Poly (ADP-ribose) polymerase inhibitor

Abstract

Disclosed are a phthalic hydrazide (phthalazine ketone) compound, and a pharmaceutical composition comprising the same. As a DNA repair enzyme poly (ADP-ribozyme) polymerase inhibitor, the compound and the pharmaceutical composition can effectively treat diseases involving PARP enzymatic activity, including cancer, neural degenerative diseases, inflammation and the like.

Claims

1. A compound represented by Formula (II) or (III): ##STR00149## or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R is selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, nitro, hydroxyl, amino, branched or straight-chain C.sub.1-C.sub.6 alkyl, haloalkyl, CF.sub.3, CN, NR.sup.11R.sup.12, NH—CO—R.sup.13 and O—C.sub.1-C.sub.4 alkyl, wherein R.sup.11 and R.sup.12 are each independently hydrogen or C.sub.1-C.sub.4 alkyl, R.sup.13 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl-phenyl or benzyl; X.sub.1, X.sub.2 are each independently selected from —CH or —N, but they are not —N simultaneously; and R′ is selected from the group consisting of —H, —C(O)R.sub.1, —C(O)NR.sub.1R.sub.2, —CO.sub.2R.sub.1, substituted or unsubstituted C.sub.1-10 alkyl, substituted or unsubstituted C.sub.2-10 alkenyl, substituted or unsubstituted C.sub.3-10 cycloalkyl, substituted or unsubstituted C.sub.5-10 cycloalkenyl, substituted or unsubstituted C.sub.1-10 alkoxy, substituted or unsubstituted C.sub.2-10 alkenyloxy, substituted or unsubstituted 3-10-membered saturated or unsaturated monocyclic heterocyclic ring comprising 1-3 heteroatoms selected from N, O and S, substituted or unsubstituted C.sub.6-10 aryl and substituted or unsubstituted C.sub.5-10 heteroaryl comprising 1-3 heteroatoms selected from N, O and S, and wherein R.sub.1 and R.sub.2 are each independently selected from the group consisting of —H, substituted or unsubstituted C.sub.1-10 alkyl, substituted or unsubstituted C.sub.2-10 alkenyl, substituted or unsubstituted C.sub.3-10 cycloalkyl, substituted or unsubstituted C.sub.5-10 cycloalkenyl, substituted or unsubstituted C.sub.1-10 alkoxy, substituted or unsubstituted C.sub.2-10 alkenyloxy, substituted or unsubstituted 3-10-membered saturated or unsaturated monocyclic heterocyclic ring comprising 1-3 heteroatoms selected from N, O and S, substituted or unsubstituted C.sub.6-10 aryl and substituted or unsubstituted C.sub.5-10 heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the substitution refers to substitution by at least one group selected from the group consisting of halogen, hydroxyl, cyano, amino, carboxyl, C.sub.2-10 hydrocarbyl ether, nitro, C.sub.1-10 sulfonyl, C.sub.1-10 hydrocarbyl sulfonamide, C.sub.6-10 aryl, C.sub.5-10 heteroaryl comprising 1-3 heteroatoms selected from N, O and S, C.sub.1-10 straight or branched chain alkyl, C.sub.1-10 straight or branched chain alkenyl, C.sub.1-10 hydrocarbyl acyl, C.sub.1-10 hydrocarbyl acyloxy, C.sub.1-10 hydrocarbyl amide, C.sub.1-10 hydrocarbyl acyl amide, ureido, (C.sub.1-10 alky).sub.1-2 amino, C.sub.1-10 hydrocarbyl ester, phenoxy, benzyloxy, C.sub.3-10 cycloalkyl, C.sub.5-10 cycloalkenyl, C.sub.1-10 alkoxy, C.sub.1-10 alkenyloxy, C.sub.1-10 alkylthiol and C.sub.1-10 haloalkyl.

2. The compound, or a pharmaceutically acceptable salt or stereoisomer thereof, of claim 1, wherein R′ is selected from the group consisting of —H, —C(O)R.sub.1, —C(O)NR.sub.1R.sub.2, —CO.sub.2R.sub.1, substituted or unsubstituted C.sub.1-10 alkyl, substituted or unsubstituted C.sub.2-10 alkenyl, substituted or unsubstituted C.sub.6-10 aryl and substituted or unsubstituted C.sub.5-10 heteroaryl comprising 1-3 heteroatoms selected from N, O and S, and wherein R.sub.1 and R.sub.2 are each independently selected from the group consisting of —H, substituted or unsubstituted C.sub.1-10 alkyl, substituted or unsubstituted C.sub.2-10 alkenyl, substituted or unsubstituted C.sub.3-7 cycloalkyl, substituted or unsubstituted C.sub.5-7 cycloalkenyl, substituted or unsubstituted C.sub.1-10 alkoxy, substituted or unsubstituted 5-7-membered saturated or unsaturated monocyclic heterocyclic ring comprising 1˜3 heteroatoms selected from N, O and S, substituted or unsubstituted C.sub.6-10 aryl and substituted or unsubstituted C.sub.5-10 heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the substitution refers to substitution by at least one group selected from the group consisting of halogen, hydroxyl, cyano, amino, nitro, C.sub.6-10 aryl, C.sub.1-10 straight or branched chain alkyl, C.sub.1-10 hydrocarbyl acyloxy, (C.sub.1-10 alky).sub.1-2 amino, C.sub.1-10 hydrocarbyl ester, phenoxy, benzyloxy, C.sub.3-7 cycloalkyl, C.sub.1-10 alkoxy and C.sub.1-10 haloalkyl.

3. The compound, or a pharmaceutically acceptable salt or stereoisomer thereof, of claim 1, wherein R′ is —C(O)R.sub.1, wherein R.sub.1 is selected from the group consisting of substituted or unsubstituted C.sub.3-6 alkyl, substituted or unsubstituted C.sub.3-6 cycloalkyl, substituted or unsubstituted 5-6-membered saturated or unsaturated monocyclic heterocyclic ring comprising 1-2 heteroatoms selected from N, O and S, and substituted or unsubstituted phenyl, wherein the substitution refers to substitution by at least one group selected from the group consisting of halogen, hydroxyl, cyano, amino, nitro, phenyl, C.sub.1-3 straight or branched chain alkyl, (C.sub.1-3 alky).sub.1-2 amino.

4. The compound, or a pharmaceutically acceptable salt or stereoisomer thereof, of claim 1, wherein R is selected from the group consisting of hydrogen, fluoro, chloro, bromo, nitro, and amino; and X.sub.1, X.sub.2 are —CH, respectively.

5. The compound, or a pharmaceutically acceptable salt or stereoisomer thereof, of claim 4, wherein R.sub.1 and R.sub.2 are independently selected from the group consisting of ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclohexyl, phenyl, pyrrolidinyl and piperidinyl optionally substituted by one or two substituents selected from fluoro, chloro, nitro, amino, methylamino, dimethylamino, methyl and phenyl.

6. A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the following compounds: 4-(2-fluoro-(4-(1-benzyloxycarbonyl-piperidine)carbonylpiperazine-1-carbonyl)phen oxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(4-nitrobenzoyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(5-methylisoxazole-4-carbonyl)piperazine-1-carbonyl)phenoxy-2H-phthalazin-1-one, 4-(2-fluoro-5-(4-oxo-3,4-2H-phthalazine-1-yl-oxyl)benzoyl)-N-phenylpiperazine-1-formamide, 5-chloro-4-(4-fluoro-3-(4-(4-fluorobenzoyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 5-chloro-4-(4-fluoro-3-(4-benzoyl piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(2-methylthiazole-4-carbonyl)piperazine-1-carbonyl)phenoxy-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(4-fluorophenyl)piperazine-1-carbonyl)phenoxy)-5-nitro-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(4-fluorobenzoyl)piperazine-1-carbonyl)phenoxy)-5-nitro-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-benzoyl piperazine-1-carbonyl)phenoxy)-5-nitro-2H-phthalazin-1-one, 5-nitro-4-(2-fluoro-(4-(1-benzyloxycarbonyl-piperidine)carbonylpiperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(4-nitrobenzoyl)piperazine-1-carbonyl)phenoxy)-5-nitro-2H-phthalazin-1-one, N-cyclohexyl-4-(2-fluoro-5-(4-oxo-3,4-2H-phthalazine-1-yl-oxyl)benzoyl)piperazine-1-formamide, 4-(3-(4-acetyl piperazine-1-carbonyl)-4-fluorophenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(thiazole-4-carbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(2-fluoro-(4-(2-benzyloxycarbonyl-piperidine)carbonylpiperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(2-fluoro-(4-(3-benzyloxycarbonyl-piperidine)carbonylpiperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(4-oxocyclohexanecarbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(4-cyanobenzoyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, (R)-4-(4-fluoro-3-(4-(2-phenylpropionyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)-4-fluorophenoxy)-2H-phthalazin-1-one, 1-(4-(2-fluoro-5-(4-oxo-3-1,4-dihydronaphthyridin-1-yl-oxyl)benzoyl)piperazine-1-yl)propane-1,2-phthalazinedione, 4-(4-fluoro-3-(4-(5-methylisoxazole-3-carbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(2,2,2-trifluoroacetyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(3,3,3-trifluoropropionyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-pivaloylpiperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(2-methoxyacetyl)piperazine-1-carbonyl)phenoxy-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(2-cyanobenzoyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(2-fluoro-5-(4-oxo-3,4-2H-phthalazin-1-yl-oxyl)benzoyl)-N-isopropyl-1-formamide, 4-(3-(4-(2-ethoxyacetyl)piperazine-1-carbonyl)-4-fluorophenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-isonicotinoylpiperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(3-(4-(2-ethylbutyryl)piperazine-1-carbonyl)-4-fluorophenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(4,4-difluoropiperidine-1-carbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(thiophene-2-carbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(3-hydroxypropyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-isobutyrylpiperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(2-fluoro-5-(4-oxo-3,4-2H-phthalazin-1-yl-oxyl)benzoyl)-N, N-dimethylpiperazine-1-formamide, 4-(4-fluoro-3-(4-(3-trifluoromethyl-4-methyl-benzoyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(3-(4-acryloylpiperazine-1-carbonyl)-4-fluorophenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(2-hydroxypropionyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(3-(4-(4-(dimethylamino)benzoyl)piperazine-1-carbonyl)-4-fluorophenoxy)-2H-phthalazin-1-one, 4-(3-(4-(3-(dimethylamino)benzoyl)piperazine-1-carbonyl)-4-fluorophenoxy)-2H-phthalazin-1-one, 4-(3-(4-tertbutylpiperazine-1-carbonyl)-4-fluorophenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(furan-2-carbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-isopropylpiperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(3-(4-allylpiperazine-1-carbonyl)-4-fluorophenoxy)-2H-phthalazin-1-one, 4-(3-(4-3-cyanobenzoylpiperazine-1-carbonyl)-4-fluorophenoxy)-2H-phthalazin-1-one, 4-(3-(4-(1H-pyrazole-1-carbonyl)piperazine-1-carbonyl)-4-fluorophenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(morpholine-4-carbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(pyrrolidine-1-carbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(piperidine-1-carbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(3-nitrobenzoyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(2-nitrobenzoyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, (E)-4-(3-(4-but-2-enoylpiperazine-1-carbonyl)-4-fluorophenoxy-)2H-phthalazin-1-one, 4-(4-fluoro-3-(4-methyl piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(oxazole-4-carbonyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(3-(4-(1H-1,2,4-triazole-1-carbonyl)piperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one, (R)-4-(4-fluoro-3-(4-(tetrahydrofuran-2-carbonyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(tetrahydrofuran-2-carbonyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, N-(4,4-difluorocyclohexyl)-4-(2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoyl)piperazine-1-formamide, N-cyclopropyl-4-(2-fluoro-5-(4-oxo-3,4-dihydro-phthalazine-1-yl-oxyl)benzoyl)piperazine-1-formamide, 4-(3-(4-(1H-imidazole-1-carbonyl)piperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one, 4-(3-(4-(cyclohexanecarbonyl)piperazine-1-carbonyl-4-fluorophenoxy)2H-phthalazin-1-one, 4-(4-fluoro-3-(4-propionylpiperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one, 5-chloro-4-(2-fluoro-(4-(4-benzyloxycarbonyl-piperidine)carbonylpiperazine-1-carbonyl)phenoxy-2H-phthalazin-1-one, 4-(3-(4-benzoylpiperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one, 5-chloro-4-(4-fluoro-3-(4-(4-fluorophenyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 5-chloro-4-(4-fluoro-3-(4-(4-nitrobenzoyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(3-(4-(4,4-difluorocyclohexanecarbonyl)piperazine-1-carbonyl)-4-fluorophenoxy) 2H-phthalazin-1-one, 1-benzyloxycarbonyl-2-(4-(2-fluoro-5-(4-oxo-3,4-dihydronaphthyridin-1-yl-oxyl)benzoyl)piperazine-1-carbonyl)pyrrolidine, 4-(4-fluoro-3-(4-(pyrrolidine-2-carbonyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(4-fluorophenyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(tetrahydrofuran-3-carbonyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, N-(4-chlorophenyl)-4-(2-fluoro-5-(4-oxo-3,4-dihydronaphthyridin-1-yl-oxyl)benzoyl)piperazine-1-formamide, N,N-diethyl-4-(2-fluoro-5-(4-oxo-3,4-dihydro-phthalazine-1-yl-oxyl)benzoyl)piperazine-1-formamide, 4-(4-fluoro-3-(4-(tetrahydropyran-4-carbonyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(4-(trifluoromethyl)benzoyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(4-fluorobenzoyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(4-fluorobenzyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one, 4-(4-fluoro-3-(piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(2-pyridyl)-formylpiperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, (S)-4-(4-fluoro-3-(4-(tetrahydrofuran-2-carbonyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(3-(4-(2-cyclopropylacetyl)piperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one, 4-(3-(4-(2-cyclopentylacetyl)piperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(1-(methylamino)cyclopropanecarbonyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(3-(4-(1-aminocyclopropanecarbonyl)piperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one, 4-(3-(4-(1-(dimethylamino)cyclobutanecarbonyl)piperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one, 4-(4-fluoro-3-(4-(1-(methylamino)cyclobutanecarbonyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one, 4-(3-(4-(1-aminocyclobutanecarbonyl)piperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one, (R)-4-(3-(4-(1,2-dimethylpyrrolidine-2-carbonyl)piperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one, and (R)-4-(4-fluoro-3-(4-(2-methylpyrrolidine-2-carbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one.

