SULFOXIMINE COMPOUNDS AS HISTONE DEACETYLASE 6 INHIBITOR, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

Abstract

The present invention relates to a sulfoximine compound having a novel structure, stereoisomers thereof or pharmaceutically acceptable salts thereof, and a use thereof for preventing or treating histone deacetylase-mediated diseases The sulfoximine compound having a novel structure according to the present invention may be represented by Formula (I) below.

##STR00001##

Claims

1. A sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the sulfoximine compound is represented by formula I below: ##STR00279## in above formula I, R.sub.1 is CF.sub.2H or CF.sub.3; L.sub.1 is (C.sub.1-3 alkylene)-, C(O), S(O).sub.2, S(O).sub.2(C.sub.1-3 alkylene)-, C(O)N(R.sub.a), ##STR00280## R.sub.a is H or C.sub.1-6 alkyl; Q.sub.1 and Q.sub.2 are each independently CH or N; a, b, c, d and k are each independently 1 or 2; {circle around (A)} is C.sub.3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, C.sub.6-C.sub.12 aryl, (C.sub.1-3 alkylene)C.sub.6-C.sub.12 aryl, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, or a 9- to 12-membered fused ring group including a structure in which an aromatic ring group and a non-aromatic ring group are fused; at least one H of above {circle around (A)} may be each independently substituted with C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-12 cycloalkenyl, C.sub.1-6 alkoxy, 3- to 12-membered heterocycloalkyl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S (in which at least one H of heterocycloalkyl may be substituted with C(O)(C.sub.1-6 alkyl), 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, CF.sub.3, S(CF.sub.3), halogen or S(NH)(O)R.sub.c; R.sub.c is H or C.sub.1-6 alkyl; {circle around (B)} is C.sub.6-C.sub.12 aryl or 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; at least one H of above {circle around (B)} may be each independently substituted with C.sub.1-6 alkyl or halogen; {circle around (D)} is ##STR00281## at least one H of above {circle around (D)} may be each independently substituted with C.sub.1-6 alkyl or halogen; Z is CH or N; m and n are each independently 0, 1 or 2; p, q, r, s and t are each independently 1 or 2; L.sub.2 is a single bond, (CO), C(O)O, C(O)O(C.sub.1-3 alkylene)- or S(O).sub.2; R.sub.2 is H, C.sub.1-6 alkyl, C.sub.6-C.sub.12 aryl, CF.sub.3 or (PO)(OR.sub.b).sub.2; R.sub.b is H or C.sub.1-6 alkyl; and R.sub.3 is C.sub.1-6 alkyl.

2. The sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1, wherein: L.sub.1 is C(O), S(O).sub.2, S(O).sub.2(C.sub.1-3 alkylene)-, C(O)N(R.sub.a), ##STR00282## {circle around (A)} is C.sub.6-C.sub.12 aryl, (C.sub.1-3 alkylene)C.sub.6-C.sub.12 aryl, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, or ##STR00283## Y.sub.1, Y.sub.2 and Y.sub.3 are each independently CH.sub.2 or O; at least one H of above {circle around (A)} may be each independently substituted with C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, C.sub.1-6 alkoxy, 3- to 12-membered heterocycloalkyl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S {in which at least one H of heterocycloalkyl may be substituted with C(O)(C.sub.1-6 alkyl)}, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, CF.sub.3, S(CF.sub.3), halogen or S(NH)(O)R.sub.c; {circle around (B)} is C.sub.6-C.sub.12 aryl or 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; at least one H of above {circle around (B)} may be each independently substituted with halogen; {circle around (D)} is ##STR00284## {in which, in ##STR00285## at least one H of ##STR00286## may be each independently substituted with C.sub.1-6 alkyl or halogen}, ##STR00287## and R.sub.1, R.sub.2, R.sub.3, R.sub.a, R.sub.b, R.sub.c, Q.sub.1, Q.sub.2, L.sub.2, Z, a, b, c, d, k, m, n, p, q, r, s and t are same as defined in claim 1, respectively.

3. The sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1, wherein the sulfoximine compound is represented by formula Ia below: ##STR00288## in above formula Ia, L.sub.1 is C(O), S(O).sub.2, S(O).sub.2(C.sub.1-3 alkylene)-, C(O)N(R.sub.a), ##STR00289## {circle around (A)} is C.sub.6-C.sub.12 aryl, (C.sub.1-3 alkylene)C.sub.6-C.sub.12 aryl, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, or a 9- to 12-membered fused ring group including a structure in which an aromatic ring group and a non-aromatic ring group are fused; at least one H of above {circle around (A)} may be each independently substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, 3- to 12-membered heterocycloalkyl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S {in which at least one H of heterocycloalkyl may be substituted with C(O)(C.sub.1-6 alkyl)}, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, CF.sub.3, S(CF.sub.3), halogen or S(NH)(O)R.sub.c; and Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 are each independently CH, CX or N, in which at least one of Z.sub.1 to Z.sub.4 is CX or N; X is halogen; {circle around (E)} is ##STR00290## in above ##STR00291## at least one H of ##STR00292## may be substituted with C.sub.1-6 alkyl; and R.sub.1, R.sub.2, R.sub.3, R.sub.a, R.sub.c, Q.sub.1, Q.sub.2, L.sub.2, Z, k, m, n, p, q, r, s and t are same as defined in claim 1, respectively.

4. The sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 3, wherein in above formula Ia: Z.sub.1 is CX or N; Z.sub.2 is CH, CX or N; Z.sub.3 and Z.sub.4 are each independently CH or N; X is halogen; L.sub.1 is C(O), S(O).sub.2, S(O).sub.2(C.sub.1-3 alkylene)-, C(O)NH, ##STR00293## {circle around (A)} is C.sub.6-C.sub.12 aryl, benzyl, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, or ##STR00294## Y.sub.1, Y.sub.2 and Y.sub.3 are each independently CH.sub.2 or O; At least one H of above {circle around (A)} may be each independently substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, 3- to 12-membered heterocycloalkyl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S {in which at least one H of heterocycloalkyl may be substituted with C(O)(C.sub.1-6 alkyl)}, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, CF.sub.3, S(CF.sub.3), halogen or S(NH)(O)R.sub.c; and R.sub.c is same as defined in claim 3.

5. The sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 3, wherein in above formula Ia: Z.sub.1 is CF or N; Z.sub.2 is CH, CF or N; Z.sub.3 and Z.sub.4 are each independently CH or N; L.sub.1 is C(O), S(O).sub.2, S(O).sub.2(C.sub.1-3 alkylene)-, C(O)NH, ##STR00295## R.sub.2 is H, C.sub.1-6 alkyl, C.sub.6-C.sub.12 aryl, CF.sub.3 or (PO)(OR.sub.b).sub.2; R.sub.b is C.sub.1-6 alkyl; {circle around (A)} is C.sub.6-C.sub.12 aryl, benzyl, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, ##STR00296## in above {circle around (A)}, at least one H of C.sub.6-C.sub.12 aryl or 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S may be each independently substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, CF.sub.3, S(CF.sub.3), halogen or S(NH)(O)R.sub.c; and R.sub.c is C.sub.1-6 alkyl.

6. The sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1, wherein the sulfoximine compound is represented by formula Ib below: ##STR00297## in above formula Ib {circle around (G)} is ##STR00298## Z.sub.5, Z.sub.6, Z.sub.7 and Z.sub.8 are each independently CH, CX or N, in which at least one of Z.sub.5 to Z.sub.6 is CX or N; Z.sub.9 is CH.sub.2, CHX, CX.sub.2, NR.sub.7, O or S; R.sub.7 is H or C.sub.1-6 alkyl; X is halogen; {circle around (A)}, R.sub.1, R.sub.2, L.sub.2, Z, m and n are same as defined in claim 1, respectively.

7. A sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the sulfoximine compound is any one selected from the group consisting of compounds shown in table below: TABLE-US-00019 Com- pound No. Structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92

8. A pharmaceutical composition comprising the sulfoximine compound according to claim 1, stereoisomers thereof or pharmaceutically acceptable salts thereof as an active ingredient.

9. The pharmaceutical composition according to claim 8, wherein the composition is for preventing or treating histone deacetylase-mediated diseases.

10. The pharmaceutical composition according to claim 9, wherein the histone deacetylase-mediated diseases comprise infectious diseases; neoplasm; endocrinopathy, nutritional and metabolic diseases; mental and behavioral disorders; neurological diseases; eye and ocular adnexal diseases; circulatory diseases; respiratory diseases; digestive troubles; renal failure; skin and subcutaneous tissue diseases; musculoskeletal system and connective tissue diseases; or teratosis, deformities and chromosomal aberration.

11. The pharmaceutical composition according to claim 10, wherein the endocrinopathy, nutritional and metabolic diseases comprise Wilson's disease, amyloidosis or diabetes; the mental and behavioral disorders comprise depression or Rett syndrome; the neurological diseases comprise central nervous system atrophy, neurodegenerative disease, motor disorder, neuropathy, motor neuron disease, central nervous system demyelinating disease, or Charcot-Marie-Tooth (CMT) disease; the eye and ocular adnexal diseases comprise uveitis; the skin and subcutaneous tissue diseases comprise psoriasis; the musculoskeletal system and connective tissue diseases comprise rheumatoid arthritis, osteoarthritis or systemic lupus erythematosis; the teratosis, deformities and chromosomal aberration comprise autosomal dominant polycystic kidney disease; the infectious disease comprises prion disease; the neoplasm comprises benign tumor or malignant tumor; the circulatory disease comprises atrial fibrillation, stroke, heart failure, or pulmonary hypertension; the respiratory disease comprises asthma or idiopathic pulmonary fibrosis; and the digestive troubles comprise alcoholic liver disease, inflammatory bowel disease, Crohn's disease or ulcerative bowel disease; and the renal failure comprises acute renal failure and chronic renal failure.

12. A method for preventing or treating HDAC-mediated diseases including administering the sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1 into an individual.

13. Use of the sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1 for inhibiting histone deacetylase.

14. Use of the sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1 in preparing a medicament for preventing or treating HDAC-mediated diseases.

15. The use according to claim 13, wherein the histone deacetylase is a histone deacetylase 6 (HDAC6).

Description

MODE FOR INVENTION

[0183] Hereinafter, the present invention will be described in more detail through preparation examples and exemplary examples. However, the following preparation examples and exemplary examples are provided for the purpose of illustrating the present invention, and thus the present invention is not limited to the preparation examples and exemplary examples.

Preparation Example

[0184] Each of the compounds according to the present invention was synthesized by a method described below, and a conventional method derived by combining the following specific synthesis methods may be used by those skilled in the art.

[0185] Each of the compounds used in the synthesis was purchased from a supplier outside or synthesized by using an organic synthesis method apparent to those skilled in the art, and was used without a separate purification process. The compound of each example was identified through 400 MHz .sup.1H-NMR (Agilent, 400-MR), LC-Mass (Waters, SQD2) analysis.

Example 1: Synthesis of Compound 1, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenylthiomorpholin-4-carboxamide 1-oxide

[Step 1] Synthesis of N-phenylthiomorpholin-4-carboxamide

##STR00141##

[0186] Isocyanatobenzene (100.00%, 2.000 g, 16.790 mmol) and thiomorpholine (100.00%, 1.000 equiv., 16.790 mmol) were dissolved in dichloromethane (10 mL) at room temperature, after which the resulting solution was stirred at the same temperature for four hours. Solvent was removed from the reaction mixture under reduced pressure, after which hexane (20 mL) and ethyl acetate (10 mL) were added into the resulting concentrate and stirred to filter out a precipitated solid, which was then washed with hexane and dried to obtain the title compound (3.000 g, 80.38%) in a white solid form.

[Step 2] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholin-4-carboxamide

##STR00142##

[0187] N-phenylthiomorpholin-4-carboxamide (100.00%, 2.270 g, 10.210 mmol) prepared in step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 C., after which sodium hydride (100.00%, 1.500 equiv., 15.320 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equiv., 10.210 mmol) was added into the reaction mixture and further stirred at room temperature for two hours. Solvent was removed from the reaction mixture under reduced pressure, after which saturated aqueous solution of sodium hydrogen carbonate was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 40 g cartridge; dichloromethane/methanol=0 to 10%) and concentrated to obtain the title compound (2.940 g, 64.19%) in a colorless oil form.

[Step 3] Synthesis of Compound 1

##STR00143##

[0188] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholin-4-carboxamide (100.00%, 2.940 g, 6.555 mmol) prepared in step 2, ammonium carbamate (100.00%, 2.000 equiv., 13.110 mmol) and (diacetoxyiodo)benzene (100.00%, 2.500 equiv., 16.390 mmol) were dissolved in methanol (50 ML) at room temperature, after which the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, after which saturated aqueous solution of sodium hydrogen carbonate was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 40 g cartridge; dichloromethane/methanol=0 to 10%) and concentrated to obtain the title compound (2.500 g, 79.54%) in a colorless oil form.

[0189] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.86 (dd, J=8.0, 1.5 Hz, 1H), 7.74 (dd, J=10.1, 1.5 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.36 (t, J=7.8 Hz, 2H), 7.23-7.19 (m, 1H), 7.13-7.11 (m, 2H), 7.03 (s, 0.25H), 6.90 (s, 0.5H), 6.77 (s, 0.25H), 4.92 (s, 2H), 3.79-3.72 (m, 2H), 3.67-3.60 (m, 2H), 2.80 (t, J=5.2 Hz, 4H), 2.46 (s, 1H); LRMS (ES) m/z 480.9 (M.sup.++1)

Example 2: Synthesis of Compound 2, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenyl-1-((2,2,2-trifluoroacetyl)imino)thiomorpholin-4-carboxamide 1-oxide

[Step 1] Synthesis of N-phenyl-1-((2,2,2-trifluoroacetyl)imino)thiomorpholin-4-carboxamide 1-oxide

##STR00144##

[0190] Isocyanatobenzene (0.590 g, 4.953 mmol) and 2,2,2-trifluoro-N-(1-oxidothiomorpholin-1-ylidene)acetamide (1.140 g, 4.953 mmol) were dissolved in dichloromethane (10 mL) at room temperature, after which the resulting solution was stirred at the same temperature for five hours. Solvent was removed from the resulting mixture under reduced pressure, after which the resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to obtain the title compound (0.160 g, 9.2%) in a white solid form.

[Step 2] Synthesis of Compound 2

##STR00145##

[0191] N-phenyl-1-((2,2,2-trifluoroacetyl)imino)thiomorpholin-4-carboxamide 1-oxide (0.120 g, 0.344 mmol) prepared in step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 C., after which sodium hydride (60.00%, 0.014 g, 0.344 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.100 g, 0.344 mmol) was added into the reaction mixture and further stirred at room temperature for three hours. Water was poured into the reaction mixture and extracted with ethyl acetate. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to obtain the title compound (0.052 g, 27.1%) in a colorless oil form.

[0192] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.25 (d, J=1.6 Hz, 1H), 8.43 (dd, J=8.0, 2.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.39 (t, J=7.8 Hz, 2H), 7.25-7.19 (m, 3H), 7.08 (s, 0.25H), 6.95 (s, 0.5H), 6.82 (s, 0.25H), 5.13 (s, 2H), 3.98-3.94 (m, 2H), 3.74-3.69 (m, 2H), 3.53-3.37 (m, 4H); LRMS (ES) m/z 559.9 (M.sup.++1)

Example 3: Synthesis of Compound 3, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-imino-N-phenylthiomorpholin-4-carboxamide 1-oxide

##STR00146##

[0193] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenyl-1-((2,2,2-trifluoroacetyl)imino)thiomorpholin-4-carboxamide 1-oxide (0.052 g, 0.093 mmol) prepared in step 2 of example 2 and potassium carbonate (0.051 g, 0.372 mmol) were dissolved in methanol (5 mL) at room temperature, after which the resulting solution was stirred at the same temperature for one hour. Solvent was removed from the resulting mixture under reduced pressure, after which the resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to obtain the title compound (0.013 g, 30.2%) in a yellow oil form.

[0194] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.26 (d, J=1.6 Hz, 1H), 8.38 (dd, J=8.2, 2.2 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.39-7.32 (m, 2H), 7.21-7.17 (m, 3H), 7.07 (s, 0.25H), 6.95 (s, 0.5H), 6.82 (s, 0.25H), 5.11 (s, 2H), 3.81-3.63 (m, 4H), 3.02-2.91 (m, 4H), 2.50 (brs, 1H); LRMS (ES) m/z 463.9 (M.sup.++1)

Example 4: Synthesis of Compound 4, Benzyl (4-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)carbamoyl)-1-oxidothiomorpholin-1-ylidene)carbamate

[Step 1] Synthesis of benzyl (1-oxido-4-(phenylcarbamoyl)thiomorpholin-1-ylidene)carbamate

##STR00147##

[0195] Benzyl (1-oxidothiomorpholin-1-ylidene)carbamate (100.00%, 2.000 g, 7.454 mmol) and isocyanatobenzene (100.00%, 1.000 equiv., 7.454 mmol) were dissolved in diethyl ether (50 mL) at room temperature, after which the resulting solution was stirred at the same temperature for five hours. A precipitated solid was filtered, washed with hexane, and dried to obtain the title compound (2.65 g, 91.76%, in a yellow solid form).

[Step 2] Synthesis of Compound 4

##STR00148##

[0196] The title compound (2.08 g, 49.56%, colorless oil) was obtained according to substantially the same reaction as described in step 2 of example 1 except for using benzyl (1-oxido-4-(phenylcarbamoyl)thiomorpholin-1-ylidene)carbamate (100.00%, 2.650 g, 6.840 mmol) prepared in step 1 instead of N-phenylthiomorpholin-4-carboxamide.

[0197] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (d, J=8.0 Hz, 1H), 7.74 (d, J=10.0 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.39-7.28 (m, 7H), 7.25-7.21 (m, 1H), 7.12 (d, J=8.0 Hz, 2H), 7.05 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 5.09 (s, 2H), 4.93 (s, 2H), 3.90-3.85 (m, 2H), 3.89-3.85 (m, 2H), 3.56-3.50 (m, 2H), 3.42-3.38 (m, 2H); LRMS (ES) m/z 614.9 (M.sup.++1)

Example 5: Synthesis of Compound 5, Benzyl (4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(phenyl)carbamoyl)-1-oxidothiomorpholin-1-ylidene)carbamate

##STR00149##

[0198] The title compound (0.12 g, 15.58%, white solid) was obtained according to substantially the same reaction as described in step 2 of example 2 except for using benzyl (1-oxido-4-(phenylcarbamoyl)thiomorpholin-1-ylidene)carbamate instead of N-phenyl-1-((2,2,2-trifluoroacetyl)imino)thiomorpholin-4-carboxamide 1-oxide.

[0199] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.25 (d, J=1.6 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.41-7.30 (m, 7H), 7.22-7.18 (m, 3H), 7.08 (s, 0.25H), 6.95 (s, 0.5H), 6.82 (s, 0.25H), 5.11 (s, 2H), 5.10 (s, 2H), 3.92-3.87 (m, 2H), 3.57-3.50 (m, 4H), 3.28-3.22 (m, 2H); LRMS (ES) m/z 597.9 (M.sup.++1)

Example 6: Synthesis of Compound 6, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholin-4-carboxamide 1-oxide

[Step 1] Synthesis of N-(3,4-difluorophenyl)thiomorpholin-4-carboxamide

##STR00150##

[0200] The title compound (1.500 g, 90.07%) was obtained in a white solid form according to substantially the same reaction as described in step 1 of example 1 except for using 1,2-difluoro-4-isocyanato-benzene instead of isocyanatobenzene.

[Step 2] Synthesis of N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)thiomorpholin-4-carboxamide

##STR00151##

[0201] The title compound (0.300 g, 53.32%) was obtained in a white foam solid form according to substantially the same reaction as described in step 2 of example 1 except for using N-(3,4-difluorophenyl)thiomorpholin-4-carboxamide (100.00%, 0.300 g, 1.161 mmol) prepared in step 1 instead of N-phenylthiomorpholin-4-carboxamide.

[Step 3] Synthesis of Compound 6

##STR00152##

[0202] The title compound (0.22 g, 68.91%) was obtained in a colorless oil form according to substantially the same reaction as described in step 3 of example 1 except for using N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)thiomorpholin-4-carboxamide prepared in step 2 instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholin-4-carboxamide.

