NOVEL PHTHALAZINE DERIVATIVE HAVING ECTONUCLOEOTIDE PYROPHOSPHATASE/PHOSPHODIESTE RASE INHIBITORY ACTIVITY, AND USE THEREOF

Abstract

The present invention relates to a compound for inhibiting ENPP1, a composition for inhibiting ENPP1, and a novel phthalazine derivative compound related to a method for inhibiting ENPP1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a stereoisomer thereof.

Claims

1. A compound selected from a phthalazine derivative compound represented by the following Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof and a stereoisomer thereof: ##STR00255## wherein Y.sub.1 and Y.sub.2 are each independently hydrogen, a hydroxyl up, a halogen group, a C.sub.1-C.sub.13 alkyl group, a C.sub.3-C.sub.10 cyclicgroup, a C.sub.1-C.sub.6 alkoxy group, or a C.sub.3-C.sub.10 heterocyclic group; R.sub.1 and R.sub.2 are each independently hydrogen, a hydroxyl group, a halogen group, a C.sub.1-C.sub.13 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.6-C.sub.10 aryl group, a C.sub.3-C.sub.10 cyclic group, a C.sub.3-C.sub.10 heteroaryl group, a C.sub.3-C.sub.10 heterocyclic group, or —C(O)—(C.sub.1-C.sub.13 alkyl), or a 4- to 7-membered saturated, unsaturated or aromatic ring, which includes at least one N, O, S, NH, C═N, C═O, —NHC(O)—, —NHC(O)NH—, —NHS(O).sub.2—, or SO.sub.2, and is substituted with at least one of a C.sub.1-C.sub.13 alkyl group, a C.sub.6-C.sub.10 aryl group, a C.sub.3-C.sub.10 heteroaryl group, a hydroxyl group, a halide group or a cyano group; R.sub.3 is hydrogen, a hydroxyl group, a halogen group, a C.sub.1-C.sub.13 alkyl group, a C.sub.1-C.sub.6 alkc group, a C.sub.6-C.sub.10 aryl group, a C.sub.3-C.sub.10 cyclic group, a C.sub.3-C.sub.10 heteroaryl group, a C.sub.3-C.sub.10 heterocyclic group, or —C(O)—(C.sub.1-C.sub.13 alkyl); R.sub.4 is hydrogen, a hydroxyl group, a halogen group, a C.sub.1-C.sub.13 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.1-C.sub.6 alkenyl group, a C.sub.6-C.sub.10 aryl group, a C.sub.3-C.sub.10 cyclic group, a C.sub.3-C.sub.10 heteroaryl group, a C.sub.3-C.sub.10 heterocyclic group,an amino group, a nitro group, an amide group, a carboxylic group, nitrile group, a urea group, a sulfonamide group, a sulfide group, a sulfonic group, or a phosphoryl group, wherein the C.sub.1-C.sub.6 alkyl group, the C.sub.1-C.sub.13 alkyl group or the C.sub.3-C.sub.10 cyclic group includes at least one substituent selected from the group consisting of hydrogen, a hydroxyl group, a halogen group, a C.sub.1-C.sub.13 alkyl group, a C.sub.1-C.sub.6 alkoxy group, an amino group (—NR.sub.5R.sub.6), a nitro group (—N(O).sub.2), an amide group (—(C═O)NR.sub.5R.sub.6), a carboxylic group (—C(O)OH), a nitrile group (—CN), a urea group (—NR.sub.5(C═O)NR.sub.6—), a sulfonamide group (—NHS(O).sub.2—), a sulfide group (—S—), a sulfonyl group (—S(O).sub.2—), a phosphoryl group (—P(O)R.sub.5R.sub.6), a C.sub.6-C.sub.10 aryl group, a C.sub.3-C.sub.10 heteroaryl group, and a C.sub.3-C.sub.10 heterocyclic group, and the C.sub.6-C.sub.10 aryl group, the C.sub.3-C.sub.10 heteroaryl group or the C.sub.3-C.sub.10 heterocyclic group includes at least one substituent selected from the group consisting of hydrogen, a hydroxyl group, a halogen group, a carbonyl group (—(C═O)R.sub.5R.sub.6), a C.sub.1-C.sub.3 alkyl group substituted or unsubstituted with halogen or a C.sub.3-C.sub.10 heterocyclic group, a C.sub.1-C.sub.3 alkoxy group substituted or unsubstituted with halogen or a C.sub.3-C.sub.10 heterocyclic group, C.sub.6-C.sub.10 phenoxy, an amino group (—NR.sub.5R.sub.6), a nitro group (—N(O).sub.2), an amide group (—(C═O)NR.sub.5R.sub.6), a carboxylic group (—C(O)OH), a nitrile group (—CN), a urea group (—NR.sub.5(C═O)NR.sub.6—), a sulfonamide group (—NHS(O).sub.2—), a sulfide group (—S—), a sulfonyl group (—S(O).sub.2—), a phosphoryl group (—P(O)R.sub.5R.sub.6), a C.sub.6-C.sub.10 aryl group, a C.sub.3-C.sub.10 heteroaryl group, and a C.sub.3-C.sub.10 heterocyclic group; and R.sub.5 and R.sub.6 are each independently hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkenyl group, a C.sub.1-C.sub.6 alkynyl group, a C.sub.6-C.sub.10 aryl group, a C.sub.3-C.sub.10 heteroaryl group, a C.sub.3-C.sub.10 heterocyclic group, or R.sub.5, together with a nitrogen or carbon atom bonded to R.sub.6, forms a 3- to 7-membered saturated ring, which includes at least one of N, O, S, NH, C═N, C═O, —NHC(O)—, —NHC(O)NH—, —NHS(O).sub.2—, or SO.sub.2, and is substituted with at least one of hydrogen, a C.sub.1-C.sub.13 alkyl group, a C.sub.6-C.sub.10 aryl group, a C.sub.3-C.sub.10 heteroaryl group, a hydroxyl group, a halide group or a cyano group, wherein the C.sub.3-C.sub.10 heteroaryl group and the C.sub.3-C.sub.10 heterocyclic group include at least one heteroatom selected from the group consisting of N, O, and S.

2. The compound according to claim 1, wherein Y.sub.1 and Y.sub.2 are each independently hydrogen or a C.sub.1-C.sub.13 alkyl group, R.sub.1 and R.sub.2 are each independently hydrogen, a hydroxyl group, a C.sub.1-C.sub.13 alkyl group, or a C.sub.1-C.sub.6 alkoxy group, R.sub.3 is hydrogen, a C.sub.1-C.sub.13 alkyl group, or a C.sub.6-C.sub.10 aryl group, and R.sub.4 is a C.sub.1-C.sub.13 alkyl group, a C.sub.6-C.sub.10 aryl group, a C.sub.3-C.sub.10 cyclic group, a C.sub.3-C.sub.10 heteroaryl group, a C.sub.3-C.sub.10 heterocyclic group, an amino group, a nitro group, an amide group, a carboxylic group, a nitrile group, a urea group, a sulfonamide group. a sulfide group, a sulfonic group, or a phosphoryl group.

3. The compound according to claim 1, wherein Y.sub.1 and Y.sub.1 are each hydrogen, R.sub.1 and R.sub.2 are each independently hydrogen, a C.sub.1-C.sub.4 alkyl group, or a C.sub.1-C.sub.4 alkoxy group, R.sub.3 is hydrogen, a C.sub.1-C.sub.4 alkyl group, or a C.sub.6-C.sub.10 aryl group, and R.sub.4 is a substituted or unsubstituted C.sub.1-C.sub.6 alkyl group, substituted or unsubstituted benzene, substituted or unsubstituted hexane, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted pyridine, substituted or unsubstituted benzofuran, substituted or unsubstituted naphthalene, substituted or unsubstituted anthracene, substituted or unsubstituted phenanthrene, substituted or unsubstituted pyridazine, substituted or unsubstituted piperidine, substituted or unsubstituted morpholine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazine, substituted or unsubstituted imidazole, substituted or unsubstituted pyraz substituted or unsubstituted quinoline, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrrole, substituted or unsubstituted indole, substituted or unsubstituted purine, substituted or unsubstituted cyclopropane, or substituted or unsubstituted cyclobutane.

4. The compound according to claim 1, wherein Y.sub.1 and Y.sub.2 are each hydrogen, R.sub.1 and R.sub.2 are each independently hydrogen or a methoxy group, R.sub.3 is hydrogen, a C.sub.1-C.sub.4 alkyl group, a phenyl group, or a benzyl group, and R.sub.4 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261##

5. The compound according to claim 1, wherein the compound resented by Formula 1 is selected from the group consisting of the following Compounds Nos. 1 to 203: Compound No. 1: 4-phenylphthalazin-1(2H)-one; Compound No. 2: tert-butyl (3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate; Compound No. 3: tert-butyl (3(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate; Compound No. 4: tert-butyl (3(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate; Compound No. 5: tert-butyl(3-(4-oxo-3,4-dihydrophthalazin-1-yl)carbamate; Compound No. 6: tert-butyl 3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl carbamate; Compound No. 7: tert-butyl (3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 8: tert-butyl (4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 9: tert-butyl (4-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 10: tert-butyl (4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 11: tert-butyl 4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl carbamate; Compound No. 12: tert-butyl (4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 13: tert-butyl (4-3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 14: tert-butyl (4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 15: tert-butyl (4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 16: tert-butyl 4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl carbamate; Compound No. 17: tert-butyl 4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl carbamate; Compound No. 18: tert-butyl (4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 19: tert-butyl (4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 20: tert-butyl (4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 21: tert-butyl (1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)carbamate; Compound No. 22: tert-butyl (R)-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)carbamate; Compound No. 23: tert-butyl (2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)carbamate; Compound No. 24: tert-butyl 4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl carbamate; Compound No. 25: tert-butyl methyl(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 26: tert-butyl 6-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; Compound No. 27: tert-butyl-6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; Compound No. 28: tert-butyl 6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; Compound No. 29: tert-butyl-6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; Compound No. 30: 4-(3-aminophenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 31: 4-(3-aminophenyl)-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 32: 4-(3-aminophenyl)-2-benzylphthalazin-1(2H)-one hydrochloride; Compound No. 33: 4-(3-(aminomethyl)phenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 34: 4-(3-(aminomethyl)phenyl)-2-methylphthalazin-1-(2H)-one hydrochloride; Compound No. 35: 4-(3-(aminomethyl)phenyl)-2-benzylphthalazin-1(2H)-one hydrochloride; Compound No. 36: 4-(4-(aminomethyl)phenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 37: 4-(4-aminomethyl)phenyl)-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 38: 4-(4-(aminomethyl)phenyl)-2-ethylphthalazin-1(2H)-one hydrochloride; Compound No. 39: 4-(4-(aminomethyl)phenyl)-2-isopropylphthalazin-1-(2H)-one hydrochloride; Compound No. 40: 4-(4-aminomethyl)phenyl)-2-phenylphthalazin-1(2H)-one hydrochloride; Compound No. 41: 4-(4-aminomethyl)phenyl)-2-benzylphthalazin-1(2H)-one hydrochloride; Compound No. 42: 4-(4-(aminomethyl)phenyl)-2-(4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; Compound No. 43: 4-(4-(aminomethyl)phenyl)-6-methoxyphthalazin-1(2H)-one hydrochloride; Compound No. 44: (4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methanaminium chloride; Compound No. 45: (4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methanaminium chloride; Compound No. 46: 4-(4-(aminomethyl)phenyl)-7-methoxy-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 47: 4-(4-(aminomethyl)-phenyl)-7-methoxyphthalazin-1(2H)-one hydrochloride; Compound No. 48: 4-(4-(aminomethyl)phenyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride; Compound No. 49: 4-(4-(aminomethyl)phenyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 50: 4-(4-(1-aminoethyl)phenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 51: (R)-4-(4-(1-aminoethyl)phenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 52: 4-(4-(2-aminopropan-2-yl)phenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 53: 4-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 54: 4-(4-((methylamino)methyl)phenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 55: 4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride; Compound No. 56: 2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride; Compound No. 57: 6,7-dimethoxy-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride; Compound No. 58: 6,7-dimethoxy-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride; Compound No. 59: 6,7-dimethoxy-4-(1,2,3,4-tetrahydroisoquinolin-7-yl) phthalazin-1(2H)-one; Compound No. 60: tert-butyl (N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate; Compound No. 61: tert-butyl (N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate; Compound No. 62: tert-butyl (N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate; Compound No. 63: tert-butyl (N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 64: tert-butyl N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin yl)benzyl)sulfamoyl carbamate; Compound No. 65: tert-butyl (N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin yl)benzyl)sulfamoyl)carbamate; Compound No. 66: tert-butyl (N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin yl)benzyl)sulfamoyl)carbamate; Compound No. 67: tert-butyl (N-(4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 68: tert-butyl N-(4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl carbamate; Compound No. 69: tert-butyl (N-(4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 70: tert-butyl (N-(4-3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 71: tert-butyl (N-(4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 72: tert-butyl (4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 73: tert-butyl N-(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl carbamate; Compound No. 74: tert-butyl N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl carbamate; Compound No. 75: tert-butyl (N-(4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 76: tert-butyl (N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 77: tert-butyl (N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 78: tert-butyl (N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamoyl)carbamate; Compound No. 79: tert-butyl (R)-(N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamoyl)carbamate; Compound No. 80: tert-butyl (N-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)sulfamoyl)carbamate; Compound No. 81: tert-butyl N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfamoyl carbamate; Compound No. 82: tert-butyl (N-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 83: tert-butyl ((6-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate; Compound No. 84: tert-butyl ((6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate; Compound No. 85: tert-butyl ((6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate; Compound No. 86: tert-butyl ((6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate; Compound No. 87: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide; Compound No. 88: N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide Compound No. 89: N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide hydrochloride; Compound No. 90: N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 91: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide Compound No. 92: N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide; Compound No. 93: N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide; Compound No. 94: N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide trifluoroacetic acid; Compound No. 95: N-(3-(3-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 96: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl) sulfamide hydrochloride; Compound No. 97: N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 98: N-(4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 99: N-(4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide trifluoroacetic acid; Compound No. 100: N-(4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 101: N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 102: N-(4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 103: N-(4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 104: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 105: N-(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 106: N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 107: N-(4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 108: N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride; Compound No. 109: N-(3-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-benzyl) sulfamide; Compound No. 110: N-(3-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-benzyl) sulfamide; Compound No. 111: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-fluorobenzyl)sulfamide hydrochloride; Compound No. 112: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-fluorobenzyl)sulfamide hydrochloride; Compound No. 113: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-fluorobenzyl)-N-methyl sulfamide hydrochloride; Compound No. 114: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-fluorobenzyl)-N-methyl sulfamide hydrochloride; Compound No. 115: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2,3-difluorobenzyl)sulfamide hydrochloride; Compound No. 116: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-(trifluorobenzyl methyl)benzyl) sulfamide hydrochloride; Compound No. 117: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2,3-difluorobenzyl)-N-methyl sulfamide hydrochloride; Compound No. 118: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-(trifluorobenzyl methyl)benzyl)-N-methyl sulfamide hydrochloride; Compound No. 119: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluorobenzyl methyl)benzyl)sulfamide hydrochloride; Compound No. 120: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluorobenzyl methyl)benzyl)-N-methyl sulfamide hydrochloride; Compound No. 121: 7-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H) sulfamide hydrochloride; Compound No. 122: 7 -(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfamide; Compound No. 123: N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamide hydrochloride; Compound No. 124: (R)-N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamide hydrochloride; Compound No. 125: N-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)sulfamide hydrochloride; Compound No. 126: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfamide hydrochloride; Compound No. 127: N-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide; Compound No. 128: 6-(4-oxo-3,4-dihydrophthalazin-1-yl-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride; Compound No. 129: 6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride; Compound No. 130: 6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride; Compound No. 131: 6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride; Compound No. 132: tert-butyl ((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)carbamate; Compound No. 133: tert-butyl ((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)carbamate; Compound No. 134: 4-(4-(aminomethyl)piperidin-1-yl)phthalazin-1(2H)-one Compound No. 135: 4-(4-(aminomethyl)piperidin-1-yl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride; Compound No. 136: tert-butyl N-((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamoyl carbamate; Compound No. 137: tert-butyl N-((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamoyl carbamate; Compound No. 138: N-((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamide hydrochloride; Compound No. 139: N-((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamide hydrochloride; Compound No. 140: N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-amino)phenyl)sulfamide hydrochloride; Compound No. 141: N-(3-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-amino)phenyl)sulfamide hydrochloride; Compound No. 142: N-(2-(1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)ethyl)sulfamide trifluoroacetic acid; Compound No. 143: 4-benzylphthalazin-1(2H)-one; Compound No. 144: 4-benzyl-6,7-dimethoxyphthalazin-1(2H)-one; Compound No. 145: tert-butyl (3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate; Compound No. 146: tert-butyl (3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate; Compound No. 147: tert-butyl (4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate; Compound No. 148: tert-butyl (4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate; Compound No. 149: tert-butyl (4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate; Compound No. 150: tert-butyl (4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate; Compound No. 151: tert-butyl (4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl) (methyl)carbamate; Compound No. 152: tert-butyl (4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl) (methyl)carbamate; Compound No. 153: tert-butyl (4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl) (methyl)carbamate; Compound No. 154: tert-butyl (5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-carboxylate; Compound No. 155: tert-butyl (5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-carboxylate; Compound No. 156: 4-(3-aminobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride; Compound No. 157: 4-(3-aminobenzyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 158: 4-(4-aminobenzyl)-phthalazin-1(2H)-one hydrochloride; Compound No. 159: 4-(4-aminobenzyl)-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 160: 4-(4-aminobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride; Compound No. 161: 4-(4-aminobenzyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 162: 4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride; Compound No. 163: 6,7-dimethoxy-4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride; Compound No. 164: 6,7-dimethoxy-2-methyl-4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride; Compound No. 165: 4-(indolin-5-yl-methyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride; Compound No. 166: 4-(indolin-5-yl-methyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 167: tert-butyl (N-(3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate; Compound No. 168: tert-butyl (N-(3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate; Compound No. 169: tert-butyl (N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate; Compound No. 170: tert-butyl (N-(4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate; Compound No. 171: tert-butyl (N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate; Compound No. 172: tert-butyl (N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate; Compound No. 173: tert-butyl N-methyl-N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl carbamate; Compound No. 174: tert-butyl N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamoyl carbamate; Compound No. 175: tert-butyl N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamoyl carbamate; Compound No. 176: tert-butyl (5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indolin-1-yl)sulfonyl carbamate; Compound No. 177: tert-butyl (5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indolin-1-yl)sulfonyl carbamate; Compound No. 178: N-(3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride; Compound No. 179: N-(34(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride; Compound No. 180: N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide Compound No. 181: N-(4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride; Compound No. 182: N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride; Compound No. 183: N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride; Compound No. 184: N-methyl-N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride; Compound No. 185: N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamide hydrochloride; Compound No. 186: N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamide hydrochloride; Compound No. 187: 5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-sulfonamide hydrochloride; Compound No. 188: 5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-sulfonamide hydrochloride; Compound No. 189: N-(3-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride; Compound No. 190: N-(2-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride; Compound No. 191: N-(3-(trifluorobenzyl methyl)-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride; Compound No. 192: N-(2-(trifluorobenzyl methyl)-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride; Compound No. 193: 4-(3-bromobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one; Compound No. 194: 4-(4-bromobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one; Compound No. 195: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)methanesulfonamide; Compound No. 196: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)cyclopropanesulfonamide; Compound No. 197: 4-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)benzenesulfonamide; Compound No. 198: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)thiophene-2-sulfonamide; Compound No. 199: (4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide; Compound No. 200: N-methyl-1-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methanesulfonamide; Compound No. 201: 2-methyl-4-(4-((morpholinosulfonyl)methyl)phenyl)phthalazin-1(2H)-one; Compound No. 202: 2-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethane-1-sulfonamide; and Compound No. 203: 4-(4-(aminomethyl)-3-(trifluoromethyl)phenyl-6,7-dimethoxy phthalazin-1(2H)-one hydrochloride.