7. The compound, or a pharmaceutical acceptable salt or stereoisomer thereof, of claim 6, wherein the compound is selected from the following compounds: 4-(4-fluoro-3-(4-(piperidine-1-carbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one; 4-(4-fluoro-3-(4-(2-nitrobenzoyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one; 4-(3-(4-(4,4-difluorocyclohexanecarbonyl)piperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one; 4-(3-(4-(1-(dimethylamino)cyclobutanecarbonyl)piperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one; (R)-4-(4-fluoro-3-(4-(2-methylpyrrolidine-2-carbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one.

8. The compound, or a pharmaceutical acceptable salt or stereoisomer thereof, of claim 6, wherein the compound is selected from the following compounds: 4-(4-fluoro-3-(4-pivaloylpiperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one; 4-(4-fluoro-3-(4-isopropylpiperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one; 4-(4-fluoro-3-(4-propionylpiperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one; 4-(3-(4-(1-aminocyclopropanecarbonyl)piperazine-1-carbonyl)-4-fluorophenoxy)2H-phthalazin-1-one; 4-(4-fluoro-3-(4-(1-(methylamino)cyclobutanecarbonyl)piperazine-1-carbonyl)phenoxy)2H-phthalazin-1-one.

9. The compound, or a pharmaceutical acceptable salt or stereoisomer thereof, of claim 6, wherein the compound is 4-(3-(4-(2-ethylbutyryl)piperazine-1-carbonyl)-4-fluorophenoxy)-2H-phthalazin-1-one.

10. A pharmaceutical composition comprising an effective amount of the compound, or a pharmaceutically acceptable salt or stereoisomer thereof, of claim 1, and a pharmaceutically acceptable carrier.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a result in Test Example 3 that shows the relationship between the peak area of compound AZD-2281 (as a standard) measured by HPLC and the concentration of the compound.

EMBODIMENTS

(2) The followings further explain the general methods of the present invention. The compounds of the present invention may be prepared by the methods known in the art. The following illustrate the detailed preparation methods of the preferred compounds of the present invention. However, they are by no means limiting the preparation methods of the compounds of the present application.

(3) ##STR00137##

(4) Phthalic anhydride (1a) was reacted with hydrazine hydrate in the presence of glacial acetic acid to give phthalhydrazide (1b), which was then reacted with ethyl 3-chloromethylbenzoate (1c) in the presence of sodium hydride to give ethyl 3-((4-oxo-3-1,4-dihydro-phthalazin-1-yl-oxyl)methyl)benzoate (1d), after that, 1d was hydrolyzed into 3-((4-oxo-3,4-dihydrophthalazin-1-yl-oxy)methyl)benzoic acid (1e) under alkali condition, 1e finally condensated with R′ substituted nitrogen heterocycles, e.g. piperazine, piperidine, 4-hydroxypiperidine, tetrahydropyridine and 1,4-diazacycloheptane (homopiperazine) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), triethylamine, 1-hydroxy-7-azabenzotriazole (HOAt) to generate target compounds, wherein the definition of R′ is as described above.

(5) ##STR00138##

(6) Under the action of phosphorus oxychloride, phthalhydrazide (1b) generated 1,4-dichlorophthalazine (2a), which was then reacted with 3-hydroxy-ethyl benzoate (2b) to give the crude product of 3-(4-chloronaphthyridine-1-yl-oxyl)ethyl benzoate (2c). Sodium acetate was added to the crude product in glacial acetic acid to generate ethyl 3-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)benzoate (2d), which was then hydrolyzed under alkali condition into intermediate 3-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (2e), which finally condensated with R′ substituted nitrogen heterocycles, e.g. piperazine, piperidine, 4-hydroxypiperidine, tetrahydropyridine and 1,4-diazacycloheptane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), triethylamine and 1-hydroxy-7-azabenzotriazole (HOAt) to generate target compounds, wherein the definition of R′ is as described above.

(7) ##STR00139##

(8) In the presence of hydrazine hydrate/glacial acetic acid, phthalic anhydride (3a) with substituent R was transformed into R-substituted phthalhydrazide (3b), which subsequently generated substituted dichlorophthalazine compounds (3c) under the action of phosphorus pentachloride. In another aspect, under the action of hydrobromic acid, 2-fluoro-5-methoxybenzonitrile (3d) was converted to 2-fluoro-5-hydroxybenzoic acid (3e), which was esterificated with methanol to give methyl 2-fluoro-5-hydroxybenzoate (3f). Under the action of sodium hydride, the prepared dichlorophthalazine compounds with substituent R (3c) was reacted with methyl 2-fluoro-5-hydroxybenzoate (3f) to give methyl 5-((4-chloronaphthyridine-1-yl)oxy)-2-fluorobenzoate with substituent R (3 g), 3 g was transformed into methyl 2-fluoro-5-((4-oxo-3,4-dihydro-phthalazin-1-yl)oxy)benzoate (3h) in the presence of AcOH/NaOAc under the reflux condition, 3h was then hydrolyzed under alkali condition into substituent-contained 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (3i), which finally condensated with R′ substituted nitrogen heterocycles, e.g. piperazine, piperidine, 4-hydroxypiperidine, tetrahydropyridine and 1,4-diazacycloheptane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), triethylamine and 1-hydroxy-7-azabenzotriazole (HOAt) to generate target compounds, wherein the definition of R and R′ is as described above.

(9) ##STR00140##

(10) Under the action of sodium hydride, dichlorophthalazine (2a) was reacted with methyl 2-fluoro-5-hydroxybenzoate (3f) to give methyl 5-((4-chloronaphthyridine-1-yl)oxy)-2-fluorobenzoate (4a). 4a was transformed into methyl 2-fluoro-5-((4-oxo-3,4-dihydro-phthalazin-1-yl)oxyl)benzoate (4b) in the presence of AcOH/NaOAc under the reflux condition, 4b was then hydrolyzed under alkali condition into 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (4c), which finally condensated with R′ substituted nitrogen heterocycles, e.g. piperazine, piperidine, 4-hydroxypiperidine, tetrahydropyridine and 1,4-diazacycloheptane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), triethylamine and 1-hydroxy-7-azabenzotriazole (HOAt) to generate target compounds, wherein the definition of R′ is as described above.

(11) The present invention is further explained by the following examples. However, it shall be understood by a person skilled in the art that the present invention is not limited to these specific examples.

EXAMPLES

(12) The structures of the compounds in the following examples were characterized by nuclear magnetic resonance (NMR) or/and mass spectrometry (ESI). NMR shift (δ) was given in the unit of 10.sup.−6 (ppm). .sup.1H-NMR spectra was recorded in dimethyl sulfoxide-d.sub.6 (DMSO-d.sub.6) or CDCl.sub.3 on a Varian Mercury-600 MHz NMR with tetramethylsilane (TMS) as an internal standard.

(13) ESI-MS measurement was carried out using Finnigan LCQ Deca mass spectrometer.

(14) High Performance Liquid Chromatography (HPLC) measurement was carried out on Agilent 1200 LC using the Phenomen C18 column (4.6 mm*150 mm, 0.4 μm).

(15) IC.sub.50 values were determined using Envision 2104 microplate reader (Perkin Elmer Inc.).

(16) Thin layer chromatography was carried out using Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used for thin layer chromatography (TLC) were 0.15 mm˜0.2 mm. The silica gel plates used for separating and purifying products by TLC were 0.4 mm˜0.5 mm.

(17) Purified chromatographic column uses the silica gel as the carrier (300˜400 mesh, producted by Yantai Huanghai co.).

(18) The known starting materials of the present invention can be synthesized by using or according to the known methods in the art, or can be purchased from Alfa Aesar, Langcaster, TCI, Shanghai Shaoyuan Co. Ltd. and AstaTech (Chengdu) BioPharm. Co., Ltd.

(19) Unless otherwise specified, the reactions in the examples were all carried out under argon or nitrogen atmosphere. Argon or nitrogen atmosphere refers to that the reaction flask is connected to an argon or nitrogen ballon with a volume of about 1 L. Hydrogenation was usually carried out under vacuum, filled with hydrogen, and repeated for three times. Unless otherwise specified, the reaction temperature in the examples was room temperature. Room temperature was the optimized reaction temperature, which was 20° C.˜30° C.

(20) The reaction progress in the examples was monitored by thin layer chromatography (TLC). The eluent systems used for the reactions include: A: dichloromethane-methanol system, B: n-hexane-ethyl acetate system, C: petroleum ether-ethyl acetate system. The volume ratios of the solvents were adjusted according to the different polarities of compounds.

(21) The elution system of column chromatography used for purifying compounds and eluent system of TLC include A: dichloromethane-methanol system, B: n-hexane-ethyl acetate system, C: petroleum ether-ethyl acetate system. The volume ratios of the solvents were adjusted according to the different polarities of compounds. A small amount of alkaline or acidic agents such as triethylamine and acetic acid can be added for adjustment.

Intermediate Preparation Example 1. Synthesis of methyl 2-fluoro-5-hydroxybenzoate

(22) ##STR00141##

(23) 2-Fluoro-5-methoxybenzonitrile (3d, purchased from Alfa Aesar) (5 g, 33 mmol) was dissolved in hydrobromic acid (50 mL) and glacial acetic acid (30 mL), refluxed for 28 hours at 140° C., and then the reaction mixture was diluted with 100 mL ethyl acetate. The reaction mixture was then washed with 50 mL water and saturated sodium chloride solution successively for three times. The organic layers were combined and concentrated to give a crude product of 2-fluoro-5-hydroxybenzoic acid (3e), 2.88 g white solid (yield 56%). .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.19-7.17 (m, 1H), 7.08-7.04 (m, 1H), 6.95-6.92 (m, 1H); ESI-MS m/z: calculated for 156.02, found 154.91 [M−H].sup.−.

(24) The obtained 2-fluoro-5-hydroxybenzoic acid (3e) (780 mg, 5 mmol) was dissolved in 100 mL methanol. Thionyl chloride (0.8 mL, 10 mmol) was added dropwise under the condition of ice bath (0° C.) and stirring, and then refluxed for two hours. The reaction solution was concentrated, and then column chromatography (petroleum ether:ethyl acetate=2:1) was performed to isolate methyl 2-fluoro-5-hydroxybenzoate (3f), 833 mg white solid (yield 98%). .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.73 (s, 1H), 7.20-7.18 (m, 1H), 7.13-7.09 (m, 1H), 6.99-6.97 (m, 1H), 3.80 (s, 3H); ESI-MS m/z: calculated for 170.04, found 171.25 [M+H].sup.+.

Intermediate Preparation Example 2. Preparation of 3-(((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)methyl)benzoic acid (1e)

(25) ##STR00142##

(26) Phthalic anhydride (1a, purchased from Shanghai Shaoyuan Co. Ltd.) (10 g, 67.6 mmol) was dissolved in glacial acetic acid (100 mL), hydrazine hydrate (20 mL) was added dropwise under the condition of ice bath (0° C.) and stirring, and then refluxed for two hours at 125° C. The reaction was monitored by TLC. The solution was cooled to room temperature, filtrated and washed with water until the pH of the filtrate was 6.0, and then dried to give phthalhydrazide (1b), 10.5 g white solid (yield 96%). ESI-MS m/z calculated for: 162.04. found: 163.15 [M+H].sup.+.

(27) Phthalhydrazide (1b) (10 g, 61.7 mmol) was dissolved in dried N,N-dimethylformamide (100 mL) in a round-bottom flask. Sodium hydride (1.63 g, 67.9 mmol) was added at 0° C., and then stirred for half an hour. Ethyl 3-chloromethylbenzoate (1c, purchased from Shanghai Shaoyuan Co. Ltd.) (13.49 g, 67.9 mmol) dissolved in N,N-dimethylformamide (20 mL) solution was dropwise added slowly at room temperature and reacted for 24 hours, and then ethyl acetate was added. The reaction solution was successively washed with 50 mL saturated sodium bicarbonate and saturated sodium chloride solution for three times, the organic layer was dried and concentrated. Column chromatography was performed for the crude product (petroleum ether:ethyl acetate=10:1) to give ethyl 3-(((4-oxo-3-1,4-dihydrophthalazin-1-yl)oxy)methyl)benzoate (1d), 6 g white solid (yield 30%). .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.94 (s, 1H), 8.24 (d, 1H, J=7.50 Hz), 7.97-7.95 (m, 1H), 7.93-7.87 (m, 3H), 7.85-7.83 (m, 1H), 7.57-7.56 (m, 1H), 7.48-7.45 (m, 1H), 5.23 (s, 2H), 4.29-4.25 (m, 2H), 1.28-1.25 (m, 3H); ESI-MS m/z: calculated for 324.1, found 346.9 [M+Na].sup.+.

(28) Ethyl 3-(((4-oxo-3-1,4-dihydro-phthalazin-1-yl)oxyl)methyl)benzoate (1d) (1 g, 3.1 mmol) was completely dissolved in 1M potassium hydroxide aqueous solution, concentrated hydrochloric acid was added dropwise until a white solid was completely separate out, stirred for one hour and then filtrated, washed with water until the filtrate become faintly acid to give 3-(((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)methyl)benzoic acid (1e), a crude product of 0.9 g white solid (yield 98%). ESI-MS m/z: calculated for 269.08, found 270.02 [M+H].sup.+.