[0203] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.90 (dd, J=8.0, 1.6 Hz, 1H), 7.78 (dd, J=10.1, 1.5 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.20-7.14 (m, 1H), 7.06 (s, 0.25H), 7.03-6.98 (m, 1H), 6.93 (s, 0.5H), 6.89-6.85 (m, 1H), 6.80 (s, 0.25H), 4.90 (s, 2H), 3.79-3.62 (m, 4H), 2.93-2.90 (m, 4H), 2.50 (brs, 1H); LRMS (ES) m/z 516.9 (M.sup.++1)

Example 7: Synthesis of Compound 7, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholin-4-carboxamide 1-oxide

[Step 1] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)thiomorpholin-4-carboxamide

##STR00153##

[0204] The title compound (0.220 g, 40.53%) was obtained in a colorless oil form according to substantially the same reaction as described in step 2 of example 6 except for using 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole in step 2 of example 6.

[Step 2] Synthesis of Compound 7

##STR00154##

[0205] The title compound (0.15 g, 64.82%) was obtained in a colorless oil form according to substantially the same reaction as described in step 3 of example 6 by using N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)thiomorpholin-4-carboxamide obtained from step 1.

[0206] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.25 (d, J=1.6 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.18-7.08 (m, 2H), 7.08 (s, 0.25H), 6.97-6.93 (m, 1H), 6.96 (s, 0.5H), 6.82 (s, 0.25H), 5.06 (s, 2H), 3.79-3.61 (m, 4H), 3.07-2.98 (m, 4H), 2.40 (brs, 1H); LRMS (ES) m/z 499.9 (M.sup.++1)

Example 8: Synthesis of Compound 8, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenyltetrahydro-2H-thiopyran-4-carboxamide 1-oxide

[Step 1] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenyltetrahydro-2H-thiopyran-4-carboxamide

##STR00155##

[0207] N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluoro-phenyl)methyl)aniline (100.00%, 0.600 g, 1.879 mmol) was dissolved in N,N-dimethylformamide (10 mL) at 0 C., after which sodium hydride (60.00%, 1.500 equiv., 2.819 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. Tetrahydrothiopyran-4-carbonyl chloride (100.00%, 1.000 equiv., 1.879 mmol) was added into the reaction mixture and further stirred at room temperature for two hours. Solvent was removed from the reaction mixture under reduced pressure, after which saturated aqueous solution of sodium hydrogen carbonate was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%) and concentrated to obtain the title compound (0.510 g, 60.65%) in a colorless oil form.

[Step 2] Synthesis of Compound 8

##STR00156##

[0208] The title compound (0.120 g, 22.01%) was obtained in a colorless oil form according to substantially the same reaction as described in step 3 of example 1 except for using N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenyltetrahydro-2H-thiopyran-4-carboxamide prepared in step 1 instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholin-4-carboxamide.

[0209] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (d, J=8.0 Hz, 1H), 7.73 (dd, J=9.8, 1.5 Hz, 1H), 7.56-7.51 (m, 1H), 7.41-7.39 (m, 3H), 7.05-7.03 (m, 2H), 7.05 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 5.04 (d, J=2.2 Hz, 2H), 3.30-3.26 (m, 2H), 2.82-2.79 (m, 2H), 2.52-2.50 (m, 1H), 2.41-2.36 (m, 2H), 2.20 (brs, 1H), 2.09-2.05 (m, 2H); LRMS (ES) m/z 479.9 (M.sup.++1)

Example 9: Synthesis of Compound 9, 1-imino-N-phenyl-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1-oxide

[Step 1] Synthesis of N-phenyl-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide

##STR00157##

[0210] N-phenylthiomorpholin-4-carboxamide (100.00%, 0.050 g, 0.225 mmol) was dissolved in N,N-dimethylformamide (10 mL) at 0 C., after which sodium hydride (100.00%, 1.500 equiv., 0.337 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-(6-(bromomethyl)pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equiv, 0.225 mmol) was added into the reaction mixture and further stirred at room temperature for two hours. Solvent was removed from the reaction mixture under reduced pressure, after which saturated aqueous solution of sodium hydrogen carbonate was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; hexane/ethyl acetate=0 to 30%) and concentrated to obtain the title compound (0.005 g, 4.95%) in a colorless oil form.

[Step 2] Synthesis of Compound 9

##STR00158##

[0211] The title compound (0.010 g, 20.78%) was obtained in a colorless oil form according to substantially the same reaction as described in step 3 of example 1 except for using N-phenyl-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)thiomorpholin-4-carboxamide prepared in step 1 instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholin-4-carboxamide.

[0212] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.26 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.39-7.35 (m, 2H), 7.22-7.18 (m, 3H), 5.12 (s, 2H), 3.82-3.76 (m, 2H), 3.70-3.63 (m, 2H), 2.98-2.94 (m, 4H), 2.50 (brs, 1H); LRMS (ES) m/z 481.9 (M.sup.++1)

Examples 10 to 13: Synthesis of Compounds 10 to 13

[0213] Compounds 10 to 13 according to examples 10 to 13 were prepared in accordance with the same reactions as described in steps 1, 2 and 3 of example 1, respectively, except for using the reactants of table 2 below instead of isocyanatobenzene in step 1 of example 1. Table 2 shows the properties and yields of the products prepared in each of steps 1 to 3 in examples 10 to 13.

TABLE-US-00002 TABLE 2 Yield/property Yield/property Yield/property of product of product of product obtained from obtained from obtained from Classification Reactant in step 1 step 1 step 2 step 3 Example 10 5-isocyanato-1-methyl-1H- 0.700 g, 77.87% 0.072 g, 26.36% 0.040 g, 52.32% indole White solid Colorless oil Colorless oil Example 11 (4- 1.100 g, 67.71% 0.085 g, 30.75% 0.040 g, 41.82% isocyanatophenyl)(methyl)sulfan White solid Colorless oil Colorless oil Example 12 2-isocyanatothiophene 0.300 g, 92.39% 0.080 g, 40.18% 0.030 g, 32.96% White solid Colorless oil Colorless oil Example 13 1-fluoro-3-isocyanatobenzene 1.300 g, 74.18% 0.167 g, 57.36% 0.110 g, 69.68% White solid Colorless oil Colorless oil

[0214] The names of compounds 10 to 13 prepared in each of examples 10 to 13, and the NMR and LC-Mass analysis results thereof are shown in table 3 below.

TABLE-US-00003 TABLE 3 Compound Classification No. Compound name NMR/LRMS Example 10 10 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (dd, J = 1,3,4-oxadiazol-2-yl)-2- 8.0, 1.6 Hz, 1H), 7.74-7.68 (m, 2H), 7.37 fluorobenzyl)-1-imino-N- (d, J = 2.0 Hz, 1H), 7.29-7.27 (m, 1H), 7.12 (1-methyl-1H-indol-5- (d, J = 3.1 Hz, 1H), 7.05 (s, 0.25H), 6.96 (dd, yl)thiomorpholin-4- J = 8.7, 2.1 Hz, 1H), 6.92 (s, 0.5H), 6.79 (s, carboxamide 1-oxide 0.25H), 6.44 (dd, J = 3.1, 0.7 Hz, 1H), 4.97 (s, 2H), 3.84-3.78 (m, 2H), 3.70-3.64 (m, 2H), 2.74 (t, J = 5.2 Hz, 4H), 2.41 (brs, 1H); LRMS (ES) m/z 534.0 (M.sup.+ + 1) Example 11 11 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 8.01 (d, J = 1,3,4-oxadiazol-2-yl)-2- 1.9 Hz, 2H), 7.90 (dd, J = 8.0, 1.5 Hz, 1H), fluorobenzyl)-1-imino-N- 7.80 (dd, J = 10.2, 1.5 Hz, 1H), 7.68 (t, J = (4-(S- 7.7 Hz, 1H), 7.31-7.29 (m, 2H), 7.06 (s, methylsulfonimidoyl)phe- 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.02 nyl)thiomorpholin-4- (s, 2H), 3.80-3.63 (m, 4H), 3.12 (s, 3H), carboxamide 1-oxide 2.96-2.94 (m, 4H), 2.80 (brs, 1H), 2.60 (brs, 1H); LRMS (ES) m/z 557.9 (M.sup.+ + 1) Example 12 12 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.69 (dd, J = 1,3,4-oxadiazol-2-yl)-2- 164.9, 164.9 Hz, 1H), 7.80 (dd, J = 10.0, 1.6 fluorobenzyl)-1-imino-N- Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.08-7.06 (thiophen-2- (m, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.86 yl)thiomorpholin-4- (dd, J = 5.6, 3.7 Hz, 1H), 6.80 (s, 0.25H), carboxamide 1-oxide 6.68 (dd, J = 3.7, 1.3 Hz, 1H), 4.92 (s, 2H), 4.13-3.72 (m, 4H), 2.90-2.85 (m, 4H), 2.50 (brs, 1H); LRMS (ES) m/z 486.9 (M.sup.+ + 1) Example 13 13 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (dd, J = 1,3,4-oxadiazol-2-yl)-2- 8.0, 1.6 Hz, 1H), 7.77 (dd, J = 10.1, 1.6 Hz, fluorobenzyl)-N-(3- 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.36-7.30 (m, fluorophenyl)-1- 1H), 7.05 (s, 0.25H), 6.95-6.87 (m, 3H), iminothiomorpholin-4- 6.91 (s, 0.5H), 6.79 (s, 0.25H), 4.94 (s, 2H), carboxamide 1-oxide 3.81-3.62 (m, 4H), 2.93-2.86 (m, 4H), 2.50 (brs, 1H); LRMS (ES) m/z 500.0 (M.sup.+ + 1)

Examples 14 to 17: Synthesis of Compounds 14 to 17

[0215] Compounds 14 to 17 according to examples 14 to 17 were prepared in accordance with the same reactions as described in steps 1, 2 and 3 of examples 10 to 13, respectively, except for using 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole in step 2 of examples 10 to 13, respectively. Table 4 shows the properties and yields of the products prepared in each of steps 1 to 3 in examples 14 to 17.

TABLE-US-00004 TABLE 4 Yield/property of product Yield/property of product Yield/property of product Classification obtained from step 1 obtained from step 2 obtained from step 3 Example 14 (Same as product in 0.137 g, 51.92% 0.110 g, 75.46% step 1 of example 10) Colorless oil Colorless oil Example 15 (Same as product in 0.080 g, 29.97% 0.030 g, 33.19% step 1 of example 11) Colorless oil Colorless oil Example 16 (Same as product in 0.085 g, 32.14% 0.030 g, 32.96% step 1 of example 12) Colorless oil Colorless oil Example 17 (Same as product in 0.129 g, 45.99% 0.110 g, 79.75% step 1 of example 13) Colorless oil Colorless oil

[0216] The names of compounds 14 to 17 prepared in each of examples 14 to 17, and the NMR and LC-Mass analysis results thereof are shown in table 5 below.

TABLE-US-00005 TABLE 5 Compound Classification No. Compound name NMR/LRMS Example 14 14 N-((5-(5- .sup.1H NMR (400 MHz, CDCl.sub.3) 9.24 (dd, J = 2.1, (difluoromethyl)- 0.6 Hz, 1H), 8.36 (dd, J = 8.2, 2.2 Hz, 1H), 7.62 1,3,4-oxadiazol-2- (d, J = 8.2 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), yl)pyridin-2- 7.30-7.28 (m, 1H), 7.11-7.06 (m, 2H), 7.08 yl)methyl)-1-imino-N- (s, 0.25H), 6.94 (s, 0.5H), 6.81 (s, 0.25H), 6.44 (1-methyl-1H-indol-5- (dd, J = 3.1, 0.7 Hz, 1H), 5.13 (s, 2H), 3.82- yl)thiomorpholin-4- 3.66 (m, 4H), 3.50 (s, 3H), 2.90-2.87 (m, 4H), carboxamide 1-oxide 2.50 (brs, 1H); LRMS (ES) m/z 516.8 (M.sup.+ + 1) Example 15 15 N-((5-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 9.27 (d, J = 1.7 1,3,4-oxadiazol-2- Hz, 1H), 8.44 (dd, J = 8.2, 2.2 Hz, 1H), 8.00- yl)pyridin-2- 7.96 (m, 2H), 7.57-7.54 (m, 1H), 7.32-7.30 yl)methyl)-1-imino-N- (m, 2H), 7.09 (s, 0.25H), 6.96 (s, 0.5H), 6.83 (s, (4-(S-methyl- 0.25H), 5.16 (s, 2H), 3.85-3.68 (m, 4H), 3.14- sulfonimidoyl)phenyl)thio- 3.03 (m, 4H), 3.12 (s, 3H), 2.60 (brs, 2H); morpholin-4-carboxamide LRMS (ES) m/z 540.9 (M.sup.+ + 1) 1-oxide Example 16 16 N-((5-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 9.26 (d, J = 1.7 1,3,4-oxadiazol-2- Hz, 1H), 8.38 (dd, J = 8.2, 2.2 Hz, 1H), 7.53 (d, yl)pyridin-2- J = 8.2 Hz, 1H), 7.08 (s, 0.25H), 7.02 (dd, J = yl)methyl)-1-imino- 5.6, 1.3 Hz, 1H), 6.95 (s, 0.5H), 6.84-6.82 (m, N-(thiophen- 1H), 6.82 (s, 0.25H), 6.71 (dd, J = 3.7, 1.3 Hz, 2-yl)thiomorpholin- 1H), 5.07 (s, 2H), 3.91-3.72 (m, 4H), 3.01- 4-carboxamide 1-oxide 2.88 (m, 4H), 2.60 (s, 1H); LRMS (ES) m/z 469.9 (M.sup.+ + 1) Example 17 17 N-((5-(5- .sup.1H NMR (400 MHz, CDCl.sub.3) 9.23-9.22 (m, (difluoromethyl)- 1H), 8.37 (dd, J = 8.2, 2.2 Hz, 1H), 7.53 (d, J = 1,3,4-oxadiazol-2- 8.2 Hz, 1H), 7.32-7.26 (m, 1H), 7.08 (s, yl)pyridin-2- 0.25H), 6.96-6.84 (m, 3H), 6.92 (s, 0.5H), 6.84 yl)methyl-N-(3- (s, 0.25H), 5.09 (s, 2H), 3.80-3.61 (m, 4H), fluorophenyl)-1- 3.06-3.00 (m, 4H), 2.40 (s, 1H); LRMS (ES) iminothiomorpholin-4- m/z 481.9 (M.sup.+ + 1) carboxamide 1-oxide

Example 18: Synthesis of Compound 18, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenylthiomorpholin-4-sulfonamide 1-oxide

[Step 1] Synthesis of 1-((1H-imidazol-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate

##STR00159##

[0217] 1,1-sulfonylbis(1H-imidazole) (100.00%, 3.000 g, 15.136 mmol) and methyl trifluoromethanesulfonate (100.00% solution, 1.4903 mL, 13.623 mmol) were dissolved in dichloromethane (10 mL) at room temperature, after which the resulting solution was stirred at the same temperature for three days. Solvent was removed from the reaction mixture under reduced pressure, after which hexane (20 mL) and ethyl acetate (10 mL) were added into the resulting concentrate and stirred to filter out a precipitated solid, which was then washed with hexane and dried to obtain the title compound (4.000 g, 72.94%) in a white solid form.

[Step 2] Synthesis of 4-((1H-imidazol-1-yl)sulfonyl)thiomorpholine

##STR00160##

[0218] 1-((1H-imidazol-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (100.00%, 4.000 g, 11.040 mmol) prepared in step 1 and thiomorpholine (100.00%, 1.100 equiv., 12.140 mmol) were dissolved in acetonitrile (50 mL) at room temperature, after which the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, after which saturated aqueous solution of sodium hydrogen carbonate was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 40 g cartridge; hexane/ethyl acetate=0 to 30%) and concentrated to obtain the title compound (0.500 g, 19.41%) in a white solid form.

[Step 3] Synthesis of 3-methyl-1-(thiomorpholinosulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate

##STR00161##

[0219] 4-((1H-imidazol-1-yl)sulfonyl)thiomorpholine (100.00%, 2.260 g, 9.687 mmol) prepared in step 2 and methyl triflate (100.00%, 1.100 equiv., 10.660 mmol) were dissolved in dichloromethane (50 mL) at room temperature, after which the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, after which dichloromethane (20 mL) and methanol (10 mL) were added into the resulting concentrate and stirred to filter out a precipitated solid, which was then washed with hexane and dried to obtain the title compound (1.500 g, 38.96%) in a white solid form.

[Step 4] Synthesis of N-phenylthiomorpholin-4-sulfonamide

##STR00162##

[0220] 3-methyl-1-(thiomorpholinosulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate (100.00%, 1.500 g, 3.775 mmol) prepared in step 3 and aniline (100.00%, 1.000 equiv., 3.775 mmol) were dissolved in acetonitrile (30 mL) at 80 C., after which the resulting solution was stirred overnight at the same temperature and then a reaction was finished by lowering the temperature to room temperature. Solvent was removed from the reaction mixture under reduced pressure, after which saturated aqueous solution of sodium hydrogen carbonate was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 40 g cartridge; hexane/ethyl acetate=0 to 50%) and concentrated to obtain the title compound (0.800 g, 82.02%) in a white solid form.

[Step 5] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholin-4-sulfonamide

##STR00163##

[0221] The title compound (0.204 g, 47.93%) was obtained in a colorless oil form according to substantially the same reaction as described in step 2 of example 1 except for using N-phenylthiomorpholin-4-sulfonamide prepared in step 4 instead of N-phenylthiomorpholin-4-carboxamide.

[Step 6] Synthesis of Compound 18

##STR00164##

[0222] The title compound (0.150 g, 69.11%) was obtained in a colorless oil form according to substantially the same reaction as described in step 3 of example 1 except for using N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholin-4-sulfonamide prepared in step 5 instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholin-4-carboxamide.

[0223] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.81 (dd, J=8.0, 1.5 Hz, 1H), 7.73 (dd, J=9.9, 1.5 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.36-7.26 (m, 5H), 7.04 (s, 0.25H), 6.91 (s, 0.5H), 6.78 (s, 0.25H), 4.92 (s, 2H), 3.76-3.60 (m, 4H), 3.10-3.04 (m, 4H), 2.60 (brs, 1H); LRMS (ES) m/z 516.9 (M.sup.++1)

Example 19: Synthesis of Compound 19, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-imino-N-phenylthiomorpholin-4-sulfonamide 1-oxide

[Step 1] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholin-4-sulfonamide

##STR00165##

[0224] The title compound (0.300 g, 78.96%) was obtained in a colorless oil form according to substantially the same reaction as described in step 5 of example 18 except for using 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole in step 5 of example 18.

[Step 2] Synthesis of Compound 19

##STR00166##

[0225] The title compound (0.250 g, 78.15%) was obtained in a colorless oil form according to substantially the same reaction as described in step 3 of example 1 except for using N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholin-4-sulfonamide prepared in step 1.

[0226] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.25-9.24 (m, 1H), 8.36 (dd, J=8.2, 2.2 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.42-7.28 (m, 5H), 7.08 (s, 0.25H), 6.95 (s, 0.5H), 6.82 (s, 0.25H), 5.06 (s, 2H), 3.84-3.68 (m, 4H), 3.11-3.03 (m, 4H), 2.50 (brs, 1H); LRMS (ES) m/z 499.9 (M.sup.++1)

Examples 20 to 22: Synthesis of Compounds 20 to 22

[0227] Compounds 20 to 22 according to examples 20 to 22 were prepared in accordance with the same reactions as described in steps 1, 2 and 3 of example 1, respectively, except for using the reactants of Table 6 below instead of isocyanatobenzene in step 1 of example 1. Table 6 shows the properties and yields of the products prepared in each of steps 1 to 3 in examples 20 to 22.

TABLE-US-00006 TABLE 6 Yield/property Yield/property Yield/property of product of product of product obtained from obtained from obtained from Classification Reactant in step 1 step 1 step 2 step 3 Example 20 1-bromo-4-isocyanato- 1.480 g, 97.30% 1.170 g, 66.82% 0.068 g, 64.22% benzene White solid White solid White solid Example 21 (4-isocyanato- 0.950 g, 92.23% 0.478 g, 40.14% 0.039 g, 36.91% phenyl)(trifluoro- Light yellow oil Colorless oil White solid methyl)sulfan Example 22 5-isocyanato-2,3- 0.187 g, 57.01% 0.813 g, 54.90% 0.060 g, 56.43% dihydrobenzofuran White solid White solid White solid

[0228] The names of compounds 20 to 22 prepared in each of examples 20 to 22, and the NMR and LC-Mass analysis results thereof are shown in table 7 below.

