6,7-unsaturated-7-carbamoyl substituted morphinan derivative

Abstract

A novel compound which is useful as an agent for treating and/or preventing emesis, vomiting and/or constipation. A compound represented by the formula (I): ##STR00001## wherein R.sup.1 and R.sup.2 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted aryl etc., R.sup.3 is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy etc., R.sup.4 is hydrogen or lower alkyl, R.sup.5 is hydrogen, lower alkyl, cycloalkyl lower alkyl or lower alkenyl, or a pharmaceutically acceptably salt, or a solvate thereof is provided.

Claims

1. A compound represented by the formula (I): ##STR00428## wherein R.sup.1 and R.sup.2 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkylsulfonyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, an optionally substituted heterocyclic group, optionally substituted arylsulfonyl, or R.sup.1 and R.sup.2 are taken together with the nitrogen atom to which they are attached to form optionally substituted heterocycle; R.sup.3 is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, mercapto, optionally substituted lower alkylthio, optionally substituted amino, optionally substituted carbamoyl, optionally substituted acyl, optionally substituted acyloxy, optionally substituted aryl, or an optionally substituted heterocyclic group; .Iadd.or .Iaddend. .[.a.]. .Iadd.the .Iaddend.group represented by the formula: ##STR00429## .[.may be.]. .Iadd.is selected from: .Iaddend. ##STR00430## wherein ring A and ring B are each independently optionally substituted nitrogen-containing heterocycle optionally containing additional nitrogen atom, oxygen atom, and/or sulfur atom in the ring; broken line indicates the presence or the absence of a bond; when broken line indicates the presence of a bond, p is 0; when a broken line indicates the absence of a bond, p is 1; R.sup.a is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, or optionally substituted lower alkynyl; and R.sup.b is hydrogen or oxo; R.sup.4 is hydrogen or lower alkyl; .Iadd.and .Iaddend. R.sup.5 is hydrogen, lower alkyl, cycloalkyl lower alkyl or lower alkenyl, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R.sup.3 is hydroxy, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein R.sup.3 is optionally substituted amino, or a pharmaceutically acceptable salt thereof.

4. The compound in any one of claims 1 to 3, wherein R.sup.1 is hydrogen or lower alkyl, R.sup.2 is optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted cycloalkyl, or an optionally substituted heterocyclic group, and R.sup.5 is cyclopropylmethyl, or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition containing a compound in any one of claims 1 to .[.4.]. .Iadd.3.Iaddend., or a pharmaceutically acceptable salt thereof.

6. A composition having an opioid receptor antagonistic activity containing a compound in any one of claims 1 to .[.4.]. .Iadd.3.Iaddend., or a pharmaceutically acceptable salt thereof.

7. A composition for treating and/or preventing emesis, vomiting and/or constipation containing a compound in any one of claims 1 to .[.4.]. .Iadd.3.Iaddend., or a pharmaceutically acceptable salt thereof.

8. A composition for alleviating and/or preventing a side effect induced by a compound having opioid receptor agonistic activity containing a compound in any one of claims 1 to .[.4.]. .Iadd.3.Iaddend., or a pharmaceutically acceptable salt thereof.

9. An agent for treating and/or preventing a side effect according to claim 8, wherein the side effect is emesis, vomiting and/or constipation.

10. A composition for treatment and/or prevention according to claim 8 .[.or 9.]., wherein the compound having the opioid receptor agonistic activity is morphine, oxycodone, or a pharmaceutically acceptable salt thereof.

11. A composition for analgesic containing a compound having an opioid receptor agonistic activity, and an effective amount of compound according to any one of claims 1 to .[.4.]. .Iadd.3.Iaddend., or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administrating of the compound having an opioid receptor agonistic activity.

12. A compound represented by the formula (I): ##STR00431## wherein R.sup.1 is hydrogen; R.sup.2 is selected from lower alkyl optionally substituted with lower alkoxy, lower alkoxycarbonyl, or a heterocyclic group optionally substituted with lower alkyl or phenyl; phenyl optionally substituted with lower alkyl, lower alkoxy, halogen, or cyano lower alkyl; cycloalkyl optionally substituted with lower alkoxycarbonyl or lower alkoxy lower alkyl; or a heterocyclic group optionally substituted with lower alkoxy or oxo; R.sup.3 is hydroxyl; R.sup.4 is hydrogen; and R.sup.5 is cyclopropylmethyl; or a pharmaceutically acceptable salt thereof.

13. A compound represented by the formula (I): ##STR00432## wherein R.sup.1 is hydrogen; R.sup.2 is lower alkyl optionally substituted with lower alkoxy or with a heterocyclic group that is optionally substituted with aryl; phenyl optionally substituted with lower alkyl or with lower alkoxy; cycloalkyl substituted with lower alkylcarbonyl; or a heterocyclic group substituted with lower alkoxy or with aryl; R.sup.3 is hydroxyl; R.sup.4 is hydrogen; and R.sup.5 is cyclopropylmethyl; or a pharmaceutically acceptable salt thereof.

14. A compound, wherein the compound is ##STR00433## ##STR00434## ##STR00435## ##STR00436## or a pharmaceutically acceptable salt thereof.

15. A compound, wherein the compound is ##STR00437## ##STR00438## or a pharmaceutically acceptable salt thereof.

16. A composition for analgesic containing: a compound having an opioid receptor agonistic activity, and an effective amount of compound according to claim 12 or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administrating of the compound having an opioid receptor agonistic activity.

17. A composition for analgesic containing: a compound having an opioid receptor agonistic activity, and an effective amount of compound according to claim 13 or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administrating of the compound having an opioid receptor agonistic activity.

18. A composition for analgesic containing: a compound having an opioid receptor agonistic activity, and an effective amount of compound according to claim 14 or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administrating of the compound having an opioid receptor agonistic activity.

19. A composition for analgesic containing: a compound having an opioid receptor agonistic activity, and an effective amount of compound according to claim 15 or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administrating of the compound having an opioid receptor agonistic activity.

.Iadd.20. A compound of the formula: ##STR00439## or a pharmaceutically acceptable salt thereof..Iaddend.

.Iadd.21. The compound of claim 20 wherein the compound is ##STR00440## .Iaddend.

.Iadd.22. The compound of claim 20 wherein the compound is a pharmaceutically acceptable salt of ##STR00441## .Iaddend.

.Iadd.23. The compound of claim 22 wherein the pharmaceutically acceptable salt is the p-toluene sulfonic acid salt..Iaddend.

.Iadd.24. A pharmaceutical composition comprising the compound of claim 20 or a pharmaceutically acceptable salt thereof..Iaddend.

.Iadd.25. A pharmaceutical composition comprising the compound of claim 23..Iaddend.

.Iadd.26. A composition comprising a compound having an opioid receptor agonistic activity and an effective amount of the compound of claim 20 or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administering of the compound having an opioid receptor agonistic activity..Iaddend.

.Iadd.27. A composition comprising a compound having an opioid receptor agonistic activity and an effective amount of the compound of claim 23, for alleviating and/or preventing a side effect induced by administering of the compound having an opioid receptor agonistic activity..Iaddend.

.Iadd.28. The composition of claim 27 wherein the compound having the opioid receptor agonistic activity is morphine, oxycodone, or a pharmaceutically acceptable salt thereof..Iaddend.

.Iadd.29. The composition according to claim 25 in the form of a tablet..Iaddend.

.Iadd.30. The composition according to claim 27 in the form of a tablet..Iaddend.

Description

EXAMPLE 1

Production of Compound (I-4)

(1) ##STR00135##
wherein Bn indicates benzyl, Et indicates ethyl, and Pr.sup.i indicates isopropyl.
(First Step) 7-ethoxycarbonylnaltrexone

(2) To a suspension of 3-O-benzyl-7-ethoxycarbonylnaltrexone described in Non-Patent Literature 2 (11.16 g, 22.15 mmol) in ethyl acetate (50 mL) and methanol (50 mL) was added palladium hydroxide (Perlman's catalyst) (1.2 g), and the mixture was vigorously stirred for 2 hours under a hydrogen atmosphere. After filtration of the catalyst, the filtrate was concentrated, and the residue was crystallized from ethyl acetate and hexane to obtain 8.96 g (92%) of the title compound as colorless crystals.

(3) NMR (300 MHz, CDCl.sub.3) 0.14-0.17 (m, 2H), 0.55-0.58 (m, 2H), 0.86 (m, 1H), 1.23-1.29 (m, 3H), 1.67 (d, 1H, J=9.6 Hz), 2.02 (dd, 1H, J=1.2, 16.2 Hz), 2.20-2.79 (m, 8H), 3.08 (d, 1H, J =18.6 Hz), 3.24 (br, 1H), 4.12-4.20 (m, 2H), 4.96 (s, 1H), 5.17 (br, 1H), 6.59 (d, 1H, J=8.1 Hz), 6.72 (d, 1H, J=8.1 Hz), 12.12 (s, 1H).

(4) Elemental analysis (C23H27NO6.0.2H2O) (Calculated value) C, 66.24; H, 6.62; N, 3.36. (Found value) C, 66.29; H, 6.50; N, 3.45.

(5) (Second Step) 7-isopropylaminocarbonylnaltrexone

(6) A solution of 7-ethoxycarbonylnaltrexone obtained in the first step (200 mg, 0.484 mmol), isopropylamine (0.412 mL, 4.84 mmol) and triethylamine (0.202 mL, 1.45 mmol) in 2-methoxyethanol (1.5 mL) was stirred at 180 C. for 45 minutes under microwave irradiation. After cooled to room temperature, 7 mL of 5 mol/L hydrochloric acid was added to the reaction mixture, and stirring was continued at 70 C. for 20 minutes. After the reaction solution was cooled, pH value was adjusted to 8.5 with aqueous ammonia, followed by extraction with ethyl acetate. The organic layer was washed with water, and dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=99:1 to 94:6) to obtain 140 mg of the title compound at a yield of 68%.

(7) NMR (300 MHz, d6-DMSO) 0.12-0.15 (m, 2H), 0.44-0.53 (m, 2H), 0.83 (m, 1H), 1.02 (d, 3H, J=6.6 Hz), 1.08 (d, 3H, J=6.6 Hz), 1.41 (d, 1H, J=11.4 Hz), 1.85 (d, 1H, J=15.6 Hz), 2.04-2.62 (m, 8H), 3.04 (d, 1H, J=18.6 Hz), 3.24 (m, 1H), 3.96 (m, 1H), 4.71 (s, 1H), 4.74 (s, 1H), 6.51 (d, 1H, J=8.4 Hz), 6.56 (d, 1H, J=8.4 Hz), 7.40 (br d, 1H, J=7.2 Hz), 9.16 (s, 1H), 14.50 (s, 1H).

(8) Elemental analysis (C24H30N2O5.0.2H2O) (Calculated value) C, 67.02; H, 7.12; N, 6.51. (Found value) C, 67.02; H, 7.20; N, 6.49.

EXAMPLE 2

Preparation of Compound (I-44)

(9) ##STR00136##
wherein Bn indicates benzyl, Me indicates methyl, Et indicates ethyl, and Pr.sup.i indicates isopropyl.
(First Step) 3-O-benzyl-7-ethoxycarbonyl-6-O-methylnaltrexone

(10) To a solution of 3-O-benzyl-7-ethoxycarbonylnaltrexone described in Non-Patent Literature 2 (504 mg, 1 mmol) in tetrahydrofuran (10 mL) were successively added 1,1-azodicarbonylpiperidine (379 mg, 1.5 mmol), tri-n-butylphosphine (370 L, 1.5 mmol) and methanol (41 l, 1 mmol), and the mixture was stirred at room temperature for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (421 mg, 81%) as colorless oil.

(11) .sup.1H NMR (CDCl.sub.3, ppm): 0.10-0.20 (m, 2H), 0.50-0.65 (m, 2H), 0.88 (m, 1H), 1.26 (t, J=6.6 Hz, 3H), 1.67 (d, J=11.4 Hz, 1H), 2.15-2.80 (m, 8H), 3.00-3.30 (m, 2H), 3.93 (s, 3H), 4.05-4.20 (m, 2H), 4.86 (br s, 1H), 5.15 (s, 2H), 5.18 (br s, 1H), 6.57 (d, J=8.1 Hz, 1H), 6.72 (d, J=8.1 Hz, 1H), 7.28-7.45 (m, 5H)

(12) (Second Step) 3-O-benzyl-7-isopropylaminocarbonyl-6-O-methylnaltrexone

(13) To a mixed solution of 3-O-benzyl-7-ethoxycarbonyl-6-O-methylnaltrexone obtained in the first step (145 mg, 0.28 mmol) in methanol (6 mL) and dioxane (2 mL) was added a 50% potassium hydroxide aqueous solution (2 mL), and the mixture was stirred at 50 C. for 30 minutes. The reaction solution was cooled to room temperature, and adjusted to pH=4 with 0.5M an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was successively washed with water, brinebrine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crystalline residue, 3-O-benzyl-7-carboxy-6-O-methylnaltrexone was used in the next reaction without purification. To a solution of the above residue in dimethylformamide (3 mL) were successively added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (40 mg, 0.2 mmol), 1-hydroxybenzotriazole (27 mg, 0.2 mmol) and isopropylamine (16 L, 0.182 mmol), and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into water and this was extracted with ethyl acetate, and the organic layer was washed with water, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain the title compound (39 mg, 44%) as a colorless foam.