Intermediate Preparation Example 3. Synthesis of 3-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (2e)

(29) ##STR00143##

(30) Phthalhydrazide (1b) (1 g, 6.2 mmol), phosphorus oxychloride (2.8 g, 18.6 mmol) and N,N-dimethylformamide were added into a reaction flask successively and refluxed for two hours, and then the reaction solution was carefully and slowly poured into ice water, and then warmed to room temperature, filtrated to remove the solid, the filtrate was concentrated under decreased pressure, and rapid column chromatography was performed with dichloromethane to give 1,4-dichlorophthalazine (2a), 281 mg pale yellow solid (yield 22.8%).

(31) 1,4-Dichlorophthalazine (2a) (277 mg, 1.4 mmol), N,N-dimethylformamide (10 mL), potassium carbonate (192 mg, 1.4 mmol), and ethyl 3-hydroxybenzoate (2b, purchased from Shanghai Shaoyuan Co. Ltd.) (231 mg, 1.4 mol) were added successively at room temperature, refluxed for two hours at 120° C. The reaction mixture was diluted with 50 mL ethyl acetate, then the reaction solution was washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times, the organic phases were combined and concentrated to give a crude product of ethyl 3-((4-chloronaphthyridine-1-yl)oxy)benzoate (2c), 340 mg white solid (yield 74%).

(32) The crude product of ethyl 3-((4-chloronaphthyridine-1-yl)oxy)benzoate (2c) (670 mg, 2 mmol), acetic acid (20 mL) and sodium acetate (420 mg, 3 mmol) were added into a reaction flask successively, refluxed for one hour and then diluted with 50 mL ethyl acetate. The reaction solution was washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times, the organic phases were combined and concentrated to give a crude product of ethyl 3-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)benzoate (2d), 589 mg white solid (yield 95%). .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.95 (s, 1H), 8.26 (d, 1H, J=7.7 Hz), 8.12 (d, 1H, J=7.7 Hz), 8.01-8.00 (m, 1H), 7.97-7.95 (m, 1H), 7.83-7.80 (m, 2H), 7.60-7.58 (m, 2H), 4.27 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H); ESI-MS m/z: calculated for 310.1, found 309.4 [M−H].sup.−.

(33) Ethyl 3-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)benzoate (2d) (1 g, 3.2 mmol) obtained in the last step was dissolved in 1M potassium hydroxide solution, stirred for two hours at room temperature, and then concentrated hydrochloric acid was added dropwise to adjust pH=3, stirred for two hours at room temperature, filtrated to give a white solid intermediate 3-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (2e), 893 mg white solid (yield 99%). .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.96 (s, 1H), 8.26 (d, 1H, J=7.9 Hz), 8.12 (d, 1H, J=7.9 Hz), 8.02-7.99 (m, 1H), 7.97-7.94 (m, 1H), 7.82-7.81 (m, 2H), 7.56-7.55 (m, 2H); ESI-MS m/z: calculated for 282.1, found 281.1 [M−H].sup.+.

Intermediate Preparation Example 4. Synthesis of 2-fluoro-5-(8-chloro-4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (5f)

(34) ##STR00144##

(35) 3-Chloro-phthalic anhydride (5a, purchased from TCI) (10 g, 54.95 mmol) was dissolved in glacial acetic acid (100 mL), and hydrazine hydrate (20 mL) was added dropwise at 0° C., and then refluxed for two hours at 125° C. When the reaction was completed, the solution was cooled down to room temperature, filtrated, and washed with water until the filtrate pH=6.0, and then dried to give 5-chloro-2,3-dihydrophthalazin-1,4-dione (5b), 10.08 g white solid (yield 93%).

(36) 5-Chloro-2,3-dihydrophthalazin-1,4-dione (5b) (1 g, 5.10 mmol) and phosphorus pentachloride (2.5 g, 12 mmol) were added into a reaction flask successively, and gradually warmed to 150° C. After the solid was melted, the mixture was reflux for two hours at 150° C., and then cooled down to room temperature. 200 mL dried dichloromethane was added, filtrated to remove insoluble substances, and the filtrate was concentrated. Rapid column chromatography was performed with dichloromethane, and the solvent was dried to give 1,4-dichloro-5-chloro-phthalazine (5c), 307 mg white solid (yield 26%).

(37) Methyl 2-fluoro-5-hydroxy benzoate (3f) (940 mg, 5.5 mmol) was dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (140 mg, 6 mmol) was added slowly. Half an hour later, the reaction solution was slowly dropwise added to the N,N-dimethylformamide (4 mL) solution of 1,4-dichloro-5-chloro-phthalazine (5c) (1000 mg, 4.3 mmol), and stirred for another one hour. The reaction solution was diluted with 250 mL ethyl acetate, and washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times, the organic phases were combined, concentrated and dried to give methyl 5-((4,8-dichlorophthalazin-1-yl)oxy)-2-fluorobenzoate (5d), 1.8 g white solid (yield 95%).

(38) Methyl 5-((4,8-dichlorophthalazin-1-yl)oxy)-2-fluorobenzoate (5d) (700 mg, 1.9 mmol), acetic acid (20 mL) and sodium acetate (420 mg, 3 mmol) were added into a reaction flask successively, the mixture was refluxed for one hour, and diluted with 50 mL ethyl acetate. The reaction solution was washed with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution successively for three times, the organic layers were combined, concentrated and dried to give methyl 5-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)-2-fluorobenzoate (5e), 650 mg white solid (yield 95%). .sup.1H NMR (600 MHZ, DMSO-d.sub.6): δ 12.12 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.95-8.00 (m, 1H), 7.83-7.87 (m, 1H), 7.74-7.77 (m, 1H), 7.61-7.64 (m, 1H), 7.42-7.47 (m, 1H), 3.86 (s, 3H); ESI-MS m/z; calculated for 348.0, found 371.6 [M+Na].sup.+.

(39) Methyl 5-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)-2-fluorobenzoate (5e) (1 g, 2.87 mmol) was dissolved in 1M potassium hydroxide solution, stirred for two hours at room temperature, and then concentrated hydrochloric acid was added dropwise to adjust the reaction mixture pH=3, stirred for two hours at room temperature, and filtrated to give 2-fluoro-5-(8-chloro-4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (5f), 900 mg white solid (yield 90%). ESI-MS m/z: calculated for 334.02, found 357.10 [M+Na].sup.+.

(40) The procedures for synthesizing 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid substituted by 5-nitro and 5-fluoro are similar with the synthesis of 2-fluoro-5-(8-chloro-4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (Intermediate Preparation Example 4).

Intermediate Preparation Example 5. Synthesis of 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (4d)

(41) ##STR00145##

(42) The procedures for synthesizing 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (4d) are similar with the synthesis of 2-fluoro-5-(8-chloro-4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (5f) (Intermediate Preparation Example 4), except that the starting material 1,4-dichloro-5-chloro-phthalazine (5c) was replaced by 1,4-dichlorophthalazine (2a).

(43) 2-Fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (4d), a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 11.93 (s, 1H), 8.24 (d, J=7.8 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H), 7.99-7.96 (m, 1H), 7.95-7.92 (m, 1H), 7.73-7.58 (m, 1H), 7.60-7.58 (m, 1H), 7.40-7.36 (m, 1H); ESI-MS m/z calculated for 300.1, found 301.24 [M+H].sup.+.

Intermediate Preparation Example 6. Synthesis of 1-tertbutoxycarbonyl-4-(4-fluorobenzoyl)piperazine (6c)

(44) ##STR00146##

(45) 4-Fluorobenzoic acid (6b) (7 g, 50 mmol) was dissolved in dichloromethane (100 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (10.5 g, 55 mmol), triethylamine (7.7 mL, 55 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (7.5 g, 55 mmol) were added successively, stirred for half an hour at room temperature, and then 1-tertbutoxycarbonylpiperazine (6a) (10.2 g, 55 mmol) was added and stirred overnight. On the next day, water was added to quench the reaction. The reaction solution was washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times, the organic phases were concentrated to give 1-tertbutoxycarbonyl-4-(4-fluorobenzoyl)piperazine (6c), 14.8 g white solid (yield 96%). ESI-MS m/z calculated for: 308.15. found: 309.25 [M+H].sup.+.

Intermediate Preparation Example 7. Synthesis of 1-tertbutoxycarbonyl-4-(cyclopropylmethyl)piperazine

(46) ##STR00147##

(47) 1-Tertbutoxycarbonylpiperazine (6a) (1.86 g, 10 mmol) was dissolved in dichloromethane (20 mL), and anhydrous potassium carbonate (829 mg, 6 mmol) was added. The dichloromethane solution of chloromethyl cyclopropane (7a) (1.1 mL, 12 mmol) was added dropwise, and reacted overnight at room temperature, after that, the reaction mixture was washed with water. The water layer was extracted with dichloromethane for twice, the organic phases were combined, washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times, dried with anhydrous sodium sulfate. Column chromatography (petroleum ether:ethyl acetate=2:1) was performed to isolate white solid powder 1-tertbutoxycarbonyl-4-(cyclopropylmethyl)piperazine (7b), 2.01 g white solid (yield 79.0%). ESI-MS m/z calculated for: 240.18. found: 241.05 [M+H].sup.+.

Intermediate Preparation Example 8. Synthesis of 1-tertbutoxycarbonyl-4-(isopropylamineformyl)piperazine

(48) ##STR00148##

(49) N,N′-carbonyldiimidazole (CDI) (1.62 g, 10 mmol) was added into the tetrahydrofuran (20 mL)/triethylamine (1.36 mL, 10 mmol) of 1-tertbutoxycarbonylpiperazine (6a) (1.86 g, 10 mmol) in ice bath (0° C.) under the protection of nitrogen, stirred for one hour, and then isopropamide (8a) (0.71 g, 12 mmol) was added, reacted overnight at room temperature. The reaction solution was diluted with water, extracted with ethyl acetate for three times, the organic phases were combined and washed with 50 mL saturated sodium chloride solution for three times. The organic phases were dried with anhydrous sodium sulfate. The organic phases were concentrated to give 1-tertbutoxycarbonyl-4-(isopropylformamyl) piperazine (8b), 1.68 g pale yellow solid (yield 62%). ESI-MS m/z calculated for: 271.19. found: 294.28 [M+Na].sup.+.

(50) When the substituent at the fourth position of tertbutoxycarbonylpiperazine is aryl, alkane or formamyl, and the substituent at the fourth position of 1,4-diazacycloheptane is aryl or alkane, the synthetic methods are similar with the above Intermediate Preparation Examples 6, 7, and 8, and are not described herein.

Example 1

(51) Compound 1 of the present invention was prepared according to Scheme 1.

(52) 1-Tertbutoxycarbonyl-4-(cyclopropanecarbonyl)piperazine (190 mg, 0.75 mmol) was dissolved in dichloromethane, and then trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature until completely reacted, and then washed with saturated sodium bicarbonate solution for three times. The organic phases were concentrated to give 112 mg (yield 97%) pale yellow solid of N-(cyclopropanecarbonyl) piperazine for use.

(53) 3-((4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)methyl)benzoic acid (148 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (115 mg, 0.63 mmol), triethylamine (83.6 μl, 0.63 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (81.6 mg, 0.63 mmol) were added successively. The mixture was stirred at room temperature for half an hour, and then N-(cyclopropanecarbonyl)piperazine was added and reacted at room temperature overnight, and then the reaction was quenched with water. The mixture was extracted with ethyl acetate, and washed with water for two times. The organic phases were combined and washed with saturated saline, dried with anhydrous sodium sulfate, concentrated and then purified by column chromatography (dichloromethane:methanol=20:1) to give a white solid 173 mg (yield 88%). .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.94 (s, 1H), 8.21 (d, 1H, J=7.68 Hz), 7.99 (d, 1H, J=7.86 Hz), 7.94-7.92 (m, 1H), 7.90-7.88 (m, 1H), 7.61 (d, 1H, J=7.62 Hz), 7.55 (s, 1H), 7.49 (t, 1H, J=7.62 Hz), 7.39 (d, 1H, J=7.62 Hz), 5.38 (s, 2H), 3.87-3.47 (m, 8H), 1.95 (brs, 1H), 0.69-0.72 (m, 4H); ESI-MS m/z: calculated for 432.1, found 455.1 [M+Na].sup.+.

Example 2

(54) Compound 2 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 2 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.93 (s, 1H), 8.20 (d, 1H, J=8.64 Hz), 8.00-7.98 (m, 1H), 7.89-7.87 (m, 2H), 7.60 (d, 1H, J=7.14 Hz), 7.54 (br, 1H), 7.49-7.40 (m, 7H), 5.37 (s, 2H), 3.64-3.34 (m, 8H); ESI-MS m/z: calculated for 468.1, found 490.9 [M+Na].sup.+.

Example 3

(55) Compound 3 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 3 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.94 (s, 1H), 8.21 (d, 1H, J=7.80 Hz), 7.99 (d, 1H, J=7.74 Hz), 7.94-7.92 (m, 1H), 7.90-7.87 (m, 1H), 7.60 (d, 1H, J=7.68 Hz), 7.54 (s, 1H), 7.49 (t, 1H, J=7.62 Hz), 7.38 (d, 1H, J=7.56 Hz), 5.38 (m, 2H), 3.63-3.41 (m, 8H), 2.30 (br, 2H), 0.97 (t, 3H, J=7.26 Hz); ESI-MS m/z: calculated for 420.1, found 443.1 [M+Na].sup.+.