TABLE-US-00007 TABLE 7 Compound Classification No. Compound name NMR/LRMS Example 20 20 N-(4-bromophenyl)-N-(4- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (d, J = (5-(difluoromethyl)-1,3,4- 8.0 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.68 oxadiazol-2-yl)-2- (t, J = 7.7 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), fluorobenzyl)-1- 7.06-6.80 (m, 3H), 5.32 (s, 2H), 3.79-3.73 iminothiomorpholin-4- (m, 2H), 3.69-3.63 (m, 2H), 2.91-2.88 (m, carboxamide 1-oxide 4H); LRMS (ES) m/z 558.8 (M.sup.+ + 1) Example 21 21 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.90 (d, J = 1,3,4-oxadiazol-2-y1)-2- 8.0 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.69- fluorobenzyl)-1-imino-N- 7.65 (m, 3H), 7.20 (d, J = 8.7 Hz, 2H), 6.93 (4-((trifluoro- (t, J = 51.7 Hz, 1H), 4.99 (s, 2H), 3.79-3.74 methyl)thio)phenyl)thio- (m, 2H), 3.69-3.64 (m, 2H), 2.92-2.89 (m, morpholin-4- 4H); LRMS (ES) m/z 580.8 (M.sup.+ + 1). carboxamide 1-oxide Example 22 22 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (d, J = 1,3,4-oxadiazol-2-y1)-2- 8.0 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.68 fluorobenzyl)-N-(2,3- (t, J = 7.6 Hz, 1H), 7.06-6.80 (m, 3H), 6.73 dihydrobenzofuran-5-yl)- (d, J = 8.4 Hz, 1H), 4.87 (s, 2H), 4.62 (t, J = 1-iminothiomorpholin-4- 8.7 Hz, 2H), 3.81-3.76 (m, 2H), 3.70-3.64 carboxamide 1-oxide (m, 2H), 3.21 (t, J = 8.7 Hz, 2H), 2.85 (t, J = 5.2 Hz, 4H); LRMS (ES) m/z 522.9 (M.sup.+ + 1).

Example 23: Synthesis of Compound 23, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(4-(furan-2-yl)phenyl)-1-iminothiomorpholin-4-carboxamide 1-oxide

[Step 1] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(4-(furan-2-yl)phenyl)thiomorpholin-4-carboxamide

##STR00167##

[0229] N-(4-bromophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluoro-benzyl)thiomorpholin-4-carboxamide (100.00%, 0.200 g, 0.379 mmol), 2-furylboronic acid (100.00%, 0.051 g, 0.456 mmol), (1,1-bis(di-tert-butylphosphino)ferrocene)dichloropalladium(II) (Pd(dtbpf)Cl.sub.2, 100.00%, 0.012 g, 0.018 mmol) and cesium carbonate (100.00%, 0.247 g, 0.758 mmol) were mixed in 1,4-dioxane (2 mL)/water (0.5 mL) at room temperature, after which the resulting mixture was irradiated with microwave, then heated at 100 C. for 30 minutes, and then a reaction was finished by lowering the temperature to room temperature. Solvent was removed from the reaction mixture under reduced pressure, after which saturated aqueous solution of sodium hydrogen carbonate was poured into the resulting concentrate, and extraction was performed with dichloromethane, then filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=0 to 20%) and concentrated to obtain the title compound (0.110 g, 56.38%) in a light yellow solid form.

[Step 2] Synthesis of Compound 23

##STR00168##

[0230] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(4-(furan-2-yl)phenyl)thiomorpholin-4-carboxamide (100.00%, 0.100 g, 0.194 mmol) prepared in step 1, iodobenzene diacetate (100.00%, 0.153 g, 0.475 mmol) and ammonium carbamate (100.00%, 0.030 g, 0.384 mmol) were dissolved in methanol (3 mL) at room temperature, after which the resulting solution was stirred at the same temperature. Solvent was removed from the resulting mixture under reduced pressure, after which the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate=100%) and concentrated to obtain the title compound (0.038 g, 35.84%) in a yellow solid form.

[0231] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.72-7.65 (m, 3H), 7.49 (d, J=1.2 Hz, 1H), 7.15 (d, J=8.7 Hz, 2H), 6.92 (t, J=51.7 Hz, 1H), 6.67-6.66 (m, 1H), 6.50-6.49 (m, 1H), 4.97 (s, 2H), 3.82-3.77 (m, 2H), 3.72-3.67 (m, 2H), 2.88 (t, J=5.2 Hz, 4H); LRMS (ES) m/z 546.8 (M.sup.++1).

Examples 24 to 28: Synthesis of Compounds 24 to 28

[0232] Compounds 24 to 28 according to examples 24 to 28 were prepared in accordance with the same reactions as described in steps 1, 2 and 3 of example 1, respectively, except for using the reactants of Table 8 below instead of isocyanatobenzene in step 1 of example 1. Table 8 shows the properties and yields of the products prepared in each of steps 1 to 3 in examples 24 to 28.

TABLE-US-00008 TABLE 8 Yield/property of Yield/property of Yield/property of product product product obtained from obtained from obtained from Classification Reactant in step 1 step 1 step 2 step 3 Example 24 Isocyanatomethylbenzene 0.753 g, 84.86% 0.040 g, 10.22% 0.017 g, 39.83% White solid White solid White solid Example 25 1-isocyanato-2-methoxy- 0.696 g, 82.29% 0.134 g, 35.33% 0.063 g, 44.15% benzene White solid White solid Light yellow solid Example 26 3-isocyanatothiophene 0.395 g, 43.31% 0.167 g, 41.94% 0.079 g, 44.28% White solid White solid Light yellow oil Example 27 1-isocyanato-4-methoxy- 0.700 g, 82.76% 0.195 g, 51.41% 0.100 g, 48.16% benzene White solid Colorless oil Colorless oil Example 28 5-isocyanato-2,3- 0.700 g, 84.93% 0.190 g, 68.04% 0.100 g, 47.49% dihydro-1h-indene White solid Colorless oil Colorless oil

[0233] The names of compounds 24 to 28 prepared in each of examples 24 to 28, and the NMR and LC-Mass analysis results thereof are shown in table 9 below.

TABLE-US-00009 TABLE 9 Compound Classification No. Compound name NMR/LRMS Example 24 24 N-benzyl-N-(4-(5- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.91 (dd, J = (difluoromethyl)-1,3,4- 7.9, 1.6 Hz, 1H), 7.83 (dd, J = 10.1, 1.6 oxadiazol-2-y1)-2- Hz, 1H), 7.42-7.35 (m, 4H), 7.18 (d, J = fluorobenzyl)-1- 8.2 Hz, 2H), 6.95 (t, J = 51.7 Hz, 1H), 4.46 iminothiomorpholin-4- (s, 2H), 4.42 (s, 2H), 3.85-3.82 (m, 2H), carboxamide 1-oxide 3.81-3.78 (m, 2H), 3.14-3.13 (m, 4H); LRMS (ES) m/z 494.9 (M.sup.+ + 1). Example 25 25 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (dd, J = 1,3,4-oxadiazol-2-y1)-2- 8.1, 1.5 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), fluorobenzyl)-1-imino-N- 7.69 (dd, J = 9.9, 1.4 Hz, 1H), 7.29-7.25 (2-methoxy- (m, 1H), 7.05-6.79 (m, 4H), 4.85 (s, 2H), phenyl)thiomorpholin- 3.85 (s, 3H), 3.79-3.73 (m, 2H), 3.65- 4-carboxamide 1-oxide 3.59 (m, 2H), 2.72-2.67 (m, 4H); LRMS (ES) m/z 510.8 (M.sup.+ + 1). Example 26 26 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.88 (d, J = 1,3,4-oxadiazol-2-yl)-2- 8.0 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.63 fluorobenzyl)-1-imino-N- (t, J = 7.6 Hz, 1H), 7.34-7.32 (m, 1H), (thiophen-3- 6.93-6.80 (m, 3H), 4.92 (s, 2H), 3.83- yl)thiomorpholin-4- 3.77 (m, 2H), 3.72-3.66 (m, 2H), 2.92- carboxamide 1-oxide 2.90 (m, 4H); LRMS (ES) m/z 486.8 (M.sup.+ + 1). Example 27 27 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (dd, J = 1,3,4-oxadiazol-2-y1)-2- 8.0, 1.6 Hz, 1H), 7.74 (dd, J = 10.0, 1.6 fluorobenzyl)-1-imino-N- Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.05- (4-methoxy- 7.00 (m, 2H), 7.01 (s, 0.25H), 6.92 (s, phenyl)thiomorpholin- 0.5H), 6.88-6.84 (m, 2H), 6.79 (s, 0.25H), 4-carboxamide 1-oxide 4.88 (s, 2H), 3.80-3.50 (m, 4H), 3.80 (s, 3H), 2.83-2.80 (m, 4H), 2.50 (brs, 1H); LRMS (ES) m/z 510.9 (M.sup.+ + 1) Example 28 28 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.88 (dd, J = 1,3,4-oxadiazol-2-y1)-2- 8.0, 1.6 Hz, 1H), 7.77 (dd, J = 10.0, 1.6 fluorobenzyl)-N-(2,3- Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.18 (d, dihydro-1H-inden-5-yl)-1- J = 8.0 Hz, 1H), 7.05 (s, 0.25H), 7.00 (d, J = iminothiomorpholin-4- 1.6 Hz, 1H), 6.92 (s, 0.5H), 6.87 (dd, J = carboxamide 1-oxide 8.0, 2.0 Hz, 1H), 6.80 (s, 0.25H), 4.91 (s, 2H), 3.82-3.62 (m, 4H), 2.91-2.87 (m, 4H), 2.84-2.82 (m, 4H), 2.50 (s, 1H), 2.14- 2.10 (m, 2H); LRMS (ES) m/z 520.9 (M.sup.+ + 1)

Example 29: Synthesis of Compound 29, Diethyl (4-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(3,4-difluorophenyl)carbamoyl)-1-oxidothiomorpholin-1-ylidene)phosphoramidate

##STR00169##

[0234] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholin-4-carboxamide 1-oxide (100.00%, 0.080 g, 0.155 mmol) obtained according to substantially the same reactions as described in example 6, 1-ethoxyphosphoryloxyethane (100.00%, 1.000 equiv., 0.155 mmol), iodine (100.00%, 0.100 equiv., 0.016 mmol) and hydrogen peroxide (100.00%, 1.000 equiv., 0.155 mmol) were dissolved in dichloromethane (10 mL) at room temperature, after which the resulting solution was stirred overnight at the same temperature. Saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%) and concentrated to obtain the title compound (0.040 g, 39.56%) in a colorless oil form.

[0235] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.90 (dd, J=8.0, 1.6 Hz, 1H), 7.78 (dd, J=10.4, 1.6 Hz, 1H), 7.69-7.65 (m, 1H), 7.21-7.14 (m, 1H), 7.06 (s, 0.25H), 7.03-6.97 (m, 1H), 6.93 (s, 0.5H), 6.89-6.86 (m, 1H), 6.80 (s, 0.25H), 4.90 (s, 2H), 4.29-4.25 (m, 2H), 4.06-4.02 (m, 4H), 3.91-3.87 (m, 2H), 3.60-3.54 (m, 2H), 3.40-3.35 (m, 2H), 3.05-3.00 (m, 2H), 1.33-1.30 (m, 6H); LRMS (ES) m/z 652.9 (M.sup.++1)

Example 30: Synthesis of Compound 30, 1-(acetylimino)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)thiomorpholin-4-carboxamide 1-oxide

##STR00170##

[0236] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholin-4-carboxamide 1-oxide (100.00%, 0.034 g, 0.068 mmol) obtained according to substantially the same reactions as described in example 7, acetyl chloride (100.00%, 2.000 equiv., 0.136 mmol) and triethylamine (100.00%, 1.500 equiv., 0.102 mmol) were dissolved in dichloromethane (5 mL) at room temperature, after which the resulting solution was stirred overnight at the same temperature. Saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%) and concentrated to obtain the title compound (0.015 g, 40.68%) in a colorless oil form.

[0237] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.27 (dd, J=2.0, 0.4 Hz, 1H), 8.43 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (dd, J=8.4, 0.4 Hz, 1H), 7.22-7.05 (m, 2H), 7.09 (s, 0.25H), 7.00-6.94 (m, 1H), 6.96 (s, 0.5H), 6.83 (s, 0.25H), 5.08 (s, 2H), 3.90-3.80 (m, 2H), 3.60-3.50 (m, 4H), 3.30-3.20 (m, 2H), 2.09 (s, 3H); LRMS (ES) m/z 541.9 (M.sup.++1)

Examples 31 to 34: Synthesis of Compounds 31 to 34

[0238] Compounds 31 to 34 according to examples 31 to 34 were prepared in accordance with the same reactions as described in steps 1, 2 and 3 of example 1, respectively, except for using the reactants of Table 10 below instead of isocyanatobenzene in step 1 of example 1. Table 10 shows the properties and yields of the products prepared in each of steps 1 to 3 in examples 31 to 34.

TABLE-US-00010 TABLE 10 Yield/property of Yield/property of Yield/property of product product product obtained from obtained from obtained from Classification Reactant in step 1 step 1 step 2 step 3 Example 31 1-isocyanato-3- 0.436 g, 56.21% 0.092 g, 51.71% 0.065 g, 64.55% (trifluoromethyl)- White solid Light yellow solid White solid benzene Example 32 1-isocyanato-3- 0.738 g, 83.17% 0.125 g, 63.86% 0.110 g, 82.47% methyl-benzene White solid Colorless oil White solid Example 33 1,4-difluoro-2- 0.583 g, 70.01% 0.101 g, 53.86% 0.090 g, 83.73% isocyanato-benzene White solid Colorless oil White solid Example 34 1-(3- 0.633 g, 81.14% 0.030 g, 16.79% 0.005 g, 15.71% isocyanatophenyl)-1H- White solid White solid White solid pyrrole

[0239] The names of compounds 31 to 34 prepared in each of examples 31 to 34, and the NMR and LC-Mass analysis results thereof are shown in table 11 below.

TABLE-US-00011 TABLE 11 Compound Classification No. Compound name NMR/LRMS Example 31 31 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.91 (d, J = 1,3,4-oxadiazol-2-y1)-2- 8.0 Hz, 1H), 7.79 (d, J = 10.2 Hz, 1H), 7.69 fluorobenzyl)-1-imino-N- (t, J = 7.6 Hz, 1H), 7.54-7.42 (m, 2H), (3-(trifluoro- 7.42 (s, 1H), 7.34-7.06 (m, 1H), 6.93 (t, J = methyl)phenyl)thio- 51.7 Hz, 1H), 4.98 (s, 2H), 3.79-3.73 morpholin-4-carboxamide (m, 2H), 3.68-3.62 (m, 2H), 2.89 (t, J = 1-oxide 5.2 Hz, 4H); LRMS (ES) m/z 548.7 (M.sup.+ + 1). Example 32 32 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.88 (d, J = 1,3,4-oxadiazol-2-y1)-2- 8.0 Hz, 1H), 7.76 (d, J = 10.1 Hz, 1H), 7.67 fluorobenzyl)-1-imino-N- (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), (m-tolyl)thiomorpholin-4- 7.06-6.80 (m, 4H), 4.93 (s, 2H), 3.80- carboxamide 1-oxide 3.76 (m, 2H), 3.69-3.64 (m, 2H), 2.83 (t, J = 5.2 Hz, 4H), 2.35 (s, 3H); LRMS (ES) m/z 494.8 (M.sup.+ + 1). Example 33 33 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (dd, J = 1,3,4-oxadiazol-2-y1)-2- 8.0, 1.5 Hz, 1H), 7.79-7.72 (m, 2H), fluorobenzyl)-N-(2,5- 7.16-7.10 (m, 1H), 7.06-6.80 (m, 3H), difluorophenyl)-1- 4.90 (s, 2H), 3.78-3.74 (m, 2H), 3.69- iminothiomorpholin-4- 3.64 (m, 2H), 2.88 (t, J = 5.2 Hz, 4H); carboxamide 1-oxide LRMS (ES) m/z 516.8 (M.sup.+ + 1). Example 34 34 N-(3-(1H-pyrrol-1- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.91 (dd, J = yl)phenyl)-N-(4-(5- 8.0, 1.5 Hz, 1H), 7.79 (dd, J = 10.1, 1.5 (difluoromethyl)-1,3,4- Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.41 (t, J = oxadiazol-2-y1)-2- 8.0 Hz, 1H), 7.27-7.25 (m, 1H), 7.21- fluorobenzyl)-1- 7.20 (m, 1H), 7.06-6.39 (m, 4H), 6.39 (t, iminothiomorpholin-4- J = 2.2 Hz, 2H), 5.00 (s, 2H), 3.83-3.78 carboxamide 1-oxide (m, 2H), 3.73-3.66 (m, 2H), 2.91 (t, J = 5.2 Hz, 4H); LRMS (ES) m/z 545.8 (M.sup.+ + 1).

Example 35: Synthesis of Compound 35, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-fluorophenyl)-1-iminothiomorpholin-4-sulfonamide 1-oxide

[Step 1] Synthesis of N-(3-fluorophenyl)thiomorpholin-4-sulfonamide

##STR00171##

[0240] 3-methyl-1-(thiomorpholinosulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate (100.00%, 0.580 g, 1.459 mmol) prepared in step 3 of example 18 and 3-fluoroaniline (100.00% solution, 0.14 mL, 1.462 mmol) were dissolved in acetonitrile (10 mL) at room temperature, after which the resulting solution was heated under reflux for 18 hours, and a reaction was finished by lowering the temperature to room temperature. Solvent was removed from the reaction mixture under reduced pressure, after which saturated aqueous solution of sodium hydrogen carbonate was poured into the resulting concentrate, and extraction was performed with dichloromethane, then filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=5 to 20%) and concentrated to obtain the title compound (0.253 g, 62.72%) in a light yellow solid form.

[Step 2] Synthesis of N-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorobenzyl]-N-(3-fluorophenyl)thiomorpholin-4-sulfonamide

##STR00172##

[0241] The title compound (0.153 g, 70.13%) was obtained in a white solid form according to substantially the same reaction as described in step 2 of example 1 except for using N-(3-fluorophenyl)thiomorpholin-4-sulfonamide prepared in step 1.

[Step 3] Synthesis of Compound 35

##STR00173##

[0242] The title compound (0.151 g, 92.96%) was obtained in a white solid form according to substantially the same reaction as described in step 3 of example 1 except for using N-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorobenzyl]-N-(3-fluorophenyl)thiomorpholin-4-sulfonamide prepared in step 2.

[0243] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.86 (dd, J=8.0, 1.5 Hz, 1H), 7.79 (dd, J=9.9, 1.5 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.37-7.31 (m, 1H), 7.09-6.80 (m, 4H), 0.94 (s, 2H), 3.82-3.76 (m, 2H), 3.73-3.67 (m, 2H), 3.19-3.09 (m, 4H); LRMS (ES) m/z 534.7 (M.sup.++1).

Example 36: Synthesis of Compound 36, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-iminothiomorpholin-4-sulfonamide 1-oxide

[Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]-N-(3-fluorophenyl)thiomorpholin-4-sulfonamide

##STR00174##

[0244] The title compound (0.208 g, 98.68%) was obtained in a colorless oil form according to substantially the same reaction as described in step 2 of example 35 except for using 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole.

[Step 2] Synthesis of Compound 36

##STR00175##

[0245] The title compound (0.105 g, 47.5%) was obtained in a white solid form according to the same reaction as described in step 3 of example 1 except for using N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]-N-(3-fluorophenyl)thiomorpholin-4-sulfonamide obtained from step 1.

[0246] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.29 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.38-7.32 (m, 1H), 7.23-7.20 (m, 2H), 7.08-6.83 (m, 2H), 5.06 (s, 2H), 3.86-3.82 (m, 2H), 3.78-3.74 (m, 2H); LRMS (ES) m/z 517.7 (M.sup.++1).

Example 37: Synthesis of Compound 37, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-((methylsulfonyl)imino)-N-phenylthiomorpholin-4-carboxamide 1-oxide

##STR00176##

[0247] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenylthiomorpholin-4-carboxamide 1-oxide (100.00%, 0.200 g, 0.417 mmol) obtained according to substantially the same reactions as described in example 1, methanesulfonyl chloride (100.00%, 1.500 equiv., 0.626 mmol) and triethylamine (100.00%, 2.000 equiv., 0.834 mmol) were dissolved in dichloromethane (10 mL) at room temperature, after which the resulting solution was stirred overnight at the same temperature. Saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%) and concentrated to obtain the title compound (0.180 g, 77.39%) in a colorless oil form.