6. The compound according to claim 1, wherein the pharmaceutically acceptable salt is a salt of an inorganic or organic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid.

7. A pharmaceutical composition for preventing, alleviating or treating cancer comprising the compound according to claim 1 as an active ingredient.

8. An ENPP 1 inhibitor comprising the compound according to claim 1 as an active ingredient.

9. The pharmaceutical composition according to claim 7, wherein the cancer is associated with activation of STING pathway.

10. The pharmaceutical composition according to claim 7, wherein the cancer is associated with inhibition of ENPP 1.

Description

PREPARATION EXAMPLE 1

[0579] Preparation Example 1 includes a process of preparing Product 4 (Preparation Example 1-1) or Product 6 (Preparation Example 1-2). Then, a phthalazine derivative was prepared through Preparation Example 1-3 using the product 4 or 6 as Reactant 7.

PREPARATION EXAMPLE 1-1

Preparation of Reactant 4

[0580] ##STR00017##

[0581] Step 1: Reactant 1 (1.0 eq.) and hydrazine-hydrate (1.7 eq.) were added to ethanol in a round-bottom flask, followed by refluxing for 2 hours. The reaction product was cooled to room temperature and filtered to obtain a solid 2 (71-94% yield).

[0582] Examples of Reactant 1 used in step 1 are as follows.

Reactant 1-1: 2,3-dihydrophthalazine-1,4-dione

[0583] ##STR00018##

[0584] .sup.1H NMR (400 MHz, DMSO) δ 11.51 (s, 2H), 8.15-7.95 (m, 2H), 7.92-7.79 (m, 2H).

Reactant 1-2: 6,7-dimethoxy-2,3-dihydrophthalazine-1,4-dione

[0585] ##STR00019##

[0586] .sup.1H NMR (400 MHz, DMSO) δ 11.25 (br s, 2H), 7.42 (s, 2H), 3.93 (s, 6H).

Reactant 1-3: 6-methoxy-2,3-dihydrophthalazine-1,4-dione

[0587] ##STR00020##

[0588] .sup.1H NMR (400 MHz, DMSO) δ 11.44 (s, 2H), 8.00 (d, J=9.2 Hz, 1H), 7.60-7.20 (m, 2H), 3.92 (s, 3H).

[0589] Step 2-1: Reactant 2 (1.0 eq.) obtained in step 1 and anhydrous pyridine (5.0 eq.) were dissolved in anhydrous acetonitrile (0.61 M) under a nitrogen atmosphere in a round bottom flask and the resulting solution was cooled to 0° C., followed by stirring for 10 minutes. Triflic anhydride 1.05 eq.) was added thereto at 0° C. and then the resulting mixture was warmed to room temperature and stirred for 6 hours. The mixture was poured into ethyl acetate, the result, was washed with a 5% aqueous hydrochloric acid solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized using ethyl acetate to obtain 3 (yield: 67-79%).

Reactant 3-1: 4-oxo-3,4-dihydrophthalazin-1-yl trifluoromethanesulfonate

[0590] ##STR00021##

[0591] .sup.1H NMR (400 MHz, DMSO) δ 12.91 (s, 1H), 8.36-8.29 (m, 1H), 8.22 (td, J=7.6, 1.4 Hz, 1H), 8.05 (td, J=7.6, 2.3 Hz, 1H), 7.88 (apparent d, J=7.7 Hz 1H).

Reactant 3-2: 6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl trifluoromethanesulfonate

[0592] ##STR00022##

[0593] .sup.1H NMR (400 MHz, DMSO) δ 12.82 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.70 (d, J=2.6 Hz, 1H), 7.67 (dd, J=8.8, 2.7 Hz, 1H), 3.99 (s, 3H).

Reactant 3-3: 7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl trifluoromethanesulfonate

[0594] ##STR00023##

[0595] .sup.1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 8.24 (d, J=8.9 Hz, 1H), 7.61 (dd, J=8.8, 2.6 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 3.97 (s, 3H).

Reactant 3-4: 6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl trifluoromethanesulfonate

[0596] ##STR00024##

[0597] .sup.1H NMR (400 MHz, DMSO) δ 12.77 (s, 1H), 7.67 (s, 1H), 7.13 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H).

[0598] Step 2-2: Reactant 3 (1.0 eq.) obtained in step 2-1 above was dissolved in anhydrous acetonitrile (0.2 M) in a round bottom flask, and K.sub.2CO.sub.3 (3.0 eq.) and alkyl halide (3.0 eq.) were added thereto, followed by stirring at 80° C. for 4 hours. The resulting product was washed with ethyl acetate and filtered through celite remove solids, and the compound was purified by column chromatography (60-87% yield).

Reactant 3-5: 3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0599] ##STR00025##

[0600] .sup.1H NMR (400 MHz, DMSO) δ 8.36 (dt, J=8.0, 1.1 Hz, 1H), 8.6-8.02 (m, 2H), 7.90 (d, J=7.8 Hz, 1H), 3.69 (s, 3H).

Reactant 3-6: 3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0601] ##STR00026##

[0602] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.47 (dt, J=6.9, 1.7 Hz, 1H), 7.96-7.80 (m, 3H), 7.25 (dd, J=5.2, 2.8 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 1.41 (td, J=7.2 Hz, 3H).

Reactant 3-7: 3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0603] ##STR00027##

[0604] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.46 (dd, J=7.8, 1.5 Hz, 1H), 8.04 (dd, J=7.8, 1.4 Hz, 1H), 7.80 (dtd, J=15.0, 7.6, 1.5 Hz, 2H), 5.18 (p, J=6.2 Hz, 1H), 1.43-1.41 (m, 3H), 1.41-1.39 (m, 3H).

Reactant 3-8: 3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0605] ##STR00028##

[0606] .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.48-8.44 (m, 1H), 7.94-7.84 (m, 2H), 7.83 (dd, J=8.0, 1.3 Hz, 1H), 7.49-7.45 (m, 2H), 7.44-7.26 (m, 3H), 5.31 (s, 2H).

Reactant 3-9: 6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0607] ##STR00029##

[0608] .sup.1H NMR (600 MHz, DMSO) δ 7.67 (s, 1H), 7.13 (s, 1H), 3.99 (d, J=7.4 Hz, 6H), 3.68 (s, 3H).

PREPARATION EXAMPLE 1-2

Preparation of Reactant 6

[0609] ##STR00030##

[0610] Step 1: 1 (1.0 eq.) and arylhydrazine (3.0 eq.) were refluxed in the presence of a 10% HCl aqueous solution in a round bottom flask for 10 hours. The reaction product was cooled to room temperature, a 1M aqueous Na.sub.2CO.sub.3 solution was added to the residue against to remove solids, and the residue was filtered to obtain a solid 5 (65% yield).

Reactant 5-1: 2-phenyl-2,3-dihydrophthalazine-1,4-dione

[0611] ##STR00031##

[0612] .sup.1H NMR (400 MHz, DMSO) δ 11.83 (s, br, 1H), 8.30 (dd, J=7.5, 1.6 Hz, 1H), 8.06-7.39 (m, 3H), 7.66-7.61 (m, 2H), 7.49 (dd, J=8.6, 7.1 Hz, 2H), 7.40-7.34 (m, 1H).

[0613] Step 2: Reactant 5 (1.0 eq.) Prepared in Step 1 above and anhydrous pyridine (5.0 eq.) were dissolved in anhydrous acetonitrile (0.61 M) under a nitrogen atmosphere in a round bottom flask and the resulting solution was cooled to 0° C., followed by stirring for 10 minutes. Triflic anhydride (1.05 eq.) was added thereto at 0° C. and then the resulting mixture was warmed to room temperature and stirred for 6 hours. The mixture was poured into ethyl acetate, the result was washed with a 5% aqueous hydrochloric acid solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the compound was recrystallized using ethyl acetate to obtain 6 (77% yield).

Reactant 6-1: 4 oxo 3 phenyl-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0614] ##STR00032##

[0615] .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.55 (d, J=7.7 Hz, 1H), 8.02-7.93 (m, 2H), 7.91 (d, J=7.8 Hz, 1H), 7.69 (d, J=7.9 Hz, 2H), 7.50 (t, J=7.8 Hz, 2H), 7.40 (t, J=7.5 Hz, 1H).

PREPARATION EXAMPLE 1-3

[0616] A preparation process was performed in accordance with the following Reaction Scheme 1-3 using 4 prepared in Preparation Example 1-1 or 6 prepared in Preparation Example 1-2 as Reactant 7.

##STR00033## ##STR00034##

[0617] Step 1 (Representative Synthesis Method A): in Reaction Scheme 1-3, 7 (1.0 eq.) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.1 eq.), 8 (1.05 eq.) and potassium triphosphate (1.5 eq.) were dissolved in 1,4-dioxane 0.3 M) in a round bottom flask and refluxed under a nitrogen atmosphere for 4 hours. After the reaction was completed, the mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (EtOAc:Hexane 1:1) to obtain 9 (40 80% yield).

[0618] Step 1 (Representative Synthesis Method B): in Reaction Scheme 1-3, 7 (1.0 eq.), tetrakis (triphenylphosphine) palladium (0) (0.06 ea.), 8 (1.25 eq.) and potassium carbonate (3.75 eq.) were dissolved in 1,4-dioxane (0.09 M) and water (0.9 M) in a round bottom flask and refluxed under a nitrogen atmosphere for 4 hours. After the reaction was complete, the mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (EtOAc:Hexane=1:1) to obtain 9 (40-80% yield).

[0619] Examples of the present invention prepared according to Preparation Example 1 as described above are as follows.

EXAMPLE 1

4-phenylphthalazin-1(2H)-one

[0620] ##STR00035##

[0621] .sup.1H NMR (400 MHz, DMSO): δ 12.87 (s, 1H), 8.39-8.32 (m, 1H), 7.91 (td, J=6.0, 5.2, 3.2 Hz, 2H), 7.71-7.67 (m, 1H), 7.62-7.54 (m, 5H).

EXAMPLE 2

tert-butyl (3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

[0622] ##STR00036##

[0623] .sup.1H NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 9.55 (s, 1H), 8.99-8.16 (m, 1H), 7.94-7.86 (m, 2H), 7.71 (d, J=9.2 Hz, 2H), 7.58 (d, J=7.2 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 1.47 (s, 9H).

EXAMPLE 3

tert-butyl (3(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

[0624] ##STR00037##

[0625] .sup.1H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 8.61-8.20 (m, 1H), 8.00-7.82 (m, 2H), 7.73 (s, 1H), 7.69 (dd, J=6.1, 3.0 Hz, 1H), 7.58 (d, J=3.4 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.17 (dt, J=7.6, 1.3 Hz, 1H), 3.78 (s, 3H), 1.47 (s, 9H).

EXAMPLE 4

tert-butyl (3(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

[0626] ##STR00038##

[0627] .sup.1H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 8.45-8.26 (m, 1H), 7.99-7.88 (m, 2H), 7.79-7.67 (m, 2H), 7.60 (dd, 1H), 7.48-7.21 (m, 7H), 7.18 (d, J=7.3 Hz, 1H), 5.39 (s, 2H), 1.47 (s, 9H).

EXAMPLE 5

tert-butyl(3-(4-oxo-3,4-dihydrophthalazin-1-yl)carbamate

[0628] ##STR00039##

[0629] .sup.1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 8.38-8.31 (m, 1H), 7.93-7.85 (m, 2H), 7.72-7.67 (m, 1H), 7.53-7.43 (m, 4H), 7.40 (d, J=7.5 Hz, 1H), 4.22 (d, J=6.2 Hz, 2H), 1.38 (s, 9H).

EXAMPLE 6

tert-butyl 3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl carbamate

[0630] ##STR00040##

[0631] .sup.1H NMR (400 MHz, MeOD) δ 8.50-8.44 (m, 1H), 7.94-7.84 (m, 2H), 7.81 (d, J=7.0 Hz, 1H), 7.58-7.45 (m, 4H), 4.35 (s, 2H), 3.90 (s, 3H), 1.46 (s, 9H).

EXAMPLE 7

tert-butyl (3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0632] ##STR00041##

[0633] .sup.1H NMR (400 MHz, CDCl3 δ 8.53 (d, J=7.1 Hz, 1H), 7.90-7.61 (m, 3H), 7.58-7.37 (m, 7H), 7.37-7.28 (m, 3H), 5.47 (s, 2H), 4.42 (d, J=5.6 Hz, 2H), 1.46 (s, 9H).

EXAMPLE 8

tart-butyl (4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0634] ##STR00042##

[0635] .sup.1H NMR (400 MHz, MeOD) δ 8.44 (dd, J=6.3, 2.9 Hz, 1H), 7.95-7.84 (m, 2H), 7.80 (d, J=3.3 Hz, 1H), 7.70 (d, J=7.3 Hz, 1H), 7.47 (d, J=8.1 Hz, 2H), 7.26 (d, J=7.7 Hz, 1H), 4.35 (s, 2H), 1.48 (s, 9H).

EXAMPLE 9

tert-butyl (4-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0636] ##STR00043##

[0637] .sup.1H NMR (400 MHz, DMSO) δ 8.40-8.33 (m, 1H), 7.94-7.86 (m, 2H), 7.69 (s, 1H), 7.55 (d, J=7.9 Hz, 2H), 7.49 (s, 1H), 7.41 (d, J=7.8 Hz, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.78 (s, 3H), 1.42 (s, 9H).

EXAMPLE 10

tert-butyl (4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0638] ##STR00044##

[0639] .sup.1H NMR (400 MHz, MeOD) δ 8.50-8.40 (m, 1H), 7.91-7.35 (m, 2H), 7.82-7.77 (m, 1H), 7.58 (d, J=7.9 Hz, 2H), 7.48 (d, J=7.9 Hz, 2H), 4.37-4.32 (m, 4H), 1.48 (s, 9H), 1.44 (t, J=7.2 Hz, 3H).