Example 4

(56) Compound 4 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 4 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.94 (s, 1H), 8.21 (d, 1H, J=7.86 Hz), 7.99 (d, 1H, J=7.86 Hz), 7.94-7.88 (m, 1H), 7.90-7.88 (m, 1H), 7.60 (d, 1H, J=7.26 Hz), 7.54 (s, 1H), 7.49 (t, 1H, J=7.68 Hz), 7.38 (d, 1H, J=7.50 Hz), 5.38 (s, 2H), 3.64-3.40 (m, 8H), 2.09-2.06 (m, 3H), 1.60-1.67 (m, 5H), 1.29-1.30 (m, 3H); ESI-MS m/z: calculated for 474.2, found 497.2[M+Na].sup.+.

Example 5

(57) Compound 5 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 5 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.94 (s, 1H), 8.21 (d, 1H, J=7.86 Hz), 7.99 (d, 1H, J=7.80 Hz), 7.94-7.92 (m, 1H), 7.90-7.87 (m, 1H), 7.60 (d, 1H, J=7.62 Hz), 7.54 (s, 1H), 7.48 (t, 1H, J=7.62 Hz), 7.38 (d, 1H, J=7.62 Hz), 5.38 (s, 2H), 3.56-3.49 (m, 8H), 2.96-2.90 (m, 1H), 1.49-1.73 (m, 8H); ESI-MS m/z: calculated for 460.2, found 483.2 [M+Na].sup.+.

Example 6

(58) Compound 6 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 6 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.94 (s, 1H), 8.21 (d, 1H, J=7.68 Hz), 7.99 (d, 1H, J=7.92 Hz), 7.95-7.92 (m, 1H), 7.90-7.88 (m, 1H), 7.61 (d, 1H, J=7.74 Hz), 7.54 (s, 1H), 7.48 (m, 1H), 7.39 (d, 1H, J=7.62 Hz), 5.38 (s, 2H), 3.63-3.45 (m, 8H), 2.07 (s, 3H); ESI-MS m/z: calculated for 406.1, found 429.1 [M+Na].sup.+.

Example 7

(59) Compound 7 of the present invention was prepared according to Scheme 2. The preparation of Compound 7,4-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenoxy)-2H-phthalazin-1-one:

(60) 1-Tertbutoxycarbonyl-4-(cyclopropanecarbonyl)piperazine (254 mg, 1 mmol) was dissolved in dichloromethane, and then trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at room temperature until completely reacted, and then washed with saturated sodium bicarbonate solution for three times. The organic phases were concentrated. N-(cyclopropanecarbonyl)piperazine was obtained for use.

(61) 3-(4-Oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (54 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (220 mg, 1.2 mmol), triethylamine (150 μl, 1.2 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt)(165 mg, 1.2 mmol) were added successively. The mixture was stirred at room temperature for half an hour, and then N-(cyclopropanecarbonyl)piperazine was added and reacted at room temperature overnight, and then the reaction was quenched with water, extracted with ethyl acetate, and washed with water for three times. The organic phases were combined and washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated for column chromatography isolation (dichloromethane:methanol=20:1) to give Compound 7. A white solid was obtained. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.98 (s, 1H), 8.27 (d, 1H, J=7.38 Hz), 8.10 (d, 1H, J=7.74 Hz), 7.99-8.01 (m, 1H), 7.94-7.96 (m, 1H), 7.52 (t, 1H, J=7.86 Hz), 7.39-7.38 (m, 2H), 7.28 (d, 1H, J=7.62 Hz), 3.33-3.81 (m, 8H), 1.96 (brs, 1H), 0.69-0.74 (m, 4H); ESI-MS m/z: calculated for 418.16, found 417.89 [M−H].sup.−.

Example 8

(62) Compound 8 of the present invention was prepared according to Scheme 2. The synthetic method was similar with Example 7. Compound 8 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.98 (s, 1H), 8.27 (d, 1H, J=7.62 Hz), 8.10 (d, 1H, J=7.74 Hz), 7.99-8.01 (m, 1H), 7.94-7.96 (m, 1H), 7.51 (t, 1H, J=7.83 Hz), 7.39-7.36 (m, 2H), 7.28 (d, J=7.62 Hz, 1H), 3.60-3.48 (m, 8H), 2.33-2.29 (brs, 2H), 0.97 (t, 3H, J=7.38 Hz); ESI-MS m/z: calculated for 406.16, found 407.09 [M+H].sup.+.

Example 9

(63) Compound 9 of the present invention was prepared according to Scheme 2. The synthetic method was similar with Example 7. Compound 9 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.98 (s, 1H), 8.26 (d, 1H, J=7.80 Hz), 8.09-8.10 (m, 1H), 7.98-8.00 (m, 1H), 7.96-7.93 (m, 1H), 7.49-7.52 (m, 1H), 7.43-7.44 (m, 3H), 7.40-7.36 (m, 4H), 7.28-7.27 (m, 1H), 3.64-3.40 (m, 8H); ESI-MS m/z: calculated for 454.16, found 453.31 [M−H].sup.−.

Example 10

(64) Compound 10 of the present invention was prepared according to Scheme 2. The synthetic method was similar with Example 7. Compound 10 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.98 (s, 1H), 8.26 (d, 1H, J=7.56 Hz), 8.10 (d, 1H, J=7.80 Hz), 7.98-8.01 (m, 1H), 7.93-7.96 (m, 1H), 7.51 (t, 1H, J=7.86 Hz), 7.36-7.39 (m, 2H), 7.27 (d, 1H, J=7.56 Hz), 3.33-3.65 (m, 8H), 2.50-2.64 (m, 1H), 1.68-1.67 (m, 2H), 1.62-1.60 (m, 3H), 1.21-1.33 (m, 5H). ESI-MS m/z: calculated for 460.20, found 460.98 [M+H].sup.+.

Example 11

(65) Compound 11 of the present invention was prepared according to Scheme 2. The synthetic method was similar with Example 7. Compound 11 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.98 (s, 1H), 8.26 (d, 1H, J=7.68 Hz), 8.10 (d, 1H, J=7.98 Hz), 7.98-8.02 (m, 1H), 7.92-7.97 (m, 1H), 7.51 (m, 1H), 7.33-7.40 (m, 2H), 7.27 (d, 1H, J=7.80 Hz), 3.33-3.65 (m, 8H), 2.87-3.02 (m, 1H), 1.68-1.80 (m, 2H), 1.53-1.67 (m, 6H); ESI-MS m/z: calculated for 446.20, found 446.64 [M+H].sup.+.

Example 12

(66) Compound 12 of the present invention was prepared according to Scheme 2. The synthetic method was similar with Example 7. Compound 12 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.98 (s, 1H), 8.26 (d, 1H, J=7.74 Hz), 8.10 (d, 1H, J=7.98 Hz), 7.99-8.01 (m, 1H), 7.94-7.96 (m, 1H), 7.51 (t, 1H, J=7.83 Hz), 7.39-7.36 (m, 2H), 7.27 (d, 1H, J=7.62 Hz), 3.33-3.65 (m, 8H), 2.51 (s, 3H); ESI-MS m/z: calculated for 392.15, found 393.26 [M+H].sup.+.

Example 13

(67) Compound 13 of the present invention was prepared according to Scheme 2. The synthetic method was similar with Example 7. Compound 13 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.18 (s, 1H), 7.47-7.46 (d, 1H, J=7.2 Hz), 7.30-7.29 (d, 1H, J=7.8 Hz), 7.21-7.18 (m, 1H), 7.16-7.13 (m, 1H), 6.72-6.70 (m, 1H), 6.59-6.47 (m, 8H), 4.25 (s, 2H), 3.20-3.18 (m, 2H), 2.77-2.54 (m, 8H), 2.10-2.01 (brs, 3H), 0.83-0.80 (m, 2H), 0.64-0.58 (m, 2H); ESI-MS m/z: calculated for 595.2, found 617.9 [M+Na].sup.+.

Example 14

(68) Compound 14 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 14 was obtained as a pale yellow solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.52 (s, 1H), 8.41 (d, 1H, J=7.32 Hz), 8.11-8.09 (m, 2H), 8.04 (d, 1H, J=7.08 Hz), 7.84-7.80 (m, 2H), 7.62 (brs, 1H), 7.59 (d, 1H, J=7.68 Hz), 7.49 (t, 1H, J=7.62 Hz), 7.44-7.43 (m, 1H), 6.79-6.78 (m, 2H), 5.40 (s, 2H), 3.94 (brs, 2H), 3.69 (brs, 2H), 3.46 (brs, 4H); ESI-MS m/z: calculated for 485.17, found 508.05 [M+Na].sup.+.

Example 15

(69) Compound 15 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 15 was obtained as a pale yellow solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.52 (s, 1H), 8.42-8.40 (m, 1H), 8.30-8.29 (m, 2H), 8.04-8.03 (m, 1H), 7.85-7.81 (m, 2H), 7.59-7.57 (m, 4H), 7.48 (brs, 1H), 7.40-7.38 (m, 1H), 5.38 (s, 2H), 3.81-3.46 (m, 8H); ESI-MS m/z: calculated for 513.16, found 536.17 [M+Na].sup.+.

Example 16

(70) Compound 16 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 7. Compound 16 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.51 (s, 1H), 8.41-8.39 (m, 1H), 8.04-8.02 (m, 1H), 7.81-7.80 (m, 2H), 7.53-7.49 (m, 2H), 7.45-7.40 (m, 1H), 7.39-7.32 (m, 3H), 7.28-7.27 (m, 2H), 7.24-7.20 (m, 1H), 5.36 (d, 2H, J=13.2 Hz), 3.81-3.79 (m, 2H), 3.67 (brs, 1H), 3.60 (brs, 1H), 3.47-3.45 (m, 2H), 2.83 (brs, 1H), 2.73-2.72 (m, 1H), 2.63-2.58 (m, 2H), 1.99 (brs, 1H), 1.78 (brs, 1H); ESI-MS m/z: calculated for 468.22, found 491.36 [M+Na].sup.+.

Example 17

(71) Compound 17 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 17 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 11.92 (s, 1H), 8.18 (m, 1H), 8.00 (d, 1H, J=7.26 Hz), 7.96 (brs, 1H), 7.88-7.83 (m, 2H), 7.80 (d, 1H, J=8.28 Hz), 7.65 (d, 1H, J=8.52 Hz), 7.59-7.58 (m, 2H), 7.50-7.47 (m, 1H), 7.45-7.44 (d, 1H, J=7.50 Hz), 5.49 (s, 1H), 5.39 (s, 1H), 4.46 (brs, 1H), 3.46-3.43 (m, 2H), 3.14 (brs, 1H), 2.10-1.94 (m, 2H), 1.68 (brs, 1H), 1.46 (brs, 1H); ESI-MS m/z: calculated for 557.13, found 580.2 [M+Na].sup.+.

Example 18

(72) Compound 18 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 18 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.65 (s, 1H), 8.40 (d, 1H, J=9.0 Hz), 8.05 (s, 1H), 7.81-7.79 (m, 2H), 7.60-7.55 (m, 2H), 7.50-7.45 (m, 2H), 7.32-7.30 (m, 2H), 7.02 (d, 2H, J=8.4 Hz), 6.09-5.80 (m, 1H), 5.40 (s, 2H), 4.41 (brs, 1H), 4.11-4.10 (m, 2H), 3.66 (brs, 1H), 2.50-2.37 (m, 2H); ESI-MS m/z: calculated for 455.16, found 478.43 [M+Na].sup.+.

Example 19

(73) Compound 19 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 19 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.95 (s, 1H), 8.41 (d, 1H, J=7.68 Hz), 8.30 (d, 2H, J=4.68 Hz), 8.04 (d, 1H, J=7.92 Hz), 7.85-7.83 (m, 1H), 7.82-7.79 (m, 1H), 7.61 (s, 1H), 7.57 (d, 1H, J=7.20 Hz), 7.48 (t, 1H, J=7.56 Hz), 7.42 (d, 1H, J=7.56 Hz), 6.52 (m, 1H), 5.39 (s, 2H), 3.94-3.79 (m, 6H), 3.53 (brs, 2H); ESI-MS m/z: calculated for 442.19, found 465.40 [M+Na].sup.+.

Example 20

(74) Compound 20 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 20 was obtained as a white solid. .sup.1H NMR (600 Hz, CDCl.sub.3): δ 10.44 (s, 1H), 8.41 (d, 1H, J=6.48 Hz), 8.03 (d, 1H, J=7.50 Hz), 7.83-7.79 (m, 2H), 7.53-7.50 (m, 2H), 7.43 (brs, 1H), 7.34 (brs, 1H), 5.36 (d, 2H, J=9.72 Hz), 3.81 (brs, 1H), 3.71 (brs, 1H), 3.64 (brs, 1H), 3.49-3.35 (m, 5H), 2.02-1.97 (m, 1H), 1.64-1.60 (m, 1H), 1.47 (s, 9H); ESI-MS m/z: calculated for 478.54, found 501.44 [M+Na].sup.+.

Example 21

(75) Compound 21 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 21 was obtained as a white solid. .sup.1H NMR (600 Hz, CDCl.sub.3): δ 9.87 (s, 1H), 8.39-8.38 (m, 1H), 8.05-8.03 (m, 1H), 7.82-7.77 (m, 2H), 7.57 (s, 1H), 7.54 (d, 1H, J=7.50 Hz), 7.47-7.44 (m, 2H), 7.42 (d, 1H, J=7.62 Hz), 7.32 (d, 1H, J=7.62 Hz), 7.28 (t, 1H, J=7.74 Hz), 7.25-7.24 (m, 1H), 5.39 (s, 2H), 4.69 (brs, 1H), 3.68 (m, 1H), 3.58 (m, 1H), 3.32 (brs, 1H), 2.11 (brs, 2H), 1.87 (brs, 2H); ESI-MS m/z: calculated for 489.95, found 512.28[M+Na].sup.+.