[0248] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (dd, J=8.0, 1.6 Hz, 1H), 7.75 (dd, J=10.0, 1.6 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.38 (t, J=7.8 Hz, 2H), 7.28-7.24 (m, 1H), 7.13-7.11 (m, 2H), 7.05 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 4.94 (s, 2H), 4.00-3.96 (m, 2H), 3.57-3.44 (m, 4H), 3.08 (s, 3H), 3.06-3.01 (m, 2H); LRMS (ES) m/z 558.9 (M.sup.++1)

Example 38: Synthesis of Compound 38, Methyl (4-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)carbamoyl)-1-oxidothiomorpholin-1-ylidene)carbamate

##STR00177##

[0249] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenylthiomorpholin-4-carboxamide 1-oxide (100.00%, 0.200 g, 0.417 mmol) obtained according to substantially the same reactions as described in example 1, methyl carbonochloridate (100.00%, 1.500 equiv., 0.626 mmol) and triethylamine (100.00%, 2.000 equiv., 0.834 mmol) were dissolved in dichloromethane (5 mL) at room temperature, after which the resulting solution was stirred overnight at the same temperature. Saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%) and concentrated to obtain the title compound (0.150 g, 66.91%) in a colorless oil form.

[0250] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.88 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (dd, J=10.0, 1.6 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.40-7.36 (m, 2H), 7.26-7.23 (m, 1H), 7.14-7.12 (m, 2H), 7.05 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 4.94 (s, 2H), 3.93-3.92 (m, 2H), 3.58 (s, 3H), 3.56-3.52 (m, 2H), 3.43-3.38 (m, 2H), 3.05-2.99 (m, 2H); LRMS (ES) m/z 538.9 (M.sup.++1)

Example 39: Synthesis of Compound 39, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-(methylimino)-N-phenylthiomorpholin-4-carboxamide 1-oxide

##STR00178##

[0251] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenylthiomorpholin-4-carboxamide 1-oxide (100.00%, 0.200 g, 0.417 mmol) obtained according to substantially the same reactions as described in example 1, sodium carbonate (100.00%, 5.000 equiv., 2.086 mmol) and trimethyloxonium tetrafluoroborate (100.00%, 1.000 equiv., 0.417 mmol) were dissolved in dichloromethane (5 mL) at room temperature, after which the resulting solution was stirred overnight at the same temperature. Saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%) and concentrated to obtain the title compound (0.015 g, 7.29%) in a colorless oil form.

[0252] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.88 (dd, J=8.0, 1.2 Hz, 1H), 7.75 (dd, J=10.0, 1.6 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.39-7.35 (m, 2H), 7.24-7.20 (m, 1H), 7.14-7.12 (m, 2H), 7.05 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 4.94 (s, 2H), 3.82-3.76 (m, 2H), 3.58-3.51 (m, 2H), 2.87-2.78 (m, 4H), 2.74 (s, 3H); LRMS (ES) m/z 494.9 (M.sup.++1)

Example 40: Synthesis of Compound 40, 1-(acetylimino)-N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholin-4-carboxamide 1-oxide

##STR00179##

[0253] The title compound (0.020 g, 36.78%) was obtained in a colorless oil form according to substantially the same reaction as described in example 30 except for using N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenylthiomorpholin-4-carboxamide 1-oxide obtained in substantially the same manner as in example 1, instead of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholin-4-carboxamide 1-oxide.

[0254] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.88 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (dd, J=10.0, 1.6 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.41-7.37 (m, 2H), 7.27-7.23 (m, 1H), 7.15-7.12 (m, 2H), 7.05 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 4.95 (s, 2H), 3.88-3.81 (m, 2H), 3.60-3.55 (m, 2H), 3.49-3.39 (m, 2H), 3.01-2.97 (m, 2H), 2.05 (s, 3H); LRMS (ES) m/z 522.9 (M.sup.++1)

Examples 41 and 42: Synthesis of Compounds 41 and 42

[0255] Compounds 41 and 42 according to examples 41 and 42 were prepared in accordance with the same reactions as described in steps 1, 2 and 3 of example 1, respectively, except for using the reactants of Table 12 below instead of isocyanatobenzene in step 1 of example 1. Table 12 shows the properties and yields of the products prepared in each of steps 1 to 3 in examples 41 and 42.

TABLE-US-00012 TABLE 12 Yield/property of Yield/property of Yield/property of product product product Reactant obtained from obtained from obtained from Classification in step 1 step 1 step 2 step 3 Example 41 1-bromo-3- 2.500 g, 82.18% 2.500 g, 71.39% 0.080 g, 75.56% isocyanato-benzene White solid Colorless oil Colorless oil Example 42 1,2-dichloro-4- 0.600 g, 77.48% 0.065 g, 18.29% 0.020 g, 29.03% isocyanato-benzene White solid Colorless oil Colorless oil

[0256] The names of compounds 41 and 42 prepared in each of examples 41 and 42, and the NMR and LC-Mass analysis results thereof are shown in table 13 below.

TABLE-US-00013 TABLE 13 Compound Classification No. Compound name NMR/LRMS Example 41 41 N-(3-bromophenyl)-N-(4- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.90 (dd, J = (5-(difluoromethyl)-1,3,4- 8.0, 1.6 Hz, 1H), 7.79 (dd, J = 10.4, 1.6 oxadiazol-2-yl)-2- Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.37- fluorobenzyl)-1- 7.33 (m, 2H), 7.26-7.24 (m, 1H), 7.08- iminothiomorpholin-4- 7.06 (m, 1H), 7.08 (s, 0.25H), 6.93 (s, carboxamide 1-oxide 0.5H), 6.80 (s, 0.25H), 4.93 (s, 2H), 3.80- 3.63 (m, 4H), 2.93-3.86 (m, 4H), 2.55 (brs, 1H); LRMS (ES) m/z 560.9 (M.sup.+ + 1) Example 42 42 N-(3,4-dichlorophenyl)-N- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.91 (dd, J = (4-(5-(difluoromethyl)- 8.0, 1.6 Hz, 1H), 7.80 (dd, J = 10.0, 1.6 1,3,4-oxadiazol-2-yl)-2- Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.45- fluorobenzyl)-1- 7.42 (m, 1H), 7.28-7.25 (m, 1H), 7.06 (s, iminothiomorpholin-4- 0.25H), 6.99 (dd, J= 8.6, 2.6 Hz, 1H), 6.93 carboxamide 1-oxide (s, 0.5H), 6.80 (s, 0.25H), 4.92 (s, 2H), 3.78-3.63 (m, 4H), 2.95-2.92 (m, 4H), 2.55 (brs, 1H); LRMS (ES) m/z 549.9 (M.sup.+ + 1)

Example 43: Synthesis of Compound 43, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-(3-(thiazole-5-yl)phenyl)thiomorpholin-4-carboxamide 1-oxide

[Step 1] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(thiazol-5-yl)phenyl)thiomorpholin-4-carboxamide

##STR00180##

[0257] N-(3-bromophenyl)-N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)thiomorpholin-4-carboxamide (100.00%, 0.200 g, 0.379 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (100.00%, 1.500 equiv., 0.569 mmol), (1,1-bis(di-tert-butylphosphino)ferrocene)palladium(II) dichloride (100.00%, 0.100 equiv., 0.038 mmol) and cesium carbonate (100.00%, 2.500 equiv, 0.948 mmol) were mixed in 1,4-dioxane (10 mL)/water (3 mL), after which the resulting mixture was irradiated with microwave, then heated at 100 C. for 30 minutes, and then a reaction was finished by lowering the temperature to room temperature. Solvent was removed from the reaction mixture under reduced pressure, after which saturated aqueous solution of sodium hydrogen carbonate was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 30%) and concentrated to obtain the title compound (0.013 g, 6.45%) in a colorless oil form.

[Step 2] Synthesis of Compound 43

##STR00181##

[0258] The title compound (0.004 g, 29.07%) was obtained in a colorless oil form according to substantially the same reaction as described in step 3 of example 1 except for using N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(thiazol-5-yl)phenyl)thiomorpholin-4-carboxamide prepared in step 1 instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholin-4-carboxamide.

[0259] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.81 (s, 1H), 8.07 (s, 1H), 7.91 (dd, J=8.0, 1.6 Hz, 1H), 7.79 (dd, J=10.2, 1.4 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.43-7.39 (m, 2H), 7.35 (s, 1H), 7.11-7.09 (m, 1H), 7.05 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.00 (s, 2H), 3.83-3.50 (m, 4H), 2.91-2.88 (m, 4H), 2.50 (brs, 1H); LRMS (ES) m/z 563.9 (M.sup.++1)

Example 44: Synthesis of Compound 44, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(furan-2-yl)phenyl)-1-iminothiomorpholin-4-carboxamide 1-oxide

[Step 1] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(furan-2-yl)phenyl)thiomorpholin-4-carboxamide

##STR00182##

[0260] The title compound (0.030 g, 15.38%) was obtained in a colorless oil form according to substantially the same reaction as described in step 1 of example 43 except for using 2-furylboronic acid instead of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole.

[Step 2] Synthesis of Compound 44

##STR00183##

[0261] The title compound (0.010 g, 36.28%) was obtained in a colorless oil form according to substantially the same reaction as described in step 2 of example 43 except for using N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(furan-2-yl)phenyl)thiomorpholin-4-carboxamide obtained from step 1.

[0262] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (dd, J=8.0, 1.6 Hz, 1H), 7.78 (dd, J=10.0, 1.6 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.51-7.48 (m, 3H), 7.37 (t, J=7.8 Hz, 1H), 7.05 (s, 0.25H), 7.01-6.99 (m, 1H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 6.68-6.67 (m, 1H), 6.51-6.50 (m, 1H), 4.98 (s, 2H), 3.85-3.66 (m, 4H), 2.90-2.86 (m, 4H), 2.55 (brs, 1H); LRMS (ES) m/z 546.9 (M.sup.++1)

Example 45: Synthesis of Compound 45, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(2,5-difluorophenyl)-1-iminothiomorpholin-4-carboxamide 1-oxide

[Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]-N-(2,5-difluorophenyl)thiomorpholin-4-carboxamide

##STR00184##

[0263] The title compound (0.074 g, 40.89%) was obtained in a white solid form according to substantially the same reaction as described in step 1 of example 7 except for using N-(2,5-difluorophenyl)thiomorpholin-4-carboxamide instead of N-(3,4-difluorophenyl)thiomorpholin-4-carboxamide in step 1 of example 7.

[Step 2] Synthesis of Compound 45

##STR00185##

[0264] The title compound (0.047 g, 59.56%) was obtained in a white solid form according to substantially the same reaction as described in step 2 of example 7 except for using N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]-N-(2,5-difluorophenyl)thiomorpholin-4-carboxamide obtained from step 1.

[0265] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.24 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.16-6.83 (m, 4H), 5.02 (s, 2H), 3.82-3.76 (m, 2H), 3.71-3.65 (m, 2H), 2.97-2.93 (m, 4H); LRMS (ES) m/z 499.9 (M.sup.++1).

Example 46: Synthesis of Compound 46, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-N-(2,5-difluorophenyl)-1-iminothiomorpholin-4-carboxamide 1-oxide

[Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-N-(2,5-difluorophenyl)thiomorpholin-4-carboxamide

##STR00186##

[0266] The title compound (0.057 g, 30.33%) was obtained in a white solid form according to substantially the same reaction as described in step 1 of example 45 except for using 2-(6-(bromomethyl)-5-fluoropyridine-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole instead of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole in step 1 of example 45.

[Step 2] Synthesis of Compound 46

##STR00187##

[0267] The title compound (0.048 g, 79.16%) was obtained in a light yellow solid form according to substantially the same reaction as described in step 2 of example 7 except for using N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-N-(2,5-difluorophenyl)thiomorpholin-4-carboxamide obtained from step 1.

[0268] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.10 (s, 1H), 8.12 (dd, J=9.3, 1.7 Hz, 1H), 7.17-6.84 (m, 4H), 5.09 (s, 2H), 3.82-3.76 (m, 2H), 3.70-3.64 (m, 2H), 3.11-3.00 (m, 4H), 3.11-3.00 (m, 4H); LRMS (ES) m/z 517.8 (M.sup.++1).

Example 47: Synthesis of Compound 47, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-(3-(pyridin-3-yl)phenyl)thiomorpholin-4-carboxamide 1-oxide

[Step 1] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(pyridin-3-yl)phenyl)thiomorpholin-4-carboxamide

##STR00188##

[0269] The title compound (0.113 g, 28.35%) was obtained in a colorless oil form according to substantially the same reaction as described in step 1 of example 44 except for using 3-pyridylboronic acid instead of 2-furylboronic acid.

[Step 2] Synthesis of Compound 47

##STR00189##

[0270] The title compound (0.080 g, 66.84%) was obtained in a colorless oil form according to substantially the same reaction as described in step 2 of example 44 except for using N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(pyridin-3-yl)phenyl)thiomorpholin-4-carboxamide prepared from step 1.

[0271] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.78 (d, J=1.6 Hz, 1H), 8.63 (dd, J=4.8, 1.6 Hz, 1H), 7.89 (dd, J=8.0, 1.6 Hz, 1H), 7.82-7.70 (m, 3H), 7.49-7.36 (m, 4H), 7.16-7.13 (m, 1H), 7.05 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 5.01 (s, 2H), 3.83-3.64 (m, 4H), 2.92-2.85 (m, 4H), 2.50 (brs, 1H); LRMS (ES) m/z 557.9 (M.sup.++1)

Example 48: Synthesis of Compound 48, (1S,4S)N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(2-fluorophenyl)-5-(1-imino-1-oxidotetrahydro-2H-thiopyran-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxamide

[Step 1] Synthesis of (1S,4S)N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-pyridyl)methyl)-N-(2-fluorophenyl)-5-(tetrahydro-2H-thiopyran-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxamide

##STR00190##

[0272] (1S,4S)N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(2-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxamide (100.00%, 0.300 g, 0.675 mmol), tetrahydrothiopyran-4-one (100.00%, 1.000 equiv., 0.675 mmol) and sodium triacetoxyborohydride (100.00%, 2.000 equiv., 1.350 mmol) were dissolved in dichloromethane (10 mL) at room temperature, after which the resulting solution was stirred overnight at the same temperature. Saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%) and concentrated to obtain the title compound (0.284 g, 77.25%) in a colorless oil form.

[Step 2] Synthesis of Compound 48

##STR00191##

[0273] The title compound (0.200 g, 66.63%) was obtained in a colorless oil form according to substantially the same reaction as described in step 3 of example 1 except for using (1S,4S)N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-pyridyl)methyl)-N-(2-fluorophenyl)-5-(tetrahydro-2H-thiopyran-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxamide prepared in step 1 instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholin-4-carboxamide.

[0274] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.16 (d, J=1.6 Hz, 1H), 8.35 (dd, J=8.2, 2.2 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.26-7.17 (m, 2H), 7.11-7.07 (m, 2H), 7.07 (s, 0.25H), 6.94 (s, 0.5H), 6.81 (s, 0.25H), 5.09-4.95 (m, 2H), 4.34 (s, 1H), 3.40 (s, 1H), 3.37-3.27 (m, 2H), 3.05-2.90 (m, 2H), 2.88-2.82 (m, 2H), 2.65-2.64 (m, 1H), 2.58-2.52 (m, 2H), 2.50 (brs, 1H), 2.22-2.12 (m, 2H), 2.06-1.85 (m, 2H), 1.78-1.60 (m, 2H); LRMS (ES) m/z 576.9 (M.sup.++1)

Examples 49 to 51: Synthesis of Compounds 49 to 51

[0275] Compounds 49 to 51 according to examples 49 to 51 were prepared in accordance with the same reactions as described in steps 1, 2 and 3 of example 1, respectively, except for using 2,4-dichloro-1-isocyanato-benzene instead of isocyanatobenzene in step 1 of example 1, and using the reactant of Table 14 below instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole in step 2. Table 14 shows the properties and yields of the products prepared in each of steps 1 to 3 in examples 49 to 51.

TABLE-US-00014 TABLE 14 Yield/property of Yield/property of Yield/property of product product product Reactant obtained from obtained from obtained from Classification in step 2 step 1 step 2 step 3 Example 49 2-(6- 0.740 g, 95.55% 0.088 g, 51.21% 0.044 g, 47.08% (bromomethyl)pyridin- White solid Yellow solid Light yellow solid 3-y1)-5- (difluoromethyl)-1,3,4- oxadiazole Example 50 2-(6-(bromomethyl)-5- Same as step 1 0.041 g, 23.04% 0.023 g, 52.92% fluoropyridin-3-y1)-5- of example 49 Yellow solid White solid (difluoromethyl)-1,3,4- oxadiazole Example 51 2-[4-(bromomethyl)-3- Same as step 1 0.072 g, 40.52% 0.054 g, 70.76% fluoro-phenyl]-5- of example 49 White solid White solid (difluoromethyl)-1,3,4- oxadiazole

[0276] The names of compounds 49 to 51 prepared in each of examples 49 to 51, and the NMR and LC-Mass analysis results thereof are shown in table 15 below.

TABLE-US-00015 TABLE 15 Compound Classification No. Compound name NMR/LRMS Example 49 49 N-(2,4-dichlorophenyl)-N- .sup.1H NMR (400 MHz, CDCl.sub.3) 9.22 (d, J = ((5-(5-(difluoromethyl)- 1.7 Hz, 1H), 8.38 (dd, J = 8.2, 2.2 Hz, 1H), 1,3,4-oxadiazol-2- 7.63 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 2.0 yl)pyridin-2-yl)methyl)-1- Hz, 1H), 7.34-7.30 (m, 2H), 6.95 (t, J = iminothiomorpholin-4- 51.7 Hz, 1H), 4.95 (s, 2H), 3.76-3.70 (m, carboxamide 1-oxide 2H), 3.65-3.59 (m, 2H), 2.96-2.91 (m, 4H), 2.58 (brs, 1H); LRMS (ES) m/z 533.8 (M.sup.+ + 1). Example 50 50 N-(2,4-dichlorophenyl)-N- .sup.1H NMR (400 MHz, CDCl.sub.3) 9.10 (s, ((5-(5-(difluoromethyl)- 1H), 8.10 (dd, J= 9.3, 1.7 Hz, 1H), 7.53 (d, 1,3,4-oxadiazol-2-y1)-3- J = 2.3 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), fluoropyridin-2-yl)methyl)- 7.32-7.30 (m, 1H), 6.96 (t, J = 51.6 Hz, 1-iminothiomorpholin-4- 1H), 5.01 (s, 2H), 3.74-3.70 (m, 2H), 3.65- carboxamide 1-oxide 3.59 (m, 2H), 3.10-3.05 (m, 4H), 2.58 (brs, 1H); LRMS (ES) m/z 551.8 (M.sup.+ + 1). Example 51 51 N-(2,4-dichlorophenyl)-N- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (dd, J = (4-(5-(difluoromethyl)- 8.0, 1.4 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 1,3,4-oxadiazol-2-y1)-2- 7.71 (dd, J = 9.9, 1.3 Hz, 1H), 7.51 (d, J = fluorobenzyl)-1- 2.4 Hz, 1H), 7.24 (dd, J = 8.5, 2.4 Hz, 1H), iminothiomorpholin-4- 7.06-6.80 (m, 2H), 4.87 (s, 2H), 3.75- carboxamide 1-oxide 3.68 (m, 2H), 3.64-3.58 (m, 2H), 2.85 (t, J = 5.2 Hz, 4H); LRMS (ES) m/z 550.7 (M.sup.+ + 1).

Example 52: Synthesis of Compound 52, 1-(acetylimino)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholin-4-carboxamide 1-oxide

##STR00192##

[0277] The title compound (0.100 g, 57.30%) was obtained in a colorless oil form according to substantially the same reactions as described in example 30 except for using N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-imino-N-phenylthiomorpholin-4-carboxamide 1-oxide obtained according to substantially the same reaction as described in example 3, instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholin-4-carboxamide 1-oxide.

[0278] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.26 (d, J=1.6 Hz, 1H), 8.41 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.40-7.36 (m, 2H), 7.23-7.19 (m, 3H), 7.08 (s, 0.25H), 6.95 (s, 0.5H), 6.82 (s, 0.25H), 5.12 (s, 2H), 3.87-3.83 (m, 2H), 3.60-3.55 (m, 4H), 3.23-3.17 (m, 2H), 2.10 (s, 3H); LRMS (ES) m/z 505.9 (M.sup.++1)

Example 53: Synthesis of Compound 53, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-((methylsulfonyl)imino)-N-phenylthiomorpholin-4-carboxamide 1-oxide

##STR00193##

[0279] The title compound (0.110 g, 47.05%) was obtained in a colorless oil form according to substantially the same reaction as described in example 37 except for using N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-imino-N-phenylthiomorpholin-4-carboxamide 1-oxide obtained according to substantially the same reaction as described in example 3, instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholin-4-carboxamide 1-oxide.