(14) .sup.1H NMR (CDCl.sub.3, ppm): 0.10-0.20 (m, 2H), 0.50-0.65 (m, 2H), 0.88 (m, 1H), 1.13 (d, J=2.1 Hz, 3H), 1.15 (d, J=1.8 Hz, 3H), 1.58 (d, J=11.4 Hz, 1H), 2.08-2.80 (m, 8H), 2.99-3.30 (m, 2H), 3.94 (s, 3H), 4.06 (m, 1H), 4.83 (br s, 1H), 5.14 (d, J=2.4 Hz, 2H), 5.23 (br s, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 7.28-7.45 (m, 6H)

(15) (Third Step) 7-isopropylaminocarbonyl-6-O-methylnaltrexone

(16) To a solution of 3-O-benzyl-7-isopropylaminocarbonyl-6-O-methylnaltrexone obtained in the second step (33 mg, 0.073 mmol) in tetrahydrofuran (5 mL) was added palladium hydroxide (33 mg), and the mixture was stirred for 1 hour under a hydrogen atmosphere. The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain the title compound (13 mg, 41%) as a colorless foam.

(17) .sup.1H NMR (CDCl.sub.3, ppm): 0.10-0.15 (m, 2H), 0.50-0.70 (m, 2H), 0.85 (m, 1H), 1.12 (d, J=0.9 Hz, 3H), 1.14 (d, J=0.9 Hz, 3H), 1.66 (d, J=11.4 Hz, 1H), 2.06-2.80 (m, 8H), 3.00-3.30 (m, 2H), 3.92 (s, 3H), 4.05 (m, 1H), 4.80 (br s, 1H), 5.26 (br s, 1H), 6.56 (d, J=8.1 Hz, 1H), 6.69 (d, J=8.1 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H)

EXAMPLE 3

(18) ##STR00137##
wherein Bn indicates benzyl, Me indicates methyl, and Et indicates ethyl.
(First Step)

(19) A solution of compound (1) (28.7 g, 57.0 mmol) in tetrahydrofuran (250 mL) was cooled to 10 C. and to the solution were 1,1-azodicarbonylpiperidine (21.6 g, 85.5 mol), tri-n-butylphosphine (21.4 mL, 85.5 mmol) and benzyl alcohol (6.50 mL, 62.7 mmol) successively added, and the mixture was stirred at room temperature for 6 hours and 45 minutes. The reaction solution was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform.fwdarw.chloroform/methanol=50/1) to obtain quantitatively the objective compound (2) (33.8 g) as a pale yellow oil.

(20) .sup.1H NMR (CDCl.sub.3, ppm): 0.10-0.20 (m, 2H), 0.50-0.65 (m, 2H), 0.88 (m, 1H), 0.94 (t, J=7.2 Hz, 3H), 1.20-3.60 (m, 11H), 4.14 (q, J=7.2 Hz, 2H), 5.10-5.35 (m, 5H), 6.58 (d, J=8.1 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 7.15-7.50 (m, 10H)

(21) (Second Step)

(22) To a mixed solution of compound (2) obtained in the first step (33.8 g, 57.0 mmol) in methanol (130 mL) and dioxane (43 mL) was added a 4N-potassium hydroxide aqueous solution (43 mL), and the mixture was stirred at 50 C. for 14 hours and 35 minutes. The reaction solution was cooled to room temperature, and concentrated under reduced pressure, and the residue was adjusted to pH=3 to 4 with ice-water and 2N-hydrochloric acid, followed by extraction with a mixed solution of ethyl acetate and tetrahydrofuran. The organic layer was successively washed with water, and brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was converted into a powder with ether to obtain the objective compound (3) (24.8 g, 77%) as a colorless powder.

(23) .sup.1H NMR (DMSO-d.sub.6, ppm): 0.20-0.40 (m, 2H), 0.50-0.65 (m, 2H), 0.95 (m, 1H), 1.30-3.60 (m, 11H), 5.00-5.25 (m, 5H), 5.39 (s, 1H), 6.68 (d, J=8.1 Hz, 1H), 6.88 (d, J=8.1 Hz, 1H), 7.27-7.52 (m, 10H)

(24) (Third Step)

(25) To a solution of compound (3) obtained in the second step (350 mg, 0.619 mmol) in tetrahydrofuran (4 mL) were successively added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (142 mg, 0.743 mmol), 1-hydroxybenzotriazole (100 mg, 0.743 mmol.), dimethylglycine methyl ester hydrochloride (114 mg, 0.743 mmol) and N-methyl-morpholine (82 L, 0.743 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice-water and a saturated sodium bicarbonate aqueous solution, followed by extracted with ethyl acetate, and the organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated under the reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to obtain the objective compound (4) (300 mg, 73%) as a pale yellow foam.

(26) .sup.1H NMR (CDCl.sub.3, ppm): 0.08-0.20 (m, 2H), 0.50-0.60 (m, 2H), 0.87 (m, 1H), 1.13 (s, 3H), 1.22 (s, 3H), 1.55-2.80 (m, 11H), 3.62 (s, 3H), 4.85 (br s, 1H), 5.13-5.40 (m, 5H), 6.58 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 7.26-7.48 (m, 10H), 7.94 (s, 1H)

(27) (Fourth Step)

(28) To a solution of compound (4) obtained in the third step (290 mg, 0.436 mmol) in methanol (4 mL) was added palladium hydroxide (60 mg), followed by stirring for 3 hours under a hydrogen atmosphere. The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure. The residue was crystallized with hexane/ethyl acetate to obtain the objective compound (I-49) (181 mg, 86%) as colorless crystals.

(29) .sup.1H NMR (DMSO-d.sub.6, ppm): 0.10-0.20 (m, 2H), 0.40-0.57 (m, 2H), 0.84 (m, 1H), 1.33 (s, 3H), 1.37 (s, 3H), 1.40-3.40 (m, 11H), 3.55 (s, 3H), 4.72 (s, 1H), 4.77 (br s, 1H), 6.52 (d, J=8.1 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 7.68 (br s, 1H), 9.18 (br s, 1H), 13.78 (br s, 1H)

(30) According to the same procedure, other compounds (I) can be synthesized. Structural formulas and physical constants are shown below.

(31) In Tables, Me indicates methyl, Et indicates ethyl, Pr.sup.i indicates isopropyl, and Ph indicates phenyl.

(32) In addition, in Tables,

(33) ##STR00138##

(34) TABLE-US-00009 TABLE 9 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-1 0.10-0.25 (m, 2H), 0.50-0.60 (m, 2H), 1.87 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H), 1.68 (d, J = 11.4 Hz, 1H), 2.20-2.80 (m, 7H), 3.00-3.35 (m, 5H), 4.94 (s, 1H), 5.40 (m, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 14.20 8br s, 1H) I-2 0 0.10-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.85 (m, 1H), 1.41 (d, J = 11.4 Hz, 1H), 1.90-3.40 (m, 14H), 4.71 (s, 1H), 4.73 (br s, 1H), 6.50 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 7.77 (br s, 1H) I-3 (CDCl3) 0.10-0.25 (m, 2H), 0.50-0.62 (m, 2H), 0.81- 0.98 (m, 4H), 1.24-1.74 (m, 6H), 2.21-2.77 (m, 7H), 3.05-3.30 (m, 5H), 4.93 (s, 1H), 5.40 (br t, 1H), 6.57 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 14.21 (s, 1H). I-4 0.12-0.15 (m, 2H), 0.44-0.53 (m, 2H), 0.83 (m, 1H), 1.02 (d, 3H, J = 6.6 Hz), 1.08 (d, 3H, J = 6.6 Hz), 1.41 (d, 1H, J = 11.4 Hz), 1.85 (d, 1H, J = 15.6 Hz), 2.04-2.62 (m, 8H), 3.04 (d, 1H, J = 18.6 Hz), 3.24 (m, 1H), 3.96 (m, 1H), 4.71 (s, 1H), 4.74 (s, 1H), 6.51 (d, 1H, J = 8.4 Hz), 6.56 (d, 1H, J = 8.4 Hz), 7.40 (br d, 1H, J = 7.2 Hz), 9.16 (s, 1H), 14.50 (s, 1H) I-5 0.10-0.25 (m, 2H), 0.50-0.62 (m, 2H), 0.85 (m, 1H), 1.40-1.60 (m, 4H), 1.83-3.20 (m, 11H), 4.41 (br s, 1H), 4.72 (s, 1H), 4.74 (s, 1H), 6.51 (d, J = 8.7 Hz), 6.56 (d, J = 8.7 Hz, 1H), 7.70 (s, 1H). 9.15 (br s, 1H), 14.42 (s, 1H). I-6 0.10-0.25 (m, 2H), 0.50-0.62 (m, 2H), 0.85 (m, 1H), 1.42 (d, J = 11.7 Hz, 1H), 1.83-2.64 (m, 10H), 2.10 (s, 6H), 3.00-3.18 (m, 3H), 4.72 (s, 1H), 4.74 (s, 1H), 6.51 (d, J = 8.7 Hz), 6.56 (d, J = 8.7 Hz, 1H), 7.65 (s, 1H), 9.10 (br s, 1H). I-7 0.10-0.25 (m, 2H), 0.50-0.60 (m, 2H), 1.90 (m, 1H), 1.57 (dd, J = 2.4, 12.6 Hz, 2H), 1.85-2.80 (m, 10H), 3.00-3.25 (m, 3H), 3.35-3.60 (m, 3H), 4.20 (m, 1H), 4.76 (br s, 1H), 5.85 (br s, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H)

(35) TABLE-US-00010 TABLE 10 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-8 0.10-0.20 (m, 2H), 0.45-0.68 (m, 2H), 1.88 (m, 1H), 1.35 (d, J = 11.4 Hz, 1H), 1.65-2.20 (m, 4H), 2.30-3.60 (m, 13H), 4.29 (dd, J = 4.8, 12.6 Hz, 1H), 5.08 (s, 1H), 5.23 (br s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 9.25 (br s, 1H) I-9 (CDCl3) 0.10-0.25 (m, 2H), 0.50-0.62 (m, 2H), 0.85 (m, 1H), 1.62-2.77 (m, 6H), 3.07 (d, J = 18.6 Hz, 1H), 3.23 (d, J = 7.2 Hz, 1H), 4.42 (d, J = 5.4 Hz, 2H), 4.93 (s, 1H), 5.66 (br s, 1H), 6.55 (d, J = 8.7 Hz), 6.72 (d, J = 8.7 Hz, 1H), 7.22-7.39 (m,5H), 14.15 (s, 1H). I-10 0.10-0.24 (m, 2H), 0.45-0.60 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 11.1 Hz, 1H), 1.70-3.40 (m, 10H), 4.78 (s, 1H), 4.82 (s, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 7.05 (m, 1H), 7.29 (t, J = 7.8 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 9.14 (s, 1H), 9.24 (br s, 1H), 13.90 (br s, 1H) I-11 0.10-0.22 (m, 2H), 0.44-0.58 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.75-3.40 (m, 10H), 4.78 (s, 1H), 4.83 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.13 (t, J = 8.7 Hz, 2H), 7.48- 7.56 (m, 2H), 9.17 (s, 1H), 9.27 (br s, 1H), 13.90 (br s, 1H) I-12 0 0.10-0.18 (m, 2H), 0.52-0.60 (m, 2H), 0.80-0.98 (m, 2H), 0.98-3.21 (m, 26H), 4.41 (br, s, 1H), 4.70 (d, J = 12.3 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H) I-13 0.10-0.25 (m, 2H), 0.50-0.60 (m, 2H), 0.87 (m, 1H), 1.58 (d, J = 111.7 Hz, 1H), 2.05-2.50 (m, 6H), 2.55- 2.90 (m, 5H), 3.00-3.30 (m, 2H), 4.42 (s, 1H), 4.81- 4.87 (m, 2H), 5.55 (br s, 1H), 6.60 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 7.20-7.40 (m,5H) I-14 0.10-0.22 (m, 2H), 0.45-0.60 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 2.10-3.40 (m, 10H), 3.78 (s, 3H), 4.96 (s, 1H), 6.36 (br s, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 9.0 Hz, 2H), 6.98 (br s, 1H), 7.29 (d, J = 9.0 Hz, 2H), 14.00 (br s, 1H)

(36) TABLE-US-00011 TABLE 11 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-15 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.88 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 2.00-3.35 (m, 10H), 3.78 (s, 3H), 4.34 (d, J = 5.1 Hz, 2H), 4.91 (s, 1H), 5.61 (br s, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 14.13 (br s, 1H) I-16 0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.77 (s, 1H), 4.84 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.30-7.38 (m, 2H), 7.53-7.60 (m, 2H), 9.17 (s, 1H), 9.28 (br s, 1H), 13.80 (br s, 1H) I-17 0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 13H), 4.77 (s, 1H), 4.82 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 9.17 (s, 1H), 9.27 (br s, 13.90 (br s, 1H) I-18 0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.65-3.40 (m, 10H), 3.80 (s, 3H), 4.81 (br s, 2H), 6.52 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.87 (m, 1H), 6.98-7.10 (m, 2H), 7.82 (m, 1H), 9.19 (s, 1H), 9.70 (br s, 1H), 12.90 (br s, 1H) I-19 I-20 0.12-0.14 (d, J = 4.5 Hz, 2H), 0.46-0.52 (t, J = 8.3 Hz, 2H), 0.71- 0.85 (m, 4H), 0.98-1.06 (dd, J = 6.8, 17.3 Hz, 4H), 1.35-1.45 (m, 4H), 1.82-1.92 (m, 2H), 2.44-2.61 (m), 3.04 (d, J = 18.9 Hz, 1H), 3.19-3.24 (m, 1H), 3.71-3.82 (m, 1H), 4.71-4.76 (m, 2H), 6.50- 6.57 (dd, J = 8.1, 14.4 Hz, 2H), 7.31-7.38 (m, 1H), 9.15 (br s, 1H), 14.52 (br s, 1H) I-21 0.12-0.14 (d, J = 4.2 Hz, 2H), 0.49 (t, J = 8.1 Hz, 2H), 0.69-0.86 (m, 6H), 1.32-1.47 (m, 5H), 1.88 (d, J = 15.3 Hz, 1H), 2.06-2.30 (m, 4H), 2.45-2.61 (m), 3.04 (d, J = 18.0 Hz, 1H), 3.19-3.24 (m, 1H), 4.71-4.75 (m, 2H), 6.05-6.58 (dd, J = 8.8, 14.4 Hz, 2H), 7.24 (d, J = 7.8 Hz, 1H), 9.15 (br s, 1H), 14.55 (br s, 1H)