Example 22

(76) Compound 22 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 22 was obtained as a white solid. .sup.1H NMR (600 Hz, CDCl.sub.3): δ 9.50 (s, 1H), 8.40-8.38 (m, 1H), 8.05-8.03 (m, 1H), 7.81-7.79 (m, 2H), 7.56 (s, 1H), 7.54 (d, 1H, J=7.50 Hz), 7.46 (t, 1H, J=7.56 Hz), 7.42-7.39 (m, 3H), 7.34-7.32 (m, 2H), 5.39 (s, 2H), 4.70 (brs, 1H), 3.68-3.58 (m, 2H), 3.33 (brs, 1H), 2.14-2.12 (m, 1H), 1.86 (brs, 2H), 1.70 (brs, 1H); ESI-MS m/z: calculated for 489.95, found 512.30 [M+Na].sup.+.

Example 23

(77) Compound 23 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 23 was obtained as a white solid. .sup.1H NMR (600 Hz, CDCl.sub.3): δ 9.86 (s, 1H), 8.42-8.40 (m, 1H), 8.06-8.04 (m, 1H), 7.84-7.79 (m, 2H), 7.59 (s, 1H), 7.56 (d, 1H, J=7.56 Hz), 7.47 (t, 1H, J=7.56 Hz), 7.42 (d, 1H, J=7.56 Hz), 7.29-7.28 (m, 2H), 6.92-6.90 (m, 3H), 5.40 (s, 2H), 3.95-3.61 (m, 4H), 3.26-3.13 (m, 4H); ESI-MS m/z: calculated for 440.49, found 463.26 [M+Na].sup.+.

Example 24

(78) Compound 24 of the present invention was prepared according to Scheme 1. The synthetic method was similar with Example 1. Compound 24 was obtained as a white solid. .sup.1H NMR (600 Hz, CDCl.sub.3): δ 9.67 (s, 1H), 8.41-8.40 (m, 1H), 8.06-8.05 (m, 1H), 7.82-7.78 (m, 2H), 7.61 (s, 1H), 7.56-7.55 (m, 1H), 7.48-7.43 (m, 2H), 7.36-7.32 (m, 4H), 7.28-7.27 (m, 1H), 6.16-6.15 (m, 1H), 5.40 (s, 2H), 4.41 (brs, 1H), 4.12 (brs, 1H), 4.00 (brs, 1H), 3.64 (brs, 1H), 2.68-2.55 (m, 2H); ESI-MS m/z: calculated for 437.49, found 460.32 [M+Na].sup.+.

Example 25

(79) Compound 25 of the present invention was prepared according to Scheme 2. The synthetic method was similar with Example 7. Compound 25 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.97 (s, 1H), 8.28 (d, 1H, J=7.8 Hz), 8.13 (d, 1H, J=8.4 Hz), 8.03-8.00 (m, 1H), 7.80-7.95 (m, 1H), 7.54 (m, 1H), 7.48 (m, 2H), 7.42-7.40 (m, 2H), 7.33-7.32 (d, 1H, J=7.8 Hz), 7.19-7.16 (d, 2H, J=7.8 Hz), 6.21 (m, 1H), 4.24 (m, 1H), 4.10 (m, 1H), 4.04-4.02 (m, 1H), 3.83 (m, 1H), 3.54 (m, 1H), 1.99 (brs, 1H); ESI-MS m/z: calculated for 441.15, found 442.03 [M+H].sup.+.

Example 26

(80) Compound 26 of the present invention was prepared according to Scheme 2. The synthetic method was similar with Example 7. Compound 26 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.99 (s, 1H), 8.66-8.65 (m, 2H), 8.27-8.26 (m, 1H), 8.10-8.08 (m, 1H), 8.01-7.98 (m, 1H), 7.96-7.94 (m, 1H), 7.53-7.49 (m, 1H), 7.39-7.35 (m, 4H), 7.29-7.25 (m, 1H), 3.73-3.44 (m, 4H), 3.26-3.21 (m, 4H); ESI-MS m/z: calculated for 455.47, found 454.40 [M−H].sup.−.

Example 27

(81) Compound 27 of the present invention was prepared according to Scheme 2. The synthetic method was similar with Example 7. Compound 27 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.98 (s, 1H), 8.27 (d, 1H, J=7.2 Hz), 8.10-8.09 (m, 1H), 8.01-7.98 (m, 1H), 7.96-7.93 (m, 1H), 7.53-7.46 (m, 3H), 7.39-7.36 (m, 2H), 7.28-7.25 (m, 3H), 3.63-3.41 (m, 8H); ESI-MS m/z: calculated for 472.47, found 471.28 [M−H].sup.−.

Example 28

(82) Compound 28 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 1. Compound 28 was obtained as a pale yellow solid. .sup.1H NMR (600 MHZ, DMSO-d.sub.6): δ 11.89 (s, 1H), 8.27 (brs, 2H), 7.90 (brs, 1H), 7.80 (brs, 1H), 7.67-7.58 (m, 7H), 5.36 (s, 2H), 3.68-3.42 (m, 8H); ESI-MS m/z: calculated for 531.1, found 554.0 [M+Na].sup.+.

Example 29

(83) Compound 29 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 1. Compound 29 was obtained as a white solid. .sup.1H NMR (600 MHZ, DMSO-d.sub.6): δ 11.90 (s, 1H), 7.93-7.91 (m, 1H), 7.82-7.80 (m, 1H), 7.67-7.58 (m, 2H), 7.54 (brs, 1H), 7.50-7.48 (m, 1H), 7.40-7.39 (m, 1H), 7.37-7.34 (m, 4H), 7.31-7.28 (m, 1H), 5.36 (s, 2H), 5.06 (s, 2H), 4.00-3.98 (m, 2H), 3.64-3.33 (m, 8H), 2.86 (brs, 3H), 1.61 (brs, 2H), 1.42 (m, 2H); ESI-MS m/z: calculated for 627.2, found 650.0 [M+Na].sup.+.

Example 30

(84) Compound 30 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 30 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.90 (s, 1H), 8.43 (d, J=7.80 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.93-7.91 (m, 2H), 7.89-7.87 (m, 1H), 7.35-7.30 (m, 7H), 7.18-7.15 (m, 1H), 5.12 (s, 2H), 4.22 (brs, 2H), 3.83-3.75 (m, 2H), 3.67-3.56 (m, 4H), 3.50-3.38 (m, 2H), 2.88 (brs, 2H), 2.70-2.63 (m, 1H), 1.80-1.66 (m, 4H); ESI-MS m/z: calculated for 613.23, found 612.41 [M−H].sup.−.

Example 31

(85) Compound 31 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 31 was obtained as a yellow solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 11.97 (s, 1H), 8.27-8.26 (m, 3H), 8.12-8.08 (m, 1H), 8.01-7.98 (m, 1H), 7.96-7.93 (m, 1H), 7.72-7.67 (m, 2H), 7.47-7.34 (m, 3H), 3.76-3.63 (m, 4H), 3.40-3.28 (m, 4H). ESI-MS m/z: calculated for 517.14, found 516.37[M−H].sup.−.

Example 32

(86) Compound 32 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 32 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.63 (s, 1H), 8.44 (d, J=7.74 Hz, 1H), 8.14 (d, J=8.04 Hz, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.33-7.31 (m, 2H), 7.29-7.27 (m, 1H), 7.20-7.17 (m, 1H), 3.95-3.65 (m, 4H), 3.59-3.41 (m, 4H), 1.65 (s, 3H). ESI-MS m/z: calculated for 477.14, found 478.25 [M+H].sup.+.

Example 33

(87) Compound 33 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 33 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 9.79 (s, 1H), 8.43 (d, J=7.62 Hz, 1H), 8.14 (d, J=7.74 Hz, 1H), 7.93-7.90 (m, 1H), 7.88-7.86 (m, 1H), 7.33-7.27 (m, 6H), 7.18 (t, 1H, J=8.52 Hz), 7.06-7.03 (m, 1H), 6.57 (s, 1H), 3.70-3.57 (m, 5H), 3.54-3.47 (m, 3H); ESI-MS m/z: calculated for 487.2, found 510.1 [M+Na].sup.+.

Example 34

(88) Compound 34 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 7. Compound 34 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 12.22 (s, 1H), 8.28-8.26 (m, 1H), 8.05 (d, J=8.04 Hz, 1H), 7.88 (t, 1H, J=7.95 Hz), 7.49-7.48 (m, 2H), 7.36-7.34 (m, 3H), 7.26 (t, 2H, J=8.46 Hz), 3.67-3.39 (m, 8H); ESI-MS m/z: calculated for 524.0, found 523.0 [M−H].sup.−.

Example 35

(89) Compound 35 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 7. Compound 35 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 12.22 (s, 1H), 8.27-8.26 (d, J=7.92 Hz, 1H), 8.05 (d, J=7.38 Hz, 1H), 7.88 (t, 1H, J=7.89 Hz), 7.44-7.34 (m, 8H), 3.66-3.36 (m, 8H); ESI-MS m/z: calculated for 506.0, found 505.1 [M−H].sup.−.

Example 36

(90) Compound 36 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 36 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.17 (s, 1H), 8.43 (s, 1H), 8.13 (d, J=7.62 Hz, 1H), 7.94-7.83 (m, 3H), 7.33-7.30 (m, 2H), 7.17-7.16 (m, 1H), 4.07-3.83 (m, 6H), 3.51 (brs, 2H), 2.73 (s, 3H); ESI-MS m/z: calculated for 493.12, found 493.95 [M+H].sup.+.

Example 37

(91) Compound 37 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 7. Compound 37 was obtained as a pale yellow solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 12.31 (s, 1H), 8.32 (d, J=7.92 Hz, 1H), 8.24 (d, J=7.74 Hz, 1H), 8.18 (t, 1H, J=7.95 Hz), 7.50-7.48 (m, 2H), 7.42 (t, 1H, J=8.67 Hz), 7.08-7.05 (m, 2H), 7.00-6.97 (m, 2H), 3.78 (brs, 2H), 3.40-3.39 (m, 2H), 3.16-3.14 (m, 2H), 3.07-3.05 (m, 2H); ESI-MS m/z: calculated for 507.1, found 506.2 [M−H].sup.−.

Example 38

(92) Compound 38 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 7. Compound 38 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 12.30 (s, 1H), 8.32 (d, J=8.04 Hz, 1H), 8.24 (d, J=7.68 Hz, 1H), 8.16 (t, 1H, J=7.92 Hz), 7.50-7.45 (m, 4H), 7.41-7.37 (m, 1H), 7.28-7.25 (m, 2H), 3.67-3.49 (m, 4H), 3.29-3.16 (m, 4H); ESI-MS m/z: calculated for 535.1, found 534.3 [M−H].sup.−.

Example 39

(93) Compound 39 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 7. Compound 39 was obtained as a pale yellow solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 12.32 (s, 1H), 8.34-8.33 (m, 1H), 8.26 (d, J=7.74 Hz, 1H), 8.18 (t, 1H, J=7.86 Hz), 7.46-7.42 (m, 8H), 3.68-3.42 (m, 8H); ESI-MS m/z: calculated for 517.1, found 516.1 [M−H].sup.−.

Example 40

(94) Compound 40 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 7. Compound 40 was obtained as a yellow solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 12.32 (s, 1H), 8.33 (d, J=7.74 Hz, 1H), 8.24 (d, J=7.74 Hz, 1H), 8.18 (t, 1H, J=7.92 Hz), 7.48-7.47 (m, 2H), 7.42-7.40 (m, 1H), 7.38-7.34 (m, 4H), 7.32-7.30 (m, 1H), 5.07 (s, 2H), 4.01-3.99 (m, 2H), 3.66-3.47 (m, 6H), 3.29-3.24 (m, 2H), 2.90-2.78 (m, 3H), 1.65-1.62 (m, 2H), 1.46-1.40 (m, 2H); ESI-MS m/z: calculated for 658.2, found 657.3 [M−H].sup.−.

Example 41

(95) Compound 41 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 7. Compound 41 was obtained as a yellow solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): 12.29 (s, 1H), 8.34-8.15 (m, 4H), 8.18 (s, 1H), 7.71 (brs, 2H), 7.49-7.39 (m, 3H), 3.76-3.65 (m, 4H), 3.44-3.36 (m, 2H), 3.31-3.25 (m, 2H); ESI-MS m/z: calculated for 562.1, found 561.1 [M−H].sup.−.

Example 42

(96) Compound 42 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 42 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 9.27 (s, 1H), 8.44 (d, J=7.6 Hz, 1H), 8.14 (d, J=7.4 Hz, 1H), 7.90 (m, 2H), 7.30 (m, 2H), 7.17 (m, 1H), 5.35 (s, 1H), 4.29 (m, 1H), 3.33 (m, 8H), 1.98 (m, 4H), 1.69 (s, 3H), 1.59 (s, 3H); ESI-MS m/z: calculated for 493.5, found 516.1 [M+Na].sup.+.

Example 43

(97) Compound 43 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 43 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 9.71 (s, 1H), 8.44 (d, 1H, J=7.74 Hz), 8.13 (d, 1H, J=7.80 Hz), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.33-7.31 (m, 2H), 7.19-7.16 (m, 1H), 3.82-3.65 (m, 4H), 3.57-3.41 (m, 4H), 2.16 (s, 3H); ESI-MS m/z: calculated for 410.1, found 433.1 [M+Na].sup.+.

Example 44

(98) Compound 44 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 44 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.57 (s, 1H), 8.81-8.79 (m, 1H), 8.44 (d, J=7.68 Hz, 1H), 8.14 (d, J=7.92 Hz, 1H), 8.09 (brs, 1H), 7.93-7.91 (m, 1H), 7.89-7.86 (m, 1H), 7.35-7.31 (m, 2H), 7.18 (brs, 1H), 4.08-4.03 (m, 2H), 3.91-3.83 (m, 4H), 3.52 (brs, 2H); ESI-MS m/z: calculated for 479.11, found 480.24 [M+H].sup.+.