[0280] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.26 (d, J=1.6 Hz, 1H), 8.41 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.39-7.35 (m, 2H), 7.23-7.17 (m, 2H), 7.08 (s, 0.25H), 6.96 (s, 0.5H), 6.83 (s, 0.25H), 5.13 (s, 2H), 4.04-3.98 (m, 2H), 3.62-3.51 (m, 4H), 3.33-3.28 (m, 2H), 3.11 (s, 3H); LRMS (ES) m/z 541.9 (M.sup.++1)

Examples 54 to 57: Synthesis of Compounds 54 to 57

[0281] Compounds 54 to 57 according to examples 54 to 57 were prepared in accordance with the same reactions as described in steps 1, 2 and 3 of example 1, respectively, except for using 1-fluoro-2-isocyanato-benzene instead of isocyanatobenzene in step 1 of example 1, and using the reactant of table 16 below instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole in step 2. Table 16 shows the properties and yields of the products prepared in each of steps 1 to 3 in examples 54 to 57.

TABLE-US-00016 TABLE 16 Yield/property of Yield/property of Yield/property of product product product Reactant obtained from obtained from obtained from Classification in step 2 step 1 step 2 step 3 Example 54 2-(4-(bromomethyl)-3,5- 1.200 g, 68.44% 0.078 g, 38.69% 0.057 g, 68.67% difluoro-phenyl)-5- White solid White solid White solid (difluoromethyl)-1,3,4- oxadiazole Example 55 2-(6-(bromomethyl)-5- Same as step 1 0.041 g, 49.3%, 0.041 g, 49.29% fluoropyridin-3-yl)-5- of example 54 White solid White solid (difluoromethyl)-1,3,4- oxadiazole Example 56 2-(4-(bromomethyl)-3- Same as step 1 0.147 g, 75.74% 0.137 g, 73.81% fluoro-phenyl)-5- of example 54 White solid White solid (difluoromethyl)-1,3,4- oxadiazole Example 57 2-(6- Same as step 1 0.054 g, 28.87% 0.036 g, 62.35% (bromomethyl)pyridin- of example 54 Light yellow oil Light yellow solid 3-y1)-5- (difluoromethyl)-1,3,4- oxadiazole

[0282] The names of compounds 54 to 57 prepared in each of examples 54 to 57, and the NMR and LC-Mass analysis results thereof are shown in table 17 below.

TABLE-US-00017 TABLE 17 Compound Classification No. Compound name NMR/LRMS Example 54 54 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.64 (d, J = 1,3,4-oxadiazol-2-y1)-2,6- 7.2 Hz, 2H), 7.32-7.28 (m, 1H), 7.19- difluorobenzyl)-N-(2- 7.14 (m, 3H), 6.94 (t, J = 51.6 Hz, 1H), fluorophenyl)-1- 4.89 (s, 2H), 3.75-3.71 (m, 2H), 3.64- iminothiomorpholin-4- 3.58 (m, 2H), 2.75 (t, J = 5.1 Hz, 4H); carboxamide 1-oxide LRMS (ES) m/z 516.8 (M.sup.+ + 1). Example 55 55 N-((5-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 9.10 (s, 1,3,4-oxadiazol-2-y1)-3- 1H), 8.10 (dd, J = 9.3, 1.7 Hz, 1H), 7.34- fluoropyridin-2-yl)methyl- 7.25 (m, 3H), 7.20-7.15 (m, 2H), 6.96 (t, N-(2-fluorophenyl)-1- J = 51.6 Hz, 1H), 5.10 (s, 2H), 3.80-3.75 iminothiomorpholin-4- (m, 2H), 3.69-3.63 (m, 2H), 3.01-2.98 carboxamide 1-oxide (m, 4H); LRMS (ES) m/z 499.8 (M.sup.+ + 1). Example 56 56 N-(4-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (dd, J = 1,3,4-oxadiazol-2-yl)-2- 8.0, 1.6 Hz, 1H), 7.78 (t, J = 7.6 Hz, fluorobenzyl)-N-(2- 1H), 7.70 (dd, J = 10.0, 1.6 Hz, 1H), 7.29- fluorophenyl)-1- 7.25 (m, 1H), 7.18-7.13 (m, 3H), 6.92 (t, iminothiomorpholin-4- J = 51.7 Hz, 1H), 4.90 (s, 2H), 3.79-3.73 carboxamide 1-oxide (m, 2H), 3.67-3.61 (m, 2H), 2.79 (t, J = 5.2 Hz, 4H); LRMS (ES) m/z 498.8 (M.sup.+ + 1). Example 57 57 N-((5-(5-(difluoromethyl)- .sup.1H NMR (400 MHz, CDCl.sub.3) 9.21 (d, J = 1,3,4-oxadiazol-2- 1.7 Hz, 1H), 8.37 (dd, J = 8.2, 2.2 Hz, 1H), yl)pyridin-2-yl)methyl-N- 7.65 (d, J = 8.2 Hz, 1H), 7.33-7.22 (m, (2-fluorophenyl)-1- 2H), 7.19-7.13 (m, 2H), 6.95 (t, J = 51.6 iminothiomorpholin-4- Hz, 1H), 5.02 (s, 2H), 3.80-3.76 (m, 2H), carboxamide 1-oxide 3.68-3.64 (m, 2H), 2.89-2.88 (m, 4H); LRMS (ES) m/z 481.7 (M.sup.+ + 1).

Example 58: Synthesis of Compound 58, N-(4-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-phenylureido)-1-oxidotetrahydro-2H-thiopyran-1-yliden)-2,2,2-trifluoroacetamide

Example 59: Synthesis of Compound 59, 1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-(1-imino-1-oxidotetrahydro-2H-thiopyran-4-yl)-1-phenylurea

[Step 1] Synthesis of (4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)carbamic chloride

##STR00194##

[0283] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)aniline (1.380 g, 4.322 mmol) and N,N-diisopropylethylamine (0.753 mL, 4.322 mmol) were dissolved in dichloromethane (20 mL), after which triphosgene (0.898 g, 3.025 mmol) was added to the resulting solution at 0 C., stirred at the same temperature for 30 minutes, and further stirred at room temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to obtain the title compound (0.880 g, 53.3%) in a white solid form.

[Step 2] Synthesis of Compounds 58 and 59

##STR00195##

[0284] N-(4-amino-1-oxidotetrahydro-2H-thiopyran-1-ylidene)-2,2,2-trifluoroacetamide 2,2,2-trifluoroacetate (0.500 g, 1.396 mmol) was dissolved in N,N-dimethylformamide (10 mL) at 0 C., after which sodium hydride (60.00%, 0.140 g, 3.489 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. (4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)carbamic chloride (0.586 g, 1.535 mmol) prepared in step 1 was added to the reaction mixture and further stirred at room temperature for three hours. Water was poured into the reaction mixture and extracted with ethyl acetate. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to obtain each of compound 58 (0.110 g, 13.4%) and compound 59 (0.160 g, 23.2%) in a white solid form.

[0285] <Compound 58> .sup.1H NMR (400 MHz, CDCl.sub.3) 7.86 (dd, J=8.0, 1.2 Hz, 1H), 7.72 (dd, J=9.8, 1.4 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.43-7.34 (m, 3H), 7.13-7.12 (m, 2H), 7.05 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 5.02 (s, 2H), 4.39 (d, J=7.2 Hz, 1H), 4.11-4.02 (m, 1H), 3.89-3.85 (m, 2H), 3.35-3.28 (m, 2H), 2.38-2.33 (m, 2H), 1.92-1.83 (m, 2H); LRMS (ES) m/z 590.9 (M.sup.++1)

[0286] <Compound 59> .sup.1H NMR (400 MHz, CDCl.sub.3) 7.84 (d, J=7.6 Hz, 1H), 7.68 (d, J=9.6 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.39-7.30 (m, 3H), 7.11-7.08 (m, 2H), 7.04 (s, 0.25H), 6.90 (s, 0.5H), 6.78 (s, 0.25H), 4.97 (s, 2H), 4.34 (d, J=7.6 Hz, 1H), 3.90-3.93 (m, 1H), 3.18-3.00 (m, 4H), 2.80 (brs, 1H), 2.18-2.14 (m, 2H), 1.93-1.87 (m, 2H); LRMS (ES) m/z 494.9 (M.sup.++1)

Example 60: Synthesis of Compound 60, 3-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)amino)-4-(1-imino-1-oxidothiomorpholino)cyclobut-3-en-1,2-dione

[Step 1] Synthesis of 3-(phenylamino)-4-thiomorpholinocyclobut-3-en-1,2-dione

##STR00196##

[0287] 3-methoxy-4-(phenylamino)cyclobut-3-en-1,2-dione (100.00%, 2.000 g, 9.843 mmol), thiomorpholine (100.00%, 1.200 equiv., 11.812 mmol) and N,N-diisopropylethylamine (100.00%, 3.000 equiv., 29.529 mmol) were dissolved in methanol (30 mL) at room temperature, after which the resulting solution was stirred at the same temperature for three days. A precipitated solid was filtered, washed with hexane, and dried to obtain the title compound (2.000 g, 74.08%) in a white solid form.

[Step 2] Synthesis of 3-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)amino)-4-thiomorpholinocyclobut-3-en-1,2-dione

##STR00197##

[0288] 3-(phenylamino)-4-thiomorpholinocyclobut-3-en-1,2-dione (100.00%, 0.300 g, 1.094 mmol) prepared in step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 C., after which sodium hydride (100.00%, 1.500 equiv., 1.641 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equiv., 1.094 mmol) was added into the reaction mixture and further stirred at room temperature for two hours. Saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture, and extracted with ethyl acetate. An organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; hexane/ethyl acetate=0 to 50%) and concentrated to obtain the title compound (0.300 g, 54.81%) in a white solid form.

[Step 3] Synthesis of Compound 60

##STR00198##

[0289] 3-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)amino)-4-thiomorpholinocyclobut-3-en-1,2-dione (100.00%, 0.150 g, 0.300 mmol) prepared in step 2, iodobenzene diacetate (100.00%, 2.500 equiv., 0.749 mmol) and ammonium carbamate (100.00%, 2.000 equiv., 0.599 mmol) were dissolved in methanol (10 mL) at room temperature, after which the resulting solution was stirred overnight at the same temperature. A precipitated solid was filtered, washed with hexane, and dried to obtain the title compound (0.080 g, 50.22%) in a white solid form.

[0290] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.86-7.81 (m, 2H), 7.67-7.63 (m, 1H), 7.66 (s, 0.25H), 7.53 (s, 0.5H), 7.42-7.38 (m, 2H), 7.40 (s, 0.25H), 7.25-7.18 (m, 3H), 5.57 (s, 2H), 3.80 (s, 1H), 3.56-3.36 (m, 4H), 3.02-2.93 (m, 4H); LRMS (ES) m/z 532.9 (M.sup.++1)

Example 61: Synthesis of Compound 61, 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)(phenyl)amino)-4-(1-imino-1-oxidothiomorpholino)cyclobut-3-en-1,2-dione

[Step 1] Synthesis of 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)(phenyl)amino)-4-thiomorpholinocyclobut-3-en-1,2-dione

##STR00199##

[0291] The title compound (0.128 g, 35.01%) was obtained in a colorless oil form according to substantially the same reaction as described in step 2 of example 60 except for using 2-(6-(bromomethyl)-5-fluoro-3-pyridyl)-5-(difluoromethyl)-1,3,4-oxadiazole instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole.

[Step 2] Synthesis of Compound 61

##STR00200##

[0292] The title compound (0.05 g, 51.09%) was obtained in a colorless oil form according to substantially the same reaction as described in step 3 of example 60 except for using 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)(phenyl)amino)-4-thiomorpholinocyclobut-3-en-1,2-dione.

[0293] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.99 (s, 1H), 8.40 (dd, J=10.0, 1.6 Hz, 1H), 7.70 (s, 0.25H), 7.57 (s, 0.5H), 7.45 (s, 0.25H), 7.40 (t, J=8.0 Hz, 2H), 7.19-7.17 (m, 3H), 5.68 (s, 2H), 3.66 (s, 1H), 3.60-3.40 (m, 4H), 3.05-2.97 (m, 4H); LRMS (ES) m/z 533.9 (M.sup.++1)

Example 62: Synthesis of Compound 62, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)-1-imino-1-oxo-1,4-thiazinan-4-carboxamide

[Step 1] Synthesis of N-(4-fluorophenyl)thiomorpholin-4-carboxamide

##STR00201##

[0294] 1-fluoro-4-isocyanato-benzene (100.00%, 0.500 g, 3.647 mmol) and thiomorpholine (100.00%, 0.376 g, 3.644 mmol) were dissolved in diethyl ether (20 mL) at room temperature, and then the resulting solution was stirred at the same temperature for 18 hours. The resulting precipitated solid was filtered, washed with diethyl ether, and dried to obtain a title compound (0.667 g, 76.12%) in a white solid form.

[Step 2] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholin-4-carboxamide

##STR00202##

[0295] N-(4-fluorophenyl)thiomorpholin-4-carboxamide (100.00%, 0.100 g, 0.416 mmol) and sodium hydride (60.00%, 0.018 g, 0.450 mmol) were dissolved in N,N-dimethylformamide (2 mL) at 0 C., and then 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.121 g, 0.417 mmol) was added into the resulting solution and stirred at room temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and then water was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=5 to 40%), and concentrated to obtain a title compound (0.040 g, 21.39%) in a light yellow oil form.

[Step 3] Synthesis of Compound 62

##STR00203##

[0296] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholin-4-carboxamide (100.00%, 0.040 g, 0.089 mmol), iodobenzene diacetate (100.00%, 0.072 g, 0.224 mmol) and ammonium carbamate (100.00%, 0.014 g, 0.179 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for 18 hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to obtain a title compound (0.010 g, 23.38%) in a light yellow solid form.

[0297] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.06-6.80 (m, 3H), 5.32 (s, 2H), 3.79-3.73 (m, 2H), 3.69-3.63 (m, 2H), 2.91-2.88 (m, 4H); LRMS (ES) m/z 481.8 (M.sup.++1).

Example 63: Synthesis of Compound 63, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)-1-imino-1-oxo-1,4-thiazinan-4-carboxamide

[Step 1] Synthesis of N-(4-fluorophenyl)thiomorpholin-4-carboxamide

##STR00204##

[0298] N-(4-fluorophenyl)thiomorpholin-4-carboxamide (100.00%, 0.100 g, 0.416 mmol) and sodium hydride (60.00%, 0.018 g, 0.450 mmol) were dissolved in N,N-dimethylformamide (2 mL) at 0 C., and then 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.128 g, 0.417 mmol) was added into the resulting solution and stirred at room temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and then water was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=5 to 40%), and concentrated to obtain a title compound (0.033 g, 17.00%) in a white solid form.

[Step 3] Synthesis of Compound 63

##STR00205##

[0299] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)thiomorpholin-4-carboxamide (100.00%, 0.033 g, 0.071 mmol), iodobenzene diacetate (100.00%, 0.057 g, 0.177 mmol) and ammonium carbamate (100.00%, 0.011 g, 0.141 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for 18 hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to obtain a title compound (0.025 g, 71.02%) in a light yellow solid form.

[0300] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.90 (d, J=7.92 Hz, 1H), 7.77 (dd, J=10.1, 1.3 Hz, 1H), 7.13-6.80 (m, 5H), 4.91 (s, 2H), 3.79-3.75 (m, 2H), 3.67-3.63 (m, 2H), 2.88-2.87 (m, 4H); LRMS (ES) m/z 498.8 (M.sup.++1)

Example 64: Synthesis of Compound 64, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)-1-imino-2,6-dimethyl-1-oxo-1,4-thiazinan-4-carboxamide

[Step 1] Synthesis of N-(4-fluorophenyl)-2,6-dimethyl-thiomorpholin-4-carboxamide

##STR00206##

[0301] 1-fluoro-4-isocyanato-benzene (100.00% solution, 0.4098 mL, 3.647 mmol) and 2,6-dimethylthiomorpholine (100.00%, 0.376 g, 2.865 mmol) were dissolved in diethyl ether (10 mL) at room temperature, and then the resulting solution was stirred at the same temperature for 18 hours. The resulting precipitated solid was filtered, washed with diethyl ether, and dried to obtain a title compound (0.568 g, 58.03%) in a light orange colored solid form.

[Step 2] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)-2,6-dimethyl-thiomorpholin-4-carboxamide

##STR00207##

[0302] N-(4-fluorophenyl)-2,6-dimethyl-thiomorpholin-4-carboxamide (100.00%, 0.100 g, 0.373 mmol) and sodium hydride (60.00%, 0.016 g, 0.400 mmol) were dissolved in N,N-dimethylformamide (2 mL) at 0 C., and then 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.108 g, 0.372 mmol) was added into the resulting solution and stirred at room temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and then water was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=5 to 40%), and concentrated to obtain a title compound (0.050 g, 28.10%) in a light yellow oil form.

[Step 3] Synthesis of Compound 64

##STR00208##

[0303] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)-2,6-dimethyl-thiomorpholin-4-carboxamide (100.00%, 0.050 g, 0.105 mmol), iodobenzene diacetate (100.00%, 0.084 g, 0.261 mmol) and ammonium carbamate (100.00%, 0.016 g, 0.205 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for 18 hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=50 to 100%) and concentrated to obtain a title compound (0.033 g, 61.98%) in a light yellow solid form.

[0304] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.25 (d, J=1.8 Hz, 1H), 8.36 (dd, J=8.1, 2.3 Hz, 1H), 7.60 (d, J=8.12 Hz, 1H), 7.28-7.21 (m, 2H), 7.09-7.06 (m, 2H), 7.05-6.83 (m, 1H), 5.18-4.86 (m, 2H), 3.97-3.92 (m, 0.6H), 3.79-3.74 (m, 0.6H), 3.69 (dd, J=14.2, 2.8 Hz, 0.6H), 3.52-3.47 (m, 0.6H), 3.31-3.25 (m, 0.6H), 3.03-2.93 (m, 3H), 1.25-1.21 (m, 6H); LRMS (ES) m/z 509.9 (M.sup.++1)

Example 65: Synthesis of Compound 65, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)-1-imino-2,6-dimethyl-1-oxo-1,4-thiazinan-4-carboxamide

[Step 1] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)-2,6-dimethyl-thiomorpholin-4-carboxamide

##STR00209##

[0305] N-(4-fluorophenyl)-2,6-dimethyl-thiomorpholin-4-carboxamide (100.00%, 0.100 g, 0.373 mmol) and sodium hydride (60.00%, 0.016 g, 0.400 mmol) were dissolved in N,N-dimethylformamide (2 mL) at 0 C., and then 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.114 g, 0.371 mmol) was added into the resulting solution and stirred at room temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and then water was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=5 to 40%), and concentrated to obtain a title compound (0.146 g, 79.24%) in a colorless oil form.

[Step 2] Synthesis of Compound 65

##STR00210##

[0306] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)-2,6-dimethyl-thiomorpholin-4-carboxamide (100.00%, 0.146 g, 0.295 mmol), iodobenzene diacetate (100.00%, 0.238 g, 0.739 mmol) and ammonium carbamate (100.00%, 0.046 g, 0.589 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for 18 hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=50 to 100%) and concentrated to obtain a title compound (0.126 g, 81.21%) in a white solid form.

[0307] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.88 (d, J=8.0 Hz, 1H), 7.78-7.69 (m, 2H), 7.13-7.06 (m, 4H), 7.05-6.80 (m, 1H), 5.00-4.73 (m, 2H), 3.98 (d, J=15.0 Hz, 0.6H), 3.76 (d, J=14.2 Hz, 0.6H), 3.68 (d, J=14.0 Hz, 0.6H), 3.31-3.26 (m, 0.6H), 2.99-2.93 (m, 1H), 2.81-2.77 (m, 2H), 2.14-2.04 (m, 0.6H), 1.24-1.18 (m, 6H); LRMS (ES) m/z 526.9 (M.sup.++1)

Example 66: Synthesis of Compound 66, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-1-imino-1-oxo-N-(3-pyridyl)-1,4-thiazinan-4-carboxamide

[Step 1] Synthesis of benzyl N-[l-oxo-4-(3-pyridylcarbamoyl)-1,4-thiazinan-1-ylidene]carbamate

##STR00211##

[0308] Pyridin-3-amine (100.00%, 0.200 g, 2.125 mmol) and di(imidazol-1-yl)methanone (100.00%, 0.448 g, 2.763 mmol) were dissolved in tetrahydrofuran (5 mL), and then the resulting solution was stirred at room temperature for one hour, after which benzyl N-(1-oxo-1,4-thiazinan-1-ylidene)carbamate (100.00%, 0.684 g, 2.549 mmol) was added thereto and further stirred at the same temperature for 18 hours. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=50 to 100%) and concentrated to obtain a title compound (0.112 g, 13.57%) in a light yellow solid form.

