20 hours. The reaction solution was cooled, concentrated under reduced pressure, dissolved in water and acidified to pH=2 with 6M hydrochloric acid solution. The mixture was extracted with ethyl acetate (100 mL3), and the organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give oxazolidine-2,4-dione (1.2 g, crude product).

(469) .sup.1H NMR (400 MHz, DMSO) 4.75 (s, 2H), 3.91 (s, 1H).

Step 2

3-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)oxazolidine-2,4-dione

(470) (4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (150 mg, 0.33 mmol) and potassium carbonate (91 mg, 0.66 mmol) were dissolved in N,N-dimethylformamide (2 mL), added with oxazolidine-2,4-dione (67 mg, 0.66 mmol) and stirred at 80 C. for 1.5 hours. The reaction solution was quenched with water and extracted with dichloromethane (50 mL3). The organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated on a thin layer chromatography plate to give 3-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)oxazolidine-2,4-dione 215 (70 mg, yield: 44.7%).

(471) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.36-7.31 (m, 1H), 7.19-7.12 (m, 2H), 5.70 (s, 1H), 4.96 (s, 1H), 4.78 (s, 1H), 4.68 (s, 1H), 4.22 (d, J=11.6 Hz, 1H), 3.68-3.45 (m, 4H), 2.48-1.78 (m, 6H), 1.69 (s, 3H), 1.28-1.25 (m, 3H), 0.79 (s, 3H).

Compound 230

3-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)tetrahydroimidazole-2,4-dione

(472) ##STR00167##

Step 1

3-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)tetrahydroimidazole-2,4-dione

(473) NaH (16 mg, 0.4 mmol) was dissolved in N,N-dimethylformamide (10 mL) and tetrahydroimidazole-2,4-dione (66 mg, 0.66 mmol) was added at 0 C., and stirred at 0 C. for 15 minutes. (3R,4aR,6aS,7R,10bR)-7-(2-bromoethyl)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin (150 mg, 0.33 mmol) was added to the reaction mixture and stirred at 25 C. for 16 hours. The reaction solution was added to water (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated by column chromatography to give 3-(2-((3R,4aR,6aS,7R,10bR)-3-(3,4-difluorophenyl)-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)tetrahydroimidazole-2,4-dione 230 (70 mg, yield: 44.8%).

(474) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.37-7.22 (m, 3H), 5.81 (s, 1H), 4.83 (s, 1H), 4.31 (d, J=11.6 Hz, 1H), 3.94 (d, J=8.4 Hz, 4H), 3.68-3.39 (m, 4H), 2.47-1.71 (m, 8H), 1.42 (s, 3H), 1.34-1.32 (m, 4H), 0.82 (s, 3H).

Compound 265

(1R,2R,4aS,5R)-1-(hydroxymethyl)-5-(2-(4-(hydroxymethyl)piperidin-1-yl)ethyl-1,4a-dimethyl-6-methylene-decahydro-naphthalenemethanol-2-ol

(475) ##STR00168##

Step 1

(1R,2R,4aS,5R)-1-(hydroxymethyl)-5-(2-(4-(hydroxymethyl)piperidin-1-yl)ethyl-1,4a-dimethyl-6-methylene-decahydro-naphthalenemethanol-2-ol

(476) (1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidin-4-yl)methanol (300.00 mg, 673.13 umol) was dissolved in hydrochloric acid (2.5 mL, 3M), then stirred at 70 C. under nitrogen atmosphere for 12 hours. The system was adjusted to pH=8 with sodium hydroxide solution (4M) and then separated by preparative liquid chromatography to give (1R,2R,4aS,5R)-1-(hydroxymethyl)-5-(2-(4-(hydroxymethyl)piperidin-1-yl)ethyl-1,4a-dimethyl-6-methylene-decahydro-naphthalenemethanol-2-ol 265 (50.5 mg, yield: 20.52%).

(477) MS m/z (ESI):366.1[M+1]

(478) .sup.1H NMR (400 MHz, CDCl3) 4.24 (d, J=11.3 Hz, 1H), 3.59-3.42 (m, 4H), 3.34 (d, J=11.3 Hz, 1H), 3.06 (br. s., 2H), 2.37 (br. s., 1H), 2.19-1.58 (m, 15H), 1.58-1.17 (m, 9H), 0.92 (s, 3H).

(479) Test of IL-6 Release from THP-1 Cells

Experimental Purpose

(480) The inhibitory effect of the compound on LPS-induced IL-6 release level from THP-1 cells was evaluated by measuring the level of IL-6 in the cell culture supernatant.