Example 45

(99) Compound 45 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 45 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.50 (s, 1H), 8.44 (d, J=7.86 Hz, 1H), 8.15-8.13 (m, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.36-7.31 (m, 7H), 7.20-7.18 (m, 1H), 5.15 (s, 2H), 4.22-4.14 (m, 2H), 3.95-3.39 (m, 9H), 2.99-2.77 (m, 2H), 1.91-1.87 (m, 1H), 1.77-1.74 (m, 2H), 1.52-1.42 (m, 1H); ESI-MS m/z: calculated for 613.13, found 636.29 [M+Na].sup.+.

Example 46

(100) Compound 46 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 46 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.72 (s, 1H), 8.42 (d, J=7.26 Hz, 1H), 8.12 (d, J=7.44 Hz, 1H), 7.91-7.87 (m, 1H), 7.87-7.84 (m, 1H), 7.30 (brs, 6H), 7.16-7.14 (m, 2H), 5.10 (s, 2H), 3.99-3.65 (m, 4H), 3.50-3.33 (m, 6H), 1.96 (brs, 1H), 1.88-1.63 (m, 5H), 1.42 (brs, 1H); ESI-MS m/z: calculated for 613.13, found 636.48 [M+Na].sup.+.

Example 47

(101) Compound 47 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 47 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.50 (s, 1H), 8.42 (d, J=7.74 Hz, 1H), 8.12 (d, J=7.86 Hz, 1H), 7.92-7.90 (m, 1H), 7.88-7.85 (m, 1H), 7.32-7.31 (m, 2H), 7.18-7.15 (m, 1H), 3.84-3.62 (m, 6H), 3.50-3.43 (m, 2H), 2.97-2.86 (m, 1H), 2.53 (brs, 2H), 2.37-2.25 (m, 2H), 2.04 (brs, 4H); ESI-MS m/z: calculated for 492.18, found 493.28 [M+H].sup.+.

Example 48

(102) Compound 48 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 48 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.98 (s, 1H), 8.28 (d, 1H, J=7.80 Hz), 8.12 (brs, 1H), 8.03-8.00 (m, 1H), 7.97-7.94 (m, 3H), 7.62 (brs, 2H), 7.49-7.36 (m, 3H), 3.76-3.65 (m, 4H), 3.44-3.37 (m, 4H); ESI-MS m/z: calculated for 497.15, found 520.12 [M+Na].sup.+.

Example 49

(103) Compound 49 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 49 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.73 (s, 1H), 8.41 (d, J=7.74 Hz, 1H), 8.10-8.09 (m, 1H), 7.90-7.88 (m, 1H), 7.86-7.84 (m, 1H), 7.31-7.27 (m, 3H), 7.23-7.20 (m, 4H), 7.13-7.08 (m, 1H), 3.98-3.76 (m, 3H), 3.48-3.40 (m, 4H), 3.22 (brs, 1H), 2.92-2.74 (m, 1H), 1.45-1.44 (m, 3H); ESI-MS m/z: calculated for 500.19, found 523.03 [M+Na].sup.+.

Example 50

(104) Compound 50 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 50 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 10.43 (s, 1H), 8.43 (d, J=7.86 Hz, 1H), 8.13 (d, J=7.86 Hz, 1H), 7.92-7.90 (m, 1H), 7.88-7.85 (m, 1H), 7.32-7.30 (m, 2H), 7.16 (t, 1H, J=8.67 Hz), 3.85-3.68 (m, 6H), 3.49-3.42 (m, 2H), 1.76-1.69 (m, 1H), 1.01 (brs, 2H), 0.81-0.75 (m, 2H); ESI-MS m/z: calculated for 436.1, found 459.1 [M+Na].sup.+.

Example 51

(105) Compound 51 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 51 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.97 (s, 1H), 8.44 (d, J=7.62 Hz, 1H), 8.13 (d, J=7.74 Hz, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.33-7.32 (m, 2H), 7.20-7.15 (m, 1H), 3.86 (brs, 2H), 3.74 (brs, 1H), 3.68 (brs, 1H), 3.62 (brs, 1H), 3.57 (brs, 1H), 3.49 (brs, 2H), 1.66 (s, 3H); SI-MS m/z: calculated for 438.13, found 460.91 [M+Na].sup.+.

Example 52

(106) Compound 52 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 52 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.51 (s, 1H), 8.44 (d, J=7.62 Hz, 1H), 8.14 (d, J=6.90 Hz, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.34-7.30 (m, 2H), 7.21-7.15 (m, 1H), 6.33 (d, J=4.86 Hz, 1H), 4.01-3.82 (m, 6H), 3.51 (brs, 2H), 2.48 (s, 3H); ESI-MS m/z: calculated for 477.14, found 475.82 [M−H].sup.−.

Example 53

(107) Compound 53 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 53 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.70 (s, 1H), 8.42 (d, 1H, J=7.80 Hz), 8.13 (d, 1H, J=7.80 Hz), 7.90-7.93 (m, 1H), 7.88-7.86 (m, 1H), 7.34-7.33 (m, 2H), 7.19-7.17 (m, 1H), 3.87-3.66 (m, 6H), 3.52 (brs, 2H); ESI-MS m/z: calculated for 464.11, found 486.93 [M+Na].sup.+.

Example 54

(108) Compound 54 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 54 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.18 (s, 1H), 8.43 (d, 1H, J=7.62 Hz), 8.13 (d, 1H, J=7.62 Hz), 7.93-7.87 (m, 2H), 7.33-7.32 (m, 2H), 7.19-7.16 (m, 1H), 3.85-3.71 (m, 4H), 3.59-3.45 (m, 4H), 3.33-3.23 (m, 2H); ESI-MS m/z: calculated for 478.13, found 500.96 [M+Na].sup.+.

Example 55

(109) Compound 55 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 55 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.01 (s, 1H), 8.43 (d, J=7.86 Hz, 1H), 8.13 (d, J=7.74 Hz, 1H), 7.93-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.32-7.28 (m, 2H), 7.18-7.14 (m, 1H), 3.79-3.75 (m, 4H), 3.68-3.67 (m, 2H), 3.42 (brs, 2H), 1.29 (s, 9H); ESI-MS m/z: calculated for 452.19, found 475.05 [M+Na].sup.+.

Example 56

(110) Compound 56 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 56 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.85 (s, 1H), 8.44 (d, J=7.62 Hz, 1H), 8.13 (d, J=7.86 Hz, 1H), 7.93-7.92 (m, 1H), 7.89-7.92 (m, 1H), 7.32-7.31 (m, 2H), 7.18-7.16 (m, 1H), 4.12 (d, 2H, J=26.4 Hz), 3.81-3.57 (m, 6H), 3.44-3.40 (m, 5H); ESI-MS m/z: calculated for 440.15, found 462.85 [M+Na].sup.+.

Example 57

(111) Compound 57 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 57 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.61 (s, 1H), 8.44 (d, J=7.20 Hz, 1H), 8.14 (brs, 1H), 7.93-7.90 (m, 1H), 7.89-7.87 (m, 1H), 7.76-7.67 (m, 2H), 7.57-7.48 (m, 2H), 7.33-7.31 (m, 2H), 7.22-7.11 (m, 1H), 3.96-3.88 (m, 4H), 3.58-3.36 (m, 4H); ESI-MS m/z: calculated for 497.15, found 520.00 [M+Na].sup.+.

Example 58

(112) Compound 58 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 58 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.96 (s, 1H), 8.26 (d, J=7.80 Hz, 1H), 8.10 (d, J=7.80 Hz, 1H), 8.01-7.99 (m, 1H), 7.96-7.93 (m, 1H), 7.45-7.43 (m, 1H), 7.41-7.36 (m, 2H), 6.22 (d, J=7.38 Hz, 1H), 3.75-3.70 (m, 1H), 3.58 (brs, 2H), 3.52-3.34 (m, 2H), 3.28-3.26 (m, 2H), 3.21-3.20 (m, 2H), 1.03 (d, J=6.54 Hz, 6H); ESI-MS m/z: calculated for 453.18, found 476.12 [M+Na].sup.+.

Example 59

(113) Compound 59 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 59 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3) δ 10.38 (s, 1H), 8.43 (d, J=7.74 Hz, 1H), 8.12 (d, J=7.92 Hz, 1H), 7.92-7.89 (m, 1H), 7.88-7.85 (m, 1H), 7.32-7.30 (m, 2H), 7.17-7.14 (m, 1H), 4.17-4.13 (m, 2H), 3.81 (brs, 2H), 3.71-3.53 (m, 6H), 3.48-3.39 (brs, 2H), 1.24-1.19 (m, 3H). ESI-MS m/z: calculated for 454.17, found 453.18[M−H].sup.−.

Example 60

(114) Compound 60 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 60 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 9.25 (s, 1H), 8.77-8.71 (m, 2H), 8.45 (d, J=6.5 Hz, 1H), 8.14-8.13 (m, 1H), 7.94-7.92 (m, 1H), 7.90-7.88 (m, 1H), 7.35-7.30 (m, 4H), 7.21-7.11 (m, 1H), 3.93-3.75 (m, 4H), 3.56-3.39 (m, 4H); ESI-MS m/z: calculated for 473.1, found 474.02 [M+H].sup.+.

Example 61

(115) Compound 61 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 61 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3) δ 9.45 (s, 1H), 8.44 (d, J=7.98 Hz, 1H), 8.14 (d, J=7.68 Hz, 1H), 7.94-7.91 (m, 1H), 7.90-7.87 (m, 1H), 7.33-7.31 (m, 2H), 7.19-7.17 (m, 1H), 3.80-3.60 (m, 6H), 3.44-3.41 (m, 2H), 2.55-2.45 (m, 1H), 1.70-1.67 (m, 2H), 1.51-1.50 (m, 2H), 0.90-0.87 (m, 6H). ESI-MS m/z: calculated for 466.20, found 465.23[M−H].sup.−.

Example 62

(116) Compound 62 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 62 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.61 (s, 1H), 8.41 (d, J=7.74 Hz, 1H), 8.11 (d, J=7.80 Hz, 1H), 7.91-7.88 (m, 1H), 7.86-7.84 (m, 1H), 7.29-7.28 (m, 2H), 7.15-7.10 (m, 1H), 3.84-3.74 (m, 2H), 3.43 (brs, 2H), 3.38-3.35 (m, 6H), 3.30 (brs, 2H), 1.99-1.94 (m, 4H); ESI-MS m/z: calculated for 515.1, found 537.95 [M+Na].sup.+.

Example 63

(117) Compound 63 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 63 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.58 (s, 1H), 8.44 (d, J=7.92 Hz, 1H), 8.13 (d, J=7.74 Hz, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.49-7.48 (m, 1H), 7.34-7.31 (m, 3H), 7.18 (t, 1H, J=8.70 Hz), 7.07-7.06 (m, 1H), 3.87 (brs, 3H), 3.80-3.79 (m, 3H), 3.50 (brs, 2H); ESI-MS m/z: calculated for 478.1, found 477.2 [M−H].sup.−.

Example 64

(118) Compound 64 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 64 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.50 (s, 1H), 8.44 (d, J=7.74 Hz, 1H), 8.14 (d, J=7.62 Hz, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.30-7.29 (m, 2H), 7.17-7.14 (m, 1H), 3.82 (t, 2H, J=5.22 Hz), 3.45 (brs, 2H), 2.69-2.66 (m, 6H), 2.56 (brs, 2H), 1.78-1.75 (m, 2H); ESI-MS m/z: calculated for 426.1, found 427.0 [M+H].sup.+.

Example 65

(119) Compound 65 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 65 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.28 (s, 1H), 8.45 (d, J=7.68 Hz, 1H), 8.14 (d, J=7.92 Hz, 1H), 7.93-7.91 (m, 1H), 7.90-7.87 (m, 1H), 7.32-7.30 (m, 2H), 7.19-7.16 (m, 1H), 3.94-3.82 (m, 2H), 3.59 (brs, 1H), 3.40 (brs, 1H), 2.95 (brs, 1H), 2.06-1.88 (m, 4H); ESI-MS m/z: calculated for 393.1, found 394.1 [M+H].sup.+.

Example 66

(120) Compound 66 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 66 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.15 (s, 1H), 8.43 (d, J=7.74 Hz, 1H), 8.13 (d, J=7.92 Hz, 1H), 7.93-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.32-7.31 (m, 2H), 7.18-7.15 (m, 1H), 3.81-3.56 (m, 6H), 3.46-3.41 (m, 2H), 2.82-2.74 (m, 1H), 1.14-1.13 (m, 6H); ESI-MS m/z: calculated for 438.1, found 461.07 [M+Na].sup.+.

Example 67

(121) Compound 67 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 67 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.87 (s, 1H), 8.44 (d, J=7.80 Hz, 1H), 8.13 (d, J=7.74 Hz, 1H), 7.92-7.90 (m, 1H), 7.88-7.86 (m, 1H), 7.31-7.28 (m, 2H), 7.17-7.14 (m, 1H), 3.80 (brs, 2H), 3.43 (brs, 2H), 3.33-3.31 (m, 2H), 3.26 (m, 2H), 2.85 (s, 6H); ESI-MS m/z: calculated for 439.1, found 439.95 [M+H].sup.+.

Example 68

(122) Compound 68 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 68 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.60 (s, 1H), 8.44 (d, J=7.86 Hz, 1H), 8.13 (d, J=7.62 Hz, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.69 (s, 1H), 7.48 (d, J=7.56 Hz, 1H), 7.37-7.35 (m, 1H), 7.32-7.30 (m, 2H), 7.17 (brs, 1H), 3.81-3.48 (m, 8H), 2.52 (s, 3H); ESI-MS m/z: calculated for 554.1, found 576.98 [M+Na].sup.+.