(37) TABLE-US-00012 TABLE 12 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-22 0 0.12-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 8.1 Hz, 2H), 0.85 (m, 1H), 1.06 (m, 1H), 1.16-1.28 (m, 4H), 1.39-1.43 (d, J = 11.4 Hz, 1H), 1.54-1.70 (m, 6H), 1.84-1.89 (d, J = 15.6 Hz, 1H), 2.08-2.60 (m, 6H), 3.00-3.07 (d, J = 18.6 Hz, 1H), 3.17-3.24 (m, 1H), 3.60 (br s, 1H), 4.71-4.76 (m, 2H), 6.49-6.57 (dd, J = 8.1, 14.7 Hz, 2H), 7.37 (d, J = 9.0 Hz, 1H), 9.13 (br s, 1H), 14.47 (br s, 1H) I-23 0.12-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 7.8 Hz, 2H), 0.83-0.92 (m, 4H), 1.19-1.70 (m, 9H), 1.83-1.93 (m, 1H), 2.06-2.61 (m, 9H), 3.01- 3.07 (d, J = 18.3 Hz, 1H), 3.18-3.20 (d, J = 4.2 Hz, 1H), 3.67 (m, 1H), 4.71-4.76 (m, 2H), 6.52-6.55 (dd, J = 8.1, 14.4 Hz, 2H), 9.13 (br s, 1H), 14.48 (br s, 1H) I-24 0.12-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 8.0 Hz, 2H), 0.83-0.87 (m, 1H), 1.34-1.55 (m, 12H), 1.84-1.89 (d, J = 15.6 Hz, 1H), 2.09-2.60 (m, 9H), 3.00-3.07 (d, J = 18.3 Hz, 1H), 3.17-3.19 (d, J = 6.0 Hz, 1H), 3.78-3.81 (m, 1H), 4.71-4.76 (m, 2H), 6.49- 6.57 (dd, J = 8.1, 14.7 Hz, 2H), 7.39 (d, J = 8.1 Hz, 1H), 9.13 (br s, 1H), 14.46 (br s, 1H) I-25 0.13-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 7.8 Hz, 2H), 0.85 (m, 1H), 1.39-1.43 (d, J = 11.1 Hz, 1H), 1.56-1.64 (m, 2H), 1.85- 2.32 (m, 12H), 2.43-2.61 (m), 3.01-3.07 (d, J = 18.3 Hz, 1H), 3.18-3.20 (d, J = 6.0 Hz, 1H), 4.16-4.27 (m, 1H), 4.72-4.73 (m, 2H), 6.50-6.57 (dd; J = 8.1, 18.9 Hz, 2H), 7.77 (d, J = 7.5 Hz, 1H), 9.12 (br s, 1H), 14.41 (br s, 1H) I-26 0.16-0.19 (m, 2H), 0.48-0.57 (m, 2H), 0.88 (m, 1H), 1.46 (d, J = 11.2 Hz, 1H), 1.92 (d, J = 15.6 Hz, 1H), 2.04-2.66 (m, 6H), 3.08 (d, J = 18.8 Hz, 1H), 3.17-3.40 (m, 6H), 3.24 (s, 3H), 4.77 (s, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 7.76 (br t, 1H), 9.15 (s, 1H), 14.33 (s, 1H). I-27 0.16-0.19 (m, 2H), 0.48-0.57 (m, 2H), 0.90 (m, 1H), 1.10 (t, J = 6.8 Hz, 3H), 1.46 (d, J = 11.2 Hz, 1H), 1.92 (d, J = 15.6 Hz, 1H), 2.04-2.66 (m, 6H), 3.08 (d, J = 18.8 Hz, 1H), 3.17-3.46 (m, 8H),, 4.77 (s, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 7.77 (br, 1H), 9.15 (s, 1H), 14.32 (s, 1H). I-28 0.16-0.17 (m, 2H), 0.50-0.63 (m, 2H), 0.89 (m, 1H), 1.46 (d, J = 12.0 Hz, 1H), 1.92 (d, J = 15.2 Hz, 1H), 2.06 (s, 3H), 2.06-2.70 (m, 6H), 3.08 (d, J = 18.4 Hz, 1H), 3.20-3.32 (m, 6H), 4.77 (s, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 7.76 (br s, 1H), 9.16 (s, 1H), 14.31 (s, 1H).

(38) TABLE-US-00013 TABLE 13 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-29 0.17-0.18 (m, 2H), 0.51-0.57 (m, 2H), 0.90 (m, 1H), 1.46 (d, J = 11.6 Hz, 1H), 1.93 (d, J = 16.0 Hz. 1H), 2.11-2.78 (m, 6H), 3.08 (d, J = 18.4 Hz, 1H), 3.21 (d, J = 6.0 Hz, 1H), 3.27-3.32 (m, 5H), 4.77 (s, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 7.19-7.32 (m, 5H), 7.86 (br s, 1H), 9.16 (s, 1H), 14.38 (s, 1H). I-30 0.16-0.19 (m, 2H), 0.48-0.57 (m, 2H), 0.88 (m, 1H), 1.46 (d, J = 11.2 Hz, 1H), 1.94 (d, J = 15.6 Hz, 1H), 2.11-2.71 (m, 6H), 3.08 (d, J = 18.8 Hz, 1H), 3.49-3.51 (m, 2H), 3.96-4.4.05 (m, 2H), 4.79 (s, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.94-6.97 (m, 3H), 7.27-7.34 (m, 2H), 7.94 (br, 1H), 9.17 (s, 1H), 14.28 (s, 1H). I-31 0.10-0.28 (m, 2H), 0.44-0.65 (m, 2H), 0.94 (m, 1H), 1.50 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.72 (br s, 1H), 4.86 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.54-7.80 (m, 4H), 9.16 (s, 1H), 9.32 (s, 1H), 13.90 (br s, 1H) I-32 0 0.10-0.25 (m, 2H), 0.42-0.62 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.75 (br s, 1H), 4.84 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.41-7.54 (m, 4H), 9.17 (s, 1H), 9.28 (s, 1H), 13.85 (br s, 1H) I-33 0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.77 (s, 1H), 4.81 (s, 1H), 5.98 (s, 2H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.82-6.95 (m, 2H), 7.15 (d, J = 1.8 Hz, 1H), 9.16 (s, 1H), 9.26 (s, 1H), 13.98 (br s, 1H) I-34 0.20-0.40 (m, 2H), 0.45-0.65 (m, 2H), 0.96 (m, 1H), 1.50 (m, 1H), 1.70-3.40 (m, 10H), 4.65 (br s, 1H), 4.88 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 7.60-7.80 (m, 4H), 9.17 (s, 1H), 9.30 (s, 1H), 14.00 (br s, 1H) I-35 0.10-0.20 (m, 2H), 0.50-0.62 (m, 2H), 0.88 (m, 1H), 1.65 (d, J = 10.8 Hz, 1H), 2.00-3.60 (m, 14H), 3.78 (s, 3H), 4.93 (s, 1H), 5.46 (br s, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 14.17 (br s, 1H)

(39) TABLE-US-00014 TABLE 14 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-36 0.10-0.25 (m, 2H), 0.43-0.63 (m, 2H), 0.88 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 3.71 (s, 3H), 4.77 (s, 1H), 4.82 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.64 (m, 1H), 7.00-7.25 (m, 3H), 9.17 (s, 1H), 9.27 (s, 1H), 13.90 (br s, 1H) I-37 0.12-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 8.1 Hz, 2H), 0.85 (m, 1H), 1.06 (m, 1H), 1.39-1.62 (m, 18H), 1.84-1.89 (d, J = 15.6 Hz, 1H), 2.08-2.34 (m, 5H), 2.43-2.54 (m), 2.58- 2.60 (d, J = 6.9 Hz, 1H), 3.00-3.07 (d, J = 18.6 Hz, 1H), 3.18-3.20 (d, J = 6 Hz, 1H), 3.87 (br s, 1H), 4.71-4.76 (m, 2H), 6.49-6.57 (dd, J = 8.1, 14.7 Hz, 2H), 7.38 (d, J = 7.8 Hz, 1H), 9.13 (br s, 1H), 14.47 (br s, 1H) I-38 0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 13H), 4.78 (s, 1H), 4.82 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 9.17 (s, 1H), 9.27 (s, 1H), 14.00 (br s, 1H) I-39 0.10-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.87 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 16H), 4.76 (s, 1H), 4.80 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 9.10 (br s, 2H), 14.20 (br s, 1H) I-40 0.10-0.30 (m, 2H), 0.45-0.65 (m, 2H), 0.90 (m, 1H), 1.48 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.77 (s, 1H), 4.85 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.25-7.35 (m, 2H), 7.64 (d, J = 9.0 Hz, 2H), 9.18 (s, 1H), 9.29 (s, 1H), 13.90 (br s,

(40) TABLE-US-00015 TABLE 15 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-41 0.20-0.40 (m, 2H), 0.45-0.70 (m, 2H), 0.96 (m, 1H), 1.50 (m, 1H), 1.70-3.40 (m, 13H), 4.67 (br s, 1H), 4.88 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 7.76 (s, 4H), 9.18 (s, 1H), 9.31 (s, 1H), 14.00 (br s, 1H) I-42 0 0.18 (br, s, 2H), 0.42-0.63 (m, 3H), 0.80-0.97 (m, 2H), 1.20- 3.43 (m, 24H), 4.92 (s, 1H), 5.89 (br, s, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 14.13 (br, s, 1H) I-43 0.12-0.19 (m, 2H), 0.41-0.58 (m, 2H), 0.74 (d, J = 3.3 Hz, 6H), 1.43 (m, 1H), 1.88-3.41 (m, 16H), 4.56 (br, s, 1H), 4.65-4.80 (m, 2H), 6.50-6.62 (m, 2H), 7.51 (br, s, 1H), 9.13 (s, 1H), 14.23 (br, s, 1H) I-44 0.10-0.15 (m, 2H), 0.50-0.70 (m, 2H), 0.85 (m, 1H), 1.12 (d, J = 0.9 Hz, 3H), 1.14 (d, J = 0.9 Hz, 3H), 1.66 (d, J = 11.4 Hz, 1H), 2.06-2.80 (m, 8H), 3.00-3.30 (m, 2H), 3.92 (s, 3H), 4.05 (m, 1H), 4.80 (br s, 1H), 5.26 (br s, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H) I-45

(41) TABLE-US-00016 TABLE 16 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-46 0.15-0.35 (m, 2H), 0.45-0.70 (m, 2H), 0.92 (m, 1H), 1.50 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.72 (br s, 1H), 4.86 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.54-7.74 (m, 4H), 9.16 (s, 1H), 9.27 (s, 1H), 14.00 (br s, 1H) I-47 0.10-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.86 (m, 1H), 1.42 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 3.61 (s, 3H), 3.82 (d, J = 5.7 Hz, 2H), 4.77 (s, 2H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 8.21 (br t, J = 5.7 Hz, 1H), 9.17 (s, 1H), 13.87 (br s, 1H) I-48 0.10-0.20 (m, 2H), 0.50-0.65 (m, 2H), 0.89 (m, 1H), 0.90 (d, J = 4.5 Hz, 3H), 0.94 (d, J = 4.5 Hz, 3H), 1.45 (s, 9H), 1.66 (d, J = 10.8 Hz, 1H), 2.10-3.40 (m, 11H), 4.43 (dd, J = 4.5, 8.1 Hz, 1H), 4.94 (s, 1H), 6.00 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 13.99 (br s, 1H) I-49 0.10-0.30 (m, 2H), 0.45-0.70 (m, 2H), 0.90 (m, 1H), 1.34 (s, 3H), 1.38 (s, 3H), 1.50-3.40 (m, 11H), 3.56 (s, 3H), 4.77 (br s, 2H), 6.58 (br s, 2H), 7.69 (br s, 1H), 9.20 (br s, 1H), 13.76 (br s, 1H) I-50 0.10-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.88 (m, 1H), 1.44 (d, J = 11.7 Hz, 1H), 1.90-3.40 (m, 10H), 3.68 (d, J = 4.5 Hz, 2H), 4.77 (s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 8.00 (br t, J = 4.5 hz, 1H), 9.18 (br s, 1H), 14.00 (br s, 1H)

(42) TABLE-US-00017 TABLE 17 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-51 0 0.30-0.50 (m, 2H), 0.55-0.75 (m, 2H), 0.89 (d, J = 3.3 Hz, 3H), 0.91 (d, J = 3.3 Hz, 3H), 1.04 (m, 1H), 1.65 (d, J = 13.5 Hz, 1H), 2.00- 3.92 (m, 11H), 4.10 (t, J = 6.6 Hz, 1H), 4.95 (s, 1H), 6.64 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 9.43 (s, 1H), 13.66 (br s, 1H) I-52 0.10-0.25 (m, 2H), 0.45-0.60 (m, 2H), 0.89 (m, 1H), 1.34 (s, 3H), 1.36 (s, 3H), 1.46 (d, J = 9.6 Hz, 1H), 1.90-3.40 (m, 10H), 4.75 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 7.68 (s, 1H), 9.21 (br s, 1H), 14.11 (br s, 1H) I-53 0.13-0.14 (m, 2H), 0.47-0.49 (m, 2H), 0.88 (m, 1H), 1.30 (m, 1H), 1.63-2.10 (m, 6H), 2.30-2.70 (m, 4H), 2.96-3.58 (m, 6H), 4.06- 4.23 (m, 3H), 5.04 (s, 1H), 5.23 (br, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 8.08 (br, 1H), 9.23 (br, 1H). I-54 0.13-0.14 (m, 2H), 0.47-0.49 (m, 2H), 0.88 (m, 1H), 1.30 (d, J = 12.0 Hz, 1H), 1.63-2.12 (m, 6H), 2.28-2.70 (m, 4H), 2.97-3.53 (m, 6H), 4.06-4.23 (m, 3H), 5.06 (s, 1H), 5.22 (br, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 6.4 Hz, 1H), 8.32 (s, 1H), 9.23 (br, 1H), 10.97 (s, 1H).