EXAMPLE 11

tert-butyl 4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl carbamate

[0640] ##STR00045##

[0641] .sup.1H NMR (400 MHz, CDCl3) δ 10.53-10.43 (m, 1H), 9.79-9.65 (m, 3H), 9.55 (d, J=8.2 Hz, 2H), 9.42 (d, J=7.9 Hz, 2H), 7.44 (dt, J=13.3, 6.8 Hz, 1H), 6.39 (d, J=6.1 Hz, 2H), 3.45 (s, 9H), 3.40 (d, J=6.6 Hz, 6H).

EXAMPLE 12

tert-butyl (4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0642] ##STR00046##

[0643] .sup.1H NMR (400 MHz, MeOD) δ 8.53 (dd, J=6.1, 3.3 Hz, 1H), 7.93 (dt, J=7.2, 3.6 Hz, 2H), 7.85 (dd, J=6.2, 3.4 Hz, 1H), 7.71-7.61 (m, 4H), 7.49 (ddd, J=22.9, 15.2, 7.4 Hz, 5H), 4.34 (s, 2H), 1.47 (s, 9H).

EXAMPLE 13

tert-butyl (4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0644] ##STR00047##

[0645] .sup.1H NMR (400 MHz, MeOD) δ 8.49-8.42 (m, 1H), 7.91-7.84 (m, 2H), 7.81 (d, J=6.0 Hz, 1H), 7.56 (d, J=7.9 Hz, 2H), 7.49-7.40 (m, 4H), 7.36-7.24 (m, 3H), 5.46 (s, 2H), 4.34 (s, 2H), 1.48 (s, 9H).

EXAMPLE 14

tert-butyl (4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0646] ##STR00048##

[0647] .sup.1H NMR (400 MHz, DMSO) δ 8.38 (dd, J=5.9, 3.2 Hz, 1H), 7.91 (dd, J=6.0, 3.3 Hz, 2H), 7.75-7.67 (m, 1H), 7.55 (d, J=8.1 Hz, 2H), 7.49 (s, 1H), 7.42 (t, J=9.3 Hz, 5H), 7.16 (t, J=8.9 Hz, 2H), 5.36 (s, 2H), 1.41 (s, 9H).

EXAMPLE 15

tert-butyl (4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0648] ##STR00049##

[0649] .sup.1H NMR (400 MHz, DMSO): δ 12.70 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 7.58 (d, J=0 Hz, 2H), 7.52-7.44 (m, 2H), 7.40 (d, J=7.9 Hz, 2H), 7.03 (d, J=2.5 Hz, 1H), 4.23 (d, J=6.1 Hz, 2H), 3.82 (s, 3H), 1.41 (s, 9H).

EXAMPLE 16

tert-butyl 4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl carbamate

[0650] ##STR00050##

[0651] .sup.1H NMR (400 MHz, MeOD) δ 3.36 (d, J=8.9 Hz, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.50-7.42 (m, 3H), 7.10 (d, J=2.5 Hz, 1H), 4.35 (s, 2H), 3.86 (.sup.s, 3H), 3.84 (s, 3H), 1.48 (s, 9H).

EXAMPLE 17

tert-butyl 4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl carbamate

[0652] ##STR00051##

[0653] .sup.1H NMR (400 MHz, MeOD) δ 7.84 (d, J=2.8 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.59-7.50 (m, 2H), 7.50-7.36 (m, 3H), 4.34 (s, 2H), 3.99 (s, 3H), 1.48 (s, 9H).

EXAMPLE 18

tert-butyl (4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0654] ##STR00052##

[0655] .sup.1H NMR (400 MHz, DMSO) δ 7.74 (d, J=2.8 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.55-7.43 (m, 4H), 7.40 (d, J=8.2 Hz, 2H), 4.23 (d, J=6.1 Hz, 2H), 3.96 (s, 3H), 3.77 (s, 3H), 1.41 (s, 9H).

EXAMPLE 19

tert-butyl (4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0656] ##STR00053##

[0657] .sup.1H NMR (400 MHz, CDCl.sub.3): 9.92 (s, 1H), 7.88 (d, J=2.8 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.54 (d, J=8.1 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 7.33 (dd, J=8.9, 2.8 Hz, 1H), 4.93 (s, 1H), 4.42 (d, J=5.9 Hz, 2H), 3.99 (s, 3H), 1.49 (s, 9H).

EXAMPLE 20

tert-butyl (4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0658] ##STR00054##

[0659] .sup.1H NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.59 (d, J=7.9 Hz, 2H), 7.48 (d, J=7.9 Hz, 2H), 7.11 (s, 1H), 4.35 (s, 2H), 4.03 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 1.48 (s, 9H).

EXAMPLE 21

tert-butyl (1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)carbamate

[0660] ##STR00055##

[0661] .sup.1H NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 8.33 (s, 1H), 8.08-7.79 (m, 2H), 7.69 (s, 1H), 7.54 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 1.39 (s, 9H), 1.23 (s, 3H), 0.85 (m, 1H).

EXAMPLE 22

tert-butyl (R)-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)carbamate

[0662] ##STR00056##

[0663] .sup.1H NMR (400 MHz, MeOD) δ 8.44 (dd, J=6.3, 3.1 Hz, 1H), 7.93-7.84 (m, 2H), 7.84-7.77 (m, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.1 Hz, 2H), 1.47 (d, J=7.1 Hz, 3H), 1.45 (s, 9H).

EXAMPLE 23

tert-butyl (2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)carbamate

[0664] ##STR00057##

[0665] .sup.1H NMR (400 MHz, MeOD) δ 8.44 (dd, J=6.3, 3.2 Hz, 1H), 7.89 (dd, J=5.9, 3.4 Hz, 2H), 7.86-7.80 (m, 1H), 7.57 (q, J=8.2 Hz, 4H), 1.65 (s, 6H), 1.42 (s, 9H).

EXAMPLE 24

tert-butyl 4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl carbamate

[0666] ##STR00058##

[0667] .sup.1H NMR (DMSO, 600 MHz) δ 12.93 (s, 1H), 8.37-8.34 (m, 1H), 7.94-7.89 (m, 4H), 7.68-7.62 (m, 3H), 4.42 (d, J=6 Hz, 2H), 1.43 (s, 9H).

EXAMPLE 25

test-butyl methyl(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0668] ##STR00059##

[0669] .sup.1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 8.56-8.50 (m, 1H), 7.85-7.74 (m, 3H), 7.56 (d, J=7.8 Hz, 2H), 7.39 (d, J=7.3 Hz, 2H), 4.53 (s, 2H), 2.83 (d, J=14.3 Hz, 3H), 1.51 (s, 9H)

EXAMPLE 26

tert-butyl 6-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0670] ##STR00060##

[0671] .sup.1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.59-8.46 (m, 1H), 7.90-7.69 (m, 3H), 7.44-7.34 (m, 2H), 7.28 (s, 1H), 4.67 (s, 2H), 3.71 (t, J=5.8 Hz, 2H), 2.92 (t, J=5.9 Hz, 2H), 1.52 (s, 9H).

EXAMPLE 27

tert-butyl-6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0672] ##STR00061##

[0673] .sup.1H NMR (400 MHz, DMSO) δ 8.42-8.33 (m, 1H), 7.90 (d, J=9.2 Hz, 2H), 7.72 (s, 1H), 7.38 (d, J=12.1 Hz, 3H), 4.60 (s, 2H), 3.78 (s, 3H), 3.61 (t, 2H), 2.87 (t, 2H), 1.45 (s, 9H).

EXAMPLE 28

tert-butyl 6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0674] ##STR00062##

[0675] .sup.1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 7.70 (s, 1H), 7.48-7.40 (m, 2H), 7.34 (d, J=7.9 Hz, 1H), 7.09 (s, 1H), 4.60 (s, 2H), 3.97 (s, 3H), 3.79 (s, 3H), 3.61 (t, J=6.0 Hz, 2H), 2.88 (t, J=5.9 Hz, 2H), 1.45 (s, 9H).

EXAMPLE 29

tert-butyl-6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0676] ##STR00063##

[0677] .sup.1H NMR (400 MHz, DMSO) δ 7.71 (s, 1H), 7.45 (d, J=9.5 Hz, 2H), 7.36 (s, 1H), 7.07 (s, 1H), 4.60 (s, 2H), 3.97 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 3.61 (t, 2H), 2.88 (t, 2H), 1.45 (s, 9H).

[0678] Step 2: In Reaction Scheme 1-3, 9 (1.0 eq.) was dissolved in dichloromethane (0.04 M) in a round bottom flask. Then, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) was added thereto, followed by stirring at room temperature for 4 hours. After the reaction was complete, the reaction product was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, filtered and dried to obtain 10 (50-90% yield).

EXAMPLE 30

4-(3-aminophenyl)phthalazin-1(2H)-one hydrochloride

[0679] ##STR00064##

[0680] .sup.1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 8.33 (m, J=7.2 Hz, 1H), 7.90 (m, J=5.7 Hz, 2H), 7.73 (d, J=7.2 Hz, 1H), 7.31 (m, 1H), 6.91 (m, 3H).

EXAMPLE 31

4-(3-aminophenyl)-2-methylphthalazin-1(2H)-one hydrochloride

[0681] ##STR00065##

[0682] .sup.1H NMR (400 MHz, DMSO) δ 8.41-8.31 (m, 1H), 7.98-7.80 (m, 2H), 7.79-7.68 (m, 1H), 7.37 (s, 1H), 7.06 (s, 3H), 3.78 (s, 3H).

EXAMPLE 32

4-(3-aminophenyl)-2-benzylphthalazin-1(2H)-one hydrochloride

[0683] ##STR00066##

[0684] .sup.1H NMR (400 MHz, DMSO) δ 8.42-8.35 (m, 1H), 8.00-7.88 (m, 2H), 7.84-7.72 (m, 1H), 7.40-7.18 (m, 6H), 6.92 (s, 3H), 5.38 (s, 2H).

EXAMPLE 33

4-(3-(aminomethyl)phenyl)phthalazin-1(2H)-one hydrochloride

[0685] ##STR00067##

[0686] 1H NMR (400 MHz, DMSO) δ 12.92 (s, 1H), 8.45-8.31 (m, 4H), 7.96-7.86 (m, 2H), 7.79-7.69 (m, 2H), 7.69-7.58 (m, 3H), 4.14 (q, J=5.8 Hz, 2H).

EXAMPLE 34

4-(3-(aminomethyl)phenyl)-2-methylphthalazin-1-(2H)-one hydrochloride

[0687] ##STR00068##

[0688] .sup.1H NMR (400 MHz, MeOD) δ 8.52-8.46 (m, 1H), 7.97-7.86 (m, 2H), 7.80 (d, J=7.1 Hz, 1H), 7.7-7.62 (m, 4H), 4.24 (s, 2H), 3.91 (s, 3H).

EXAMPLE 35

4-(3-(aminomethyl)phenyl)-2-benzylphthalazin-1(2H)-one hydrochloride

[0689] ##STR00069##

[0690] .sup.1H NMR (400 MHz, MeOD) δ 8.51-8.38 (m, 1H), 7.94-7.84 (m, 2H), 7.83-7.74 (m, 1H), 7.73-7.59 (m, 4H), 7.42 (d, J=6.8 Hz, 2H), 7.36-7.19 (m, 3H), 5.47 (s, 2H), 4.24 (s, 2H).

EXAMPLE 36

4-(4-(aminomethyl)phenyl)phthalazin-1(2H)-one hydrochloride

[0691] ##STR00070##

[0692] .sup.1H NMR (400 MHz, DMSO) δ 12.91 (s, 1H), 8.42-8.20 (m, 4H), 7.98-7.90 (m, 2H), 7.71-7.62 (m, 5H), 4.20-4.12 (m, 2H).

EXAMPLE 37

4-(4-aminomethyl)phenyl)-2-methylphthalazin-1(2H)-one hydrochloride

[0693] ##STR00071##

[0694] .sup.1H NMR (400 MHz, DMSO) δ 8.39 (dd, J=6.1, 3.3 Hz, 1H), 8.23 (s, 3H), 7.92 (dt, J=7.2, 3.6 Hz, 2H), 7.66 (qd, J=7.2, 6.1, 3.0 Hz, 5H), 4.15 (s, 2H), 3.78 (d, J=3.1 Hz, 3H).

EXAMPLE 38

4-(4-(aminomethyl)phenyl)-2-ethylphthalazin-1(2H)-one hydrochloride

[0695] ##STR00072##

[0696] .sup.1H NMR (400 MHz, MeOD) δ 8.50-8.45 (m, 1H), 7.94-7.85 (m, 2H), 7.78-7.70 (m, 3H), 7.65 (d, J=7.9 Hz, 2H), 4.34 (q, J=7.2 Hz, 2H), 4.24 (s, 2H), 1.44 (t, J=7.2 Hz, 3H).

EXAMPLE 39

4-(4-(aminomethyl)phenyl)-2-isopropylphthalazin-1-(2H)-one hydrochloride

[0697] ##STR00073##

[0698] .sup.1H NMR (400 MHz, MeOD) δ 8.40-8.34 (m, 1H), 7.83-7.74 (m, 2H), 7.71-7.67 (m, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 5.34 (p, J=6.6 Hz, 1H), 4.15 (s, 2H), 1.34 (d, J=6.6 Hz, 6H).

EXAMPLE 40

4-(4-aminomethyl)phenyl)-2-phenylphthalazin-1(2H)-one hydrochloride

[0699] ##STR00074##

[0700] 1H NMR (400 MHz, MeOD) δ 8.59-8.51 (m, 1H), 7.94 (td, J=7.1, 6.3, 3.4 Hz, 2H), 7.84-7.79 (m, 1H), 7.77 (d, =8.0 Hz, 2H), 7.70-7.63 (m, 4H), 7.53 (dd, J=8.6, 6.9 Hz, 2H), 7.44 (t, J=7.3 Hz, 1H), 4.23 (s, 2H).

EXAMPLE 41

4-(4-aminomethyl)phenyl)-2-benzylphthalazin-1(2H)-one hydrochloride

[0701] ##STR00075##

[0702] .sup.1H NMR (400 MHz, MeOD) δ 8.52-8.44 (m, 1H), 7.93-7.85 (m, 2H), 7.78-7.73 (m, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.1 Hz, 2H), 7.44-7.39 (m, 2H), 7.35-7.25 (m, 3H), 5.47 (s, 2H), 4.22 (s, 2H).

EXAMPLE 42

4-(4-(aminomethyl)phenyl)-2-(4-fluorobenzyl) phthalazin-1(2H)-one hydrochloride

[0703] ##STR00076##

[0704] 1H NMR (400 MHz, DMSO) δ 8.43-8.37 (m, 1H), 8.25-8.00 (m, 2H), 7.94 (dd, J=6.0, 3.2 Hz, 2H), 7.71-7.60 (m, 5H), 7.43 (dd, J=8.6, 5.6 Hz, 2H), 7.17 (t, J=8.9 Hz, 2H), 4.14 (s, 2H).

EXAMPLE 43

4-(4-(aminomethyl)phenyl)-6-methoxyphthalazin-1(2H)-one hydrochloride

[0705] ##STR00077##

[0706] .sup.1H NMR (400 MHz, DMSO) δ 12.74 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.50 (dd, J=8.9, 2.4 Hz, 1H), 7.00 (d, J=2.5 Hz, 1H), 4.06 (s, 2H), 3.83 (s, 3H).

EXAMPLE 44

(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methanaminium chloride

[0707] ##STR00078##

[0708] .sup.1H NMR (400 MHz, MeOD) δ 8.39 (d, J=8.9 Hz, 1H), 7.75-7.68 (m, 2H), 7.67-7.62 (m, 2H), 7.50-7.46 (m, 1H), 7.07 (d, J=2.5 Hz, 1H), 4.21 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H).

EXAMPLE 45

(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methanaminium chloride

[0709] ##STR00079##

[0710] .sup.1H NMR (400 MHz, MeOD) δ 7.87 (d, J=2.8 Hz, 1H), 7.72-7.61 (m, 2H), 7.48-7.40 (m, 2H), 7.27 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 4.24 (s, 2H), 4.01 (s, 3H).

EXAMPLE 46

4-(4-(aminomethyl)phenyl)-7-methoxy-2-methylphthalazin-1(2H)-one hydrochloride

[0711] ##STR00080##

[0712] 1H NMR (400 MHz, DMSO) δ 8.19 (s, 2H), 7.76 (d, J=2.7 Hz, 1H), 7.64 (s, 4H), 7.58 (d, J=9.0 Hz, 1H), 7.49 (dd, J=9.0, 2.7 Hz, 1H), 4.14 (s, 2H), 3.97 (s, 3H), 3.78 (s, 3H).

EXAMPLE 47

4-(4-(aminomethyl)-phenyl)-7-methoxyphthalazin-1(2H)-one hydrochloride

[0713] ##STR00081##

[0714] 1H NMR (400 MHz, DMSO) δ 12.82 (s, 1H), 8.34 (br s, 3H), 7.74 (d, J=2.7 Hz, 1H), 7.68-7.62 (m, 4H), 7.57 (d, J=9.0 Hz, 1H), 7.49 (dd, J=9.0, 2.7 Hz, 1H), 4.14 (s, 2H), 3.96 (s, 3H).