[Step 2] Synthesis of benzyl N-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl-(3-pyridyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate

##STR00212##

[0309] Benzyl N-[1-oxo-4-(3-pyridylcarbamoyl)-1,4-thiazinan-1-ylidene]carbamate (100.00%, 0.100 g, 0.258 mmol) and sodium hydride (60.00%, 0.011 g, 0.275 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0 C., and then 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.079 g, 0.257 mmol) was added into the resulting solution and stirred at room temperature for three hours. Solvent was removed from the reaction mixture under reduced pressure, and then N-dichloromethane aqueous solution was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=50 to 100%), and concentrated to obtain a title compound (0.030 g, 18.96%) in a light yellow oil form.

[Step 3] Synthesis of Compound 66

##STR00213##

[0310] Benzyl N-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl-(3-pyridyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate (100.00%, 0.030 g, 0.049 mmol) was dissolved in methanol (5 mL) and stirred at room temperature, and then 10%-Pd/C (5 mg) was slowly added thereinto at the same temperature, and stirred for three hours in the presence of a hydrogen balloon attached thereto at the same temperature. The reaction mixture was filtered via a celite pad to remove a solid therefrom, and then solvent was removed from the resulting filtrate without the solid under reduced pressure, and the obtained product was used without an additional purification process (0.022 g, 93.80%, light yellow solid).

[0311] .sup.1H NMR (400 MHz, CDCl.sub.3) 78.50-8.47 (m, 1H), 7.91 (dd, J=8.0, 1.6 Hz, 1H), 7.79 (dd, J=10.2, 1.5 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.51-7.48 (m, 1H), 7.36-7.33 (m, 1H), 7.06-6.80 (m, 1H), 4.97 (s, 2H), 3.77-3.72 (m, 2H), 3.68-3.63 (m, 2H), 2.90 (t, J=5.2 Hz, 4H); LRMS (ES) m/z 481.7 (M.sup.++1)

Example 67: Synthesis of Compound 67, N-(4-(1-acetylpiperidin-4-yl)phenyl)-N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)thiomorpholin-4-carboxamide

[Step 1] Synthesis of tert-butyl 4-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl-(thiomorpholin-4-carbonyl)amino]phenyl]-3,6-dihydro-2H-pyridin-1-carboxylate

##STR00214##

[0312] N-(4-bromophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]thiomorpholin-4-carboxamide (100.00%, 1.710 g, 3.242 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-carboxylate (100.00%, 1.200 g, 3.881 mmol), [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl.sub.2, 100.00%, 0.106 g, 0.163 mmol), and cesium carbonate (100.00%, 2.110 g, 6.476 mmol) were mixed in 1,4-dioxane (12 mL)/water (3 mL) at room temperature, and then the resulting mixture was irradiated with microwave and heated at 100 C. for 30 minutes, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 40 g cartridge; ethyl acetate/hexane=10 to 40%) and concentrated to obtain a title compound (0.950 g, 46.53%) in a brown solid form.

[Step 2] Tert-butyl 4-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl-(thiomorpholin-4-carbonyl)amino]phenyl]piperidin-1-carboxylate

##STR00215##

[0313] Tert-butyl 4-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl-(thiomorpholin-4-carbonyl)amino]phenyl]-3,6-dihydro-2H-pyridin-1-carboxylate (100.00%, 0.950 g, 1.509 mmol) was dissolved in methanol (50 mL) and stirred at room temperature, and then 10%-Pd/C (100 mg) was slowly added into the resulting solution at the same temperature and stirred at 50 C. for 18 hours in the presence of a hydrogen balloon attached thereto, and a temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered via a celite pad to remove a solid therefrom, and then solvent was removed from the resulting filtrate without the solid under reduced pressure. Then, the resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=10 to 40%), and concentrated to obtain a title compound (0.341 g, 35.78%) in a white solid form.

[Step 3] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-[4-(4-piperidyl)phenyl]thiomorpholin-4-carboxamide

##STR00216##

[0314] Tert-butyl 4-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl-(thiomorpholin-4-carbonyl)amino]phenyl]piperidin-1-carboxylate (100.00%, 0.341 g, 0.540 mmol) and trifluoroacetic acid (100.00% solution, 0.3 mL, 3.920 mmol) were dissolved in dichloromethane (3 mL) at room temperature, and then the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without a further purification process (0.287 g, 100.00%, light orange-colored solid).

[Step 4] N-[4-(1-acetyl-4-piperidyl)phenyl]-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]thiomorpholin-4-carboxamide

##STR00217##

[0315] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-[4-(4-piperidyl)phenyl]thiomorpholin-4-carboxamide (100.00%, 0.100 g, 0.188 mmol), acetyl chloride (100.00% solution, 0.02 mL, 0.281 mmol) and triethylamine (100.00% solution, 0.05 mL, 0.359 mmol) were dissolved in dichloromethane (3 mL) at 0 C., and then the resulting solution was stirred at room temperature for three hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=50 to 100%), and concentrated to obtain a title compound (0.092 g, 85.26%) in a light yellow oil form.

[Step 5] Synthesis of Compound 67

##STR00218##

[0316] N-[4-(1-acetyl-4-piperidyl)phenyl]-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]thiomorpholin-4-carboxamide (100.00%, 0.092 g, 0.160 mmol), iodobenzene diacetate (100.00%, 0.129 g, 0.401 mmol), and ammonium carbamate (100.00%, 0.025 g, 0.320 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for six hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to obtain a title compound (0.062 g, 63.94%) in a white solid form.

[0317] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.85 (d, J=7.88 Hz, 1H), 7.73 (d, J=10.0 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.17 (d, J=8.16 Hz, 2H), 7.06-6.80 (m, 3H), 4.90 (s, 2H), 4.79-4.76 (m, 1H), 3.95-3.92 (m, 1H), 3.74-3.73 (m, 2H), 3.62-3.61 (m, 2H), 3.16 (t, J=12.9 Hz, 1H), 2.88-2.79 (m, 4H), 2.75-2.69 (m, 1H), 2.64-2.58 (m, 1H), 2.12 (s, 3H), 1.90-1.83 (m, 2H), 1.61-1.52 (m, 2H); LRMS (ES) m/z 605.9 (M.sup.++1)

Example 68: Synthesis of Compound 68, (1S,4S)N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-2-imino-2-oxo-N-phenyl-2lambda6-thia-5-azabicyclo[2.2.1]heptan-5-carboxamide

[Step 1] Synthesis of (1S,4S)N-phenyl-2-thia-5-azabicyclo[2.2.1]heptan-5-carboxamide

##STR00219##

[0318] Isocyanatobenzene (100.00%, 0.500 g, 4.197 mmol), (1S,4S)-2-thia-5-azabicyclo[2.2.1]heptane; hydrochloride (100.00%, 1.000 equiv., 4.197 mmol) and N,N-diisopropylethylamine (100.00%, 2.000 equiv., 8.395 mmol) were dissolved in dichloromethane (20 mL) at room temperature and the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then dichloromethane (20 mL) and methanol (10 mL) were added into the resulting concentrate and stirred to filter out a precipitated solid, which was then washed with hexane and dried to obtain a title compound (0.700 g, 71.18%) in a white solid form.

[Step 2] Synthesis of (1S,4S)N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-2-thia-5-azabicyclo[2.2.1]heptan-5-carboxamide

##STR00220##

[0319] (1S,4S)N-phenyl-2-thia-5-azabicyclo[2.2.1]heptan-5-carboxamide (100.00%, 0.210 g, 0.896 mmol) prepared in step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 C., and then sodium hydride (100.00%, 1.500 equiv., 1.344 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equiv., 0.896 mmol) was added into the reaction mixture and further stirred at room temperature for two hours. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.021 g, 5.09%) in a colorless oil form.

[Step 3] Synthesis of Compound 68

##STR00221##

[0320] (1S,4S)N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-2-thia-5-azabicyclo[2.2.1]heptan-5-carboxamide (100.00%, 0.076 g, 0.165 mmol) prepared in step 2, (diacetoxyiodo)benzene (100.00%, 2.500 equiv., 0.413 mmol) and ammonium carbamate (100.00%, 2.000 equiv., 0.330 mmol) were dissolved in methanol (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.030 g, 36.98%) in a colorless oil form.

[0321] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.91-7.88 (m, 1H), 7.80-7.71 (m, 2H), 7.35-7.31 (m, 2H), 7.23-7.19 (m, 1H), 7.14-7.12 (m, 2H), 7.05 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 5.21-5.15 (m, 1H), 4.87-4.81 (m, 1H), 4.69 (s, 1H), 3.68-3.65 (m, 1H), 3.56-3.51 (m, 1H), 3.44 (s, 1H), 2.69-2.63 (m, 1H), 2.60-2.55 (m, 1H), 2.25-2.20 (m, 1H), 1.90 (brs, 1H); LRMS (ES) m/z 492.9 (M.sup.++1)

Example 69: Synthesis of Compound 69, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(2,5-difluorophenyl)-1-imino-1-oxo-1,4-thiazinan-4-sulfonamide

[Step 1] Synthesis of N-(2,5-difluorophenyl)thiomorpholin-4-sulfonamide

##STR00222##

[0322] 4-(3-methylimidazol-3-ium-1-yl)sulfonylthiomorpholine; trifluoromethanesulfonate (100.00%, 1.000 g, 2.516 mmol) and 2,5-difluoroaniline (100.00%, 1.100 equiv., 2.768 mmol) were dissolved in acetonitrile (30 mL) at 80 C., and then the resulting solution was stirred overnight at the same temperature and a temperature was lowered to room temperature to terminate the reaction. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; hexane/ethyl acetate=0 to 50%) and concentrated to obtain a title compound (0.500 g, 67.52%) in a white solid form.

[Step 2] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(2,5-difluorophenyl)thiomorpholin-4-sulfonamide

##STR00223##

[0323] N-(2,5-difluorophenyl)thiomorpholin-4-sulfonamide (100.00%, 0.080 g, 0.272 mmol) prepared in step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 C., and then sodium hydride (100.00%, 1.500 equiv., 0.408 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equiv., 0.299 mmol) was added into the reaction mixture and further stirred at room temperature for two hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.100 g, 70.68%) in a colorless oil form.

[Step 3] Synthesis of Compound 69

##STR00224##

[0324] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(2,5-difluorophenyl)thiomorpholin-4-sulfonamide (100.00%, 0.100 g, 0.192 mmol) prepared in step 2, ammonium carbamate (100.00%, 2.000 equiv., 0.384 mmol) and (diacetoxyiodo)benzene (100.00%, 2.500 equiv., 0.480 mmol) were dissolved in methanol (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.050 g, 47.19%) in a colorless oil form.

[0325] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (dd, J=8.0, 1.6 Hz, 1H), 7.78 (dd, J=9.6, 1.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.14-7.03 (m, 3H), 7.02 (s, 0.25H), 7.69 (s, 0.5H), 6.80 (s, 0.25H), 4.90 (s, 2H), 3.92-3.73 (m, 4H), 3.22-3.10 (m, 4H), 2.14 (brs, 1H); LRMS (ES) m/z 552.9 (M.sup.++1).

Example 70: Synthesis of Compound 70, N-(3-chlorophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-1-imino-1-oxo-1,4-thiazinan-4-sulfonamide

[Step 1] Synthesis of N-(3-chlorophenyl)thiomorpholin-4-sulfonamide

##STR00225##

[0326] 4-(3-methylimidazol-3-ium-1-yl)sulfonylthiomorpholine; trifluoromethanesulfonate (100.00%, 0.991 g, 2.494 mmol) and 3-chloroaniline (100.00%, 1.100 equiv., 2.743 mmol) were dissolved in acetonitrile (20 mL) at 80 C., and then the resulting solution was stirred overnight at the same temperature and a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%) and concentrated to obtain a title compound (0.560 g, 76.70%) in a white solid form.

[Step 2] Synthesis of N-(3-chlorophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]thiomorpholin-4-sulfonamide

##STR00226##

[0327] N-(3-chlorophenyl)thiomorpholin-4-sulfonamide (100.00%, 0.260 g, 0.888 mmol) prepared in step 1, 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equiv., 0.977 mmol), potassium carbonate (100.00%, 1.500 equiv., 1.332 mmol) and potassium iodide (100.00%, 0.100 equiv., 0.089 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.260 g, 56.42%) in a colorless oil form.

[Step 3] Synthesis of Compound 70

##STR00227##

[0328] N-(3-chlorophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]thiomorpholin-4-sulfonamide (100.00%, 0.260 g, 0.501 mmol) prepared in step 2, ammonium carbamate (100.00%, 2.000 equiv., 1.002 mmol) and (diacetoxyiodo)benzene (100.00%, 2.500 equiv., 1.252 mmol) were dissolved in methanol (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.200 g, 72.59%) in a colorless oil form.

[0329] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.86 (dd, J=8.0, 1.2 Hz, 1H), 7.78 (dd, J=10.0, 1.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.34-7.27 (m, 3H), 7.18-7.15 (m, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 4.92 (s, 2H), 3.82-3.66 (m, 4H), 3.20-3.09 (m, 4H), 2.10 (brs, 1H); LRMS (ES) m/z 550.9 (M.sup.++1).

Example 71: Synthesis of Compound 71, N-(3-chlorophenyl)-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-1-imino-1-oxo-1,4-thiazinan-4-sulfonamide

[Step 1] Synthesis of N-(3-chlorophenyl)-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]thiomorpholin-4-sulfonamide

##STR00228##

[0330] N-(3-chlorophenyl)thiomorpholin-4-sulfonamide (100.00%, 0.240 g, 0.820 mmol), 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equiv., 0.902 mmol), potassium carbonate (100.00%, 1.500 equiv., 1.230 mmol) and potassium iodide (100.00%, 0.100 equiv., 0.082 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.219 g, 53.22%) in a colorless oil form.

[Step 2] Synthesis of Compound 71

##STR00229##

[0331] N-(3-chlorophenyl)-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]thiomorpholin-4-sulfonamide (100.00%, 0.219 g, 0.436 mmol) prepared in step 1, ammonium carbamate (100.00%, 2.000 equiv., 0.873 mmol) and (diacetoxyiodo)benzene (100.00%, 2.500 equiv., 1.091 mmol) were dissolved in methanol (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.150 g, 64.51%) in a colorless oil form.

[0332] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.29 (t, J=1.0 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.48-7.47 (m, 1H), 7.32-7.29 (m, 3H), 7.09 (s, 0.25H), 6.96 (s, 0.5H), 6.83 (s, 0.25H), 5.04 (s, 2H), 3.87-3.74 (m, 4H), 3.15-3.11 (m, 4H), 2.20 (brs, 1H); LRMS (ES) m/z 533.9 (M.sup.++1).

Example 72: Synthesis of Compound 72, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-1-imino-N-(3-methoxyphenyl)-1-oxo-1,4-thiazinan-4-sulfonamide

[Step 1] Synthesis of N-(3-methoxyphenyl)thiomorpholin-4-sulfonamide

##STR00230##

[0333] 4-(3-methylimidazol-3-ium-1-yl)sulfonylthiomorpholine; trifluoromethanesulfonate salt (100.00%, 0.580 g, 1.459 mmol) and 3-methoxyaniline (100.00% solution, 0.14 mL, 1.246 mmol) were dissolved in acetonitrile (10 mL) at room temperature, and then the resulting solution was heated under reflux for 18 hours, and a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=5 to 20%), and concentrated to obtain a title compound (0.151 g, 35.87%) in a brown oil form.

[Step 2] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(3-methoxyphenyl)thiomorpholin-4-sulfonamide

##STR00231##

[0334] N-(3-methoxyphenyl)thiomorpholin-4-sulfonamide (100.00%, 0.075 g, 0.260 mmol) and sodium hydride (60.00%, 0.013 g, 0.325 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0 C., and then 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.086 g, 0.296 mmol) was added into the resulting solution and stirred at room temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=10 to 50%), and concentrated to obtain a title compound (0.106 g, 81.93%) in a light yellow oil form.

[Step 3] Synthesis of Compound 72

##STR00232##

[0335] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(3-methoxyphenyl)thiomorpholin-4-sulfonamide (100.00%, 0.106 g, 0.213 mmol), iodobenzene diacetate (100.00%, 0.172 g, 0.534 mmol) and ammonium carbamate (100.00%, 0.033 g, 0.423 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for six hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to obtain a title compound (0.057 g, 50.61%) in a light orange-colored solid form.

[0336] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.25 (d, J=1.60 Hz, 1H), 8.36 (dd, J=8.2, 2.2 Hz, 1H), 7.58 (d, J=8.00 Hz, 1H), 7.26-7.24 (m, 1H), 7.08-6.82 (m, 4H), 5.05 (s, 2H), 3.85-3.79 (m, 5H), 3.75-3.71 (m, 2H), 3.12-3.07 (m, 4H); LRMS (ES) m/z 529.8 (M.sup.++1).

Example 73: Synthesis of Compound 73, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-1-imino-N-(3-methoxyphenyl)-1-oxo-1,4-thiazinan-4-sulfonamide

[Step 1] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(3-methoxyphenyl)thiomorpholin-4-sulfonamide

##STR00233##

[0337] N-(3-methoxyphenyl)thiomorpholin-4-sulfonamide (100.00%, 0.075 g, 0.260 mmol) and sodium hydride (60.00%, 0.013 g, 0.325 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0 C., and then 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.091 g, 0.296 mmol) was added into the resulting solution and stirred at room temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=10 to 50%), and concentrated to obtain a title compound (0.085 g, 63.53%) in a light yellow oil form.

[Step 2] Synthesis of Compound 73

##STR00234##

[0338] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(3-methoxyphenyl)thiomorpholin-4-sulfonamide (100.00%, 0.085 g, 0.165 mmol), iodobenzene diacetate (100.00%, 0.143 g, 0.444 mmol) and ammonium carbamate (100.00%, 0.028 g, 0.359 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for six hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to obtain a title compound (0.051 g, 56.58%) in a white solid form.

[0339] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.85 (dd, J=8.0, 1.5 Hz, 1H), 7.77 (dd, J=9.9, 1.5 Hz, 1H), 7.51 (t, J=7.64 Hz, 1H), 7.26-7.24 (m, 1H), 7.05-6.79 (m, 4H), 4.94 (s, 2H), 3.78-3.75 (m, 5H), 3.72-3.65 (m, 2H), 3.13-3.09 (m, 4H); LRMS (ES) m/z 546.5 (M.sup.++1).

Example 74: Synthesis of Compound 74, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-2-(1-imino-1-oxo-1,4-thiazinan-4-yl)-N-phenyl-ethanesulfonamide

[Step 1] Synthesis of N-phenylethenesulfonamide

##STR00235##

[0340] Aniline (100.00%, 1.000 g, 10.740 mmol), 2-chloroethanesulfonyl chloride (100.00%, 1.000 equiv., 10.740 mmol), and triethylamine (100.00%, 2.000 equiv., 21.480 mmol) were dissolved in dichloromethane (50 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 40 g cartridge; hexane/ethyl acetate=0 to 30%) and concentrated to obtain a title compound (0.738 g, 37.51%) as a colorless oil form.

[Step 2] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-ethenesulfonamide

##STR00236##

[0341] N-phenylethenesulfonamide (100.00%, 0.738 g, 4.028 mmol) prepared in step 1, 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equiv., 4.028 mmol), potassium carbonate (100.00%, 1.500 equiv., 6.042 mmol) and potassium iodide (100.00%, 0.100 equiv., 0.403 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 40 g cartridge; hexane/ethyl acetate=0 to 50%) and concentrated to obtain a title compound (1.530 g, 92.79%) as a colorless oil form.