(43) TABLE-US-00018 TABLE 18 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-55 0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.42 (s, 2H), 4.77 (s, 1H), 5.12 (s, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 9.20 (s, 1H), 9.28 (s, 1H), 14.00 (br s, 1H) I-56 0.10-0.40 (m, 2H), 0.45-0.70 (m, 2H), 0.92 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.49 (d, J = 9.0 Hz, 1H), 1.70- 3.40 (m, 10H) 4.26 (q, J = 7.2 Hz, 2H), 4.72 (br s, 1H), 4.86 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.90 (d, J = 9.0 Hz, 2H), 9.18 (s, 1H), 9.29 (s, 1H) I-57 0.25-0.40 (m, 2H), 0.50-0.70 (m, 2H), 1.00 (m, 1H), 1.56 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.87 (s, 1H), 4.92 (s, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 9.33 (br s, 2H) I-58 0.08-0.20 (m, 2H), 0.43-0.57 (m, 2H), 0.88 (m, 1H), 1.22-3.40 (m, 11H), 4.76 (s, 1H), 4.84 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.62-6.81 (m, 3H), 7.06-7.16 (m, 2H), 7.73 (s, 1H), 9.16 (s, 1H), 9.61 (s, 1H), 13.80 (br s, 1H) I-59 0.08-0.10 (m, 2H), 0.38-0.58 (m, 2H), 0.86 (m, 1H), 1.22-3.40 (m, 17H), 4.71 (s, 2H), 6.51 (d, J = 8.1 Hz, 2H), 6.56 (d, J = 8.1 Hz, 1H), 8.58 (s, 1H), 9.15 (s, 1H), 14.30 (br s, 1H)

(44) TABLE-US-00019 TABLE 19 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-60 0.10-0.20 (m, 2H), 0.45-0.55 (m, 2H), 0.88 (m, 1H), 1.81 (t, J = 7.2 Hz, 3H), 1.20-3.75 (m, 20H), 4.07 (q, J = 7.2 Hz, 2H), 5.13 (s, 1H), 5.21 (br s, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 9.21b (br s, 1H) I-61 00 0.11-0.39 (m, 2H), 0.53-0.70 (m, 2H), 0.95 (m, 1H), 1.10-1.20 (m, 3H), 1.66-1.73 (m, 1H), 1.82-3.99(m, 24H), 4.90 (s, 1H), 6.32 (br, s, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.68-6.73 (m, 1H), 14.03 (br, s, 1H) I-62 01 0.10-0.18 (m, 2H), 0.42-0.56 (m, 2H), 0.85 (m, 1H), 1.03 (d, J = 6.9 Hz, 3H), 1.41 (m, 1H), 1.88 (d, J = 15.6 Hz, 1H), 2.04- 2.31 (m, 4H), 2.42-2.62 (m, 6H), 3.04 (d, J = 18.0 Hz, 1H), 3.17-3.35 (m, 7H), 3.87 (m, 1H), 4.64 (t, J = 5.7 Hz, 1H), 4.72 (s, 1H), 6.50-6.57 (m, 2H), 7.27 (d, J = 8.1 Hz, 1H), 9.13 (s, 1H), 14.45 (s, 1H) I-63 02 0.13 (d, J = 4.2 Hz, 2H), 0.43-0.55 (m, 2H), 0.85 (m, 1H), 0.98 (d, J = 6.9 Hz, 3H), 1.41 (d, J = 10.8 Hz, 1H), 1.89 (d, J = 15.9 Hz, 1H), 2.04-2.32 (m, 4H), 2.43-2.63 (m, 3H), 3.04 (d, J = 18.3 Hz, 1H), 3.19-3.40 (m, 11H), 3.86 (m, 1H), 4.72 (s, 1H), 6.50-6.58 (m, 2H), 7.24 (m, 1H), 9.14 (s, 1H), 14.41 (br, s, 1H)

(45) TABLE-US-00020 TABLE 20 Compound No. Chemical structure NMR 1H-NMR (d6-DMSO) ) I-64 03 0.13 (d, J = 4.8 Hz, 2H), 0.43-0.55 (m, 2H), 0.85 (m, 1H), 1.41 (d, J = 12.3 Hz, 1H), 1.92 (d, J = 16.2 Hz, 1H), 2.06- 2.32 (m, 4H), 2.43-2.61 (m, 3H), 3.04 (d, J = 18.3 Hz, 1H), 3.20 (d, J = 6.6 Hz, 1H), 3.33-3.44 (m, 4H), 3.82 (m, 1H), 4.59 (t, J = 5.7 Hz, 1H), 4.68 (t, J = 5.7 Hz, 1H), 4.73 (s, 2H), 6.50-6.59 (m, 2H), 7.14 (br, s, 1H), 9.14 (s, 1H), 14.33 (br, s, 1H) I-65 04 0.17-0.18 (m, 2H), 0.51-0.53 (m, 2H), 0.92 (m, 1H), 1.34 (m, 1H), 1.35 (br s, 9H), 1.71-3.49 (m, 14H), 3.95- 4.20 (m, 3H), 5.10 (br, 1H), 5.26 (br, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 7.10 (br, 1H), 8.35 (s, 1H), 9.24 (s, 1H). I-66 05 0.41 (m, 1H), 0.50 (m, 1H), 0.60 (m, 1H), 0.69 (m, 1H), 1.08 (m, 1H), 1.56 (m, 1H), 1.76-4.29 (m, 17H), 5.19 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 8.14 (br, 1H), 8.20 (br, 1H), 8.98 (br, 1H). I-67 06 0.41 (m, 1H), 0.50 (m, 1H), 0.59 (m, 1H), 0.69 (m, 1H), 1.09 (m, 1H), 1.30-4.29 (m, 18H), 5.19 (s, 1H), 5.75 (br, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 8.21 (br, 1H), 8.26 (br, 1H), 8.99 (br, 1H).

(46) TABLE-US-00021 TABLE 21 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-68 07 0.17-0.18 (m, 2H), 0.51-0.53 (m, 2H), 0.92 (m, 1H), 1.34 (m, 1H), 1.43 (br s, 9H), 1.71-2.03 (m, 5H), 2.18-2.74 (m, 4H), 2.92-3.69 (m, 5H), 3.95-4.20 (m, 2H), 5.07 (s, 1H), 5.26 (br, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 7.20 (br, 1H), 9.25 (s, 1H). I-69 08 0.10-0.26 (m, 2H), 0.42-0.60 (m, 2H), 0.90 (m, 1H), 1.47 (d, J = 10.5 Hz, 1H), 1.90-3.40 (m, 10H), 3.84 (s, 3H), 4.81 (br s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.80 (br s, 1H), 8.08 (br s, 1H), 9.18 (br s, 1H), 11.60 (br s, 1H) I-70 09 0.10-0.20 (m, 2H), 0.40-0.55 (m, 2H), 0.88 (m, 1H), 1.30- 4.35 (m, 20H), 5.13 (s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 9.20 (br s, 1H) I-71 0 0.25-0.45 (m, 2H), 0.45-0.70 (m, 2H), 0.97 (m, 1H), 1.64 (d, J = 11.1 Hz, 1H), 2.00-3.40(m, 10H), 4.07 (br s, 1H), 4.97 (s, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 5.4 Hz, 1H), 7.80 (d, J = 5.4 Hz, 1H), 9.44 (br s, 1H), 13.40 (br s, 1H) I-72 0.14 (d, J = 4.5 Hz, 2H), 0.40-0.58 (m, 2H), 0.79-0.92 (m, 13H), 1.25 (br, s, 1H), 1.41 (m, 1H), 1.907 (s, 1H), 2.11- 2.64 (m, 8H), 3.03 (m, 1H), 3.21-3.77 (m, 8H), 3.03 (m, 1H) 3.21-3.77 (m, 4H), 4.53 (br, s, 1H), 4.72-4.80 (m, 2H), 6.50-6.58 (m, 2H), 6.95-7.22 (m, 2H), 9.13 (s, 1H), 14.39 (br, s, 1H)

(47) TABLE-US-00022 TABLE 22 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-73 0.14 (d, J = 4.5 Hz, 2H), 0.40-0.58 (m, 3H), 0.74-1.01 (m, 10H), 1.25-1.61 (m, 4H), 1.88 (m, 1H), 2.06-2.62 (m, 8H), 3.03 (m, 1H), 3.21 (d, J = 6.0 Hz, 1H), 3.45 (t, J = 5.4 Hz, 2H) 3.68 (m, 1H), 4.57 (m, 1H), 4.72 (s, 1H), 4.76 (br, s, 1H), 6.51-6.58 (m, 2H), 7.14-7.27 (m, 2H), 9.15 (s, 1H), 14.44 (s, 1H) I-74 0.16-0.18 (m, 2H), 0.52 (br d, J = 7.6 Hz, 2H), 0.92(m, 1H), 1.35 (d, J = 11.2 Hz, 1H), 1.72-3.48 (m, 16H), 4.11-4.29 (m, 3H), 4.73-5.25 (m, 2H), 6.57 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 9.23 (s, 1H), 11.16 (s, 1H). I-75 0.14-0.15 (m, 2H), 0.43-0.57 (m, 2H), 0.87 (m, 1H), 1.44 (d, J = 11.2 Hz, 1H), 1.97 (d, J = 15.6 Hz, 1H), 2.08-3.22 (m, 10H), 4.15-4.48 (m, 2H), 4.76 (s, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 7.23-7.29 (m, 2H), 7.75 (m, 1H), 8.48-8.54 (m, 2H). I-76 0.16-0.71 (m, 2H), 0.50-0.56 (m, 2H), 0.89 (m, 1H), 1.43 (br d, 1H), 1.97 (d, J = 15.6 Hz, 1H), 2.11-3.21 (m, 10H), 4.30-4.46 (m, 2H), 4.77 (s, 1H), 6.56 (d, J = 8.0 Hz, 1H), 7.29 (s, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 8.42 (br, 1H), 9.17 (br, 1H), 14.19 (s, 1H).

(48) TABLE-US-00023 TABLE 23 Compound No. Chemical structure NMR (1H-NMR (d6-DMSO) ) I-77 0.10-0.25 (m, 2H), 0.44-0.60 (m, 2H), 0.88 (m, 1H), 1.45 (d, 2 = 11.1 Hz, 1H), 1.70-3.40 (m, 13H), 4.78 (s, 1H), 4.81 (s, 1H), 6.53 (d, 2 = 8.1 Hz, 1H), 6.58 (d, 2 = 8.1 Hz, 1H), 7.46 (d, 2 = 9.0 Hz, 2H), 7.48 (d, 2 = 9.0 Hz, 2H), 9.15 (s, 1H), 9.25 (s, 1H), 9.88 (s, 1H), 14.00 (br s, 1H) I-78 0.10-0.25 (m, 2H), 0.44-0.60 (m, 2H), 0.89 (m, 1H), 1.17 (t, 2 = 7.2 Hz, 3H), 1.45 (d, 2 = 11.4 Hz, 1H), 1.70-3.40 (m, 10H), 3.60 (s, 2H), 4.06 (q, 2 = 7.2 Hz, 2H), 4.78 (s, 1H), 4.83 (s, 1H), 6.58 (d, 2 = 8.1 Hz, 1H), 7.17 (d, 2 = 8.7 Hz, 2H), 7.45 (d, 2 = 8.7 Hz, 2H), 9.16 (s, 1H), 9.26 (s, 1H), 13.95 (br s, 1H) I-79 0.12-0.30 (m, 2H), 0.44-0.62 (m, 2H), 0.90 (m, 1H), 1.48 (d, J = 11.4 Hz, 1H), 1.70-3.40 (m, 10H), 3.51 (s, 2H), 4.81 (s, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 9.20 (s, 1H), 9.40 (br s, 1H), 14.00 (br s, 1H) I-80 0.10-0.17 (m, 2H), 0.46-0.52 (m, 2H), 0.86 (m, 1H), 1.41 (d, J = 13.2 Hz, 1H), 1.87 (m, 1H), 2.09-2.64 (m, 8H), 3.00-3.50 (m, 15H), 4.57 (m, 1H), 4.73 (br, s, 2H), 6.50-6.57 (m, 2H), 7.73 (br, s, 1H), 9.14 (s, 1H), 14.38 (br, s, 1H) I-81 0 0.30-0.50 (m, 2H), 0.50-0.70 (m, 2H) 1.05 (m, 1H), 1.50-3.40 (m, 11H), 4.58 (s, 1H), 5.39 (s, 1H), 6.52 (d, J = 6.0 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 6.84 (br s, 1H), 7.26 (m, 1H), 7.38 (m, 1H), 9.15 (m, 1H)