EXAMPLE 48

4-(4-(aminomethyphenyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride

[0715] ##STR00082##

[0716] .sup.1H NMR (400 MHz, DMSO) δ 12.76 (s, 1H), 8.27 (s, 3H), 7.77-7.68 (m, 3H), 7.63 (d, J=8.1 Hz, 2H), 7.03 (s, 1H), 4.15 (s, 2H), 3.97 (s, 3H), 3.79 (s, 3H).

EXAMPLE 49

4-(4-(aminomethyl)phenyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride

[0717] ##STR00083##

[0718] 1H NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 7.79-7.71 (m, 2H), 7.67 (d, J=8.2 Hz, 2H), 7.07 (s, 1H), 4.25 (s, 3H), 4.05 (s, 3H), 3.90 (s, 3H), 3.83 (s, 3H).

EXAMPLE 50

4-(4-(1-aminoethyl)phenyl)phthalazin-1(2H)-one hydrochloride

[0719] ##STR00084##

[0720] .sup.1H NMR (400 MHz, MeOD) δ 8.52-8.39 (m, 1H), 7.94-7.84 (m, 2H), 7.78-7.69 (m, 3H), 7.69-7.60 (m, 2H), 4.60 (q, J=6.9 Hz, 1H), 1.72 (d, J=6.9 Hz, 3H).

EXAMPLE 51

(R)-4-(4-(1-aminoethyl)phenyl)phthalazin-1(2H)-one hydrochloride

[0721] ##STR00085##

[0722] .sup.1H NMR (400 MHz, MeOD) δ 8.49-8.42 (m, 1H), 7.94-7.85 (m, 2H), 7.77-7.73 (m, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.65 (d, J=8.3 Hz, 2H), 4.59 (q, J=6.8 Hz, 1H), 1.72 (d, J=6.8 Hz, 3H).

EXAMPLE 52

4-(4-(2-aminopropan-2-yl)phenyl)phthalazin-1(2H)-one hydrochloride

[0723] ##STR00086##

[0724] .sup.1H NMR (400 MHz, MeOD) δ 8.48-8.44 (m, 1H), 7.93-7.88 (m, 2H), 7.77-7.68 (m, 5H), 1.83 (s, 6H).

EXAMPLE 53

4-(4-(aminomethyl)-3-(trifluoromethyl)phenyl) phthalazin-1(2H)-one hydrochloride

[0725] ##STR00087##

[0726] 1H NMR (DMSO, 600 MHz) δ 13.00 (s, 1H), 8.50 (br s, 3H), 8.38-8.36 (m, 1H), 8.08-8.06 (m, 1H), 8.02 (d, J=2 Hz, 1H), 7.97-7.91 (m, 3H), 7.61-7.59 (m, 1H), 4.30 (s, 2H).

EXAMPLE 54

4-(4-((methylamino)methyl)phenyl)phthalazin-1(2H)-one hydrochloride

[0727] ##STR00088##

[0728] .sup.1H NMR (400 MHz, MeOD) δ 8.49-8.41 (m, 1H), 7.91 (dt, J=6.1, 3.5 Hz, 2H), 7.82-7.65 (m, 5H), 4.32 (s, 2H), 2.80 (s, 3H).

EXAMPLE 55

4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride

[0729] ##STR00089##

[0730] .sup.1H NMR (400 MHz, DMSO) δ 12.88 (s, 1H), 9.57 (s, 2H), 8.38-8.31 (m, 1H), 7.96-7.84 (m, 2H), 7.70-7.62 (m, 1H), 7.47 (d, J=7.0 Hz, 2H), 7.40 (d, J=8.5 Hz, 1H), 3.42 (t, J=6.2 Hz, 2H), 3.10 (t, J=6.3 Hz, 2H).

EXAMPLE 56

2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl) phthalazin-1(2H) -one hydrochloride

[0731] ##STR00090##

[0732] .sup.1H NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 8.54 (dd, J=7.2, 1.9 Hz, 1H), 7.85-7.72 (m, 2H), 7.70-7.66 (m, 1H), 7.55-7.40 (m, 2H), 7.31 (d, J=8.0 Hz, 1H), 4.49 (s, 2H), 3.92 (s, 3H), 3.57 (L, 2H), 3.32 (t, 2H).

EXAMPLE 57

6,7-dimethoxy-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride

[0733] ##STR00091##

[0734] .sup.1H NMR (400 MHz, DMSO) δ 12.75 (s, 1H), 9.14 (s, 2H), 7.71 (s, 1H), 7.58-7.48 (m, 2H), 7.40 (d, J=7.9 Hz, 1H), 7.04 (s, 1H), 4.37 (s, 2H), 3.97 (s, 3H), 3.79 (s, 3H), 3.49-3.40 (t, J=6.0 Hz, 2H), 3.11 (t, J=6.1 Hz, 2H).

EXAMPLE 58

6,7-dimethoxy-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride

[0735] ##STR00092##

[0736] 1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 7.74 (s, 1H), 7.61-7.47 (m, 2H), 7.41 (d, J=7.3 Hz, 1H), 7.04 (s, 1H), 4.37 (s, 2H), 3.99 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 3.43 (t, 2H), 3.11 (t, 2H).

EXAMPLE 59

6,7-dimethoxy-4-(1,2,3,4-tetrahydroisoquinolin-7-yl)phthalazin-1(2H)-one

[0737] ##STR00093##

[0738] 1H NMR (400 MHz, DMSO) δ 12.77 (s, 1H), 9.32 (s, 2H), 7.72 (s, 1H), 7.65 (d, J=1.24 Hz, 1H), 7.53 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.06 (s, 1H), 4.38 (s, 2H), 3.98 (s, 3H), 3.82 (s, 3H), 3.44-3.45 (m, 2H), 3.09-3.13 (m, 2H)

[0739] Step 3: dichloromethane (0.2 M) was added to 10 (1.0 eq.) of Reaction. Scheme 1-3 under a nitrogen.atmosphere in a round bottom flask at 0° C. A solution of tent butanol (1.0 eq.) in dichloromethane (0.2 M) was slowly added dropwise to the resulting solution, followed.by stirring at room temperature for 30 minutes. Then, a solution of 11 (1.0 eq.) and trimethylamine (2.5 eq.) in dichloromethane (0.1 M) was slowly added dropwise at 0° C., followed by stirring at room temperature for one day. After the reaction was completed, the reaction product was concentrated under reduced pressure and dried and then the obtained residue was extracted with ethyl acetate and water. The obtained residue was purified by column chromatography (DCM:MeOH=40:1) to obtain 12 (20-40% yield).

EXAMPLE 60

tert-butyl (N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate

[0740] ##STR00094##

[0741] .sup.1H NMR (400 MHz, CDCl3) δ 10.73 (s, 1H), 8.52-8.46 (m, 1H), 8.40 (s, 1H), 7.87-7.65 (m, 2H), 7.62 (s, 2H), 7.56-7.41 (m, 2H), 7.33 (d, J=7.6 Hz, 1H), 1.44 (s, 9H).

EXAMPLE 61

tert-butyl (N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate

[0742] ##STR00095##

[0743] .sup.1H NMR (400 MHz, DMSO) δ 8.37 (d, J=7.4 Hz, 1H), 7.96-7.81 (m, 2H), 7.70 (d, J=7.2 Hz, 1H), 7.51-7.36 (m, 1H), 7.36 (s, 1H), 7.30 (d, J=9.2 Hz, 1H), 7.21 (d, J=7.5 Hz, 1H), 6.69 (s, 2H), 1.29 (s, 9H).

EXAMPLE 62

tert-butyl (N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate

[0744] ##STR00096##

[0745] .sup.1H NMR (400 MHz, DMSO) δ 8.43-8.32 (m, 1H), 8.13 (d, J=6.9 Hz, 2H), 7.99-7.83 (m, 2H), 7.73 (d, J=6.6 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.40-7.25 (m, 5H), 7.22 (d, J=7.1 Hz, 1H), 6.71 (d, J=6.8 Hz, 2H), 5.38 (s, 2H), 1.26 (s, 9H).

EXAMPLE 63

tert-butyl (N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0746] ##STR00097##

[0747] 1H NMR (400 MHz, MeOD) δ 8.49-8.43 (m, 1H), 7.95-7.87 (m, 2H), 7.87-7.83 (m, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.59-7.52 (m, 3H), 4.34 (s, 2H), 1.41 (s, 9H).

EXAMPLE 64

tert-butyl N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl carbamate

[0748] ##STR00098##

[0749] .sup.1H NMR (400 MHz, MeOD) δ 8.46 (dd, J=6.1, 3.2 Hz, 1H), 7.93-7.85 (m, 2H), 7.85-7.78 (m, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.53 (d, J=5.6 Hz, 2H), 4.26 (s, 2H), 3.90 (s, 3H), 1.33 (s, 9H).

EXAMPLE 65

tert-butyl (N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0750] ##STR00099##

[0751] 1H NMR (400 MHz, MeOD) δ 8.44 (dd, J=6.1, 3.1 Hz, 1H), 7.85 (ddq, J=13.6, 6.4, 3.4 Hz, 3H), 7.62 (s, 1H), 7.59-7.47 (m, 3H), 7.43 (d, J=7.2 Hz, 2H), 7.32 (t, J=7.3 Hz, 2H), 7.25 (dd, J=8.4, 6.1 Hz, 1H), 5.45 (s, 2H), 4.32 (s, 2H), 1.37 (s, 9H).

EXAMPLE 66

tert-butyl W-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0752] ##STR00100##

[0753] 1H NMR (400 MHz, MeOD) δ 8.51-8.41 (m, 1H), 7.91-7.82 (m, 2H), 7.82-7.77 (m, 1H), 7.57 (d, =0.8 Hz, 4H), 4.31 (s, 2H), 3.89 (s, 3H), 1.45 (d, =1.6 Hz, 9H).

EXAMPLE 67

tert-butyl (N-(4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0754] ##STR00101##

[0755] .sup.1H NMR (400 MHz, MeOD) δ 8.49-8.43 (m, 1H), 7.92-7.84 (m, 2H), 7.83-7.78 (m, 1H), 7.58 (d, J=2.0 Hz, 4H), 4.38-4.31 (m, 4H), 1.47-1.41 (m, 12H).

EXAMPLE 68

tert-butyl N-(4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl carbamate

[0756] ##STR00102##

[0757] .sup.1H NMR (400 MHz, MeOD) δ 8.52-8.43 (m, 1H), 7.94-7.85 (m, 2H), 7.86-7.81 (m, 1H), 7.62 (s, 4H), 5.51-5.39 (m, 1H), 4.35 (s, 2H), 1.46 (d, J=6.6 Hz, 6H), 1.29 (s, 9H).

EXAMPLE 69

tert-butyl (N-(4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0758] ##STR00103##

[0759] .sup.1H NMR (400 MHz, MeOD) δ 8.57-8.50 (m, 1H), 7.97-7.90 (m, 2H), 7.89-7.83 (m, 1H), 7.66 (dd, J=13.5, 7.7 Hz, 4H), 7.54 (dd, J=23.6, 7.9 Hz, 4H), 7.43 (t, J=7.5 Hz, 1H), 4.31 (s, 2H), 1.41 (s, 9H).

EXAMPLE 70

tert-butyl (N-(4-3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0760] ##STR00104##

[0761] .sup.1H NMR (400 MHz, MeOD) δ 8.55-8.38 (m, 1H), 7.93-7.84 (m, 2H), 7.84-7.78 (m, 1H), 7.56 (s, 4H), 7.42 (d, J=6.9 Hz, 2H), 7.36-7.24 (m, 3H), 5.46 (s, 2H), 4.30 (s, 2H), 1.42 (s, 9H).

EXAMPLE 71

tert-butyl (N-(4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0762] ##STR00105##

[0763] .sup.1H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.39 (dd, J=6.1, 3.1 Hz, 1H), 7.94-7.89 (m, 2H), 7.73-7.68 (m, 1H), 7.58-7.48 (m, 4H), 7.43 (dd, J=8.6, 5.6 Hz, 2H), 7.16 (t, J=8.9 Hz, 2H), 5.36 (s, 2H), 4.20 (s, 2H), 1.38 (s, 9H).

EXAMPLE 72

tert-butyl (4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0764] ##STR00106##

[0765] .sup.1H NMR (400 MHz, MeOD) δ 8.36 (d, J=8.9 Hz, 1H), 7.63-7.51 (m, 4H), 7.46 (dd, J=8.9, 2.5 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 4.33 (s, 2H), 3.85 (s, 3H), 1.46 (s, 9H).

EXAMPLE 73

tert-butyl N-(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl carbamate

[0766] ##STR00107##

[0767] 1H NMR (400 MHz, MeOD) δ 8.37 (d, J=8.9 Hz, 1H), 7.62-7.55 (m, 4H), 7.46 (dd, J=9.0, 2.5 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 4.29 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 1.46 (s, 9H).

EXAMPLE 74

tert-butyl N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl carbamate

[0768] ##STR00108##

[0769] .sup.1H NMR (400 MHz, MeOD) δ 7.86 (d, J=2.7 Hz, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.61-7.53 (m, 4H), 7.45 (dd, J=9.0, 2.8 Hz, 1H), 4.31 (s, 2H), 4.00 (s, 3H), 1.46 (s, 9H).

EXAMPLE 75

tert-butyl (N-(4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0770] ##STR00109##

[0771] .sup.1H NMR (400 MHz, MeOD) δ 7.86 (d, J=2.7 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.56 (s, 4H), 7.42 (dd, J=9.0, 2.7 Hz, 1H), 4.32 (s, 2H), 4.00 (s, 3H), 3.88 (s, 3H), 1.46 (s, 9H).

EXAMPLE 76

tert-butyl(N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0772] ##STR00110##

[0773] .sup.1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 10.89 (s, 1H), 3.25 (br m, 1H), 7.70 (s, 1H), 7.60 (d, J=7.9 Hz, 2H), 7.50 (d, J=7.9 Hz, 2H), 7.07 (s, 1H), 4.23 (d, J=6.2 Hz, 2H), 3.97 (s, 3H), 3.79 (s, 3H), 1.40 (s, 9H).

EXAMPLE 77

tert-butyl(N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin yl)benzyl)sulfamoyl)carbamate

[0774] ##STR00111##

[0775] 1H NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.64-7.54 (m, 4H), 7.09 (d, J=3.1 Hz, 1H), 4.34 (s, 2H), 4.02 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 1.48 (s, 9H).

EXAMPLE 78

tert-butyl (N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamoyl)carbamate

[0776] ##STR00112##

[0777] 1H NMR (400 MHz, MeOD) δ 8.54-8.33 (m, 1H), 7.94-7.86 (m, 2H), 7.85-7.73 (m, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 1.47 (d, J=7.1 Hz, 3H), 2.45 (s, 9H), 1.29 (m, 1H).

EXAMPLE 79

tert-butyl (R)-(N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamoyl)carbamate

[0778] ##STR00113##

[0779] .sup.1H NMR (400 MHz, MeOD) δ 8.49-8.40 (m, 1H), 7.93-7.85 (m, 2H), 7.84-7.79 (m, 1H), 7.56 (s, 4H), 4.64 (q, J=6.9 Hz, 1H), 1.55 (d, J=7.0 Hz, 3H), 1.40 (s, 9H).

EXAMPLE 80

tert-butyl (N-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)sulfamoyl)carbamate

[0780] ##STR00114##

[0781] .sup.1H NMR (400 MHz, MeOD) δ 8.53 (d, J=7.7 Hz, 2H), 7.94-7.83 (m, 2H), 7.76 (d, J=3.2 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.00 (d, J=7.7 Hz, 2H), 1.49 (s, 6H), 1.36 (s, 9H).

EXAMPLE 81

tert-butyl N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfamoyl carbamate

[0782] ##STR00115##

[0783] .sup.1H NMR (DMSO, 600 MHz) δ 12.95 (s, 1H), 11.07 (s, 1H), 8.47 (s, 1H), 8.37-8.34 (m, 1H), 7.95-7.90 (m, 5H), 7.65-7.63 (m, 1H), 4.42 (d, J=6 Hz, 2H), 1.43 (s, 9H).

EXAMPLE 82

tert-butyl (N-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0784] ##STR00116##

[0785] .sup.1H NMR (400 MHz, MeOD) δ 8.51-8.45 (m, 1H), 7.96-7.90 (m, 2H), 7.87-7.80 (m, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 4.57 (s, 2H), 2.90 (s, 3H), 1.55 (s, 9H).

EXAMPLE 83

tert-butyl ((6-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate

[0786] ##STR00117##

[0787] .sup.1H NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 11.15 (s, 1H), 8.40-8.29 (m, 1H), 7.98-7.82 (m, 2H), 7.72-7.63 (m, 1H), 7.38 (q, J=8.0 Hz, 3H), 4.56 (s, 2H), 3.57 (t, J=5.8 Hz, 2H), 2.96 (t, 3 =5.9 Hz, 2H), 1.35 (s, 9H).