[Step 3] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-2-thiomorpholino-ethanesulfonamide

##STR00237##

[0342] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-ethenesulfonamide (100.00%, 1.530 g, 3.737 mmol) prepared in step 2, thiomorpholine (100.00%, 1.300 equiv., 4.858 mmol) and N,N-diisopropylethylamine (100.00%, 2.000 equiv., 7.474 mmol) were dissolved in dichloromethane (30 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 40 g cartridge; hexane/ethyl acetate=0 to 100%) and concentrated to obtain a title compound (0.917 g, 47.87%) as a colorless oil form.

[Step 4] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-2-(1-oxo-1,4-thiazinan-4-yl)-N-phenyl-ethanesulfonamide

##STR00238##

[0343] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-2-thiomorpholino-ethanesulfonamide (100.00%, 0.900 g, 1.756 mmol) prepared in step 3, (diacetoxyiodo)benzene (100.00%, 2.500 equiv., 4.389 mmol) and ammonium carbamate (100.00%, 2.000 equiv., 3.512 mmol) were dissolved in methanol (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.239 g, 25.75%) in a colorless oil form.

[Step 5] Synthesis of Compound 74

##STR00239##

[0344] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-2-(1-oxo-1,4-thiazinan-4-yl)-N-phenyl-ethanesulfonamide (100.00%, 0.239 g, 0.452 mmol) prepared in step 4, ammonium carbamate (100.00%, 2.000 equiv., 0.904 mmol) and (diacetoxyiodo)benzene (100.00%, 2.500 equiv., 1.130 mmol) were dissolved in methanol (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.030 g, 12.21%) in a colorless oil form.

[0345] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (dd, J=8.0, 1.4 Hz, 1H), 7.75 (dd, J=9.9, 1.5 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.40-7.31 (m, 5H), 7.05 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 5.05 (s, 2H), 3.31-3.27 (m, 2H), 3.17-3.03 (m, 10H), 2.52 (s, 1H); LRMS (ES) m/z 444.3 (M.sup.++1).

Example 75: Synthesis of Compound 75, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-4-(methylsulfonimidoyl)-N-phenyl-piperidin-1-carboxamide

[Step 1] Synthesis of 4-methylsulfyl-N-phenyl-piperidin-1-carboxamide

##STR00240##

[0346] 4-methylsulfylpiperidine; hydrochloride (100.00%, 0.500 g, 2.982 mmol), isocyanatobenzene (100.00%, 1.000 equiv., 2.982 mmol) and N,N-diisopropylethylamine (100.00%, 1.000 equiv., 2.982 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then dichloromethane (20 mL) and methanol (10 mL) were added into the resulting concentrate and stirred to filter out a precipitated solid, which was then washed with hexane and dried to obtain a title compound (0.400 g, 53.58%) in a white solid form.

[Step 2] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-4-methylsulfyl-N-phenyl-piperidin-1-carboxamide

##STR00241##

[0347] 4-methylsulfyl-N-phenyl-piperidin-1-carboxamide (100.00%, 0.240 g, 0.959 mmol) prepared in step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 C., and then sodium hydride (100.00%, 1.500 equiv., 1.438 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equiv., 1.054 mmol) was added into the reaction mixture and further stirred at room temperature for two hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.025 g, 5.47%) in a colorless oil form.

[Step 3] Synthesis of Compound 75

##STR00242##

[0348] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-4-methylsulfyl-N-phenyl-piperidin-1-carboxamide (100.00%, 0.025 g, 0.052 mmol) prepared in step 2, ammonium carbamate (100.00%, 2.000 equiv., 0.105 mmol) and (diacetoxyiodo)benzene (100.00%, 2.500 equiv., 0.131 mmol) were dissolved in methanol (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.005 g, 18.78%) in a colorless oil form.

[0349] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (dd, J=8.0, 1.5 Hz, 1H), 7.75 (dd, J=10.1, 1.5 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.36-7.32 (m, 2H), 7.19-7.17 (m, 3H), 7.05 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 4.96 (s, 2H), 4.10-4.07 (m, 2H), 2.94-2.88 (m, 2H), 2.84 (s, 3H), 2.68-2.60 (m, 2H), 2.45 (s, 1H), 2.01-1.97 (m, 2H), 1.51-1.44 (m, 2H); LRMS (ES) m/z 508.9 (M.sup.++1).

Example 76: Synthesis of Compound 76, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)-1-imino-1-oxo-1,4-thiazinan-4-sulfonamide

[Step 1] Synthesis of N-(4-fluorophenyl)thiomorpholin-4-sulfonamide

##STR00243##

[0350] 4-(3-methylimidazol-3-ium-1-yl)sulfonylthiomorpholine; trifluoromethanesulfonate (100.00%, 1.000 g, 2.516 mmol) and 4-fluoroaniline (100.00% solution, 0.238 mL, 2.512 mmol) were dissolved in acetonitrile (10 mL) at room temperature, and then the resulting solution was heated under reflux for 18 hours, and a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=5 to 20%) and concentrated to obtain a title compound (0.305 g, 43.85%) in a brown solid form.

[Step 2] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholin-4-sulfonamide

##STR00244##

[0351] N-(4-fluorophenyl)thiomorpholin-4-sulfonamide (100.00%, 0.100 g, 0.362 mmol) and sodium hydride (60.00%, 0.016 g, 0.400 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0 C., and then 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.105 g, 0.362 mmol) was added into the resulting solution and stirred at room temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and then N-dichloromethane aqueous solution was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=10 to 50%), and concentrated to obtain a title compound (0.080 g, 45.54%) in a light yellow oil form.

[Step 3] Synthesis of Compound 76

##STR00245##

[0352] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholin-4-sulfonamide (100.00%, 0.080 g, 0.165 mmol), iodobenzene diacetate (100.00%, 0.143 g, 0.444 mmol) and ammonium carbamate (100.00%, 0.028 g, 0.359 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for six hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to obtain a title compound (0.068 g, 79.90%) in a light orange-colored solid form.

[0353] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.27 (d, J=1.52 Hz, 1H), 8.37 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d, J=8.20 Hz, 1H), 7.40-7.37 (m, 2H), 7.08-6.83 (m, 3H), 5.01 (s, 2H), 3.86-3.80 (m, 2H), 3.76-3.70 (m, 2H), 3.19-3.09 (m, 4H); LRMS (ES) m/z 517.8 (M.sup.++1).

Example 77: Synthesis of Compound 77, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-N-(4-fluorophenyl)-1-imino-1-oxo-1,4-thiazinan-4-sulfonamide

[Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholin-4-sulfonamide

##STR00246##

[0354] N-(4-fluorophenyl)thiomorpholin-4-sulfonamide (100.00%, 0.100 g, 0.362 mmol) and sodium hydride (60.00%, 0.016 g, 0.400 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0 C., and then 2-[6-(bromomethyl)-5-fluoro-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.111 g, 0.360 mmol) was added into the resulting solution and stirred at room temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and then N-dichloromethane aqueous solution was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=10 to 50%), and concentrated to obtain a title compound (0.126 g, 69.17%) in a light yellow oil form.

[Step 2] Synthesis of Compound 77

##STR00247##

[0355] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholin-4-sulfonamide (100.00%, 0.126 g, 0.250 mmol), iodobenzene diacetate (100.00%, 0.217 g, 0.674 mmol) and ammonium carbamate (100.00%, 0.042 g, 0.538 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for six hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to obtain a title compound (0.027 g, 20.19%) in a light yellow solid form.

[0356] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.14 (d, J=0.72 Hz, 1H), 8.07 (dd, J=9.2, 1.7 Hz, 1H), 7.43-7.39 (m, 2H), 7.09-6.83 (m, 3H), 5.06 (s, 2H), 3.88-3.83 (m, 2H), 3.79-3.73 (m, 2H), 3.16-3.11 (m, 4H); LRMS (ES) m/z 535.8 (M.sup.++1).

Example 78: Synthesis of Compound 78, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)-1-imino-1-oxo-1,4-thiazinan-4-sulfonamide

[Step 1] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)thiomorpholin-4-sulfonamide

##STR00248##

[0357] N-(4-fluorophenyl)thiomorpholin-4-sulfonamide (100.00%, 0.100 g, 0.362 mmol) and sodium hydride (60.00%, 0.016 g, 0.400 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0 C., and then 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.111 g, 0.361 mmol) was added into the resulting solution and stirred at room temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and then N-dichloromethane aqueous solution was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=10 to 50%), and concentrated to obtain a title compound (0.090 g, 49.50%) in a light yellow oil form.

[Step 2] Synthesis of Compound 78

##STR00249##

[0358] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)thiomorpholin-4-sulfonamide (100.00%, 0.090 g, 0.179 mmol), iodobenzene diacetate (100.00%, 0.155 g, 0.481 mmol) and ammonium carbamate (100.00%, 0.030 g, 0.384 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for six hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to obtain a title compound (0.080 g, 83.72%) in a white solid form.

[0359] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.85 (dd, J=8.0, 1.5 Hz, 1H), 7.77 (dd, J=9.9, 1.5 Hz, 1H), 7.50 (t, J=7.60 Hz, 1H), 7.27-7.23 (m, 2H), 7.07-6.80 (m, 3H), 4.89 (s, 2H), 3.79-3.73 (m, 2H), 3.70-3.64 (m, 2H), 3.18-3.10 (m, 4H); LRMS (ES) m/z 534.8 (M.sup.++1).

Example 79: Synthesis of Compound 79, Benzyl N-[4-[[6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl]methyl-(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate

[Step 1] Synthesis of benzyl N-[4-[(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate

##STR00250##

[0360] 1-fluoro-3-isocyanato-benzene (100.00% solution, 0.41 mL, 3.591 mmol) and benzyl N-(1-oxo-1,4-thiazinan-1-ylidene)carbamate (100.00%, 0.978 g, 3.645 mmol) were dissolved in diethyl ether (40 mL) at room temperature, and then the resulting solution was stirred at the same temperature for two hours. The resulting precipitated solid was filtered, washed with diethyl ether, and dried to obtain a title compound (1.390 g, 95.47%) in a white solid form.

[Step 2] Synthesis of Compound 79

##STR00251##

[0361] Benzyl N-[4-[(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate (100.00%, 0.270 g, 0.666 mmol), 2-[6-(bromomethyl)pyridazin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.194 g, 0.667 mmol) and cesium carbonate (100.00%, 0.434 g, 1.332 mmol) were dissolved in acetonitrile (5 mL), and then the resulting solution was stirred at room temperature for 10 minutes and further stirred at the same temperature for three hours. Solvent was removed from the reaction mixture under reduced pressure, and then water was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=20 to 80%), and concentrated to obtain a title compound (0.105 g, 25.61%) in a yellow solid form.

[0362] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.44 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.39-7.31 (m, 6H), 5.29 (s, 2H), 3.93-3.89 (m, 2H), 3.58-3.53 (m, 4H), 3.27-3.21 (m, 2H); LRMS (ES) m/z 616.9 (M.sup.++1).

Example 80: Synthesis of Compound 80, N-[[6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl]methyl]-N-(3-fluorophenyl)-1-imino-1-oxo-1,4-thiazinan-4-carboxamide

[Step 1] Synthesis of Compound 80

##STR00252##

[0363] Benzyl N-[4-[[6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl]methyl-(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate (100.00%, 0.100 g, 0.162 mmol) was dissolved in methanol (2 mL)/tetrahydrofuran (2 mL) and stirred at room temperature, and then 10%-Pd/C (10 mg) was slowly added thereinto at the same temperature, and stirred for three hours in the presence of a hydrogen balloon attached thereto at the same temperature. The reaction mixture was filtered via a celite pad to remove a solid therefrom, and then solvent was removed from the resulting filtrate without the solid under reduced pressure. Then, the resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate=100%, methanol/dichloromethane=0 to 5%), and concentrated to obtain a title compound (0.054 g, 69.05%) in a light yellow solid form.

[0364] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.42 (d, J=8.7 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.38-7.32 (m, 1H), 7.12-6.87 (m, 4H), 5.29 (s, 2H), 3.82-3.76 (m, 2H), 3.71-3.65 (m, 2H), 2.98-2.97 (m, 4H); LRMS (ES) m/z 482.5 (M.sup.++1).

Example 81: Synthesis of Compound 81, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]methyl]-N-(3-fluorophenyl)-1-imino-1-oxo-1,4-thiazinan-4-carboxamide

[Step 1] Synthesis of benzyl N-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]methyl-(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate

##STR00253##

[0365] Benzyl N-[4-[(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate (100.00%, 0.300 g, 0.740 mmol), 2-[5-(bromomethyl)pyrazin-2-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.214 g, 0.735 mmol) and cesium carbonate (100.00%, 0.482 g, 1.479 mmol) were dissolved in acetonitrile (5 mL) at room temperature, and then the resulting solution was stirred at the same temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and then water was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=20 to 80%), and concentrated to obtain a product, after which the resulting product was purified again via chromatography (SiO.sub.2 plate, 20201 mm; ethyl acetate/hexane=50%), and concentrated to obtain a title compound (0.040 g, 8.78%) in a yellow solid form.

[Step 2] Synthesis of Compound 81

##STR00254##

[0366] Benzyl N-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]methyl-(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate (100.00%, 0.040 g, 0.065 mmol) was dissolved in methanol (2 mL)/tetrahydrofuran (1 mL) and stirred at room temperature, and then 10%-Pd/C (5 mg) was slowly added thereinto at the same temperature, and stirred for 20 minutes in the presence of a hydrogen balloon attached thereto at the same temperature. The reaction mixture was filtered via a celite pad to remove a solid therefrom, and then solvent was removed from the resulting filtrate without the solid under reduced pressure. Then, the resulting concentrate was purified via chromatography (SiO.sub.2 plate, 20201 mm; ethyl acetate/=100%), and concentrated to obtain a title compound (0.005 g, 15.98%) in a light yellow solid form.

[0367] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.43 (d, J=1.2 Hz, 1H), 8.86 (d, J=1.0 Hz, 1H), 7.40-7.34 (m, 1H), 7.11-6.86 (m, 4H), 5.15 (s, 2H), 3.81-3.76 (m, 2H), 3.71-3.65 (m, 2H), 2.99-2.98 (m, 4H); LRMS (ES) m/z 482.8 (M.sup.++1).

Example 82: Synthesis of Compound 82, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-1-imino-2-methyl-1-oxo-N-phenyl-1,4-thiazinan-4-carboxamide

[Step 1] Synthesis of 2-methyl-N-phenyl-thiomorpholin-4-carboxamide

##STR00255##

[0368] 2-methylthiomorpholine (100.00%, 0.500 g, 4.266 mmol) and isocyanatobenzene (100.00%, 1.000 equiv., 4.266 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then dichloromethane (5 mL) and hexane (30 mL) were added into the resulting concentrate and stirred to filter out a precipitated solid, which was then washed with hexane and dried to obtain a title compound (0.600 g, 59.52%) in a white solid form.

[Step 2] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-2-methyl-N-phenyl-thiomorpholin-4-carboxamide

##STR00256##

[0369] 2-methyl-N-phenyl-thiomorpholin-4-carboxamide (100.00%, 0.200 g, 0.846 mmol) prepared in step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 C., and then sodium hydride (100.00%, 1.500 equiv., 1.270 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equiv., 0.931 mmol) was added into the reaction mixture and further stirred at room temperature for two hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; hexane/ethyl acetate=0 to 50%) and concentrated to obtain a title compound (0.161 g, 41.13%) as a colorless oil form.

[Step 3] Synthesis of Compound 82

##STR00257##

[0370] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-2-methyl-N-phenyl-thiomorpholin-4-carboxamide (100.00%, 0.160 g, 0.346 mmol) prepared in step 2, (diacetoxyiodo)benzene (100.00%, 2.500 equiv., 0.865 mmol) and ammonium carbamate (100.00%, 3.000 equiv., 1.038 mmol) were dissolved in methanol (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with ethyl acetate. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.110 g, 64.43%) in a colorless oil form.

[0371] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (dd, J=10.2, 1.4 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.40-7.37 (m, 2H), 7.26-7.22 (m, 1H), 7.15-7.11 (m, 2H), 7.02 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.00-4.89 (m, 2H), 4.08-3.92 (m, 2H), 3.45-3.34 (m, 1H), 3.10-2.73 (m, 4H), 1.70 (brs, 1H), 1.19-1.14 (m, 3H); LRMS (ES) m/z 494.9 (M.sup.++1).

Example 83: Synthesis of Compound 83, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-6-(1-imino-1-oxo-thiethan-3-yl)-N-phenyl-2,6-diazaspiro[3.3]heptan-2-carboxamide

[Step 1] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-6-(thiethan-3-yl)-2,6-diazaspiro[3.3]heptan-2-carboxamide

##STR00258##

[0372] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-2,6-diazaspiro[3.3]heptan-2-carboxamide (100.00%, 0.200 g, 0.451 mmol) and thietan-3-one (100.00%, 0.060 g, 0.681 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and then sodium triacetoxyborohydride (100.00%, 0.190 g, 0.901 mmol) was added into the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 2.5%) and concentrated to obtain a title compound (0.155 g, 66.65%) as a colorless oil form.

[Step 2] Synthesis of Compound 83

##STR00259##

[0373] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-6-(thietan-3-yl)-2,6-diazaspiro[3.3]heptan-2-carboxamide (100.00%, 0.155 g, 0.301 mmol), iodobenzene diacetate (100.00%, 0.242 g, 0.751 mmol) and ammonium carbamate (100.00%, 0.047 g, 0.602 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for six hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to obtain a title compound (0.023 g, 14.00%) in a white solid form.

[0374] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (dd, J=8.0, 1.5 Hz, 1H), 7.73-7.68 (m, 2H), 7.35-7.32 (m, 2H), 7.27-7.24 (m, 1H), 7.13 (dd, J=5.3, 3.2 Hz, 2H), 7.05-6.79 (m, 1H), 5.00 (s, 2H), 4.09-4.04 (m, 2H), 3.75-3.71 (m, 2H), 3.64 (s, 4H), 3.30-3.26 (m, 1H), 3.23-3.16 (m, 4H); LRMS (ES) m/z 547.8 (M.sup.++1).

Example 84: Synthesis of Compound 84, (1S,4S)N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(1-imino-1-oxo-thiethan-3-yl)-N-phenyl-2,5-diazabicyclo[2.2.1]heptan-2-carboxamide

[Step 1] Synthesis of (1S,4S)N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-phenyl-5-(thiethan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxamide

##STR00260##

[0375] (1S,4S)N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-phenyl-2,5-diazabicyclo[2.2.1]heptan-2-carboxamide (100.00%, 0.110 g, 0.258 mmol) and thietan-3-one (100.00%, 0.034 g, 0.386 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and then sodium triacetoxyborohydride (100.00%, 0.109 g, 0.517 mmol) was added into the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 2.5%) and concentrated to obtain a title compound (0.066 g, 51.31%) as a colorless oil form.

[Step 2] Synthesis of Compound 84

##STR00261##

[0376] (1S,4S)N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-phenyl-5-(thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxamide (100.00%, 0.066 g, 0.132 mmol), iodobenzene diacetate (100.00%, 0.107 g, 0.332 mmol) and ammonium carbamate (100.00%, 0.021 g, 0.269 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for six hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to obtain a title compound (0.007 g, 9.99%) in a white solid form.

[0377] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.25 (d, J=1.9 Hz, 1H), 8.37 (dd, J=8.2, 2.2 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.34-7.31 (m, 2H), 7.23-7.22 (m, 2H), 7.18-7.14 (m, 1H), 7.08-6.82 (m, 1H), 5.20 (d, J=16.3 Hz, 1H), 5.05 (d, J=16.3 Hz, 1H), 4.40 (s, 1H), 4.10-4.01 (m, 2H), 3.92-3.87 (m, 2H), 3.56-3.50 (m, 1H), 3.26 (s, 1H), 3.04 (d, J=10.1 Hz, 1H), 2.79 (q, J=6.5 Hz, 2H), 2.57 (d, J=8.6 Hz, 1H), 1.77 (d, J=9.8 Hz, 1H), 1.62 (d, J=9.9 Hz, 1H); LRMS (ES) m/z 530.9 (M.sup.++1).

Example 85: Synthesis of Compound 85, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-1-imino-2-methyl-1-oxo-N-phenyl-1,4-thiazinan-4-carboxamide

[Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-2-methyl-N-phenyl-thiomorpholin-4-carboxamide

##STR00262##

[0378] 2-methyl-N-phenyl-thiomorpholin-4-carboxamide (100.00%, 0.150 g, 0.635 mmol) was dissolved in N,N-dimethylformamide (10 mL) at 0 C., and then sodium hydride (100.00%, 1.500 equiv., 0.952 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equiv., 0.698 mmol) was added into the reaction mixture and further stirred at room temperature for two hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; hexane/ethyl acetate=0 to 50%) and concentrated to obtain a title compound (0.100 g, 35.36%) as a colorless oil form.