(49) TABLE-US-00024 TABLE 24 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) ) I-82 1H-NMR (CDCl3 + CD3OD) d: 0.17 (brs, 2H), 0.59 (brs, 2H), 0.89 (brs, 1H), 1.71 (d, J = 10.8 Hz, 1H), 2.17 (d.d, J = 17.1 & 1.8 Hz, 1H), 2.22- 2.57 (m, 4H), 2.60-2.84 (m, 3H), 3.06 (d, J = 15.6 Hz, 1H), 3.24 (brs, 1H), 4.07 (s, 3H), 5.31 (s, 1H), 6.56 (d, J = 8.4 Hz, 1 Hz, 1H), 7.02-7.10 (m, 1H), 7.26-7.32 (m, 2H), 7.39 (d.d, J = 8.4 & 0.9 Hz, 2H), 9.61 (s, 1H). I-83 1H-NMR (CDCl3 + CD3OD) d: 0.15 (brs, 2H), 0.58 (brs, 2H), 0.88 (brs, 1H), 1.49 (t, J = 6.9 Hz, 3H), 1.68 (d, J = 9.9 Hz, 1H). 2.15 (d.d, J = 17.1 & 1.5 Hz, 1H), 2.28 (brs, 2H), 2.39 (brs, 2H). 2.60-2.80 (m, 3H), 3.06 (d, J = 18.3 Hz, 1H), 3.26 (brs, 1H), 4.29 (q, J = 6.9 Hz, 1H), 4.48 (q, J = 6.9 Hz, 1H), 5.27 (s, 1H), 6.56 (d, J = 7.8 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 7.03-7.09 (m, 1H), 7.26-7.31 (m, 2H), 7.50 (d.d, J = 8.7 & 0.9 Hz, 2H). I-84 1H-NMR (CDCl3 + CD3OD) d: 0.16 (brs, 2H), 0.57 (brs, 2H), 0.86 (brs, 1H), 1.13 (d, J = 6.6 Hz, 3H), 1.14 (d, J = 6.6 Hz, 3H), 1.39 (t, J = 6.9 Hz, 3H), 1.66 (d, J = 9.0 Hz, 1H), 2.08 (d.d, J = 17.1 & 1.5 Hz, 1H), 2.21 (brs, 2H), 2.38 (brs, 2H), 2.58-2.77 (m, 3H), 3.03 (d, J = 18.6 Hz, 1H), 3.21 (brs, 1H), 4.03 (quint, J = 6.6 Hz, 1H), 4.20 (q, J = 6.9 Hz, 1H), 4.40 (q, J = 6.9 Hz, 1H), 5.19 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H).

(50) TABLE-US-00025 TABLE 25 Compound NMR No. Chemical structure (1H-NMR (d6-DMSO) ) I-85 1H-NMR (CDCl3 + CD3OD) d: 0.14 (brs, 2 H), 0.56 (brs, 2 H), 0.86 (brs, 1 H), 1.14 (d, J = 6.6 Hz, 3 H), 1.15 (d, J = 6.6 Hz, 3 H), 1.32 (d, J = 4.8 Hz, 1 H), 1.34 (d, J = 4.8 Hz, 3 H), 1.64 (d, J = 9.9 Hz, 1 H), 2.10 (d.d, J = 17.1 & 1.5 Hz, 1 H), 2.27 (brs, 2 H), 2.39 (brs, 2 H), 2.55-2.77 (m, 3 H), 3.04 (d, J = 18.3 Hz, 1 H), 3.22 (brs, 1 H), 4.03 (quint, J = 6.6 Hz, 1 H), 4.81 (quint., J = 6.0 Hz, 1 H), 5.10 (s, 1 H), 6.54 (d, J = 8.4 Hz, 1 H), 6.67 (d, J = 8.4 Hz, H), 7.76 (d, J = 6.9 Hz, 1 H). I-86 1H-NMR CDCl3 + CD3OD) d: 0.16 (brs, 2 H), 0.568 (brs, 2 H), 0.87 (brs, 1 H), 1.67 (d, J = 9.9 Hz, 1 H), 2.14 (d.d, J = 18.3 & 1.2 Hz, 1 H), 2.27 (brs, 2 H), 2.41 (brs, 2 H), 3.05 (d, J = 18.6 Hz, 1 H), 3.25 (brd, J = 4.5 Hz, 1 H), 3.92 (s, 1 H), 4.46 (d, J = 5.7 Hz, 2 H), 5.23 (s, 1 H), 6.54 (d, J = 8.1 Hz, 1 H), 6.64 (d, J = 8.1 Hz, 1 H), 7.20-7.36 (m, 5 H), 8.03 (bit, J = 5.7 Hz, 1 H). I-87 1H-NMR (CDCl3 + CD3OD) d: 0.26 (brs, 2 H), 0.63 (brs, 2 H), 0.94 brs, 1 H), 1.72 (brd, J = 9.0 Hz, 1 H), 2.09-2.93 (m, 8 H), 3.15 (d, J = 18.9 Hz, 1 H), 4.97 (s, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 6.70 (d, J = 8.1 Hz, 1H), 7.04-7.08 (m, 1 H), 7.69-7.75 (m, 1 H), 8.13 (d, J = 14.0 Hz, 2 H), 8.23 (d, J = 3.9 Hz, 1 H).

(51) TABLE-US-00026 TABLE 26 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-89 m/z 462 [M + H].sup.+ 0.94 min I-90 m/z 511 [M + H].sup.+ 0.63 min I-91 m/z 500 [M + H].sup.+ 0.44 min I-92 0 m/z 462 [M + H].sup.+ 0.44 min I-93 m/z 487 [M + H].sup.+ 0.50 min

(52) TABLE-US-00027 TABLE 27 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-94 m/z 540 [M + H].sup.+ 1.07 min I-95 m/z 537 [M + H].sup.+ 1.12 min I-96 m/z 581 [M + H].sup.+ 1.15 min I-97 m/z 512 [M + H].sup.+ 0.50 min I-98 m/z 531 [M + H].sup.+ 0.50 min

(53) TABLE-US-00028 TABLE 28 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-99 m/z 537 [M + H].sup.+ 1.17 min I-100 m/z 581 [M + H].sup.+ 1.15 min I-101 m/z 581 [M + H].sup.+ 1.03 min I-102 0 m/z 538 [M + H].sup.+ 0.85 min I-103 m/z 540 [M + H].sup.+ 1.05 min

(54) TABLE-US-00029 TABLE 29 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-104 m/z 581 [M + H].sup.+ 1.12 min I-105 m/z 538 [M + H].sup.+ 0.90 min I-106 m/z 537 [M + H].sup.+ 1.05 min I-107 m/z 581 [M + H].sup.+ 1.09 min

(55) TABLE-US-00030 TABLE 30 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-108 m/z 581 [M + H].sup.+ 1.03 min I-109 m/z 488 [M + H].sup.+ 0.50 min I-110 m/z 518 [M + H].sup.+ 0.50 min I-111 m/z 518 [M + H].sup.+ 0.56 min I-112 0 m/z 519 [M + H].sup.+ 0.50 min

(56) TABLE-US-00031 TABLE 31 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-113 m/z 511 [M + H].sup.+ 0.50 min I-114 m/z 486 [M + H].sup.+ 0.57 min I-115 m/z 462 [M + H].sup.+ 0.44 min I-116 m/z 497 [M + H].sup.+ 0.63 min I-117 m/z 513 [M + H].sup.+ 0.69 min

(57) TABLE-US-00032 TABLE 32 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-118 m/z 493 [M + H].sup.+ 1.06 min I-119 m/z 469 [M + H].sup.+ 0.44 min I-120 m/z 538 [M + H].sup.+ 0.94 min I-121 m/z 559 [M + H].sup.+ 0.69 min I-122 0 m/z 559 [M + H].sup.+ 0.69 min

(58) TABLE-US-00033 TABLE 33 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-123 m/z 555 [M + H].sup.+ 0.56 min I-124 m/z 543 [M + H].sup.+ 0.63 min I-125 m/z 425 [M + H].sup.+ 0.50 min I-126 m/z 525 [M + H].sup.+ 0.56 min I-127 (CDCl3 + CD3OD) d: 0.10-0.21 (m, 2 H), 0.48-0.63 (m, 2 H), 0.78-0.94 (m, 1 H), 1.67 (d, J = 9.6 Hz, 1 H), 2.10-2.50 (m, 6 H), 2.57-2.80 (m, 2 H), 3.06 (d, J = 18.6 Hz, 1 H), 3.27 (brs, 1 H), 5.10 (d, J = 1.7 Hz, 1 H), 6.31-6.40 (m, 1 H), 6.53 (d, J = 8.1 Hz, 1 H), 6.65 (d, J = 8.1 Hz, 1 H), 7.02-7.12 (m, 1 H), 7.22-7.34 (m, 2 H), 7.44-7.56 (m, 2 H).

(59) TABLE-US-00034 TABLE 34 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-128 m/z 553 [M + H].sup.+ 0.94 min I-129 m/z 559 [M + H].sup.+ 0.63 min I-130 m/z 529 [M + H].sup.+ 0.75 min I-131 m/z 497 [M + H].sup.+ 0.63 min I-132 0 m/z 529 [M + H].sup.+ 0.88 min

(60) TABLE-US-00035 TABLE 35 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-133 m/z 511 [M + H].sup.+ 0.97 min 0.12-0.16 (m, 2 H), 0.46-0.52 (m, 2 H), 0.86 (m, 1 H), 1.42 (d, J = 10.5 Hz, 1 H), 1.86 (d, J = 15.6 Hz, 1 H), 2.06-2.65 (m, 15 H), 3.05 (d, J = 18.3 Hz, 1 H), 3.26 (d, J = 5.9 Hz, 1 H), 3.55 (s, 3 H), 4.73 (s 1 H), 6.52 (d, J = 8.1 Hz, 1 H), 6.58 (d, J = 8.1 Hz, 1 H), 7.76 (brs, 1 H), 9.31 (brs, 1 H), 13.8 (brs, 1 H) I-134 m/z 498 [M + H].sup.+ 0.96 min 0.13-0.16 (m, 2 H), 0.48-0.54 (m, 2 H), 0.87 (m, 1 H), 1.43 (d, J = 10.5 Hz, 1 H), 1.86 (d, J = 15.6 Hz, 1 H), 2.06-2.67 (m, 15 H), 3.06 (d, J = 18.6 Hz, 1 H), 3.27 (d, J = 6.0 Hz, 1 H), 4.73 (s 1 H), 6.53 (d, J = 8.1 Hz, 1 H), 6.58 (d, J = 8.1 Hz, 1 H), 7.72 (brs, 1 H), 9.20 (brs, 1 H), 14.1 (brs, 1 H) I-135 m/z 483 [M + H].sup.+ 0.87 min 0.12-0.14 (m, 2 H), 0.46-0.51 (m, 2 H), 0.85 (m, 1 H), 1.06-1.09 (m, 2 H), 1.35-1.36 (m, 2 H), 1.41 (d, J = 11.7 Hz, 1 H), 1.86 (d, J = 15.6 Hz, 1 H), 2.17-2.61 (m, 7 H), 3.03 (d, J = 18.3 Hz, 1 H), 3.17 (d, J = 6.0 Hz, 1 H), 3.56 (s, 3 H), 4.74 (s, 1 H), 4.77 (brs, 1 H), 6.51 (d, J = 8.1 Hz, 1 H), 6.56 (d, J = 8.1 Hz, 1 H), 9.17 (brs, 1 H), 14.1 (brs, 1 H) I-136 m/z 469 [M + H].sup.+ 0.89 min 0.12-0.16 (m, 2 H), 0.43-0.51 (m, 2 H), 0.85 (m, 1 H), 1.06-1.12 (m, 2 H), 1.35-1.36 (m, 2 H), 1.42 (d, J = 11.7 Hz, 1 H), 1.86 (d, J = 15.6 Hz, 1 H), 2.06-2.63 (m, 7 H), 3.02 (d, J = 18.3 Hz, 1 H), 3.13 (d, J = 5.4 Hz, 1 H), 4.76 (s 1 H), 4.77 (brs, 1 H), 6.52 (d, J = 8.1 Hz, 1 H), 6.56 (d, J = 8.1 Hz, 1 H), 9.18 (brs, 1 H), 14.1 (brs, 1 H)

(61) TABLE-US-00036 TABLE 36 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-137 m/z 539 [M + H].sup.+ 0.50 min I-138 m/z 466 [M + H].sup.+ 0.57 min I-139 m/z 486 [M + H].sup.+ 0.44 min I-140 m/z 520 [M + H].sup.+ 0.56 min I-141 m/z 510 [M + H].sup.+ 0.75 min

(62) TABLE-US-00037 TABLE 37 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-142 0 m/z 521 [M + H].sup.+ 0.50 min I-143 m/z 553 [M + H].sup.+ 0.88 min I-144 m/z 494 [M + H].sup.+ 0.57 min I-145 m/z 469 [M + H].sup.+ 0.83 min I-146 m/z 467 [M + H].sup.+ 1.01 min

(63) TABLE-US-00038 TABLE 38 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-147 m/z 467 [M + H].sup.+ 1.00 min I-148 m/z 559 [M + H].sup.+ 1.16 min** I-149 m/z 598 [M + H].sup.+ 1.34 min** I-150 m/z 514 [M + H].sup.+ 0.50 min I-151 m/z 538 [M + H].sup.+ 0.63 min