EXAMPLE 84

tert-butyl ((6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H) yl)sulfonyl)carbamate

[0788] ##STR00118##

[0789] 1H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 8.63-8.27 (m, 1H), 8.18-7.81 (m, 2H), 7.81-7.52 (m, 1H), 7.41 (q, J=8.1 Hz, 3H), 4.57 (s, 2H), 3.79 (s, 3H), 3.58 (t, J=5.2 Hz, 2H), 2.98 (t, J=5.2 Hz, 2H), 1.37 (s, 9H).

EXAMPLE 85

tert-butyl ((6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate

[0790] ##STR00119##

[0791] 1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 7.69 (s, 1H), 7.50-7.38 (m, 2H), 7.34 (d, J=7.5 Hz, 1H), 7.07 (s, 1H), 4.49 (s, 2H), 3.97 (s, 3H), 3.79 (s, 3H), 3.51 (t, J=6.0 Hz, 2H), 2.95 (t, J=6.1 Hz, 2H), 1.33 (s, 9H).

EXAMPLE 86

tert-butyl ((6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate

[0792] ##STR00120##

[0793] 1H NMR (400 MHz, MeOD) δ 7.75 (d, J=1.6 Hz, 1H), 7.42 (d, J=9.5 Hz, 2H), 7.31 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 4.65 (s, 1H), 4.45 (s, 1H), 4.00 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.69 (t, J=5.9 Hz, 1H), 3.53 (t, J=5.9 Hz, 1H), 3.04 (t, J=5.8 Hz, 2H), 1.43 (s, 9H).

[0794] Step 4: In Reaction Scheme 1-3, 12 (1.0 eq.) was dissolved in dichloromethane (0.04 M) in a round bottom flask. Then, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.1 M) was added thereto, followed by stirring at room temperature for 24 hours. After the reaction was complete, the reaction product was concentrated under reduced pressure and the resulting residue was washed with diethyl ether and filtered and dried to obtain 13 (20-40% yield).

EXAMPLE 87

N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide hydrochloride

[0795] ##STR00121##

[0796] .sup.1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 9.71 (s, 1H), 8.50-8.23 (m, 1H), 7.94-7.83 (m, 2H), 7.71 (d, J=9.1 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.18 (d, J=8.7 Hz, 3H).

EXAMPLE 88

N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide hydrochloride

[0797] ##STR00122##

[0798] .sup.1H NMR (400 MHz, MeOD) δ 8.48-8.41 (m, 1H), 7.92-7.78 (m, 3H), 7.52-7.46 (m, 2H), 7.39 (ddd, J=8.3, 2.1, 1.0 Hz, 1H), 7.30 (dt, J=7.9, 1.4 Hz, 1H), 3.90 (s, 3H).

EXAMPLE 89

N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide hydrochloride

[0799] ##STR00123##

[0800] 1H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 8.43-8.35 (m, 1H), 7.92 (dd, J=6.0, 3.2 Hz, 2H), 7.78-7.68 (m, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.41-7.24 (m, 7H), 7.23-7.11 (m, 3H), 5.39 (s, 2H).

EXAMPLE 90

N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0801] ##STR00124##

[0802] .sup.1H NMR (400 MHz, MeOD) δ 8.49 (d, J=9.1 Hz, 1H), 7.91 (dd, J=7.1, 2.4 Hz, 2H), 7.86 (s, 1H), 7.69-7.53 (m, 4H), 7.46 (d, J=6.9 Hz, 2H), 7.39-7.25 (m, 3H), 5.50 (s, 2H), 4.34 (s, 2H).

EXAMPLE 91

N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide

[0803] ##STR00125##

[0804] 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 8.31 (dd, J=7.8, 1.7 Hz, 1H), 7.93-7.74 (m, 3H), 7.29-7.16 (m, 2H), 6.72-6.62 (m, 2H), 5.42 (s, 2H), 4.09 (t, J=5.3 Hz, 1H).

EXAMPLE 92

N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide

[0805] ##STR00126##

[0806] 1H NMR (400 MHz, DMSO) δ 8.41-8.32 (m, 1H), 7.95-7.85 (m, 2H), 7.74 (s, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.17 (s, 2H), 3.77 (d, J=6.1 Hz, 3H).

EXAMPLE 93

N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide

[0807] ##STR00127##

[0808] 1H NMR (400 MHz, MeOD) δ 8.46-8.39 (m, 1H), 7.92-7.83 (m, 3H), 7.57 (t, J=7.3 Hz, 1H), 7.42 (t, J=6.1 Hz, 3H), 7.35-7.18 (m, 7H), 6.85-6.81 (m, 2H).

EXAMPLE 94

N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide trifluoroacetic acid

[0809] ##STR00128##

[0810] 1H NMR (400 MHz, MeOD) δ 8.49-8.43 (m, 1H), 7.93-7.84 (m, 2H), 7.84-7.79 (m, 2H), 7.67 (s, 1H), 7.63-7.57 (m, 1H), 7.57-7.50 (m, 2H), 4.34 (s, 2H), 3.91 (s, 3H).

EXAMPLE 95

N-(3-(3-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0811] ##STR00129##

[0812] .sup.1H NMR (400 MHz, (CD.sub.3).sub.2CO) δ 8.46-8.37 (m, 1H), 7.94-7.84 (m, 2H), 7.84-7.76 (m, 1H), 7.73-7.63 (m, 1H), 7.63-7.46 (m, 3H), 4.38 (d, J=2.6 Hz, 2H).

EXAMPLE 96

N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl) sulfamide hydrochloride

[0813] ##STR00130##

[0814] .sup.1H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 8.43-8.29 (m, 1H), 8.01-7.84 (m, 2H), 7.71-7.66 (m, 1H), 7.59-7.50 (m, 4H), 7.18 (t, J=6.8 Hz, 1H), 6.69 (s, 2H), 4.19 (d, J=6.3 Hz, 2H).

EXAMPLE 97

N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0815] ##STR00131##

[0816] .sup.1H NMR (400 MHz, MeOD) δ 8.51-8.38 (m, 1H), 7.88 (td, J=7.2, 6.4, 3.5 Hz, 2H), 7.83-7.76 (m, 1H), 7.59 (s, 4H), 4.33 (s, 2H), 3.89 (s, 3H).

EXAMPLE 98

N-(4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0817] ##STR00132##

[0818] 1H NMR (400 MHz, MeOD) δ 8.49-8.42 (m, 1H), 7.92-7.84 (m, 2H), 7.84-7.76 (m, 1H), 7.60 (s, 4H), 4.38-4.30 (m, 4H), 1.44 (t, J=7.1 Hz, 3H).

EXAMPLE 99

N-(4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide trifluoroacetic acid

[0819] ##STR00133##

[0820] .sup.1H NMR (400 MHz, MeOD) δ 8.48-8.43 (m, 1H), 7.90-7.85 (m, 2H), 7.85-7.80 (m, 1H), 7.60 (s, 4H), 5.44 (p, J=6.6 Hz, 1H), 4.33 (s, 2H), 1.45 (d, J=6.7 Hz, 6H).

EXAMPLE 100

N-(4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0821] ##STR00134##

[0822] .sup.1H NMR (400 MHz, MeOD) δ 8.57-8.49 (m, 1H), 7.94 (t, J=4.9 Hz, 2H), 7.86 (s, 1H), 7.66 (dd, J=11.8, 7.9 Hz, 4H), 7.60 (d, J=7.5 Hz, 2H), 7.53 (t, J=7.6 Hz, 2H), 7.43 (t, J=7.2 Hz, 1H), 4.33 (s, 2H).

EXAMPLE 101

N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0823] ##STR00135##

[0824] .sup.1H NMR (400 MHz, MeOD) δ 8.54-8.32 (m, 1H), 7.92-7.84 (m, 2H), 7.83-7.78 (m, 1H), 7.58 (s, 4H), 7.43 (d, J=7.5 Hz, 2H), 7.35-7.24 (m, 3H), 5.46 (s, 2H), 4.32 (s, 2H).

EXAMPLE 102

N-(4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0825] ##STR00136##

[0826] .sup.1H NMR (400 MHz, MeOD) δ 8.48-8.43 (m, 1H), 7.90-7.86 (m, 2H), 7.83-7.77 (m, 1H), 7.58 (s, 4H), 7.48 (dd, J=8.7, 5.5 Hz, 2H), 7.05 (t, J=8.8 Hz, 2H), 5.44 (s, 2H), 4.32 (s, 2H).

EXAMPLE 103

N-(4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0827] ##STR00137##

[0828] .sup.1H NMR (400 MHz, MeOD) δ 11.70 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 7.68-7.53 (m, 5H), 7.44 (dd, J=8.8, 2.4 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 6.27 (s, 1H), 6.04 (s, 1H), 4.38 (d, J=6.3 Hz, 2H), 3.88 (s, 3H).

EXAMPLE 104

N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0829] ##STR00138##

[0830] .sup.1H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 8.43-8.29 (m, 1H), 8.01-7.84 (m, 2H), 7.71-7.66 (m, 1H), 7.59-7.50 (m, 4H), 7.18 (t, J=6.8 Hz, 1H), 6.69 (s, 2H), 4.19 (d, J=6.3 Hz, 2H).

EXAMPLE 105

N-(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0831] ##STR00139##

[0832] .sup.1H NMR (400 MHz, MeOD) δ 8.37 (d, J=8.9 Hz, 1H), 7.60 (s, 4H), 7.46 (dd, J=8.9, 2.5 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 4.33 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H).

EXAMPLE 106

N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0833] ##STR00140##

[0834] .sup.1H NMR (400 MHz, MeOD), 7.86 (d, J=2.8 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 7.63 7.50 (m, 4H), 7.45 (dd, J=9.0, 2.8 Hz, 1H), 4.32 (s, 2H), 4.00 (s, 3H).

EXAMPLE 107

N-(4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0835] ##STR00141##

[0836] .sup.1H NMR (400 MHz, DMSO) δ 7.74 (d, J=2.7 Hz, 1H), 7.62 (d, J=8.9 Hz, 1H), 7.53 (s, 4H), 7.47 (dd, J=8.9, 2.8 Hz, 1H), 7.16 (t, J=6.5 Hz, 1H), 6.67 (s, 2H), 4.18 (d, J=6.4 Hz, 2H), 3.95 (s, 3H), 3.77 (s, 3H).

EXAMPLE 108

N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide hydrochloride

[0837] ##STR00142##

[0838] .sup.1H NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.60 (s, 4H), 7.10 (s, 1H), 4.32 (s, 2H), 4.02 (s, 3H), 3.87 (s, 3H), 3.82 (s, 3H).

EXAMPLE 109

N-(3-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-benzyl) sulfamide

[0839] ##STR00143##

[0840] .sup.1H NMR (400 MHz, DMSO) δ 12.74 (s, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.49-7.53 (m, 3 H), 7.22 (brs, 1 H), 7.10 (s, 1H), 6.68 (s, 2H), 4.19 (d, J=6.08 Hz, 2 H), 3.98 (s, 3 H), 3.83 (s, 3 H)

EXAMPLE 110

N-(3-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-benzyl) sulfamide

[0841] ##STR00144##

[0842] .sup.1H NMR (400 MHz, DMSO) δ 7.73 (s, 1 H), 7.66 (s, 1H), 7.50-7.53 (m, 3 H), 7.22 (t, J=6.32 Hz, 1 H), 7.07 (s, 1H), 6.67 (s, 2H), 4.20 (d, J=6.32 Hz, 2 H), 3.98 (s, 3 H), 3.81 (s, 3 H), 3.78 (s, 3H)

EXAMPLE 111

N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-fluorobenzyl)sulfamide hydrochloride

[0843] ##STR00145##

EXAMPLE 112

N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-fluorobenzyl)sulfamide hydrochloride

[0844] ##STR00146##

EXAMPLE 113

N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-fluorobenzyl)-N-methyl sulfamide hydrochloride

[0845] ##STR00147##

EXAMPLE 114

N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-fluorobenzyl)-N-methyl sulfamide hydrochloride

[0846] ##STR00148##

EXAMPLE 115

N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2,3-difluorobenzyl)sulfamide hydrochloride

[0847] ##STR00149##

EXAMPLE 116

N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-(trifluorobenzyl methyl)benzyl) sulfamide hydrochloride

[0848] ##STR00150##

EXAMPLE 117

N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2,3-difluorobenzyl)-N-methyl sulfamide hydrochloride

[0849] ##STR00151##

EXAMPLE 118

N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-(trifluorobenzyl methyl)benzyl)-N-methyl sulfamide hydrochloride

[0850] ##STR00152##

EXAMPLE 119

N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluorobenzyl methyl)benzyl)sulfamide hydrochloride

[0851] ##STR00153##

EXAMPLE 120

N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluorobenzyl methyl)benzyl)-N-methyl sulfamide hydrochloride

[0852] ##STR00154##

EXAMPLE 121

7-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H) sulfamide hydrochloride

[0853] ##STR00155##

EXAMPLE 122

7-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfamide

[0854] ##STR00156##

[0855] 1H NMR (400 MHz, DMSO) δ 12.71(s, 1H), 7.70 (s, 1H), 7.4 (d, J=8.60 Hz, 1H), 7.34 (d, J=7.92 Hz, 1H), 7.20 (s, 1H), 7.07 (s, 3H), 6.97 (s, 1H), 4.31 (s, 2H), 3.98 (s, 3 H), 3.81 (s, 3 H), 3.07-3.11 (m, 2H), 3.01-3.05 (m, 2H)

EXAMPLE 123

N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamide hydrochloride

[0856] ##STR00157##

[0857] 1H NMR (400 MHz, MeOD) δ 8.47-8.42 (m, 1H), 7.89 (dd, J=6.0, 3.4 Hz, 2H), 7.84-7.78 (m, 1H), 7.58 (d, J=3.5 Hz, 4H), 4.66 (q, J=6.8 Hz, 1H), 1.57 (d, J=6.9 Hz, 3H).

EXAMPLE 124

(R)-N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamide hydrochloride

[0858] ##STR00158##

[0859] 1H NMR (400 MHz, MeOD) δ 8.44 (dq, J=7.4, 3.8 Hz, 1H), 7.89 (dt, J=7.2, 3.7 Hz, 2H), 7.61 (dt, J=5.9, 3.6 Hz, 1H), 7.73-7.48 (m, 4H), 4.66 (q, J=6.9 Hz, 1H), 1.57 (d, J=7.0 Hz, 3H).

EXAMPLE 125

N-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)sulfamide hydrochloride

[0860] ##STR00159##

[0861] 1H NMR (400 MHz, MeOD) δ 8.47-8.43 (m, 1H), 7.92-7.87 (m, 2H), 7.82 (s, 1H), 7.61 (d, J=1.3 Hz, 4H), 1.60 (s, 6H).

EXAMPLE 126

N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfamide hydrochloride

[0862] ##STR00160##

[0863] .sup.1H NMR (DMSO, 600 MHz) δ 12.94 (s, 1H), 8.36-8.35 (m, 1H), 7.99-7.89 (m, 5H), 7.65 (d, J=8 Hz, 1H), 7.34 (t, J=6 Hz, 1H), 6.80 (s, 2H), 4.37 (d, J=7 Hz, 2H).

EXAMPLE 127

N-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamide

[0864] ##STR00161##

[0865] .sup.1H NMR (400 MHz, MeOD) δ 8.50-8.38 (m, 1H), 7.95-7.85 (m, 2H), 7.84-7.75 (m, 1H), 7.59 (q, J=7.9 Hz, 4H), 4.31 (s, 2H), 2.71 (s, 3H).

EXAMPLE 128

6-(4-oxo-3,4-dihydrophthalazin-1-yl-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride

[0866] ##STR00162##

[0867] .sup.1H NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 8.37-8.30 (m, 1H), 7.90 (m, J=6.4, 5.4, 3.5 Hz, 2H), 7.76-7.65 (m, 1H), 7.37 (d, J=12.0 Hz, 3H), 6.96 (s, 2H), 4.30 (s, 2H), 3.00 (t, J=5.8 Hz, 2H).

EXAMPLE 129

6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride

[0868] ##STR00163##

[0869] .sup.1H NMR (400 MHz, MeOD) δ 8.49-8.42 (m, 1H), 7.93-7.84 (m, 2H), 7.83-7.76 (m, 1H), 7.43 (d, J=5.7 Hz, 2H), 7.33 (d, J=8.5 Hz, 1H), 4.42 (s, 2H), 3.89 (s, 3H), 3.57-3.38 (t, 2H), 3.08 (t, J=5.9 Hz, 2H).

EXAMPLE 130

6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride

[0870] ##STR00164##

[0871] .sup.1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.44 (d, J=7.1 Hz, 2H), 7.35-7.23 (d, J=7.9 Hz, 1H), 7.14 (s, 1H), 4.41 (s, 2H), 4.03 (s, 3H), 3.84 (s, 3H), 3.50-3.45 (t, 2H), 3.08 (t, J=6.0 Hz, 2H).