Example 69

(123) Compound 69 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 69 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.25 (s, 1H), 8.43 (d, J=7.80 Hz, 1H), 8.13 (d, J=7.98 Hz, 1H), 7.93-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.33-7.31 (m, 2H), 7.18-7.15 (m, 1H), 6.56 (brs, 1H), 6.32 (d, 1H, J=16.86 Hz), 5.75 (brs, 1H), 3.81-3.62 (m, 6H), 3.46 (brs, 2H); ESI-MS m/z: calculated for 422.1, found 444.97 [M+Na].sup.+.

Example 70

(124) Compound 70 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 70 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.09 (s, 1H), 8.43 (d, J=7.68 Hz, 1H), 8.13 (d, J=7.62 Hz, 1H), 7.92-7.90 (m, 1H), 7.88-7.86 (m, 1H), 7.31 (brs, 2H), 7.17 (t, 1H, J=8.58 Hz), 5.48-5.43 (m, 1H), 4.36-3.35 (m, 1H), 3.96-3.78 (m, 2H), 3.66-3.44 (m, 6H), 1.60-1.57 (m, 3H); ESI-MS m/z: calculated for 440.0, found 439.0 [M−H].sup.−.

Example 71

(125) Compound 71 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 71 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.40 (s, 1H), 8.44 (d, J=7.74 Hz, 1H), 8.14 (d, J=7.98 Hz, 1H), 7.94-7.91 (m, 1H), 7.89-7.86 (m, 1H), 7.32-7.28 (m, 2H), 7.16 (t, 1H, J=8.7 Hz), 4.72-4.70 (m, 1H), 3.74 (brs, 3H), 3.62 (brs, 2H), 3.17 (brs, 1H), 2.97 (brs, 1H), 2.80 (brs, 1H), 2.00 (m, 4H), 1.84 (brs, 3H), 1.71-1.69 (m, 1H); ESI-MS m/z: calculated for 514.1, found 515.1 [M+H].sup.+.

Example 72

(126) Compound 72 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 72 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.51 (s, 1H), 8.44 (d, J=7.80 Hz, 1H), 8.14 (d, J=7.98 Hz, 1H), 7.93-7.90 (m, 1H), 7.88-7.86 (m, 1H), 7.32-7.28 (m, 2H), 7.15 (t, 1H, J=8.70 Hz), 4.71-4.69 (m, 1H), 3.75-3.72 (m, 1H), 3.55 (brs, 2H), 3.45 (brs, 2H), 3.15 (brs, 1H), 2.97-2.93 (m, 1H), 2.78 (brs, 1H), 1.83 (brs, 2H), 1.70-1.66 (m, 4H), 1.58-1.54 (m, 4H); ESI-MS m/z: calculated for 478.2, found 501.1 [M+Na].sup.+.

Example 73

(127) Compound 73 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 73 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.82 (s, 1H), 8.43 (d, J=7.86 Hz, 1H), 8.13 (d, J=7.86 Hz, 1H), 7.92-7.90 (m, 1H), 7.87-7.85 (m, 1H), 7.54 (s, 1H), 7.51 (d, 2H, J=7.38 Hz), 7.31-7.29 (m, 3H), 7.15 (t, 1H, J=8.70 Hz), 7.10 (t, 1H, J=7.23 Hz), 4.74-4.72 (m, 1H), 3.78-3.76 (m, 1H), 3.16 (brs, 1H), 2.97-2.93 (m, 1H), 2.56-2.51 (m, 1H), 2.05-2.03 (m, 1H), 1.95-1.84 (m, 3H); ESI-MS m/z: calculated for 486.1, found 485.1 [M−H].sup.−.

Example 74

(128) Compound 74 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 74 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.60 (s, 1H), 8.44 (d, J=7.86 Hz, 1H), 8.13 (d, J=7.86 Hz, 1H), 7.92-7.90 (m, 1H), 7.88-7.86 (m, 1H), 7.29-7.28 (m, 2H), 7.15 (t, 1H, J=8.70 Hz), 5.54 (brs, 1H), 4.72-4.70 (m, 1H), 3.74-3.72 (m, 1H), 3.31-3.27 (m, 2H), 3.12 (brs, 1H), 2.92-2.88 (m, 1H), 2.34-2.31 (m, 1H), 1.96-1.94 (m, 1H), 1.85-1.83 (m, 1H), 1.77-1.76 (m, 2H), 1.13 (t, J=7.23 Hz, 3H); ESI-MS m/z: calculated for 438.1, found 461.1 [M+Na].sup.+.

Example 75

(129) Compound 75 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 75 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.50 (s, 1H), 8.44 (d, J=7.68 Hz, 1H), 8.13 (d, J=7.62 Hz, 1H), 7.93-7.91 (m, 1H), 7.89-7.86 (m, 1H), 7.37 (d, J=8.76 Hz, 2H), 7.33-7.29 (m, 2H), 7.17 (t, 1H, J=8.61 Hz), 6.68 (d, J=8.64 Hz, 2H), 3.82-3.69 (m, 6H), 3.45 (brs, 2H), 3.01 (s, 6H); ESI-MS m/z: calculated for 515.1, found 538.1 [M+Na].sup.+.

Example 76

(130) Compound 76 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 76 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.39 (s, 1H), 8.44 (d, J=7.62 Hz, 1H), 8.13 (d, J=7.68 Hz, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.36-7.29 (m, 3H), 7.18 (brs, 1H), 6.76-6.76 (m, 2H), 6.70-6.69 (m, 1H), 3.79 (brs, 4H), 3.49 (brs, 4H), 2.98 (s, 6H); ESI-MS m/z: calculated for 515.1, found 538.1 [M+Na].sup.+.

Example 77

(131) Compound 77 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 77 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 8.53-8.48 (m, 1H), 8.13-8.12 (m, 1H), 8.08 (d, J=6.90 Hz, 1H), 7.99-7.97 (m, 1H), 7.91-7.87 (m, 3H), 3.84-3.79 (m, 2H), 3.68-3.62 (m, 2H), 3.50-3.41 (m, 4H), 1.59 (s, 9H); ESI-MS m/z: calculated for 424.1, found 447.2 [M+Na].sup.+.

Example 78

(132) Compound 78 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 78 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.64 (s, 1H), 8.44 (d, J=7.74 Hz, 1H), 8.14 (d, J=7.92 Hz, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.49 (s 1H), 7.34-7.31 (m, 2H), 7.18 (t, 1H, J=8.64 Hz), 7.07 (d, J=3.36 Hz, 1H), 6.51-6.50 (m, 1H), 3.92-3.84 (m, 6H), 3.51 (br, 2H); ESI-MS m/z: calculated for 462.13, found 463.08 [M+H].sup.+.

Example 79

(133) Compound 79 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 79 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.07 (s, 1H), 8.44 (d, J=7.80 Hz, 1H), 8.14 (d, J=7.56 Hz, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.30-7.28 (m, 2H), 7.15 (t, 1H, J=8.52 Hz), 3.81 (brs, 2H), 3.41 (brs, 2H), 2.75 (brs, 1H), 2.60 (brs, 2H), 2.50 (brs, 2H), 1.06 (d, 6H, J=6.00 Hz); ESI-MS m/z: calculated for 410.18, found 411.14 [M+H].sup.+.

Example 80

(134) Compound 80 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 80 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.21 (s, 1H), 8.44 (d, J=7.86 Hz, 1H), 8.14 (d, J=7.98 Hz, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.29-7.28 (m, 2H), 7.17-7.14 (m, 1H), 5.89-5.81 (m, 1H), 5.22-5.20 (m, 2H), 3.82 (brs, 2H), 3.42 (brs, 2H), 3.04 (d, 2H, J=6.36 Hz), 2.54-2.53 (m, 2H), 2.44 (brs, 2H); ESI-MS m/z: calculated for 408.16, found 409.15 [M+H].sup.+.

Example 81

(135) Compound 81 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 81 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.72 (s, 1H), 8.45 (d, J=7.86 Hz, 1H), 8.15 (d, J=7.86 Hz, 1H), 7.95-7.93 (m, 1H), 7.91-7.88 (m, 1H), 7.75-7.68 (m, 2H), 7.66 (d, J=7.68 Hz, 1H), 7.58-7.56 (m, 1H), 7.34-7.32 (m, 2H), 7.21-7.14 (m, 1H), 3.83 (brs, 4H), 3.49 (brs, 4H); ESI-MS m/z: calculated for 497.15, found 496.22 [M−H].sup.−.

Example 82

(136) Compound 82 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 82 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 9.21 (s, 1H), 8.45 (d, J=6.72 Hz, 1H), 8.16-8.13 (m, 2H), 7.94-7.91 (m, 1H), 7.90-7.87 (m, 1H), 7.65 (brs, 1H), 7.35-7.28 (m, 2H), 7.20-7.17 (m, 1H), 6.39-6.38 (m, 1H), 4.03-3.94 (m, 4H), 3.56 (brs, 2H); ESI-MS m/z: calculated for 462.1, found 485.1 [M+Na].sup.+.

Example 83

(137) Compound 83 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 83 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.52 (s, 1H), 8.42 (d, J=7.74 Hz, 1H), 8.11 (d, J=7.80 Hz, 1H), 7.91-7.89 (m, 1H), 7.87-7.84 (m, 1H), 7.29-7.28 (m, 2H), 7.15-7.12 (m, 1H), 3.78 (brs, 2H), 3.67-3.65 (m, 4H), 3.43 (brs, 2H), 3.35-3.34 (m, 2H), 3.28-3.27 (m, 6H); ESI-MS m/z: calculated for 481.18, found 480.22 [M−H].sup.−.

Example 84

(138) Compound 84 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 84 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.14 (s, 1H), 8.43 (d, J=7.86 Hz, 1H), 8.12 (d, J=7.86 Hz, 1H), 7.92-7.89 (m, 1H), 7.87-7.85 (m, 1H), 7.30-7.29 (m, 2H), 7.16-7.14 (m, 1H), 3.80 (brs, 2H), 3.43-3.41 (m, 2H), 340-3.37 (m, 6H), 3.31-3.29 (m, 2H), 1.83 (brs, 4H); ESI-MS m/z: calculated for 465.18, found 464.30 [M−H].sup.−.

Example 85

(139) Compound 85 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 85 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.19 (s, 1H), 8.44 (d, J=7.74 Hz, 1H), 8.13 (d, J=7.62 Hz, 1H), 7.94-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.31-7.28 (m, 2H), 7.18-7.15 (m, 1H), 3.82-3.79 (m, 2H), 3.45-3.40 (m, 2H), 3.33-3.31 (m, 2H), 3.26-3.25 (m, 2H), 3.24-3.22 (m, 4H), 1.62-1.56 (m, 6H); ESI-MS m/z: calculated for 479.20, found 478.30 [M−H].sup.−.

Example 86

(140) Compound 86 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 86 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.52 (s, 1H), 8.43 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.92-7.86 (m, 2H), 7.64-7.62 (m, 1H), 7.57-7.56 (m, 2H), 7.42-7.38 (m, 2H), 7.42-7.38 (m, 2H), 3.62-3.59 (m, 4H), 3.53-3.48 (m, 4H); ESI-MS m/z: calculated for 555.5, found 554.0[M−H].sup.−.

Example 87

(141) Compound 87 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 87 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.96 (m, 1H), 8.29 (d, 1H, J=6.96 Hz), 8.27-8.24 (m, 2H), 8.10 (brs, 1H), 8.01-7.99 (m, 1H), 7.96-7.93 (m 1H), 7.87-7.86 (m, 1H), 7.74 (brs, 1H), 7.43 (brs, 3H), 3.75-3.65 (m, 4H), 3.41-3.32 (m, 4H); ESI-MS m/z: calculated for 517.14, found 515.99 [M−H].sup.−.

Example 88

(142) Compound 88 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 88 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.30 (m, 1H), 8.46-8.43 (m, 1H), 8.23-8.18 (m, 1H), 8.16-8.11 (m, 1H), 7.94-7.88 (m, 2H), 7.77-7.71 (m, 1H), 7.64-7.57 (m, 1H), 7.42-7.40 (m, 1H), 7.36-7.34 (m 1H), 7.31-7.30 (m, 1H), 7.23-7.20 (m, 1H), 4.24-3.68 (m, 4H), 3.59-3.28 (m, 4H); ESI-MS m/z: calculated for 517.14, found 516.10 [M−H].sup.−.

Example 89

(143) Compound 89 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 89 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3) δ 9.59 (s, 1H), 8.44 (d, J=7.68 Hz, 1H), 8.14 (d, J=7.80 Hz, 1H), 7.94-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.33-7.31 (m, 2H), 7.19-7.16 (m, 1H), 6.96-6.90 (m, 1H), 6.26 (brs, 1H), 3.82-3.60 (m, 6H), 3.44 (brs, 2H), 1.90 (brs, 3H); ESI-MS m/z: calculated for 436.15, found 435.06 [M−H].sup.−.

Example 90

(144) Compound 90 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 90 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.16 (s, 1H), 8.43 (d, 1H, J=7.74 Hz), 8.13 (d, 1H, J=7.80 Hz), 7.92-7.90 (m, 1H), 7.88-7.85 (m, 1H), 7.29-7.27 (m, 2H), 7.16-7.13 (m, 1H), 3.84 (brs, 2H), 3.45 (brs, 2H), 2.53 (brs, 2H), 2.45 (brs, 2H), 2.35 (s, 3H); ESI-MS m/z: calculated for 382.14, found 381.17 [M−H].sup.−.

Example 91

(145) Compound 91 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 91 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.73 (s, 1H), 8.44 (d, J=7.74 Hz, 1H), 8.26 (s, 1H), 8.14 (d, J=7.80 Hz, 1H), 7.93-7.86 (m, 3H), 7.35-7.30 (m, 2H), 7.19-7.16 (m, 1H), 4.23-4.09 (m, 2H), 3.89-3.79 (m, 4H), 3.51 (brs, 2H); ESI-MS m/z: calculated for 463.13, found 463.92 [M+H].sup.+.