(64) TABLE-US-00039 TABLE 39 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-152 0 m/z 494 [M + H].sup.+ 0.56 min I-153 m/z 465 [M + H].sup.+ 0.90 min I-154 m/z 465 [M + H].sup.+ 0.96 min I-155 m/z 544 [M + H].sup.+ 1.00 min I-156 m/z 483 [M + H].sup.+ 0.35 min

(65) TABLE-US-00040 TABLE 40 Com- NMR pound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-157 m/z 510 [M + H].sup.+ 0.96 min 0.11-0.14 (m, 2 H), 0.46-0.50 (m, 2 H), 0.83 (m, 1 H), 0.87 (t, J = 7.2 Hz, 1 H), 0.99 (d, J = 4.2 Hz, 3 H), 1.01 (d, J = 4.2 Hz, 3 H), 1.08-1.43 (m, 5 H), 1.95 (d, J = 17.1 Hz, 1 H), 2.11-2.65 (m, 7 H), 2.96-3.16 (m, 4 H), 3.78 (q, J = 7.5 Hz, 1 H), 4.78 (brs, 1 H), 5.21 (s, 1 H), 6.49 (d, J = 8.1 Hz, 1 H), 6.55 (d, J = 8.1 Hz, 1 H), 7.41 (t, J = 5.1 Hz, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 9.02 (brs, 1 H) I-158 m/z 496 [M + H].sup.+ 0.93 min 0.11-0.13 (m, 2 H), 0.46-0.50 (m, 2 H), 0.85 (m, 1 H), 1.01 (d, J = 4.1 Hz, 3 H), 1.02 (d, J = 4.2 Hz, 3 H), 1.07 (d, J = 4.0 Hz, 3 H), 1.09 (d, J = 4.0 Hz, 3 H), 1.40 (d, J = 11.1 Hz, 1 H), 1.95 (d, J = 17.1 Hz, 1 H), 2.09-2.63 (m, 7 H), 2.98 (d J = 18.1 Hz, 1 H), 3.13 (d, J = 5.4 Hz, 1 H), 3.82 (q, J = 6.6 Hz, 1 H), 3.88 (q, J = 6.9 Hz, 1 H), 5.24 (brs, 1 H), 5.76 (s, 1 H), 6.50 (d, J = 7.5 Hz, 1 H), 6.55 (d, J = 7.5 Hz, 1 H), 7.20 (d, J = 7.2 Hz, 1 H), 7.54 (d, J = 6.9 Hz, 1 H), 9.01 (brs, 1 H) I-159 m/z 536 [M + H].sup.+ 0.95 min 0.11-0.13 (m, 2 H), 0.46-0.50 (m, 2 H), 0.83 (m, 1 H), 0.99 (d, J = 3.0 Hz, 3 H), 1.01 (d, J = 3.0 Hz, 3 H), 1.15-1.38 (m, 6 H), 1.40 (d, J = 11.1 Hz, 1 H), 1.52-1.80 (m, 4 H), 1.97 (d, J = 17.1 Hz, 1 H), 2.09-2.65 (m, 7 H), 2.98 (d, J = 18.6 Hz, 1 H), 3.13 (d, J = 5.7 Hz, 1 H), 3.58 (m, 1 H), 3.79 (q, J = 6.9 Hz, 1 H), 5.23 (s, 1 H), 6.50 (d, J = 7.8 Hz, 1 H), 6.55 (d, J = 7.8 Hz, 1 H), 7.17 (d, J = 7.8 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 9.00 (brs, 1 H)

(66) TABLE-US-00041 TABLE 41 Com- NMR pound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-160 m/z 522 [M + H].sup.+ 1.04 min 0.12-0.13 (m, 2 H), 0.46-0.51 (m, 2 H), 0.85 (m, 1 H), 0.99 (d, J = 3.3 Hz, 3 H), 1.01 (d, J = 3.3 Hz, 3 H), 1.15-1.49 (m, 7 H), 1.91 (d, J = 16.5 Hz, 1 H), 2.08-2.65 (m, 7 H), 2.98 (d, J = 17.5 Hz, 1 H), 3.12 (d, J = 5.7 Hz, 1 H), 3.16-3.34 (m, 4 H), 3.79 (q, J = 6.9 Hz, 1 H), 4.76 (brs, 1 H), 5.01 (s, 1 H), 6.54 (d, J = 7.8 Hz, 1 H), 6.58 (d, J = 7.8 Hz, 1 H), 7.19 (d, J = 7.5 Hz, 1 H), 9.01 (brs, 1 H) I-161 m/z 524 [M + H].sup.+ 0.92 min 0.12-0.14 (m, 2 H), 0.46-0.51 (m, 2 H), 0.86 (m, 1 H), 0.99 (d, J = 3.3 Hz, 3 H), 1.01 (d, J = 3.3 Hz, 3 H), 1.41 (d, J= 11.1 Hz, 1 H), 1.95 (d, J = 17.1 Hz, 1 H), 2.08-2.67 (m, 11 H), 2.98 (d, J = 17.5 Hz, 1 H), 3.12 (d, J = 5.7 Hz, 1 H), 3.49- 3.60 (m, 4 H), 3.82 (q, J = 6.9 Hz, 1 H), 4.78 (brs, 1 H), 5.01 (s, 1 H), 6.54 (d, J = 8.1 Hz, 1 H), 6.58 (d, J = 8.1 Hz, 1 H), 7.38 (d, J = 7.8 Hz, 1 H), 9.13 (brs, 1 H) I-162 00 m/z 530 [M + H].sup.+ 0.94 min 0.13-0.14 (m, 2 H), 0.47-0.51 (m, 2 H), 0.83 (m, 1 H), 0.84 (d, J = 6.6 Hz, 3 H), 0.93 (d, J = 6.6 Hz, 3 H), 1.44 (d, J = 10.5 Hz, 1 H), 2.02 (d, J = 16.8 Hz, 1 H), 2.11-2.65 (m, 7 H), 3.03 (d, J = 18.6 Hz, 1 H), 3.17 (d, J= 5.7 Hz, 1 H), 3.58 (m, 1 H), 3.74 (q, J = 6.3 Hz, 1 H), 4.86 (brs, 1 H), 5.39 (s, 1 H), 6.52 (d, J = 8.1 Hz, 1 H), 6.57 (d, J = 8.1 Hz, 1 H), 7.03 (t, J = 7.2 Hz, 1 H), 7.26 (t, J = 7.8 Hz, 2 H), 7.56 (d, J = 7.8 Hz, 1 H), 7.64 (d, J = 8.1 Hz, 2 H), 9.01 (brs, 1 H), 9.70 (brs, 1 H)

(67) TABLE-US-00042 TABLE 42 Com- NMR pound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-163 01 m/z 445 [M + H].sup.+ 0.83 min I-164 02 0.14-0.22 (m, 2 H), 0.48-0.61 (m, 2 H), 0.91 (m, 1 H), 1.12 (d, J = 6.6 Hz, 6 H), 1.53-1.66 (m, 1 H), 2.15-2.22 (m, 2 H), 2.23-2.30 (m, 2 H), 2.35-2.49 (m, 2 H), 2.70 (d.d, J = 18.9 & 6.6 Hz, 2 H), 3.13 (d, J = 18.9 Hz, 1 H), 3.27 (d, J = 6.6 Hz, 1 H), 3.98 (quintet, J = 6.6 Hz, 1 H), 4.99-5.04 (m, 1 H), 6.32-6.36 (m, 1 H), 6.53 (d, J = 8.4 Hz, 1 H), 6.58 (d, J = 8.4 Hz, 1 H). I-165 03 m/z 543 [M + H].sup.+ 0.63 min I-166 04 m/z 446 [M + H].sup.+ 0.94 min

(68) TABLE-US-00043 TABLE 43 Com- NMR pound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-167 05 (CD3OD) d: 0.12-0.22 (m, 2 H), 0.48- 0.63 (m, 2 H), 0.82-1.00 (m, 1 H), 1.63 (d, J= 8.1 Hz, 1 H), 2.10-2.50 (m, 7 H), 2.72 (d.d, J= 18.6 & 6.6 Hz, 2 H), 3.15 (d, J = 18.6 Hz, 1 H), 5.10 (brs, 1 H), 6.50-6.65 (m, 3 H), 7.67 (d.d, J = 4.8 & 1.5 Hz, 1 H), 8.36 (d.d, J = 4.8 & 1.5 Hz, 1 H). I-168 06 m/z 582 [M + H].sup.+ 0.90 min I-169 07 m/z 541 [M + H].sup.+ 1.15 min I-170 08 m/z 480 [M + H].sup.+ 0.37 min I-171 09 m/z 509 [M + H].sup.+ 0.75 min

(69) TABLE-US-00044 TABLE 44 Com- NMR pound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-172 0 m/z 505 [M + H].sup.+ 0.97 min 0.11-0.13 (m, 2 H), 0.46-0.50 (m, 2 H), 0.84 (m, 1 H), 0.98 (d, J = 3.1 Hz, 3 H), 1.01 (d, J = 3.1 Hz, 3 H), 1.37 (d, J = 10.8 Hz, 1 H), 2.08 (d, J = 17.4 Hz, 1 H), 2.11- 2.24 (m, 2 H), 2.35 (d, J = 6.6 Hz, 1 H), 2.51-2.63 (m, 2 H), 3.01 (d, J = 18.3 Hz, 1 H), 3.13 (d, J = 5.7 Hz, 1 H), 3.54 (s, 3 H), 3.86 (q, J = 7.2 Hz, 1 H), 4.79 (brs, 1 H), 4.98 (brs, 1 H), 5.76 (s, 1 H), 6.54 (d, J = 7.8 Hz, 1 H), 6.59 (d, J = 7.8 Hz, 1 H), 7.35 (d, J = 7.5 Hz, 1 H), 9.16 (brs, 1 H) I-173 m/z 426 [M + H].sup.+ 0.90 min 0.12-0.14 (m, 2 H), 0.46-0.52 (m, 2 H), 0.85 (m, 1 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 1.38 (d, J = 10.2 Hz, 1 H), 1.86 (d, J = 15.0 Hz, 1 H), 2.02 (d, J = 15.0 Hz, 1 H), 2.10-2.17 (m, 2 H), 2.28 (dd, J = 6.9, 6.9 Hz, 1 H), 2.43 (dd, J = 6.9, 8.4 Hz, 1 H), 2.54-2.62 (m, 2 H), 3.01 (d, J = 18.3 Hz, 1 H), 3.17 (d, J = 5.7 Hz, 1H), 3.58 (m, 1 H), 3.88 (q, J = 7.2 Hz, 1 H), 4.62 (brs, 1 H), 4.68 (s, 1 H), 6.47 (d, J = 8.1 Hz, 1 H), 6.55 (d, J = 8.1 Hz, 1 H), 6.94 (brs, 1 H), 9.06 (brs, 1 H) I-174 (CD3OD) d: 0.10-0.25 (m, 2 H), 0.48-0.63 (m, 2 H), 0.83-1.00 (m, 1 H), 1.55 (d, J = 8.1 Hz, 1 H), 2.01 (d, J = 15.6 Hz, 1 H), 2.22-2.57 (m, 6 H), 2.70 (d.d, J = 18.3 & 7.2 Hz, 2 H), 3.12 (d, J = 18.3 Hz, 1 H), 4.67 (s, 1 H), 6.44-6.62 (m, 3 H), 7.54 (d.d, J = 9.6 & 3.6 Hz, 1 H), 8.00 (d, J = 3.6 Hz, 1 H).

(70) TABLE-US-00045 TABLE 45 Com- NMR pound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-175 m/z 458 [M + H]+ 0.86 min I-176 ESI: m/z 458 [M + H].sup.+ I-177 m/z 460 [M + H].sup.+ 1.20 min 0.13-0.17 (m, 2 H), 0.47-0.50 (m, 2 H), 0.87 (m, 1 H), 1.41 (d, J = 10.5 Hz, 1 H), 2.07 (d, J = 15.0 Hz, 1 H), 2.10-2.25 (m, 2 H), 2.32 (dd, J = 5.7, 6.9 Hz, 1 H), 2.45 (dd, J = 5.7, 6.0 Hz, 1 H), 2.63 (dt, J = 6.3, 11.7, 2 H), 3.05 (d, J = 18.3 Hz, 1 H), 3.19 (d, J= 6.0 Hz, 1 H), 4.67 (brs, 1 H), 4.75 (s, 1 H), 6.51 (d, J = 8.1 Hz, 1 H), 6.57 (d, J = 8.1 Hz, 1 H), 6.96 (t, J = 7.5 Hz, 1 H), 7.21 (t, J = 8.4 Hz, 1 H), 7.25 (d, J = 3.6 Hz, 2 H), 7.52 (d, J = 7.5 Hz, 2 H), 8.38 (brs, 1 H), 9.07 (brs, 1 H)