EXAMPLE 131

6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride

[0872] ##STR00165##

[0873] .sup.1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.44 (s, 2H), 7.33 (d, J=9.2 Hz, 1H), 7.12 (d, J=3.7 Hz, 1H), 4.46 (s, 1H), 4.42 (s, 1H), 4.03 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.54 (t, 1H), 3.49 (t, 1H), 3.09 (t, 2H).

PREPARATION EXAMPLE 2

[0874] A phthalazine derivative was prepared through the following Reaction Scheme 2 using, as a reactant, Product 2 obtained in Preparation Example 1.

##STR00166##

[0875] Step 1: 2 was stirred in phosphorus oxychloride (0.67 M) in a round bottom flask at. 110° C. for 1 hour. After the reaction was complete, the reaction mixture was cooled to room. temperature, slowly added to ice water, and stirred for 10 minutes. The reaction. product was filtered, and the solid was washed with distilled water and dried under reduced pressure to obtain 16. Examples of 16 are as follows.

Reactant 16-1: 1,4-didhlorophthalazine

[0876] ##STR00167##

[0877] .sup.1H NMR (400 MHz, DMSO) δ 3.43-8.35 (m, 2H), 8.32-8.25 (m, 2H).

Reactant 16-2: 1,4-dichloro-6,7-dimethoxyphthalazine

[0878] ##STR00168##

[0879] .sup.1H NMR (DMSO, 600 MHz) δ 7.53 (s, 2H), 4.08 (s, 6H).

[0880] Step 2: 16 (1.0 eq.) was dissolved in N,N-dimethylformamide (0.25 M) in a round bottom flask, amine (1.5 eq. mmol) and potassium carbonate (4.0 eq.) were added thereto, followed by stirring at 80° C. under a nitrogen atmosphere for 14 hours. After the reaction was complete, the mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was separated by column chromatography (5% MeOH/CH.sub.2Cl.sub.2) to obtain 17. Examples of 17 are as follows.

Reactant 17-1: N-(2-(1-(4-chlorophthalazin-1-yl)piperidin-4-yl)ethyl)sulfamide

[0881] ##STR00169##

[0882] .sup.1H NMR (400 MHz, DMSO) δ 8.24-8.16 (m, 1H), 8.14-8.02 (m, 3H), 6.52-6.44 (m, 3H), 3.87-3.78 (m, 2H), 3.05-2.92 (m, 4H), 1.88-1.78 (m, 2H), 1.73-1.60 (m, 1H), 1.58-1.39 (m, 4H).

Reactant 17-2: tert-butyl ((1-(4-chlorophthalazin-1-yl)piperidin-4-yl)methyl)carbamate

[0883] ##STR00170##

[0884] 1H NMR (DMSO, 600 MHz) δ 8.20-8.18 (m, 1H), 8.11-8.09 (m, 1H), 8.08-8.05 (m, 2H), 6.95 (t, J=6 Hz, 1H), 3.82 (d, J=12 Hz, 2H), 2.97 (t, J=12 Hz, 2H), 2.93 (t, J=6 Hz, 2H), 1.79 (d, J=12 Hz, 2H), 1.67-1.63 (m, 1H), 1.47-1.42 (m, 2H), 1.39 (s, 9H).

Reactant 17-3: tert-butyl ((1-(4-chloro-6,7-dimethoxyphthalazin-1-yl)piperidin-4-yl)methyl)carbamate

[0885] ##STR00171##

[0886] .sup.1H NMR (DMSO, 600 MHz) δ 7.39 (s, 1H), 7.25 (s, 1H), 6.92 (t, =6 Hz, 1H), 4.01 (s, 3H), 4.01 (s, 3H), 3.75 (d, J=12 Hz, 2H), 2.94-2.90 (m, 4H), 1.79 (d, J=13 Hz, 2H), 1.66-1.63 (m, 1H), 1.47-1.43 (m, 2H), 1.39 (s, 9H).

[0887] Step 3: 17 N-(2-(1-(4-chlorophthalazin-1-yl)piperidin-4-yl)ethyl)sulfamide was dissolved in acetic acid (0.1 M) in a round bottom flask, followed by refluxing at 120° C. for 10 hours. The reaction product was concentrated, diluted with ethyl acetate and neutralized with sodium bicarbonate. An aqueous solution layer was extracted with ethyl acetate and the organic layer was dried with sodium sulfate and concentrated under reduced pressure. The obtained residue was solidified with diethyl ether to obtain 18.

EXAMPLE 132

tert-butyl ((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)carbamate

[0888] ##STR00172##

[0889] .sup.1H NMR (DMSO, 600 MHz) δ 12.08 (s, 1H), 8.23-8.21 (m, 1H), 7.93-7.87 (m, 2H), 7.84-7.81 (m, 1H), 6.92 (t, J=6 Hz, 1H), 3.41 (d, J=12 Hz, 2H), 2.91 (t, J=2H), 2.67 (t, J=12 Hz, 2H), 1.75 (d, Hz, 2H), 1.57-1.51 (m, 1H), 1.41-1.35 (m, 11H).

EXAMPLE 133

tert-butyl ((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)carbamate

[0890] ##STR00173##

[0891] .sup.1H NMR (DMSO, 600 MHz) δ 11.96 (s, 1H), 7.57 (s, 1H), 7.16 (s, 1H), 6.92 J=6 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.41 (d, J=12 Hz, 2H), 2.91 (t, J=6 Hz, 2H), 2.67-2.63 (m, 2H), 1.75 (d, J=12 Hz, 2H), 1.58-1.51 (m, 1H), 1.38 (s, 9H), 1.37-1.35 (m, 2H).

EXAMPLE 134

4-(4-(aminomethyl)piperidin-1-yl)phthalazin-1(2H)-one hydrochloride

[0892] ##STR00174##

[0893] .sup.1H NMR (DMSO, MHz) δ 12.13 (s, 1H), 8.24-8.22 (m, 1H), 7.97-7.81 (m, 6H), 3.46 (d, J=12 Hz, 2H), 2.82-2.78 (m, 2H), 2.73-2.69 (m, 2H), 1.86 (d, J=13 Hz, 2H), 1.78-1.75 (m, 1H), 1.50-1.44 (m, 2H).

EXAMPLE 135

4-(4-(aminomethyl)piperidin-1-yl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride

[0894] ##STR00175##

[0895] .sup.1H NMR (DMSO, 600 MHz) δ 12.00 (s, 1H), 7.79 (br s, 3H), 7.58 (s, 1H), 7.16 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.46 (d, J=12 Hz, 2H), 2.82-2.80 (m, 2H), 2.69 (t, J=12 Hz, 2H), 1.85 (d, J=13 Hz, 2H), 1.79-1.72 (m, 1H), 1.51-1.45 (m, 2H).

EXAMPLE 136

tert-butyl N-((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamoyl carbamate

[0896] ##STR00176##

[0897] .sup.1H NMR (DMSO, 600 MHz) δ 12.08 (s, 1H), 10.82 (s, 1H), 8.23-8.21 (m, 1H), 7.93-7.86 (m, 2H), 7.84-7.81 (m, 1H), 7.70 (br s, 1H), 3.41 (d, J=13 Hz, 2H), 2.86 (s, 2H), 2.67 (t, J=12 Hz, 2H), 1.83 (d, J=13 Hz, 2H), 1.65-1.63 (m, 1H), 1.43-1.35 (m, 11H).

EXAMPLE 137

tert-butyl N-((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamoyl carbamate

[0898] ##STR00177##

[0899] .sup.1H NMR (DMSO, 600 MHz) δ 11.96 (s, 1H), 10.81 (s, 1H), 7.70 (br s, 1H), 7.57 (s, 1H), 7.16 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.41 (d, J=12 Hz, 2H), 2.86 (br s, 2H), 2.65 (t, J=12 Hz, 2H), 1.83 (d, J=13 Hz, 2H), 1.68-1.60 (m, 1H), 1.42 (s, 9H), 1.40-1.36 (m, 2H).

EXAMPLE 138

N-((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamide hydrochloride

[0900] ##STR00178##

[0901] .sup.1H NMR (DMSO, 600 MHz) δ 12.07 (s, 1H), 8.23-8.21 (m, 1H), 7.93-7.88 (m, 2H), 7.84-7.81 (m, 1H), 6.59 (t, J=6 Hz, 1H), 6.49 (s, 2H), 3.42 (d, j =12 Hz, 2H), 2.85 (t, J=Hz, 2H), 2.71-2.67 (m, 2H), 1.85 (d, J=12 Hz, 2H), 1.68-1.64 (m, 1H), 1.44-1.37 (m, 2H).

EXAMPLE 139

N-((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamide hydrochloride

[0902] ##STR00179##

[0903] 1H NMR (DMSO, 600 MHz) δ 11.96 (s, 1H), 7.57 (s, 1H), 7.17 (s, 1H), 6.58 (br s, 1H), 6.49 (br s, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.42 (d, J=13 Hz, 2H), 2.85 (d, J=7 Hz, 2H), 2.69-2.65 (m, 2H), 1.85 (d, J=13 Hz, 2H), 1.67-1.64 (m, 1H), 1.43-1.37 (m, 2H).

EXAMPLE 140

N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-amino)phenyl)sulfamide hydrochloride

[0904] ##STR00180##

EXAMPLE 141

N-(3-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-amino)phenyl)sulfamide hydrochloride

[0905] ##STR00181##

EXAMPLE 142

N-(2-(1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)ethyl)sulfamide trifluoroacetic acid

[0906] ##STR00182##

[0907] .sup.1H NMR (600 MHz, DMSO) δ 12.03 (s, 1H), 8.23-8.20 (m, 1H), 7.94-7.87 (m, 2H), 7.85-7.80 (m, 2H), 7.27 (s, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 3.41 (d, J=12.3 Hz, 2H), 3.10 (q, J=6.7 Hz, 2H), 2.72-2.65 (m, 2H), 1.31-1.76 (m, 2H), 1.52-1.36 (m, 5H).

PREPARATION EXAMPLE 3

[0908] Preparation EXAMPLE 3 includes a process of preparing Product 23**. Then, a phthalazine derivative was prepared through Preparation. Example 3-2 using Product 22** or 23** as Reactant 24**.

PREPARATION EXAMPLE 3-1

Reactant 23**

[0909] ##STR00183##

[0910] Step 1: 19** (1.0 eq.) was dissolved in a 37% aqueous hydrochloric acid solution (0.37 M) in a round bottom flask, and 30% formaldehyde (1.25 eq.) was added thereto, followed by stirring at 90° C. for 10 hours. The reaction product was cooled to room temperature and was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a 2.5 M sodium hydroxide aqueous solution and a brine aqueous solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (EtOAc:hexanes=4:6) to obtain 20** (59-70% yield).

Reactant 20**-1: 5,6-dimethoxyisobenzofuran-1(3H)-one

[0911] ##STR00184##

[0912] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.32 (s, 1H), 6.90 (s, 1H), 5.23 (s, 2H), 3.93 (s, 3H), 3.95 (s, 3H).

[0913] Step 2: 20** (1.0 eq.) and aryl aldehyde (1.0 eq.) were dissolved In ethyl acetate in a round bottom flask and a sodium methoxide solution (25% in methanol) (4.0 eq.) was slowly added thereto at 0° C. The reaction product was stirred at room temperature for 1 hour, and at. 80° C. for 1 hour, and then concentrated under reduced pressure. Ice water was added to the residue and then the pH of the mixture was adjusted to 2-3 with acetic acid. The reaction product was filtered to obtain Solid 21** (21-60%).

Reactant 21**-1: 3-hydroxy-5,6-dimethoxy-2-phenyl-1H-inden-1-one

[0914] ##STR00185##

[0915] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.42 (s, 2H), 7.38-7.23 (m, 3H), 7.21-7.15 (m, 2H), 4.21 (s, 1H), 4.05 (s, 6H).

Reactant 21**-2: 2-(4-bromophenyl)-3-hydroxy-5,6-dimethoxy-1H-inden-1-one

[0916] ##STR00186##

[0917] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.48 (d, J=8.5 Hz, 2H), 7.41 (s, 2H), 7.07 (d, J=8.4 Hz, 2H), 4.17 (s, 1H), 4.05 (s, 6H).

Reactant 21**-3: 2-(3-bromophenvi)-3-hydroxy-5,6-dimethoxy-1H-inden-1-one

[0918] ##STR00187##

[0919] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.44 (ddd, J=7.9, 1.9, 1.1 Hz, 1H), 7.41 (s, 2H), 7.32 (t, J=1.9 Hz, 1H), 7.23 (t, J=7.9 Hz, 1H), 7.17-7.13 (m, 1H), 4.18 (s, 1H), 4.06 (s, 6H).

[0920] Step 3-1: 21** (1.0 eq.) was added to water in a round bottom flask and 4.7M hydrazine monohydrate (24.5 eq.) was added thereto. The reaction product was stirred at 100° C. for 5 hours and cooled to room temperature. The solid was filtered and washed with ethanol to obtain 22** (40-62% yield).

[0921] Step 3-2: 23** was prepared from Reactant 22** through Step 2-2 of Preparation Example 1-1.

EXAMPLE 143

4-benzylphthalazin-1(2H)-one

[0922] ##STR00188##

[0923] .sup.1H NMR (400 MHz, DMSO) δ 12.60 (s, 1H), 3.25 (dd, J=7.3, 1.0 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.88-7.83 (m, 1H), 7.80 (t, J=7.5 Hz, 21-1), 7.33-7.25 (m, 4H), 7.18 (t, J=6.9 Hz, 1H), 4.29 (s, 2H).

EXAMPLE 144

4-benzyl-6,7-dimethoxyphthalazin-1(2H)-one

[0924] ##STR00189##

[0925] .sup.1H NMR (400 MHz, DMSO): δ 12.41 (s, 1H), 7.59 (s, 1H), 7.37-7.25 (m, 5H), 7.19 (t, J=7.2 Hz, 1H), 4.28 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H).

EXAMPLE 145

tert-butyl (3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate

[0926] ##STR00190##

[0927] .sup.1H NMR (600 MHz, CDCl.sub.3) δ 10.10 (S, 1H), 7.76 (s, 1H), 7.51 (s, 1H), 7.20 (t, J=7.8 Hz, 1H), 7.13-7.09 (m, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.46 (s, 1H), 4.23 (s, 2H), 4.01 (s, 3H), 3.88 (s, 3H), 1.49 (s, 9H).

EXAMPLE 146

tert-butyl (3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate

[0928] ##STR00191##

[0929] .sup.1H NMR (600 MHz, DMSO) δ 9.27 (s, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 7.28-7.24 (m, 2H), 7.16 (t, J=7.9 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 4.22 (s, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.72 (s, 3H), 1.43 (s, 9H).

EXAMPLE 147

tert-butyl (4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate

[0930] ##STR00192##

[0931] .sup.1H NMR (600 MHz, DMSO) δ 12.51 (s, 1H), 9.19 (s, 1H), 8.20 (dd, J=7.8, 1.5 Hz, 1H), 7.88-7.85 (m, 1H), 7.84-7.79 (m, 1H), 7.78-7.74 (m, 1H), 7.30 (d, J=8.2 Hz, 2H), 7.14 (d, J=8.6 Hz, 2H), 4.17 (s, 2H), 1.41 (s, 9H).

EXAMPLE 148

tert-butyl (4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate

[0932] ##STR00193##

[0933] .sup.1H NMR (600 MHz, DMSO) δ 9.24 (s, 1H), 8.32-8.20 (m, 1H), 7.91-7.88 (m, LH), 7.85-7.79 (m, 2H), 7.34 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 4.22 (s, 2H), 3.74 (s, 3H), 1.44 (s, 9H).

EXAMPLE 149

tert-butyl (4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate

[0934] ##STR00194##

[0935] .sup.1H NMR (600 MHz, CDCl.sub.3) δ 9.75 (s, 1H), 7.76 (s, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 7.01 (s, 1H), 6.42 (s, 1H), 4.20 (s, 2H), 4.01 (s, 3H), 3.85 (s, 3H), 1.50 (s, 9H).

EXAMPLE 150

tert-butyl (4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate

[0936] ##STR00195##

[0937] .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.77 (s, 1H), 7.29 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 6.95 (s, 1H), 6.42 (s, 1H), 4.19 (s, 2H), 4.00 (s, 3H), 3.87 (s, 3H), 3.81 (s, 3H), 1.49 (s, 9H).

EXAMPLE 151

tert-butyl (4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl) (methyl)carbamate

[0938] ##STR00196##

[0939] .sup.1H NMR (600 MHz, DMSO) δ 12.59 (s, 1H), 3.25 (dd, J=7.9, 1.4 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.87 (td, J=8.2, 7.7, 1.5 Hz, 1H), 7.81 (t, J=7.6 Hz, 1H), 7.27 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 4.28 (s, 2H), 3.12 (s, 3H), 1.36 (s, 9H).

EXAMPLE 152

tert-butyl (4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl) (methyl) carbamate

[0940] ##STR00197##

[0941] 1H NMR (600 MHz, DMSO) δ 12.41 (s, 1H), 7.59 (s, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.27 (s, 1H), 7.18 (d, J=8.5 Hz, 2H), 4.26 (s, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.12 (s, 3H), 1.35 (s, 9H).