(481) Experimental Materials: Cell line: THP-1 cell line THP-1 cell culture medium (RPMI 1640, Gibco #22400-089, 10% serum Gibco #10099-141) LPS, 1 mg/ml (Sigma # L5293) DPBS (Hyclone, # SH30028.01B) Human IL-6 CBA kit, BD #558276 CBA Human Soluble Protein Master Buffer Kit, BD #558265 Dexamethasone: J&K #308890 96-well Cell Plate, Corning # CO.sub.2 incubator, Thermo #371 Centrifuge, Eppendorf #5810R Vi-cell Cell Counter, Beckman Coulter FACSCalibur, BD #97500540 Experimental procedures and methods: a) Cell inoculation 1) The medium was preheated in a 37 C. water bath. 2) The suspension cells in the culture flask were blown well, transferred to a centrifuge tube and centrifuged at room temperature at 1200 rpm for 5 minutes, the supernatant was discarded, and resuspended to 10 mL by adding with culture medium; 3) 1 mL of cell resuspension was drawn and counted with Vi-cell. 4) THP-1 cells were diluted with culture medium to 510.sup.5/mL and the cells were added to a 96-well plate (100 ul/well, 510.sup.5 cells/well); b) Compound adding: 1) The compound was dissolved in DMSO to 30 mM and diluted 3 times with DMSO to 4 gradients, i.e. 30 mM, 10 mM, 3 mM, 1 mM, respectively. 4 ul was taken from each above solution and added to lml of culture solution to make 120 uM, 40 uM, 12 uM, 4 uM. 50 ul per well was taken and added to wells with cells to give final concentrations of 30 uM, 10 uM, 3 uM, and 1 uM, respectively. Dexamethasone was added as a positive drug into an individual cell well with a final concentration of 100 nM. c) Cell stimulation

(482) The LPS 1 mg/ml solution was diluted to 800 ng/ml with the culture solution and added to the cell culture wells at 50 ul/well. d) Cell incubation and detection

(483) The cell culture plate was placed in a 37 C. incubator, and the supernatant was collected after culturing for 24 hours. The level of IL-6 in the supernatant was detected by CBA.

(484) The experimental results are shown in Table 1:

(485) TABLE-US-00001 TABLE 1 Test results of inflammatory factor IL-6 detected by CBA- inhibition rate @ 10 uM Test sample (Title compound) Inhibition rate @ 10 uM Compound 297 A Compound 420 C Compound 321 C Compound 319 B Compound 430 B Compound 357 A Compound 339 C Compound 344 A Compound 310 A Compound 443 B Compound 442 B Compound 317 A Compound 351 A Compound 289 A Compound 422 B Compound 423 B Compound 407 A Compound 409 C Compound 441 B Compound 448 C Compound 447 C Compound 397 A Compound 410 B Compound 415 A Compound 406 C Compound 436 C Compound 431 A Compound 432 A Compound 428 B Compound 417 C Compound 349 A Compound 312 C Compound 453 A Compound 445 C Compound 452 B Compound 454 B Compound 385 A Compound 402 A Compound 416 A Compound 400 A Compound 411 A Compound 412 A Compound 429 C Compound 446 C Compound 405 C Compound 408 C Compound 399 A Compound 281 B Compound 313 B Compound 366 A Compound 482 A Compound 483 B Compound 426 B Compound 463 A Compound 484 A Compound 373 B Compound 386 C Compound 403 C Compound 404 C Compound 284 B Compound 191 C Compound 207 B Compound 345 B Compound 355 C Compound 196 B Compound 149 B Compound 163 A Compound 435 C Compound 450 A Compound 116 B Compound 455 A Compound 147 C Compound 181 C Compound 361 B Compound 123 C Compound 433 A Compound 160 A Compound 150 B Compound 451 B Compound 002 C Compound 256 C Compound 456 A Compound 457 A Compound 458 B Compound 130 C Compound 214 A Compound 212 A Compound 215 C Compound 230 A Compound 265 C Note: A > 60%; 30% < B 60%; C 30%;

(486) Conclusion: the compounds of the disclosure have a significant inhibitory effect on the inflammatory factor IL-6.

(487) The foregoing description of the embodiments has been provided for purposes of illustration and description. It is not intended to be exhaustive or to limit the disclosure. Individual elements or features of a particular embodiment are generally not limited to that particular embodiment, but, where applicable, are interchangeable and can be used in a selected embodiment, even if not specifically shown or described. The same may also be varied in many ways. Such variations are to be regarded as a departure from the disclosure, and all such modifications are intended to be included within the scope of the disclosure.