(71) TABLE-US-00046 TABLE 46 Com- NMR pound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-178 m/z 636 [M + H].sup.+ 1.11 min 0.11-0.13 (m, 2 H), 0.46-0.51 (m, 2 H), 0.86 (m, 1 H), 0.95 (d, J = 6.6 Hz, 6 H), 1.46 (d, J = 11.1 Hz, 1 H), 1.87 (d, J = 18.0 Hz, 1 H), 2.11-2.63 (m, 7 H), 2.25 (s, 3 H), 3.03 (d, J = 17.4 Hz, 1 H), 3.18 (brs, 1 H), 3.84 (q, J = 7.2 Hz, 1 H), 4.71 (brs, 1 H), 5.45 (brs, 1 H), 6.50 (brs, 1 H), 6.57 (brs, 1 H), 7.61-8.19 (m, 4 H), 9.03 (brs, 1 H), 10.7 (brs, 1 H), 12.7 (brs, 1 H) I-179 m/z 581 [M + H].sup.+ 1.06 min 0.11-0.13 (m, 2 H), 0.46-0.51 (m, 2 H), 0.86 (m, 1 H), 0.95 (d, J = 6.6 Hz, 6 H), 1.46 (d, J = 11.1 Hz, 1 H), 1.87 (d, J = 18.0 Hz, 1 H), 2.09 (s, 3 H), 2.11-2.63 (m, 7 H), 3.03 (d, J = 17.4 Hz, 1 H), 3.18 (brs, 1 H), 3.84 (q, J = 7.2 Hz, 1 H), 4.69 (brs, 1 H), 5.45 (brs, 1 H), 6.48 (d, J = 7.2 Hz, 1 H), 6.55 (d, J = 7.2 Hz, 1 H), 7.33 (brd, J = 5.4 Hz, 2 H), 7.54 (brs, 1 H), 7.74 (d, J = 7.5 Hz, 2 H), 9.11 (brs, 1 H), 12.3 (brs, 1 H)

(72) TABLE-US-00047 TABLE 47 Com- NMR pound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-180 m/z 597 [M + H].sup.+ 1.03 min 0.11-0.13 (m, 2 H), 0.46-0.51 (m, 2 H), 0.85 (m, 1 H), 0.95 (d, J = 6.6 Hz, 6 H), 1.46 (d, J = 9.9 Hz, 1 H), 1.87 (d, J = 17.4 Hz, 1 H), 2.11-2.62 (m, 7 H), 3.01 (d, J = 17.7 Hz, 1 H), 3.15 (d, J = 4.6 Hz, 1 H), 3.82 (s, 3 H), 3.83 (q, J = 5.4 Hz, 1 H), 4.67 (brs, 1 H), 5.44 (s, 1 H), 6.49 (d, J = 8.1 Hz, 1 H), 6.55 (d, J = 8.1 Hz, 1 H), 7.04 (d, J = 8.4 Hz, 2 H), 7.52 (brd, J = 9.3 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 2 H), 9.12 (brs, 1 H), 12.2 (brs, 1 H) I-181 m/z 502 [M + H].sup.+ 0.35 min I-182 0 m/z 553 [M + H].sup.+ 0.68 min I-183 m/z 539 [M + H].sup.+ FAB-MS

(73) TABLE-US-00048 TABLE 48 Com- NMR pound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-184 m/z 458 [M + H].sup.+ 0.97 min I-185 m/z 519 [M + H].sup.+ 0.43 min I-186 m/z 519 [M + H].sup.+ 1.67 min** I-187 m/z 539 [M + H].sup.+ 0.50 min

(74) TABLE-US-00049 TABLE 49 Com- NMR pound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-188 m/z 505 [M + H].sup.+ 0.35 min I-189 m/z 505 [M + H].sup.+ 0.42 min I-190 m/z 597 [M + H].sup.+ 0.77 min I-191 m/z 523 [M + H].sup.+ 1.20 min I-192 0 m/z 546 [M + H].sup.+ 1.00 min

(75) TABLE-US-00050 TABLE 50 Com- NMR pound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-193 m/z 580 [M + H].sup.+ 1.09 min I-194 m/z 474 [M + H].sup.+ 0.88 min I-195 m/z 458 [M + H].sup.+ 1.08 min I-196 0.12-0.16 (m, 2 H), 0.46-0.55 (m, 2 H), 0.88 (m, 1 H), 1.43 (d, J = 12.4 Hz, 1 H), 1.65-2.65 (m, 12 H), 2.97-3.70 (m, 6 H), 3.59 (s, 3 H), 4.74 (s 1 H), 6.55 (d, J = 8.0 Hz, 1 H), 6.59 (d, J = 8.0 Hz, 1 H), 7.68 (brs, 1 H), 9.16 (brs, 1 H), 13.5 (brs, 1 H)

(76) TABLE-US-00051 TABLE 51 Com- NMR pound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-197 0.20-0.40 (m, 2 H), 0.46-0.65 (m, 2 H), 0.97 (m, 1 H), 1.54 (d, J = 6.8 Hz, 1 H), 1.80-2.10 (m, 3 H), 2.31-3.69 (m, 15 H), 4.83 (s 1 H), 6.59 (d, J = 8.0 Hz, 1 H), 6.65 (d, J = 8.0 Hz, 1 H), 7.56 (brs, 1 H), 9.29 (brs, 1 H), 13.6 (brs, 1 H) I-198 m/z 533 [M + H].sup.+ 0.95 min 0.11-0.13 (m, 2 H), 0.46-0.52 (m, 2 H), 0.86 (m, 1 H), 1.03 (d, J = 6.3 Hz, 3 H), 1.08 (d, J = 6.3 Hz, 3 H), 1.46 (brd, J = 8.4 Hz, 1 H), 1.94 (d, J = 17.7 Hz, 1 H), 2.71-2.60 (m, 7 H), 2.81 (s, 6 H), 3.04 (d, J = 17.1 Hz, 1 H), 3.18 (brs, 1 H), 3.95 (q, J = 5.4 Hz, 1 H), 4.77 (brs, 1 H), 5.45 (s, 1 H), 6.51 (d, J = 7.5 Hz, 1 H), 6.57 (d, J = 7.5 Hz, 1 H), 7.64 (brs, 1 H), 9.14 (brs, 1 H), 12.2 (brs, 1 H) I-199 m/z 497 [M + H].sup.+ 0.97 min 0.13-0.15 (m, 2 H), 0.48-0.52 (m, 2 H), 0.86 (m, 1 H), 1.41 (d, J = 11.4 Hz, 1 H), 1.85 (t, J = 7.8 Hz, 2 H), 1.93 (d, J = 16.5 Hz, 1 H), 2.07-2.62 (m, 11 H), 3.05 (d, J = 18.3 Hz, 1 H), 3.21 (d, J = 6.0 Hz, 1 H), 3.59 (s, 3 H), 4.72 (s, 1 H), 4.77 (brs, 1 H), 6.53 (d, J = 8.1 Hz, 1 H), 6.57 (d, J = 8.1 Hz, 1 H), 8.26 (brs, 1 H), 9.15 (brs, 1 H), 14.1 (brs, 1 H) I-200 m/z 553 [M + H].sup.+ 0.47 min

(77) TABLE-US-00052 TABLE 52 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-201 m/z 601 [M + H].sup.+ 1.01 min I-202 0 m/z 563 [M + H].sup.+ 0.58 min I-203 m/z 583 [M + H].sup.+ 0.54 min I-204 m/z 539 [M + H].sup.+ 0.33 min I-205 m/z 573 [M + H].sup.+ 0.62 min

(78) TABLE-US-00053 TABLE 53 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-206 m/z 535 [M + H].sup.+ 0.41 min I-207 m/z 484 [M + H].sup.+ 0.32 min I-208 m/z 507 [M + H].sup.+ 1.05 min I-209 m/z 518 [M + H].sup.+ 1.14 min** I-210 m/z 495 [M + H].sup.+ 1.64 min**

(79) TABLE-US-00054 TABLE 54 NMR Compound (1H-NMR No. Chemical structure LC/MS*.sup.1 (d6-DMSO) ) I-211 m/z 503 [M + H].sup.+ 1.33 min** I-212 0 m/z 512 [M + H].sup.+ 1.67 min** I-213 m/z 500 [M + H].sup.+ 1.41 min** I-214 m/z 536 [M + H].sup.+ 1.69 min**

(80) TABLE-US-00055 TABLE 55 Compound NMR No. Chemical structure LC/MS*.sup.1 (1H-NMR (d6-DMSO) ) I-215 m/z 485 [M + H].sup.+ 1.60 min** I-216 m/z 565 [M + H].sup.+ 1.82 min** I-217 m/z 548 [M + H].sup.+ 1.17 min** I-218 m/z 512 [M + H].sup.+ 0.95 min** I-219 m/z 512 [M + H].sup.+ 1.66 min** I-220 m/z 525 [M + H].sup.+ 1.60 min** I-221 m/z 521 [M + H].sup.+ 1.35 min**

(81) TABLE-US-00056 TABLE 56 Compound NMR No. Chemical structure LC/MS*.sup.1 (1H-NMR (d6-DMSO) ) I-222 0 m/z 509 [M + H].sup.+ 1.57 min** I-223 m/z 479 [M + H].sup.+ 1.50 min** I-224 m/z 555 [M + H].sup.+ 1.76 min** I-225 m/z 519 [M + H].sup.+ 1.67 min** I-226 m/z 505 [M + H].sup.+ 1.53 min** I-227 m/z 505 [M + H].sup.+ 1.64 min** I-228 m/z 503 [M + H].sup.+ 1.38 min****

(82) TABLE-US-00057 TABLE 57 Compound NMR No. Chemical structure LC/MS*.sup.1 (1H-NMR (d6-DMSO) ) I-229 m/z 626 [M + H].sup.+ 1.74 min** I-230 m/z 521 [M + H].sup.+ 1.56 min** I-231 m/z 500 [M + H].sup.+ 1.40 min** I-232 0 m/z 630 [M + H].sup.+ 1.72 min** I-233 m/z 501 [M + H].sup.+ 1.25 min** I-234 m/z 505 [M + H].sup.+ 1.46 min** I-235 m/z 515 [M + H].sup.+ 1.56 min**

(83) TABLE-US-00058 TABLE 58 Compound NMR No. Chemical structure LC/MS*.sup.1 (1H-NMR (d6-DMSO) ) I-236 m/z 565 [M + H].sup.+ 1.77 min** I-237 m/z 501 [M + H].sup.+ 1.17 min** I-238 m/z 546 [M + H].sup.+ 1.29 min** I-239 m/z 518 [M + H].sup.+ 1.21 min** I-240 m/z 542 [M + H].sup.+ 1.31 min** I-241 m/z 520 [M + H].sup.+ 1.50 min** I-242 0

(84) TABLE-US-00059 TABLE 59 Compound NMR No. Chemical structure LC/MS*.sup.1 (1H-NMR (d6-DMSO) ) I-243 m/z 493 [M + H].sup.+ 1.05 min I-244 m/z 460 [M + H].sup.+ 1.02 min 0.11-0.13 (m, 2 H), 0.48-0.51 (m, 2 H), 0.87 (m, 1 H), 0.95 (d, J = 6.6 Hz, 6 H), 1.48 (d, J = 11.1 Hz, 1 H), 1.88 (d, J = 18.0 Hz, 1 H), 2.10 (s, 3 H), 2.18-2.57 (m, 7 H), 3.04 (d, J = 16.8 Hz, 1 H), 3.19 (brs, 1 H), 3.78 (q, J = 6.9 Hz, 1 H), 4.68 (brs, 1 H), 5.43 (brs, 1 H), 6.49 (d, J = 6.6 Hz, 1 H), 6.51 (d, J = 6.6 Hz, 1 H), 7.35-7.37 (m, 2 H), 7.54 (brs, 1 H), 7.85 (d, J = 6.9 Hz, 2 H), 9.09 (brs, 1 H), 12.4 (brs, 1 H) I-245 m/z 601 [M + H].sup.+ 0.76 min I-246 m/z 505 [M + H].sup.+ 1.38 min** I-247 m/z 521 [M + H].sup.+ 1.58 min**

(85) TABLE-US-00060 TABLE 60 Com- pound NMR No. Chemical structure LC/MS*.sup.1 (1H-NMR (d6-DMSO) ) I-248 m/z 493 [M + H].sup.+ 1.69 min** I-249 m/z 479 [M + H].sup.+ 1.55 min** I-250 m/z 519 [M + H].sup.+ 1.74 min** I-251 m/z 512 [M + H].sup.+ 0.38 min I-252 0 0.10-0.15 (m, 2 H), 0.34-0.38 (m, 2 H), 0.73 (m, 1 H), 1.26 (d, J = 9.6 Hz, 1 H), 1.93-2.54 (m, 10 H), 2.94 (d, J = 18.4 Hz, 1 H), 3.10 (d, J = 6.0 Hz, 1 H), 3.67 (s, 3 H), 3.72 (s, 3 H), 4.58 (s, 1 H), 4.84 (s,1 H), 6.42 (d, J = 8.0 Hz, 2 H), 6.48 (d, J = 8.0 Hz, 2 H), 6.61 (d, J = 9.3 Hz, 2 H), 6.69 (d, J = 9.2 Hz, 2 H), 7.56 (dd, J = 2.8, 8.8 Hz, 1 H), 7.66 (dd, J = 2.8, 8.8 Hz, 1 H), 8.00 (d, J = 2.4 Hz, 1 H), 8.08 (d, J = 2.0 Hz, 1 H), 8.76 (s, 1 H), 8.97 (s, 1 H), 10.78 (s, 1 H).