EXAMPLE 153

tert-butyl (4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl) (methyl)carbamate

[0942] ##STR00198##

[0943] .sup.1H NMR (600 MHz, DMSO) δ 7.60 (s, 1H), 7.32 (d, J=8.3 Hz, 2H), 7.25 (s, 1H), 7.18 (d, J=8.4 Hz, 2H), 4.27 (s, 2H), 3.90 (s, 3H), 3.82 (s, 3H), 3.72 (s, 3H), 3.11 (s, 3H), 1.34 (s, 9H).

EXAMPLE 154

tert-butyl (5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-carboxylate

[0944] ##STR00199##

[0945] .sup.1H NMR (600 MHz, DMSO) δ 12.40 (s, 1H), 7.70-7.47 (m, 2H), 7.28 (s, 1H), 7.14 (apparent s, 2H), 4.19 (s, 2H), 3.90 (s, 3H), 3.87-3.81 (m, 5H), 2.99 (t, J=8.6 Hz, 2H), 1.47 (s, 9H).

EXAMPLE 155

tert-butyl (5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-carboxylate

[0946] ##STR00200##

[0947] .sup.1H NMR (600 MHz, DMSO) δ 7.69-7.49 (m, 2H), 7.26 (s, 1H), 7.16 (apparent s, 2H), 4.20 (s, 2H), 3.90 (s, 3H), 3.87 (m, 5H), 3.72 (s, 3H), 2.99 (t, J=8.7 Hz, 2H), 1.47 (s, 9H).

PREPARATION EXAMPLE 3-2

[0948] A preparation process was performed using the following Reaction Scheme 3-2 using 22** or 23** prepared. in Preparation Example 3-i as Reactant 24**.

##STR00201##

[0949] Step 1: 25** was prepared from Reactant 24** through Step 2 of Preparation Example 1-3.

EXAMPLE 156

4-(3-aminobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride

[0950] ##STR00202##

[0951] .sup.1H NMR (600 MHz, DMSO) δ 12.48 (s, 1H), 7.60 (s, 1H), 7.45-7.34 (m, 2H), 7.26 (s, 1H), 7.17-7.04 (m, 2H), 4.32 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H).

EXAMPLE 157

4-(3-aminobenzyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride

[0952] ##STR00203##

[0953] 1H NMR (600 MHz, DMSO) δ 7.61 (s, 1H), 7.37-7.29 (m, 3H), 7.25 (s, 1H), 7.06 (d, J=29.7 Hz, 2H), 4.32 (s, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 3.72 (s, 3H).

EXAMPLE 158

4-(4-aminobenzyl)-phthalazin-1(2H)-one hydrochloride

[0954] ##STR00204##

[0955] 1H NMR (600 MHz, DMSO) δ 12.59 (s, 1H), 9.59 (hr s, 2H), 8.25 (dd, J=7.8, 1.4 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.87 (td, J=8.1, 7.6, 1.4 Hz, 1H), 7.82 (td, J=7.5, 1.2 Hz, 1H), 7.37 (apparent br s, 2H), 7.18 (apparent br s, 2H), 4.31 (s, 2H).

EXAMPLE 159

4-(4-aminobenzyl)-2-methylphthalazin-1(2H)-one hydrochloride

[0956] ##STR00205##

[0957] .sup.1H NMR (600 MHz, DMSO) δ 9.49 (s, 2H), 8.29-8.27 (m, 1H), 7.92-7.89 (m, 1H), 7.86-7.80 (m, 2H), 7.38 (d, J=7.8 Hz, 2H), 7.16 (apparent br s, 2H), 4.32 (s, 2H), 3.74 (s, 3H).

EXAMPLE 160

4-(4-aminobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride

[0958] ##STR00206##

[0959] .sup.1H NMR (600 MHz, DMSO) δ 12.44 (s, 1H), 10.02 (br s, 3H), 7.59 (s, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.31-7.25 (m, 3H), 4.32 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H).

EXAMPLE 161

4-(4-aminobenzyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride

[0960] ##STR00207##

[0961] .sup.1H NMR (600 MHz, DMSO) δ 7.60 (s, 1H), 7.38 (apparent br s, 2H), 7.24 (s, 1H), 7.13 (apparent br s, 2H), 4.29 (s, 2H), 3.91 (s, 3H), 3.83 (s, 3H), 3.71 (s, 3H).

EXAMPLE 162

4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride

[0962] ##STR00208##

[0963] .sup.1H NMR (DMSO, 600 MHz) δ 12.57 (s, 1H), 8.25 (d, J=8 Hz, 1H), 7.94 (d, J=9 Hz, 1H), 7.86 (t, J=7 Hz, 1H), 7.81 (t, =7 Hz, 1H), 7.26 (apparent br s, 2H), 6.98 (apparent br s, 2H), 4.24 (s, 2H), 2.76 (s, 3H).

EXAMPLE 163

6,7-dimethoxy-4-(4-(methylamino)benzyl)phthalazin-1(2H) -one hydrochloride

[0964] ##STR00209##

[0965] .sup.1H NMR (DMSO, 600 MHz) δ 12.41 (s, 1H), 7.59 (s, 1H), 7.36 (apparent br s, 2H), 7.28 (s, 1H), 7.12 (apparent br s, 2H), 4.26 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 2.80 (s, 3H).

EXAMPLE 164

6,7-dimethoxy-2-methyl-4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride

[0966] ##STR00210##

[0967] 1H NMR (600 MHz, DMSO) δ 7.59 (s, 1H), 7.30 (apparent br s, 2H), 7.26 (s, 1H), 6.94 (apparent br s, 2H), 4.23 (s, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.71 (s, 3H), 2.75 (s, 3H).

EXAMPLE 165

4-(indolin-5-yl-methyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride

[0968] ##STR00211##

[0969] .sup.1H NMR (DMSO, 600 MHz) δ 12.42 (s, 1H), 7.59 (s, 1H), 7.35 (br s, 1H), 7.33-7.29 (m, 2H), 7.23 (br s, 1H), 4.30 (s, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.64 (t, J=8 Hz, 2H), 3.10 (t, J=8 Hz, 2H).

EXAMPLE 166

4-(indolin-5-yl-methyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride

[0970] ##STR00212##

[0971] 1H NMR (DMSO, 600 MHz) δ 7.60 (s, 1H), 7.38-7.30 (m, 2H), 7.27 (s, 1H), 7.19 (br s, 1H), 4.30 (s, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 3.72 (s, 3H), 3.62 (t, J=8 Hz, 2H), 3.08 J=8 Hz, 2H).

[0972] Step 2: 26** was prepared from Reactant 25** through Step 3 of Preparation Example 1-3.

EXAMPLE 167

tert-butyl (N-(3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate

[0973] ##STR00213##

[0974] .sup.1H NMR (600 MHz, DMSO) δ 12.42 (s, 1H), 11.16 (s, 1H), 10.20 (s, 1H), 7.58 (s, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.12 (d, J=7.4 Hz, 1H), 7.09 (s, 1H), 7.04 (d, J=8.sup.1 Hz, 1H), 4.22 (s, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 1.24 (s, 9H).

EXAMPLE 168

tert-butyl (N-(3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate

[0975] ##STR00214##

[0976] .sup.1H NMR (600 MHz, DMSO) δ 11.16 (s, 1H), 10.19 (s, 1H), 7.59 (s, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.15 (d, J=7.7 Hz, 1H), 7.10 (s, 1H), 7.04 (d, J=8.1 Hz, 1H), 4.23 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.72 (s, 3H), 1.23 (s, 9H).

EXAMPLE 169

tert-butyl (N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate

[0977] ##STR00215##

[0978] .sup.1H NMR (600 MHz, DMSO) δ 12.57 (s, 1H), 11.15 (s, 1H), 10.14 (s, 1H), 8.24 (dd, J=7.8, 1.5 Hz, 1H), 7.96-7.89 (m, 1H), 7.86-7.83 (m, 1H), 7.80 (td, J=7.5, 1.2 Hz, 1H), 7.28-7.17 (m, 2H), 7.06 (d, J=8.1 Hz, 2H), 4.23 (s, 2H), 1.24 (s, 9H).

EXAMPLE 170

tert-butyl (N-(4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate

[0979] ##STR00216##

[0980] .sup.1H NMR (600 MHz, DMSO) δ 11.14 (s, 1H), 10.16 (s, 1H), 8.27 (dd, J=7.6, 1.6 Hz, 1H), 7.93-7.88 (m, 1H), 7.85-7.79 (m, 2H), 7.27 (d, J=8.0 Hz, 2H), 7.06 (d, J=8.2 Hz, 2H), 4.25 (s, 2H), 3.74 (s, 3H), 1.23 (s, 9H).

EXAMPLE 171

tert-butyl (N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate

[0981] ##STR00217##

[0982] 1H NMR (600 MHz, DMSO) δ 12.40 (s, 1H), 11.11 (s, 1H), 10.15 (s, 1H), 7.57 (s, 1H), 7.28 (d, J=8.3 Hz, 2H), 7.23 (s, 1H), 7.08 (d, J=8.5 Hz, 2H), 4.22 (s, 2H), 3.89 (s, 3H), 3.33 (s, 3H), 1.21 (s, 9H).

EXAMPLE 172

tert-butyl (N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate

[0983] ##STR00218##

[0984] .sup.1H NMR (600 MHz, DMSO) δ 11.12 (s, 1H), 10.18 (s, 1H), 7.58 (s, 1H), 7.30 (d, J=8.1 Hz, 2H), 7.21 (s, 1H), 7.08 (d, J=8.4 Hz, 2H), 4.23 (s, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.72 (s, 3H), 1.19 (s, 9H).

EXAMPLE 173

tert-butyl N-methyl-N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl carbamate

[0985] ##STR00219##

[0986] .sup.1H NMR (DMSO, 600 MHz) δ 12.61 (s, 1H), 11.09 (s, 1H), 8.26-8.25 (m, 1H), 7.99-7.97 (m, 1H), 7.90-7.87 (m, 1H), 7.83-7.81 (m, 1H), 7.36 (d, J=8 Hz, 2H), 7.26 (d, J=8 Hz, 2H), 4.30 (s, 2H), 3.27 (s, 3H), 1.33 (s, 9H).

EXAMPLE 174

tert-butyl N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamoyl carbamate

[0987] ##STR00220##

[0988] 1H NMR (DMSO, 600 MHz) 67 12.43 (s, 1H), 11.08 (s, 1H), 7.59 (s, 1H), 7.37 (br s, 2H), 7.28 (s, 2H), 7.26 (s, 1H), 4.27 (s, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.28 (s, 3H), 1.31 (s, 9H).

EXAMPLE 175

tert-butyl N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamoyl carbamate

[0989] ##STR00221##

[0990] .sup.1H NMR (DMSO, 600 MHz) δ 11.07 (s, 1H), 7.60 (s, 1H), 7.40 (d, J=8 Hz, 2H), 7.27 (d, J=8 Hz, 2H), 7.25 (s, 1H), 4.29 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.73 (s, 3H), 3.28 (s, 3H), 1.30 (s, 9H).

EXAMPLE 176

tert-butyl (5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indolin-1-yl)sulfonyl carbamate

[0991] ##STR00222##

[0992] .sup.1H NMR (DMSO, 600 MHz) δ 12.41 (s, 1H), 11.48 (s, 1H), 7.57 (s, 1H), 7.27 (s, 1H), 7.23 (d, J=8 Hz, 1H), 7.18 (s, 1), 7.09 (d, J=8 Hz, 1H), 4.21 (s, 2H), 4.10 (t, J=8 Hz, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.02 (t, J=8 Hz, 2H), 1.11 (s, 9H).

EXAMPLE 177

tert-butyl (5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indolin-1-yl)sulfonyl carbamate

[0993] ##STR00223##

[0994] .sup.1H NMR (DMSO, 600 MHz) δ 11.48 (s, 1H), 7.58 (s, 1H), 7.27-7.23 (m, 2H), 7.20-7.17 (m 1H), 7.09 (d, J=8 Hz, 1H), 4.22 (s, 2H), 4.13-4.05 (m, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.72 (s, 3H), 3.01 (t, j =8 Hz, 2H), 1.10 (s, 9H).

[0995] Step 3: 27** was prepared from Reactant 26** through Step 4 of Preparation Example 1-3.

EXAMPLE 178

(N-(3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride

[0996] ##STR00224##

[0997] .sup.1H NMR (600 MHz, DMSO) δ 12.42 (S, 1H), 9.45 (s, 1H), 7.58 (s, 1H), 7.25 (s, 1H), 7.17 (t, J=7.9 Hz, 1H), 7.13 (t, J=2.0 Hz, 1H), 7.06 (s, 2H), 7.01 (ddd, J=8.1, 2.3, 1.0 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 4.21 (s, 2H), 3.90 (s, 3H), 3.84 (s, 3H).

EXAMPLE 179

N-(3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride

[0998] ##STR00225##

[0999] .sup.1H NMR (600 MHz, DMSO) δ 9.44 (s, 1H), 7.60 (s, 1H), 7.23 (s, 1H), 7.19-7.14 (m, 2H), 7.06 (s, 2H), 7.02-6.99 (m, 1H), 6.94 (d, J=7.5 Hz, 1H), 4.22 (s, 2H), 3.91 (s, 3H), 3.82 (s, 3H), 3.73 (s, 3H).

EXAMPLE 180

N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride

[1000] ##STR00226##

[1001] .sup.1H NMR (DMSO, 600 MHz) δ 12.56 (s, 1H), 9.39 (s, 1H), 8.25-8.23 (m, 1H), 7.94-7.93 (m, 1H), 7.88-7.85 (m, 1H), 7.82-7.79 (m, IH), 7.21-7.20 (m, 2H), 7.08-7.05 (m, 2H), 7.01 (s, 2H), 4.22 (s, 2H).

EXAMPLE 181

N-(4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride

[1002] ##STR00227##

[1003] .sup.1H NMR (DMSO, 600 MHz) δ 9.39 (s, 1H), 8.28-8.26 (m, 1H), 7.93-7.92 (m, 1H), 7.86-7.83 (m, 1H), 7.82-7.79 (m, 1H), 7.24-7.22 (m, 2H), 7.07-7.05 (m, 2H), 7.01 (s, 2H), 4.23 (s, 2H), 3.75 (s, 3H).

EXAMPLE 182

N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride

[1004] ##STR00228##

[1005] .sup.1H NMR (600 MHz, DMSO) δ 12.38 (s, 1H), 9.37 (s, 1H), 7.58 (s, 1H), 7.28 (s, 1H), 7.23 (d, J=8.5 Hz, 2H), 7.08 (d, J=8.5 Hz, 2H), 7.00 (s, 2H), 4.20 (s, 2H), 3.90 (s, 3H), 3.85 (s, 3H).

EXAMPLE 183

N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride

[1006] ##STR00229##

[1007] .sup.1H NMR (600 MHz, DMSO) δ 9.38 (s, 1H), 7.59 (s, 1H), 7.27-7.24 (m, 3H), 7.07 (d, J=8.6 Hz, 2H), 7.00 (s, 2H), 4.21 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.72 (s, 3H).

EXAMPLE 184

N-methyl-N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride

[1008] ##STR00230##

[1009] .sup.1H NMR (DMSO, 600 MHz) δ 12.60 (s, 1H), 8.26-8.25 (m, 1H), 8.00-7.99 (m, 1H), 7.90-7.88 (m, 1H), 7.83-7.81 (m, 1H), 7.32 (d, J=9 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 6.96 (s, 2H), 4.28 (s, 2H), 3.05 (s, 3H).

EXAMPLE 185

N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamide hydrochloride

[1010] ##STR00231##

[1011] .sup.1H NMR (DMSO, 600 MHz) δ 12.43 (s, 1H), 7.59 (s, 1H), 7.34 (d, J=8 Hz,), 7.31 (s, 1H), 7.26 (d, J=8 Hz, 2H), 4.26 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.05 (s, 3H).

EXAMPLE 186

N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamide hydrochloride

[1012] ##STR00232##

[1013] .sup.1H NMF (DMSO, 600 MHz) δ 7.60 (s, 1H), 7.36 (d, J=8 Hz, 2H), 7.29 (s, 1H), 7.26 (d, J=9 Hz, 2H), 6.95 (s, 2H), 4.28 (s, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.73 (s, 3H), 3.04 (s, 3H).

EXAMPLE 187

5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-sulfonamide hydrochloride

[1014] ##STR00233##

[1015] .sup.1H NMR (DMSO, 600 MHz) δ 12.40 (s, 1H), 7.58 (s, 1H), 7.30 (s, 1H), 7.19 (br s, 2H), 7.17-7.16 (m, 3H), 4.20 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.74 (t, J=8 Hz, 2H), 2.98 (t, J=8 Hz, 2H).