[Step 2] Synthesis of Compound 85

##STR00263##

[0379] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-2-methyl-N-phenyl-thiomorpholin-4-carboxamide (100.00%, 0.030 g, 0.067 mmol) prepared in step 2, (diacetoxyiodo)benzene (100.00%, 2.500 equiv., 0.168 mmol) and ammonium carbamate (100.00%, 2.000 equiv., 0.135 mmol) were dissolved in methanol (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with ethyl acetate. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.015 g, 46.75%) in a colorless oil form.

[0380] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.25 (d, J=2.0 Hz, 1H), 8.38 (dt, J=8.4, 2.1 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.37 (td, J=6.8, 1.7 Hz, 2H), 7.22-7.18 (m, 3H), 7.08 (s, 0.25H), 6.95 (s, 0.5H), 6.82 (s, 0.25H), 5.17-5.03 (m, 2H), 4.09-4.03 (m, 1H), 3.97-3.93 (m, 1H), 3.42-3.32 (m, 1H), 3.11-2.89 (m, 4H), 1.70 (brs, 1H), 1.20-1.17 (m, 3H); LRMS (ES) m/z 477.9 (M.sup.++1).

Example 86: Synthesis of Compound 86, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-1-imino-1-oxo-N-phenyl-1,4-thiazinan-4-sulfonamide

[Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-phenyl-thiomorpholin-4-sulfonamide

##STR00264##

[0381] N-phenylthiomorpholin-4-sulfonamide (100.00%, 0.200 g, 0.774 mmol), 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equiv., 0.851 mmol), potassium carbonate (100.00%, 1.500 equiv., 1.161 mmol), and potassium iodide (100.00%, 0.100 equiv., 0.077 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with ethyl acetate. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.033 g, 9.00%) in a colorless oil form.

[Step 2] Synthesis of Compound 86

##STR00265##

[0382] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-phenyl-thiomorpholin-4-sulfonamide (100.00%, 0.033 g, 0.070 mmol) prepared in step 1, (diacetoxyiodo)benzene (100.00%, 2.500 equiv., 0.174 mmol) and ammonium carbamate (100.00%, 2.000 equiv., 0.139 mmol) were dissolved in methanol (10 mL) at room temperature, and then the resulting solution was stirred overnight at the same temperature. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 12 g cartridge; dichloromethane/methanol=0 to 10%), and concentrated to obtain a title compound (0.005 g, 14.22%) in a yellow solid form.

[0383] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.39 (s, 1H), 7.49-7.36 (m, 5H), 7.05 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.20 (s, 2H), 3.80-3.63 (m, 4H), 3.15-3.03 (m, 4H), 2.57 (brs, 1H); LRMS (ES) m/z 505.8 (M.sup.++1).

Example 87: Synthesis of Compound 87, 3-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]anilino]-4-[(1S,4S)-5-(1-imino-1-oxo-thiethane-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-en-1,2-dione

[Step 1] Synthesis of 3-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]anilino]-4-[(1S,4S)-5-(thiethan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-en-1,2-dione

##STR00266##

[0384] 3-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]anilino]cyclobut-3-en-1,2-dione (100.00%, 0.200 g, 0.418 mmol) and thietan-3-one (100.00%, 0.055 g, 0.624 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and then sodium triacetoxyborohydride (100.00%, 0.176 g, 0.834 mmol) was added into the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=60 to 90%), and concentrated to obtain a title compound (0.156 g, 67.77%) in a yellow solid form.

[Step 2] Synthesis of Compound 87

##STR00267##

[0385] 3-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]anilino]-4-[(1S,4S)-5-(thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-en-1,2-dione (100.00%, 0.156 g, 0.283 mmol), iodobenzene diacetate (100.00%, 0.228 g, 0.708 mmol) and ammonium carbamate (100.00%, 0.044 g, 0.564 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for 18 hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%), and concentrated to obtain a product, and then the resulting product was purified again via chromatography (SiO.sub.2 plate, 20201 mm; methanol/dichloromethane=5%), and concentrated to obtain a title compound (0.030 g, 18.21%) in a yellow solid form.

[0386] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.27 (d, J=1.8 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.40-7.36 (m, 2H), 7.27-7.25 (m, 1H), 7.22-7.20 (m, 2H), 7.08-6.82 (m, 1H), 5.64-5.52 (m, 2H), 4.13-4.07 (m, 1H), 4.01-3.96 (m, 1H), 3.89-3.80 (m, 2H), 3.45-3.41 (m, 1H), 3.26 (s, 1H), 3.20 (s, 1H), 2.73-2.70 (m, 3H), 1.88-1.83 (m, 2H), 1.63-1.60 (m, 1H); LRMS (ES) m/z 582.4 (M.sup.++1).

Example 88: Synthesis of Compound 88, 3-[N-[[5-[5-(difluoromethyl)-1.3.4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]anilino]-4-[(1S,4S)-5-(1-imino-1-oxo-thiethan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-en-1,2-dione

[Step 1] Synthesis of 3-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]anilino]-4-[(1S,4S)-5-(thiethan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-en-1,2-dione

##STR00268##

[0387] 3-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]anilino]cyclobut-3-en-1,2-dione (100.00%, 0.200 g, 0.403 mmol) and thietan-3-one (100.00%, 0.053 g, 0.601 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and then sodium triacetoxyborohydride (100.00%, 0.170 g, 0.806 mmol) was added into the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=60 to 80%), and concentrated to obtain a title compound (0.120 g, 52.38%) in a yellow solid form.

[Step 2] Synthesis of Compound 88

##STR00269##

[0388] 3-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]anilino]-4-[(1S,4S)-5-(thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-en-1,2-dione (100.00%, 0.120 g, 0.211 mmol), iodobenzene diacetate (100.00%, 0.170 g, 0.528 mmol) and ammonium carbamate (100.00%, 0.033 g, 0.423 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for 18 hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%), and concentrated to obtain a product, and then the resulting product was purified again via chromatography (SiO.sub.2 plate, 20201 mm; methanol/dichloromethane=5%), and concentrated to obtain a title compound (0.041 g, 32.40%) in a yellow solid form.

[0389] .sup.1H NMR (400 MHz, CDCl.sub.3) 79.10 (s, 1H), 8.08 (dd, J=9.3, 1.7 Hz, 1H), 7.39-7.35 (m, 2H), 7.28-7.25 (m, 1H), 7.19-7.16 (m, 2H), 7.09-6.83 (m, 1H), 5.73-5.64 (m, 2H), 4.16-4.15 (m, 2H), 4.13-4.09 (m, 1H), 4.02-3.97 (m, 2H), 3.48-3.44 (m, 1H), 3.21-3.20 (m, 1H), 2.76-2.72 (m, 3H), 1.87-1.84 (m, 1H), 1.65-1.63 (m, 1H); LRMS (ES) m/z 600.8 (M.sup.++1).

Example 89: Synthesis of Compound 89, 3-[N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]anilino]-4-[(1S,4S)-5-(1-imino-1-oxo-thiethan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-en-1,2-dione

[Step 1] Synthesis of 3-[N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]anilino]-4-[(1S,4S)-5-(thiethane-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-en-1,2-dione

##STR00270##

[0390] 3-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-[N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]anilino]cyclobut-3-en-1,2-dione (100.00%, 0.150 g, 0.303 mmol) and thietan-3-one (100.00%, 0.040 g, 0.454 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and then sodium triacetoxyborohydride (100.00%, 0.128 g, 0.607 mmol) was added into the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=5 to 70%), and concentrated to obtain a title compound (0.053 g, 30.84%) in a white solid form.

[Step 1] Synthesis of Compound 89

##STR00271##

[0391] 3-[N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]anilino]-4-[(1S,4S)-5-(thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-en-1,2-dione (100.00%, 0.053 g, 0.093 mmol), iodobenzene diacetate (100.00%, 0.075 g, 0.233 mmol) and ammonium carbamate (100.00%, 0.015 g, 0.192 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for 18 hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate and extracted with dichloromethane. An organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%), and concentrated to obtain a product, and then the resulting product was purified again via chromatography (SiO.sub.2 plate, 20201 mm; methanol/dichloromethane=5%), and concentrated to obtain a title compound (0.008 g, 14.31%) in a white solid form.

[0392] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (dd, J=8.0, 1.4 Hz, 1H), 7.74-7.67 (m, 2H), 7.39-7.35 (m, 2H), 7.31-7.28 (m, 1H), 7.09-7.07 (m, 2H), 7.05-6.79 (m, 1H), 5.60 (d, J=15.4 Hz, 1H), 5.47 (d, J=15.4 Hz, 1H), 4.13-4.07 (m, 1H), 4.01-3.95 (m, 1H), 3.86-3.80 (m, 2H), 3.43-3.41 (m, 1H), 3.28 (s, 1H), 3.17 (s, 1H), 2.71 (brs, 3H), 1.83 (d, J=9.9 Hz, 1H), 1.59 (d, J=10.1 Hz, 1H); LRMS (ES) m/z 599.8 (M.sup.++1).

Example 90: Synthesis of Compound 90, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(3-fluorophenyl)-3-(methylsulfonimidoyl)azetidin-1-carboxamide

[Step 1] Synthesis of N-(3-fluorophenyl)-3-methylsulfyl-azetidin-1-carboxamide

##STR00272##

[0393] 3-methylsulfylazetidine; hydrochloride (100.00%, 0.452 g, 3.237 mmol) and N,N-diisopropylethylamine (100.00% solution, 1.15 mL, 6.585 mmol) were dissolved in dichloromethane (20 mL) at room temperature, and then 1-fluoro-3-isocyanato-benzene (100.00% solution, 0.5 mL, 4.380 mmol) was added into the resulting solution and stirred at the same temperature for two hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO2, 24 g cartridge; ethyl acetate/hexane=10 to 40%), and concentrated to obtain a title compound (0.815 g, 77.44%) in a white solid form.

[Step 2] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(3-fluorophenyl)-3-methylsulfyl-azetidin-1-carboxamide

##STR00273##

[0394] N-(3-fluorophenyl)-3-methylsulfyl-azetidin-1-carboxamide (100.00%, 0.200 g, 0.832 mmol) and sodium hydride (60.00%, 0.037 g, 0.925 mmol) were dissolved in N,N-dimethylformamide (4 mL) at 0 C., and then 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.266 g, 0.917 mmol) was added into the resulting solution and stirred at room temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=10 to 40%), and concentrated to obtain a title compound (0.207 g, 55.34%) in a light yellow oil form.

[Step 3] Synthesis of Compound 90

##STR00274##

[0395] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(3-fluorophenyl)-3-methylsulfyl-azetidin-1-carboxamide (100.00%, 0.207 g, 0.461 mmol), iodobenzene diacetate (100.00%, 0.371 g, 1.152 mmol) and ammonium carbamate (100.00%, 0.072 g, 0.922 mmol) were dissolved in methanol (5 mL) at room temperature, and then the resulting solution was stirred at 50 C. for 18 hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%), and concentrated to obtain a product, and then the resulting product was purified again via chromatography (SiO.sub.2 plate, 20201 mm; methanol/dichloromethane=5%), and concentrated to obtain a title compound (0.042 g, 18.98%) in a white solid form.

[0396] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.26 (d, J=2.0 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.36-7.31 (m, 1H), 7.11-6.83 (m, 4H), 5.13-5.04 (m, 2H), 4.00-3.93 (m, 4H), 3.88-3.83 (m, 1H), 2.88 (s, 3H), 2.66 (s, 1H); LRMS (ES) m/z 481.7 (M.sup.++1).

Example 91: Synthesis of Compound 91, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(3-fluorophenyl)-3-(methylsulfonimidoyl)azetidin-1-carboxamide

[Step 1] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(3-fluorophenyl)-3-methylsulfyl-azetidin-1-carboxamide

##STR00275##

[0397] N-(3-fluorophenyl)-3-methylsulfyl-azetidin-1-carboxamide (100.00%, 0.200 g, 0.832 mmol) and sodium hydride (60.00%, 0.037 g, 0.925 mmol) were dissolved in N,N-dimethylformamide (4 mL) at 0 C., and then 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.281 g, 0.915 mmol) was added into the resulting solution and stirred at room temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=5 to 40%), and concentrated to obtain a title compound (0.194 g, 49.98%) in a white solid form.

[Step 2] Synthesis of Compound 91

##STR00276##

[0398] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(3-fluorophenyl)-3-methylsulfyl-azetidin-1-carboxamide (100.00%, 0.197 g, 0.422 mmol), iodobenzene diacetate (100.00%, 0.340 g, 1.056 mmol) and ammonium carbamate (100.00%, 0.066 g, 0.845 mmol) were dissolved in methanol (5 mL) at room temperature, and then the resulting solution was stirred at 50 C. for 18 hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%), and concentrated to obtain a title compound (0.064 g, 30.46%) in a white solid form.

[0399] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.90 (dd, J=8.0, 1.5 Hz, 1H), 7.75-7.69 (m, 2H), 7.36-7.30 (m, 1H), 7.06-6.80 (m, 4H), 5.01 (s, 2H), 3.96-3.91 (m, 4H), 3.87-3.84 (m, 1H), 2.87 (s, 3H); LRMS (ES) m/z 498.7 (M.sup.++1).

Example 92: Synthesis of Compound 92, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-2-imino-2-oxo-N-phenyl-2lambda6-thia-6-azaspiro[3.3]heptan-6-carboxamide

[Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholin-4-carboxamide

##STR00277##

[0400] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]aniline (100.00%, 0.200 g, 0.626 mmol) and N,N-diisopropylethylamine (100.00% solution, 0.55 mL, 3.149 mmol) were dissolved in dichloromethane (5 mL) at 0 C., and then triphosgene (100.00%, 0.074 g, 0.249 mmol) was added into the resulting solution and stirred at the same temperature. Oxalic acid; 2-thia-6-azaspiro[3.3]heptane (100.00%, 0.120 g, 0.375 mmol) was added into the reaction mixture, and further stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=10 to 50%), and concentrated to obtain a title compound (0.119 g, 41.26%) in a white solid form.

[Step 2] Synthesis of Compound 92

##STR00278##

[0401] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholin-4-carboxamide (100.00%, 0.040 g, 0.089 mmol), iodobenzene diacetate (100.00%, 0.072 g, 0.224 mmol) and ammonium carbamate (100.00%, 0.014 g, 0.179 mmol) were dissolved in methanol (3 mL) at room temperature, and then the resulting solution was stirred at 50 C. for 18 hours, after which a temperature was lowered to room temperature to terminate the reaction. Solvent was removed from the resulting mixture under reduced pressure, and then the resulting concentrate was purified via column chromatography (SiO.sub.2, 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to obtain a title compound (0.010 g, 23.38%) in a light yellow solid form.

[0402] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.86 (dd, J=8.0, 1.4 Hz, 1H), 7.70-7.66 (m, 2H), 7.35-7.32 (m, 2H), 7.28-7.24 (m, 1H), 7.13-7.12 (m, 2H), 7.05-6.79 (m, 1H), 4.99 (s, 2H), 4.09 (q, J=11.8 Hz, 4H), 3.77 (d, J=7.0 Hz, 4H), 3.08 (brs, 1H); LRMS (ES) m/z 492.5 (M.sup.++1).

<Experimental Example> Protocol for Measuring and Analyzing Activity of Compound of Present Invention

Experimental Example 1. Identification of HDAC Enzyme Activity Inhibition (In Vitro)

[0403] A selective HDAC6 inhibitor is important for selectivity of HDAC1 inhibition, which is a cause of side effects, and thus an experiment was performed to identify HDAC1/6 enzyme selectivity and cell selectivity (HDAC1: Histone acetylation/HDAC6: Tubulin acetylation) with respect to the compound of the present invention.

1. Experimental Method

[0404] A HDAC enzyme inhibitory capacity of a test material was measured by using HDAC1 Fluorimetric Drug Discovery Assay Kit (Enzolifesciences: BML-AK511) and HDAC6 human recombinant (Calbiochem: 382180). For a HDAC1 assay, samples were treated at a concentration of 100, 1000 and 10000 nM. For a HDAC6 assay, samples were treated at a concentration of 0.1, 1, 10, 100 and 1000 nM.

[0405] For the test on the HDAC1 enzyme activity, human recombinant HDAC1 (BML-SE456) was used as a zymogen and Fluor de Lys-SIRT1 (BNL-KI177) was used as a substrate. A 5-fold dilution of the compound was divided into a 96-well plate, after which 0.3 g of the enzyme and 10 M of the substrate were inserted into each well and subjected to reaction at 37 C. for 60 minutes, such that Fluor de Lys Developer II (BML-K1176) was inserted thereinto and subjected to reaction for 30 minutes and finished. After that, a fluorescence value (Ex 360, Em 460) was measured with a multi-plate reader (FlexStation 3, Molecular Device). An experiment on HDAC6 enzyme was conducted in accordance with the same protocol as in the HDAC1 enzyme activity test method by using human recombinant HDAC6 (382180) of Calbiochem Inc. For final result values, each IC.sub.50 value was calculated with GraphPad Prism 4.0 program.

2. Experimental Results

[0406] The results of searching HDAC enzyme activity inhibition obtained according to the above experimental method are shown in table 18 below.

TABLE-US-00018 TABLE 18 Compound HDAC6 IC.sub.50 HDAC1 IC.sub.50 Compound HDAC6 IC.sub.50 HDAC1 IC.sub.50 No. (nM) (nM) No. (nM) (nM) 1 49.4 >10,000 2 168.2 >10,000 3 151.2 >10,000 4 390.1 >10,000 5 91.4 >10,000 6 50.0 >10,000 7 40.9 >10,000 8 194.1 >10,000 9 279.8 >10,000 10 108.4 >10,000 11 1419 >10,000 12 62.6 >10,000 13 44 >10,000 14 94.4 >10,000 15 1346 >10,000 16 42.6 >10,000 17 27.2 >10,000 18 32.6 >10,000 19 19.7 >10,000 20 76.7 >10,000 21 294.4 >10,000 22 75.2 >10,000 23 64.4 >10,000 24 1009 >10,000 25 141.1 >10,000 26 98.6 >10,000 27 86.6 >10,000 28 92.2 >10,000 29 78.8 >10,000 30 54.6 >10,000 31 91.4 >10,000 32 80.6 >10,000 33 51.3 >10,000 34 91.5 >10,000 35 59.7 >10,000 36 30.8 >10,000 37 61.3 >10,000 38 67.2 >10,000 39 80.8 >10,000 40 84.8 >10,000 41 28.9 >10,000 42 37.7 >10,000 43 88.9 >10,000 44 129.7 >10,000 45 63.6 >10,000 46 65.9 >10,000 47 185.3 >10,000 48 113.3 >10,000 49 77.7 >10,000 50 66.4 >10,000 51 69.9 >10,000 52 46.9 >10,000 53 40.6 >10,000 54 200.3 >10,000 55 140.3 >10,000 56 72.6 >10,000 57 130.1 >10,000 58 256.0 >10,000 59 115.7 >10,000 60 26.7 >10,000 61 29.8 >10,000 62 88.4 >10,000 63 99.6 >10,000 64 123.3 >10,000 65 105.3 >10,000 66 90.2 >10,000 67 346.7 >10,000 68 39.0 >10,000 69 124.2 >10,000 70 52.2 >10,000 71 31.7 >10,000 72 78.8 >10,000 73 72.5 >10,000 74 63.6 >10,000 75 96.3 >10,000 76 39.9 >10,000 77 51.6 >10,000 78 78.7 >10,000 79 87.1 >10,000 80 145.5 >10,000 81 241.0 >10,000 82 93.1 >10,000 83 71.3 >10,000 84 56.0 >10,000 85 74.6 >10,000 86 50.2 >10,000 87 37.4 >10,000 88 57.0 >10,000 89 34.1 >10,000 90 47.3 >10,000 91 46.0 >10,000 92 93.9 >10,000

[0407] As can be seen in above table 18, it was confirmed from the results of testing activity inhibition against HDAC1 and HDAC6 that the sulfoximine compound of the present invention has a IC.sub.50 value at HDAC6, which is about 7 times or more and up to 500 times or more lower than that of HDAC1, thus showing excellent selective HDAC6 inhibitory activity.

[0408] The present invention has been described with reference to one exemplary embodiment of the present invention, but it will be understood by those skilled in the art that the present invention may be variously changed and modified without departing from the spirit and field of the present invention, as described in the following scope of patent claims.