(86) TABLE-US-00061 TABLE 61 Compound No. Chemical structure I-253 I-254 I-255 I-256 I-257

(87) TABLE-US-00062 TABLE 62 Com- pound No. Chemical structure I-258 I-259 I-260 I-261 I-262 00

(88) TABLE-US-00063 TABLE 63 Compound No. Chemical structure I-253 01 I-254 02 I-255 03

(89) TABLE-US-00064 TABLE 64 Com- pound No. Chemical structure I-266 04 m/z 457.91 [M + H].sup.+ 0.97 min I-267 05 m/z 457.91 [M + H].sup.+ 0.62 min I-268 06 m/z 457.91 [M + H].sup.+ 0.87 min I-269 07 m/z 473.91 [M + H].sup.+ 0.69 I-270 08 m/z 457.91 [M + H].sup.+ 0.97 min

(90) TABLE-US-00065 TABLE 65 Compound No. Chemical structure LC/MS*.sup.1 I-271 09 m/z 520 [M + H].sup.+ 1.63 min** I-272 0 m/z 513 [M + H].sup.+ 0.45 min I-273 m/z 513 [M + H].sup.+ 0.38 min I-274 m/z 499 [M + H].sup.+ 0.38 min I-275 m/z 548 [M + H].sup.+ 0.38 min

(91) TABLE-US-00066 TABLE 66 Compound No. Chemical structure LC/MS*.sup.1 I-276 m/z 559 [M + H].sup.+ 0.53 min I-277 m/z 610 [M + H].sup.+ 0.46 min I-278 m/z 545 [M + H].sup.+ 0.38 min I-279 m/z 495 [M + H].sup.+ 0.31 min I-280 m/z 545 [M + H].sup.+ 0.97 min

(92) TABLE-US-00067 TABLE 67 Compound No. Chemical structure LC/MS*.sup.1 I-281 m/z 531 [M + H].sup.+ 0.92 min I-282 0 m/z 455 [M + H].sup.+ 0.87 min I-283 m/z 469 [M + H].sup.+ 0.94 min I-284 m/z 571 [M + H].sup.+ 0.68 min I-285 m/z 509 [M + H].sup.+ 0.32 min

(93) TABLE-US-00068 TABLE 68 Compound No. Chemical structure LC/MS*.sup.1 I-286 m/z 471 [M + H].sup.+ 0.32 min I-287 m/z 455 [M + H].sup.+ 0.90 min I-288 m/z 501 [M + H].sup.+ 0.32 min I-289 m/z 584 [M + H].sup.+ 0.46 min (LC/MS conditions of measurements)*.sup.1: Column: Chromolith Flash ROD RP-18e, 25 4.6 mm LD. Flow Rate: 2 ml/min UV Detector: 280 nm Solvent System: [A] = H2O_0.05% HCOOH [B] = MeOH_0.05% HCOOH Gradient: 0 min; 90% [A]_10% [B] 0.2 mm; 90% [A]_10% [B] 1.0 mm; 10% [A]_90% [B] 1.80 mm; 10% [A]_90% [B] Proviso, values with symbol ** follow below conditions of measurement Column: Phenomenex Luna 5 C18(2) 100 A, size 50 4.60 mm Gradient: 10%-100% Acetnitrile linear during 3.0 mm at 3.0 mL/min

TEST EXAMPLE 1

Binding Assay of Opioid 8 Receptor

(94) 1) Method of Preparing Membrane Specimen for Binding Assay

(95) A rat cerebrum (Slc: SD) which had been stored at 80 C. was used. To a cerebrum which had been weighed was added a 20-fold amount of ice-cooled 10 mM Tris-HCl buffer (pH 7.0), and the mixture was homogenized (25000 rpm, 30 seconds) with Histocolon (NITI-ON), and centrifuged at 36600g for 20 minutes. To the resulting pellet was added 15 ml of the same buffer, and the mixture was treated with Histocolon similarly, and centrifuged. This washing work was performed two times. After centrifugation, to the resulting pellet was added 15 mL of a 50 mM Tris-HCl buffer (pH 7.4), and this was treated with Histocolon, and finally resuspended in a 10-fold amount of the same buffer, which was used as a crude membrane fraction (Life Sci. 48, 111-116, 1991). The prepared membrane specimen was frozen and stored at 80 C., and at an assay, the specimen was rapidly thawed, and diluted to about 900 g/mL with a 50 mM Tris-HCl buffer (pH 7.4) after the centrifugation and Histocolon treatment, and was used in an experiment. For measuring a protein concentration of the membrane specimen, Micro BCA Protein Assay Kit (PIERCE) was used.

2) Method of Receptor Binding Assay and Data Analysis

(96) To a solution of 10 l of the test compound diluted at 10-fold stage was added 10 l of final 3 nM [.sup.3H]-DADLE (51.5 Ci/mmol: PerkinElmer) as a ligand. Into a tube was placed 480 l of a rat cerebrum membrane fraction to which 100 mM choline chloride, 3 mM MnCl.sub.2 and 100 nM DAMGO had been added, and this was incubated at 25 C. for 2 hours. After incubation, this was suction-filtered with a Whatman GF/C filter which had been pre-treated with 0.5% polyethyleneimine, and washed with 2.5 mL of an ice-cooled 10 mM Tris-HCl buffer (pH7.4) four times. After washing, the filter was transferred to a mini vial for liquid scintillation counter, 5 mL of a scintillator (Cleasol I) was added, this was allowed to stand overnight, and the radioactivity was measured for 3 minutes with a liquid scintillation counter Tri-Carb 2200CA (PACKARD). DMSO was used for total binding (Total bound: TB) for data analysis, and 20 M levallorphan was used for non-specific binding (Non-specific bound: NB), and a Ki value of the test compound was calculated using a KD value (2.93 nM) obtained in advance by Scatchard plot analysis.

(97) Results are shown in Table 69.

(98) TABLE-US-00069 TABLE 69 test compound Ki (nM) I-3 8.76 I-4 7.38 I-7 7.4 I-10 19.92 I-13 5.02 I-30 5.34 I-39 41.8 I-49 3.99 I-92 5.23 I-118 27.65 I-133 9.85 I-135 9.76 I-145 13.87 I-188 3.01 I-199 12.77 I-208 13.28 I-229 5.9 I-240 11.5 I-243 5.2 I-244 0.56 I-267 41.46 I-283 3.73 I-284 0.91 I-285 5.77 I-286 2.46 I-288 5.36 I-289 0.47

(99) From the above results, it is seen that compound (1) has an affinity for an opioid receptor.

TEST EXAMPLE 2

Bindind Assay to Opioid Receptor

(100) 1) Method of Preparing Membrane Specimen for Binding Assay

(101) A rat cerebrum (Slc: SD) which had been stored at 80 C. was used. To a cerebrum which had been weighed was added a 20-fold amount of ice-cooled 10 mM Tris-HCl buffer (pH 7.0), the mixture was homogenized (25000 rpm, 30 seconds) with Histocolon (NITI-ON), and centrifuged at 36600g for 20 minutes. To the resulting pellet was added 15 ml of the same buffer, and the mixture was treated with Histocoln similarly, and centrifuged. This washing work was performed two times. After centrifugation, to the resulting pellet was added 15 mL of a 50 mM Tris-HCl buffer (pH 7.4), this was treated with Histocolon, and this was finally resuspended in a 10-fold amount of the same buffer, which was used as a crude membrane fraction (Life Sci. 48, 111-116, 1991). The prepared membrane specimen was frozen and stored at 80 C., and at a test, the specimen was rapidly thawed, and diluted to about 900 g/mL with a 50 mM Tris-HCl buffer (pH 7.4) after the centrifugation and Histocolon treatment, and was used in an experiment. For measuring a protein concentration of the membrane specimen, Micro BCA Protein Assay Kit (PIERCE) was used.

(102) 2) Method of Receptor Binding Assay and Data Analysis

(103) To a solution of 10 l of the test compound diluted at 10-fold stage diluted test compound was added 10 l of final 2 nM [.sup.3H]-DAMGO (51.5 Ci/mmol: PerkinElmer) as a ligand, further, 480 l of a rat cerebrum membrane fraction was placed into a tube, and this was incubated at 25 C. for 2 hours. After incubation, this was suction-filtered with a Whatman GF/C filter which had been pre-treated with 0.5% polyethyleneimine, and washed with 2.5 mL of an ice-cooled 10 mM Tris-HCl buffer (pH 7.4) four times. After washing, the filter was transferred to a mini vial for liquid scintillation counter, 5 mL of a scintillator (Cleasol I) was added, and this was allowed to stand overnight, and the radioactivity was measured for 3 minutes with a liquid scintillation counter Tri-Carb 2200CA (PACKARD). DMSO was used for total binding (Total bound: TB) for data analysis, and 20 M levallorphan was used for non-specific binding (Non-specific bound: NB), and a Ki value of the test compound was calculated using a KD value (1.72 nM) obtained in advance by Scatchard plot analysis (Anal.Biochem. 107(1), 220-239, 1980).

(104) Results are shown in Table 70.

(105) TABLE-US-00070 TABLE 70 test compound Ki (nM) I-4 5.18 I-10 4.05 I-39 0.33 I-49 16.49 I-118 2.29 I-122 2.7 I-123 1.68 I-124 3.9 I-133 4.99 I-135 1.58 I-138 15.53 I-145 28.09 I-188 17.27 I-199 9.45 I-208 5.89 I-229 1.3 I-240 6.85 I-243 5.28 I-244 11.02 I-267 0.84 I-283 20.14 I-284 1.13 I-285 7.29 I-286 13.98 I-288 14.38 I-289 12.95

TEST EXAMPLE 3

Mouse Carbon Powder Transport Assay

(106) 1) Preparation of Test Diet (Carbon Powder)

(107) Using a 10 w/v % arabic gum aqueous solution, a 5 w/v % active carbon solution was prepared, which was used as a test diet.

(108) 2) Animal

(109) A ddY line male mouse (5 to 6 weeks old) was used. The mouse was fasted from about 20 or more hours before assay initiation, and water was given ad lib.

(110) 3) Test Compound and Medium

(111) The test compound was dissolved in a solvent (DMAA/Solutol/5% meglumine=15/15/70).

(112) DMAA: N,N-dimethylacetamide

(113) Solutol: Solutol (registered trademark) HS15

(114) Meglumine: D()-N-methylglucamine

(115) Morphine hydrochloride was dissolved in a physiological saline. The test compound, the above solvent and morphine were all administered at a liquid amount of 10 mL/kg.

(116) 4) Assay Method

(117) The test compound 3 mg/kg (test compound administration group) or the solvent (solvent administration group) were subcutaneously administered and, after 15 minutes, amount of 3 mg/kg of morphine was administered to all groups. As a control group, the solvent was subcutaneously administered and, after 15 minutes, a physiological saline was administered.

(118) The test diet 10 mL/kg was orally administered at 15 minutes after administration of morphine. At thirty minutes after administration of the test diet (60 minutes after administration of the test substance), all mice were isolated from esophagus to an ileocecal part near a stomach cardia part. A distance from pyloric part of the stomach to an ileocecal part (full length of small intestine) and a distance until a carbon powder reaching front part (carbon powder movement distance) were measured. The antagonistic activity on the carbon powder transport of inhibitory activity by morphine was calculated as MPE (%) using the following equation. Results are shown in Table 71.
Transport rate (%)=(carbon powder movement distance)/full length of small intestine (cm))100
M.P.E.(%)={(small intestine transport rate (%) of each individual of test compound administration groupaverage small intestine transport rate (%) of solvent administration group)/(average small intestine transport rate (%) of control groupaverage small intestine transport rate (%) of solvent administration group)}100

(119) TABLE-US-00071 TABLE 71 test compound M.P.E. (%) I-39 52 I-49 80 I-118 55.6 I-122 31.5 I-123 44.1 I-124 46.6 I-133 106.9 I-135 59.7 I-138 55.8 I-145 60.2 I-188 74.6 I-199 62.8 I-208 81.2 I-229 39.7 I-240 36.3 I-243 52.6 I-244 71.6 I-267 60 I-283 63.7 I-284 79.6 I-285 82.5 I-286 70.6 I-288 101.3 I-289 67

FORMULATION EXAMPLE 1

(120) A granule containing the following ingredients is prepared.

(121) TABLE-US-00072 Ingredient Compound represented by formula (I) 10 mg Lactose 700 mg Corn starch 274 mg HPC-L 16 mg 1000 mg

(122) The compound represented by the formula (I) and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are mixed with a V-type mixer. To a mixed powder is added a HPC-L (lower viscosity hydroxypropylcellulose) aqueous solution, the materials are kneaded, granulated (extrusion granulation, pore diameter 0.5 to 1 mm), and dried. The resulting dry granule is passed through a sieve using a vibration sieve (12/60 mesh) to obtain a granule.

FORMULATION EXAMPLE 2

(123) A granule for filling into a capsule containing the following ingredients is prepared.

(124) TABLE-US-00073 Ingredient Compound represented by formula (I) 15 mg Lactose 90 mg Corn starch 42 mg HPC-L 3 mg 150 mg

(125) The compound represented by the formula (I) and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are mixed, to a mixed powder is added a HPC-L solution, the materials are kneaded, granulated, and dried. The resulting dry granule is size-adjusted, 150 mg of which is filled into a No. 4 hard gelatin capsule.

FORMULATION EXAMPLE 3

(126) A tablet containing the following ingredients is prepared.

(127) TABLE-US-00074 Ingredient Compound represented by the formula (I) 10 mg Lactose 90 mg Microcrystalline cellulose 30 mg CMC-Na 15 mg Magnesium stearate 5 mg 150 mg

(128) The compound represented by the formula (I), lactose, microcrystallinecellulose, CMC-NA (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve, and mixed. Into a mixed powder is mixed magnesium stearate to obtain a mixed powder for tabletting. The present mixed powder is compressed to obtain 150 mg of a tablet.

FORMULATION EXAMPLE 4

(129) The following ingredients are warmed, mixed, and sterilized to obtain an injectable.

(130) TABLE-US-00075 Ingredient Compound represented by the formula (I) 3 mg Nonionic surfactant 15 mg Purified water for injection 1 ml

INDUSTRIAL APPLICABILITY

(131) The present invention is useful as an agent for alleviating a side effect such as emesis, vomiting and/or constipation.