EXAMPLE 188

5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-sulfonamide hydrochloride

[1016] ##STR00234##

[1017] .sup.1H NMR (DMSO, 600 MHz) δ 7.59 (s, 1H), 7.28 (s, 1H), 7.20-7.17 (m, 5H), 4.21 (s, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.75 (d, J=8 Hz, 2H), 3.72 (s, 3H), 2.97 (t, J=8 Hz, 2H).

EXAMPLE 189

N-(3-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride

[1018] ##STR00235##

EXAMPLE 190

N-(2-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride

[1019] ##STR00236##

EXAMPLE 191

N-(3-(trifluorobenzyl methyl)-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride

[1020] ##STR00237##

EXAMPLE 192

N-(2-(trifluorobenzyl methyl)-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamide hydrochloride

[1021] ##STR00238##

EXAMPLE 193

4-(3-bromobenzyl)-6,7-dimethoxyphthalazin-1(210-one

[1022] ##STR00239##

[1023] 1H NMR (400 MHz, DMSO) δ 12.44 (s, 1H), 7.61 (s, 2H), 7.42 (d, J=7.9 Hz, 1H), 7.38-7.31 (m, 2H), 7.27 (t, J=7.7 Hz, 1H), 4.32 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H).

EXAMPLE 194

4-(4-bromobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one

[1024] ##STR00240##

[1025] 1H NMR (400 MHz, DMSO) δ 12.42 (s, 1H), 7.59 (s, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.30 (d, =8.3 Hz, 2H), 7.26 (s, 1H), 4.27 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H).

PREPARATION EXAMPLE 4-1

[1026] ##STR00241##

[1027] 28 (1.0 eq.) and RSO.sub.2Cl (1.1 eq.) were dissolved in dichloromethane (0.08 M) in a round bottom flask and triethylamine (4.5 eq.) was added thereto, followed by stirring at room temperature for 16 hours. After the reaction was complete, water was poured into the mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (MeOH:CH.sub.2Cl.sub.2=1:20) to obtain 29 (20-40% yield).

EXAMPLE 195

N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)methanesulfonamide

[1028] ##STR00242##

[1029] .sup.1H NMR (400 MHz, MeCD) 6 8.47 (s, 1H), 7.96-7.89 (m, 2H), 7.82 (s, 1H), 7.67-7.58 (m, 4H), 4.40 (s, 2H), 2.96 (s, 3H).

EXAMPLE 196

N -(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)cyclopropanesulfonamide

[1030] ##STR00243##

[1031] .sup.1H NMR (400 MHz, MeOD) δ 8.52-8.44 (m, 1H), 8.00-7.88 (m, 2H), 7.85-7.78 (m, 1H), 7.62 (s, 4H), 4.44 (s, 2H), 2.57-2.48 (m, 1H), 1.13-1.05 (m, 2H), 1.05-0.94 (m, 2H).

EXAMPLE 197

4-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)benzenesulfonamide

[1032] ##STR00244##

[1033] 1H NMR (400 MHz, MeOD) δ 8.51-8.41 (m, 1H), 7.96-7.89 (m, 2H), 7.80-7.70 (m, 3H), 7.51 (d, J=7.9 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 4.20 (s, 2H), 2.44 (s, 3H).

EXAMPLE 198

N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)thiophene-2-sulfonamide

[1034] ##STR00245##

[1035] .sup.1H NMR (400 MHz, MeOD) δ 8.47-8.41 (m, 1H), 7.93-7.85 (m, 2H), 7.80-7.71 (m, 2H), 7.61 (dd, J=3.7, 1.3 Hz, 1H), 7.52 (d, J=2 Hz, 2H), 7.45 (d, =8.3 Hz, 2H), 7.16-7.11 (m, 1H), 4.26 (s, 2H).

PREPARATION EXAMPLE 4-2

[1036] ##STR00246##

[1037] Step 1-1: 4 bromobenzvl bromide 30 (1.0 eq.) and thiourea (1.0 eq.) were refluxed in ethanol (1.0 M). The ethanol was removed by low pressure to obtain a solid or viscous oil and then the following reaction was performed without further purification.

[1038] Step 1-2: The product obtained in Step 1-1 was slowly added to a solution of N chlorosuccinimide (5.0 eq.), 2M HCl (3.1 M), and acetonitrile (0.63 M). The internal temperature of the solution was maintained at 10° C. to 20° C. in a water bath. After the reaction was complete, diethyl ether was added thereto and the layers of the solution were separated by water addition. The organic layer was separated, dried with anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain a product.

[1039] Step 1-3: (4-bromophenyl)methane sulfonylchloride (1.0 eq.) was dissolved in tetrahydrofuran (0.1 M) and then a 25% ammonium hydroxide solution was added thereto at 0° C. The reaction mixture was stirred at 5° C. for 1 hour. The reaction mixture was concentrated and the precipitate was washed with water and filtered to obtain a product (64% yield).

[1040] Step 2-1: the product (1.0 eq.) of Step 1-3, B.sub.2pin.sub.2 (1.2 eq.) and potassium acetate (3.0 eq.) were dissolved in anhydrous dioxane (0.15 M). The mixture was stirred with nitrogen bubbling for 20 minutes. Then, [1,1′-bis(diphenylphosphino)ferrocene]palladium (11) dichloride (0.1 eq.) was added thereto and a reflux condenser was attached. The reaction mixture was stirred under a nitrogen atmosphere at 65° C. for 13 hours. Then, the solution was warmed to 23° C., concentrated and separated by column chromatography to obtain a product (74% yield).

[1041] Step 2-2: the product obtained in Step 2-1, 7 (1.0 eq.), tetrakis (triphenylphosphine) palladium (0) (0.06 eq.), 8 (1.25 eq.) and potassium carbonate (3.75 eq.) were dissolved in 1,4-dioxane (0.09 M) and water (0.9 M) in a round bottom flask, followed by stirring under a nitrogen atmosphere for 4 hours. After the reaction was complete, the mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated by column chromatography (EtOAc:Hexane=1:1) to obtain 31 (70% yield).

EXAMPLE 199

(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamide

[1042] ##STR00247##

[1043] .sup.1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=7.6 Hz, 1H), 7.85-7.67 (m, 3H), 7.64 (s, 4H), 4.53 (s, 2H), 4.44 (s, 2H), 3.93 (s, 3H).

PREPARATION EXAMPLE 4-3

[1044] ##STR00248##

[1045] Step 1-1: a product was obtained in the same manner as in Step 1-1 of [Preparation Example 4-2].

[1046] Step 1-2: a product was obtained in the same manner as in Step 1-2 of [Preparation Example 4-2].

[1047] Step 1-3: the product of Step 1-2 (1.0 eq.), tetrahydrofuran (0.19M), and ter -butanol (0.37M) were stirred in a 40% aqueous methylamine solution (6.8 eq.) at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and then the organic layer was separated with ethyl acetate. The separated organic layer was washed with brine and water, dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a product (89% yield) without further purification.

[1048] Step 2-1: a product (89% yield) was obtained in the same manner as in Step 2-1 of [Preparation Example 4-2].

[1049] Step 2-2: a product 32 (15% yield) was obtained in the same manner as in Step 2-2 of [Preparation Example 4-2].

EXAMPLE 200

N methyl-1-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methanesulfonamide

[1050] ##STR00249##

[1051] .sup.1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=7 7 Hz, 1H), 7.83-7.68 (m, 3H), 7.67-7.55 (m, 5H), 4.36 (s, 2H), 3.93 (s, 3H), 2.82 (d, J=5.2 Hz, 3H).

PREPARATION EXAMPLE 4-4

[1052] ##STR00250##

[1053] Step 1-1: a product was obtained in the same manner as in Step 1-1 of [Preparation Example 4-2].

[1054] Step 1-2: a product was obtained in the same manner as in Step 1-2 of [Preparation Example 4-2].

[1055] Step 1-3: sodium carbonate (2.0 eq.) was dissolved in acetonitrile (0.21M) and then morpholine (2.0 eq.) was added to the reaction mixture. Then, the solid (4-bromophenyl)-methanesulfonyl chloride (1.0 eq.) was added thereto and a flask was stirred under a nitrogen atmosphere for 2 hours. After the reaction was complete, the reaction mixture was diluted with distilled water and the aqueous solution was extracted with ethyl. acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to obtain a white solid without further purification (96% yield).

[1056] Step 2-1: a product (89% yield) was obtained in the same manner as in Step 2-1 of [Preparation Example 4-2].

[1057] Step 2-2: a product 33 (65% yield) was obtained in the same manner as in Step 2-2 of [Preparation Example 4-2].

EXAMPLE 201

2-methyl-4-(4-((morpholinosulfonyl) methyl)phenyl)phthalazin-1 (2H)-one

[1058] ##STR00251##

[1059] 1H NMR (400 MHz, DMSO) δ 8.41-8.34 (m, 1H), 7.95-7.85 (m, 2H), 7.70-7.58 (m, 5H), 4.57 (s, 2H), 3.79 (s, 3H), 3.66-3.59 (m, 4H), 3.21-3.14 (m, 4H).

PREPARATION EXAMPLE 4-5

[1060] ##STR00252##

[1061] Step 1: potassium thioacetate (1.1 eq.) was dissolved at 0° C. in dimethylformamide (0.3 M) and then bromide 34 (1.0 eq.) was slowly added thereto. The mixture was stirred at 25° C. for 2 hours. After the reaction was complete, the mixture was poured into ethyl acetate and washed with brine. Then, the organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a product without further purification, which was used for the following reaction.

[1062] Step 2: N-chlorosuccinimide (4.0 eq.) was added to a solution of acetonitrile (0.2 M)/2M HCl (5/1 v/v) and the mixture was warmed to 0° C. Then, thioacetate (1.0 eq.) was slowly added thereto. The mixture was stirred for 1 hour. After the reaction was complete, the resulting mixture was extracted with diethyl ether and washed with brine, the organic layer was dried with anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a product (73% yield).

[1063] Step 3: (4 bromophenyl)methane sulfonylchloride (1.0 eq.) was dissolved in tetrahydrofurari (0.1 M) and then a 25% ammonium hydroxide solution was added thereto at 0° C. The reaction mixture was stirred at 5° C. for 1 hour. The reaction mixture was concentrated and then the precipitate was washed with water and filtered to obtain a product (82% yield).

[1064] Step 4: a Product (74% yield) was ained in the same manner as in Step 2-1 of [Preparation Example 4-2].

[1065] Step 5: a product 35 (70% yield) was obtained in the same manner as in Step 2-2 of [Preparation Example 4-2].

EXAMPLE 202

2-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethane-1-sulfonamide

[1066] ##STR00253##

[1067] .sup.1H NMR (400 MHz, CDCl3) δ 8.57-8.49 (m, 1H), 7.84-7.64 (m, 3H), 7.60-7.55 (m, 2H), 7.41 (d, J=8.1 Hz, 2H), 4.57 (s, 2H), 3.92 (s, 3H), 3.50-3.42 (m, 2H), 3.32-3.24 (m, 2H).

EXAMPLE 203

4-(4-(aminomethyl)-3-(trifluoromethyl)phenyl-6,7-dimethoxy phthalazin-1(2.8)-one hydrochloride

[1068] ##STR00254##

EXPERIMENTAL EXAMPLE

[1069] Examples 1 to 203 prepared as described above were subjected to the following experiment.

EXPERIMENTAL EXAMPLE 1

ENPP1 Enzyme Assay with eGAMP Substrate

[1070] ENPP1 hydrolyzes nucleotides or nucleotide derivatives to produce nucleoside -5′-monophosphate and pyrophosphate. in addition, ENPP1 hydrolyzes 2′,3′-cGAMP to produce 5′-adenosine monophosphate (AMP) and 5′-guanosine monophosphate (GMP). AMP produced from the reaction is measured using the AMP-Glo® kit (Promega). The AMP-Glo® kit contains two reagents. The first reagent terminates the AMP-producing enzymatic reaction, removes ATP and converts the produced AMP into ADP. The second reagent converts ADP to ATP which is used to generate luminescence in the luciferase reaction. The amount of luminescence measured is proportional to the amount of AMP produced by ENPP1.

[1071] The final reaction mixture contains 50 mM Tris (pH 8.5) buffer, 250 mM NaCl, 0.5 mM. CaCl.sub.2, 1 μM ZnCl.sub.2, 5% glycerol and 1% DMSO. Serially diluted ENPP1 inhibitors (typically in the range of 10 μM to 0.5 nM) were pre-stored with human recombinant ENPP1 enzymes (R & D systems) at 3 ng/reaction and room temperature (RT) for 5 to 10 minutes. The reaction was initiated by addition of cGAMP (at a final concentration of 5 μM) and reacted at 37° C. for 90 minutes. At the end of the reaction, 10 μl of the AMP-Glo first reagent was added to stop the reaction and the result was stored at room temperature for hour. After storage, 20 μl of an AMP detection solution (a mixture of AMP-Glo II reagent and Kinase-Gio at a ratio of 1:100) was added and stored at room. temperature for 1 hour. Luminescence signals were measured using a Victor® plate reader (Perkin Elmer). The maximal activity control (containing enzymes and substrates only in the presence of 1% DMSO; MAX) and the minimal activity control (containing substrates and 1% DMSO; MIN) were evaluated simultaneously. In each experiment, serially diluted reference ENPP1 inhibitors were tested together. IC.sub.50, indicating % residual activity versus compound concentration was determined by fitting inhibition curves using the 3-parameter analysis of GraphPad Prism® software. Serially diluted samples of one compound were tested two or more times and an average IC.sub.50 of each compound was calculated.

[1072] The experimental results are shown in Tables 1 and 2 below.

TABLE-US-00001 TABLE 1 Example Enzymatic activity 1 B 2 NA 3 NA 4 NA 5 C 6 NA 9 NA 10 NA 12 NA 13 C 14 C 15 NA 18 C 20 NA 24 NA 26 NA 27 NA 28 NA 29 C 132 NA 133 NA 145 NA 146 NA 147 NA 148 NA 149 NA 150 NA 151 NA 152 NA 155 NA 30 C 31 C 32 C 33 C 35 C 37 A 38 A 39 C 40 B 41 B 42 B 43 A 44 B 46 C 47 A 48 A 49 A 51 A 52 B 53 A 55 A 56 B 57 B 58 B 59 NA 134 B 135 C 156 NA 157 NA 158 NA 159 NA 160 NA 161 C 162 C 163 C 164 C 165 C 166 C 60 C 61 C 62 NA 64 C 66 C 67 C 69 NA 70 NA 71 C 72 C 73 NA 76 B 77 B 81 NA 83 NA 84 C 85 C 136 NA 137 NA 167 NA 168 NA 169 B 170 C 171 C 172 B 173 NA 174 NA 176 C 177 C 87 A 88 A 89 A 91 B 92 A 93 C 95 A 90 C 94 A 96 A 97 A 98 B 99 NA 100 A 101 B 102 B 103 A 104 A 105 B 106 B 107 C 108 B 109 B 110 B 111 A 112 B 113 B 114 B 115 B 116 B 117 C 118 C 119 B 120 C 121 A 122 A 123 A 124 A 125 B 126 A 127 A 128 B 129 B 130 B 131 B 138 A 139 A 140 C 141 B 142 C 143 C 144 C 178 C 179 C 180 A 181 A 182 A 183 A 184 B 185 A 186 A 187 A 188 A 189 A 190 A 191 A 192 A 193 NA 194 C 195 C 196 C 197 C 198 NA 199 NA 200 NA 201 NA 202 B 203 C

TABLE-US-00002 TABLE 2 Enzymatic activity A B C NA IC50 (μM) activity < 1 μM < activity > No 1 μM activity < 10 μM activity 10 μM

FORMULATION EXAMPLE

[1073] Meanwhile, the novel compound represented by Formula 1 according to the present invention may be formulated in various forms according to purpose. Examples of some formulation methods for incorporating the compound represented by Formula 1 according to the present invention as an active ingredient are as follows, but the present invention is not limited thereto.

FORMULATION EXAMPLE 1

Tablet (Direct Pressurization)

[1074] 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed therewith, and the mixture was compressed into tablets.

FORMULATION EXAMPLE 2

Tablet (Wet Granulation)

[1075] 5.0 mg of the active ingredient was sieved and mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of the resulting solution was added to the resulting mixture, followed by granulation. The granules were dried, sieved, and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were compressed into tablets.

FORMULATION EXAMPLE 3

Powders and Capsules

[1076] 5.0 mg of the active ingredient was sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone, and 0.2 mg of magnesium stearate. Hard No. 5 gelatin capsules were filled with the resulting mixture using an appropriate device.

FORMULATION EXAMPLE 4

Injection

[1077] Injections were prepared by incorporating 100 mg of the active ingredient as well as 180 mg of mannitol, 26 mg of Na.sub.2HPO.sub.4.12H.sub.2O, and 2,974 mg of distilled water.

[1078] Although embodiments of the present invention have been described above, it will be obvious to those skilled in the art that the present invention can be implemented in other specific embodiments without changing the technical concepts or essential features of the present invention. Therefore, it should be construed that the aforementioned embodiments are illustrative and not restrictive in all respects.