Example 92

(146) Compound 92 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 92 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.14 (s, 1H), 8.43 (d, J=7.80 Hz, 1H), 8.13 (d, J=7.92 Hz, 1H), 7.93-7.92 (m, 1H), 7.89-7.86 (m, 1H), 7.29-7.26 (m, 2H), 7.16-7.14 (m, 1H), 3.82 (brs, 2H), 3.67-3.65 (m, 2H), 3.43 (brs, 2H), 2.63-2.59 (m, 4H), 2.53 (brs, 2H); ESI-MS m/z: calculated for 412.15, found 411.30 [M−H].sup.−.

Example 93

(147) Compound 93 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 93 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 9.25 (s, 1H), 8.46-8.42 (m, 2H), 8.14 (d, J=7.86 Hz, 1H), 7.94-7.92 (m, 1H), 7.90-7.88 (m, 1H), 7.46-7.44 (m, 1H), 7.38-7.35 (m, 2H), 7.22-7.19 (m, 1H), 4.02-3.99 (m, 4H), 3.73-3.59 (m, 4H); ESI-MS m/z: calculated for 463.1, found 486.2 [M+Na].sup.+.

Example 94

(148) Compound 94 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 94 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 9.22 (s, 1H), 8.45 (d, J=7.56 Hz, 1H), 8.14 (d, J=7.44 Hz, 1H), 7.94-7.91 (m, 1H), 7.90-7.87 (m, 1H), 7.32-7.31 (m, 2H), 7.19-7.16 (m, 1H), 4.62-4.55 (m, 1H), 4.00-3.81 (m, 5H), 3.72-3.50 (m, 5H), 2.39-2.38 (m, 1H), 2.07-2.00 (m, 2H), 1.94-1.91 (m, 1H); ESI-MS m/z: calculated for 466.1, found 488.9 [M+Na].sup.+.

Example 95

(149) Compound 95 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 95 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.00 (s, 1H), 8.44 (d, J=7.80 Hz, 1H), 8.13 (d, J=7.86 Hz, 1H), 7.93-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.32-7.31 (m, 2H), 7.18-7.15 (m, 1H), 4.62-4.55 (m, 1H), 3.97-3.81 (m, 5H), 3.69-3.39 (m, 5H), 2.38-2.34 (m, 1H), 2.06-1.99 (m, 2H), 1.94-1.89 (m, 1H); ESI-MS m/z: calculated for 466.17, found 465.27 [M−H].sup.−.

Example 96

(150) Compound 96 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 96 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.96 (d, J=7.68 Hz, 1H), 8.43 (d, J=7.68 Hz, 1H), 8.14 (d, J=7.80 Hz, 1H), 7.99-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.31-7.30 (m, 2H), 7.18-7.15 (m, 1H), 4.53-4.48 (m, 1H), 3.80 (brs, 2H), 3.44 (brs, 6H), 2.44-2.34 (m, 1H), 2.23-2.19 (m, 1H), 2.11-1.72 (m, 5H), 1.50-1.42 (m, 1H); ESI-MS m/z: calculated for 529.19, found 528.09 [M−H].sup.−.

Example 97

(151) Compound 97 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 97 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.14 (s, 1H), 8.43 (d, J=7.74 Hz, 1H), 8.13 (d, J=7.68 Hz, 1H), 7.91-7.90 (m, 1H), 7.89-7.87 (m, 1H), 7.31-7.30 (m, 2H), 7.17-7.14 (m, 1H), 4.93 (brs, 1H), 3.78 (brs, 2H), 3.44-3.42 (m, 6H), 0.71-0.69 (m, 2H), 0.45 (brs, 2H); ESI-MS m/z: calculated for 451.17, found 450.00 [M−H].sup.−.

Example 98

(152) Compound 98 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 98 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.69 (s, 1H), 8.40 (d, J=7.62 Hz, 1H), 8.34 (s, 1H), 8.12 (d, J=7.86 Hz, 1H), 7.93-7.90 (m, 1H), 7.88-7.86 (m, 1H), 7.34-7.28 (m, 3H), 7.22-7.21 (m, 1H), 7.19-7.16 (m, 1H), 3.90 (brs, 2H), 3.74 (brs, 2H), 3.68 (brs, 2H) 3.55 (brs, 2H); ESI-MS m/z: calculated for 462.43, found 461.11 [M−H].sup.−.

Example 99

(153) Compound 99 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 99 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.78 (s, 1H), 8.41 (d, J=7.74 Hz, 1H), 8.11 (d, J=7.80 Hz, 1H), 7.91-7.88 (m, 1H), 7.86-7.84 (m, 1H), 7.30-7.29 (m, 2H), 7.15-7.12 (m, 1H), 3.80-3.54 (m, 6H), 3.44-3.39 (m, 2H), 2.48-2.41 (m, 1H), 1.78-1.69 (m, 5H), 1.54-1.48 (m, 2H), 1.29-1.21 (m, 3H); ESI-MS m/z: calculated for 478.52, found 477.22 [M−H].sup.−.

Example 100

(154) Compound 100 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 100 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.69 (s, 1H), 8.41 (d, 1H, J=7.80 Hz), 8.11 (d, 1H, J=7.86 Hz), 7.90 (t, 1H, J=7.41 Hz), 7.86 (t, 1H, J=7.38 Hz), 7.31-7.29 (m, 2H), 7.15 (t, 1H, J=8.88 Hz), 3.79-3.65 (m, 4H), 3.56-3.40 (m, 4H), 2.40-2.37 (m, 1H), 2.32-2.31 (m, 1H), 1.16-1.11 (m, 3H); ESI-MS m/z: calculated for 424.42, found 423.13 [M−H].sup.−.

Example 101

(155) Compound 101 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 101 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.14 (s, 1H), 8.43 (d, J=7.80 Hz, 1H), 8.13 (d, J=7.86 Hz, 1H), 7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.31-7.30 (m, 2H), 7.18-7.15 (m, 1H), 3.80-3.57 (m, 6H), 3.44-3.40 (m, 2H), 2.19 (brs, 1H), 1.83-1.74 (m, 8H); ESI-MS m/z: calculated for 464.49, found 463.21[M−H].sup.−.

Example 102

(156) Compound 102 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 7. Compound 102 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 12.23 (s, 1H), 8.27 (d, J=7.56 Hz, 1H), 8.06-8.05 (m, 1H), 7.88 (t, 1H, J=7.92 Hz), 7.37-7.32 (m, 7H), 7.31-7.28 (m, 1H), 5.05 (s, 2H), 3.99-3.98 (m, 2H), 3.63-3.57 (m, 3H), 3.51-3.44 (m, 5H), 2.88-2.79 (m, 3H), 1.62 (brs, 2H), 1.44-1.37 (m, 2H); ESI-MS m/z: calculated for 647.2, found 646.3 [M−H].sup.−.

Example 103

(157) Compound 103 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 103 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.98 (s, 1H), 8.28 (d, J=7.80 Hz, 1H), 8.12 (d, J=8.22 Hz, 1H), 8.03-8.00 (m, 1H), 7.98-7.95 (m, 1H), 7.51-7.49 (m, 2H), 7.47-7.40 (m, 4H), 7.28 (t, 2H, J=8.64 Hz), 3.74-3.36 (m, 8H); ESI-MS m/z: calculated for 472.15, found 471.27[M−H].sup.−.

Example 104

(158) Compound 104 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 7. Compound 104 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 12.22 (s, 1H), 8.27-8.26 (m, 1H), 8.06 (d, J=7.74 Hz, 1H), 7.88 (t, 1H, J=7.95 Hz), 7.37-7.34 (m, 3H), 7.06-7.03 (m, 2H), 6.97-6.94 (m, 2H), 3.76-3.75 (m, 2H), 3.39-3.37 (m, 2H), 3.14-3.12 (m, 2H), 3.05-3.03 (m, 2H); ESI-MS m/z: calculated for 496.0, found 497.0 [M+H].sup.+.

Example 105

(159) Compound 105 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 1. Compound 105 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 12.06 (s, 1H), 8.10-8.08 (m, 1H), 7.90-7.89 (m, 1H), 7.80-7.77 (m, 1H), 7.61 (d, J=7.50 Hz, 1H), 7.54 (s, 1H), 7.49 (t, J=7.56 Hz, 1H), 7.39 (d, J=7.62 Hz, 1H), 7.37-7.28 (m, 5H), 5.38 (s, 2H), 5.06 (s, 2H), 3.40-3.98 (m, 2H), 3.62-3.38 (m, 8H), 2.87 (brs, 3H), 1.61 (brs, 2H), 1.44-1.39 (m, 2H); ESI-MS m/z: calculated for 627.3, found 650.6 [M+Na].sup.+.

Example 106

(160) Compound 106 of the present invention was prepared according to Scheme 3. The synthetic method was similar with Example 7. Compound 106 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 12.24 (s, 1H), 8.27-8.26 (m, 3H), 8.05 (brs, 1H), 7.90-7.87 (m, 1H), 7.69 (brs, 2H), 7.36 (brs, 3H), 3.72-3.64 (m, 4H), 3.28-3.26 (m, 4H); ESI-MS m/z: calculated for 551.1, found 550.1[M−H].sup.−.

Example 107

(161) Compound 107 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 107 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.71 (s, 1H), 8.44 (d, J=7.74 Hz, 1H), 8.13 (d, J=7.80 Hz, 1H), 7.94-7.91 (m, 1H), 7.90-7.87 (m, 1H), 7.33-7.31 (m, 2H), 7.19-7.16 (m, 1H), 3.82-3.66 (m, 4H), 3.61-3.42 (m, 4H), 2.61-2.54 (m, 1H), 2.23-2.19 (m, 2H), 1.95-1.89 (m, 2H), 1.83-1.72 (m, 4H); ESI-MS m/z: calculated for 514.20, found 537.06 [M+Na].sup.+.

Example 108

(162) Compound 108 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 108 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.27 (s, 1H), 8.44 (d, J=8.3 Hz, 1H), 8.13 (br, 1H), 7.90 (m, 2H), 7.33 (m, 7H), 7.18 (s, 1H), 5.15 (m, 2H), 3.84 (br, 1H), 3.50 (m, 8H), 2.19 (m, 4H), 1.91 (br, 2H); ESI-MS m/z: calculated for 599.21, found 622.26 [M+Na].sup.+.

Example 109

(163) Compound 109 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 109 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl3): δ 8.44 (s, 1H), 8.15 (d, J=7.7 Hz, 1H), 7.88 (m, 3H), 7.43 (m, 2H), 7.19 (s, 1H), 4.06 (m, 2H), 3.74 (m, 2H), 3.53 (m, 8H), 2.63 (brs, 1H), 2.26-2.19 (m, 2H); ESI-MS m/z: calculated for 465.18, found 465.98 [M+H].sup.+.

Example 110

(164) Compound 110 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 110 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3) δ 10.20 (s, 1H), 8.42 (d, J=7.86 Hz, 1H), 8.14 (d, J=7.92 Hz, 1H), 7.93-7.90 (m, 1H), 7.86-7.84 (m, 1H), 7.34-7.30 (m, 2H), 7.17 (t, 1H, J=8.67 Hz), 6.97-6.94 (m, 2H), 6.90-6.88 (m, 2H), 3.96 (brs, 2H), 3.58 (brs, 2H), 3.18-3.17 (m, 2H), 3.10 (brs, 2H). ESI-MS m/z: calculated for 462.45, found 461.16 [M−H].sup.−.

Example 111

(165) Compound 111 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 111 was obtained as a white solid. 1H NMR (600 MHz, CDCl3): δ 10.16 (m, 1H), 8.43 (d, J=7.80 Hz, 1H), 8.13 (d, J=7.74 Hz, 1H), 7.93-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.33-7.31 (m, 2H), 7.19-7.16 (m, 1H), 4.03-3.96 (m, 1H), 3.90-3.56 (m, 9H), 3.46-3.42 (m, 3H), 2.25-2.20 (m, 1H), 2.13-2.02 (m, 1H); ESI-MS m/z: 466.16, found 488.78 [M+Na].sup.+.

Example 112

(166) Compound 112 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 112 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.59 (s, 1H), 8.43 (d, J=7.86 Hz, 1H), 8.14 (d, J=7.50 Hz, 1H), 7.94-7.91 (m, 1H), 7.89-7.86 (m, 1H), 7.33-7.28 (m, 4H), 7.24-7.23 (m, 2H), 7.20-7.17 (m, 1H), 6.51 (s, 1H), 3.87 (brs, 2H), 3.61-3.57 (m, 4H), 3.50 (brs, 2H); ESI-MS m/z: calculated for 521.13, found 521.91 (M+H].sup.+.

Example 113

(167) Compound 113 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 113 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.09 (s, 1H), 8.43 (d, J=7.68 Hz, 1H), 8.13 (d, J=7.74 Hz, 1H), 7.92-7.90 (m, 1H), 7.88-7.85 (m, 1H), 7.30-7.28 (m, 2H), 7.16-9.13 (m, 1H), 3.80 (brs, 2H), 3.44 (brs, 2H), 3.30-3.29 (m, 2H), 3.24-3.21 (m, 6H), 1.13 (t, 6H, J=7.05 Hz); ESI-MS m/z: calculated for 467.20, found 465.93 [M−H].sup.−.

Example 114

(168) Compound 114 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 114 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.57 (s, 1H), 8.41 (d, J=7.68 Hz, 1H), 8.12 (d, J=7.86 Hz, 1H), 7.91-7.89 (m, 1H), 7.87-7.85 (m, 1H), 7.31-7.30 (m, 2H), 7.17-7.14 (m, 1H), 4.00 (brs, 2H), 3.87-3.56 (m, 6H), 3.45-3.41 (m, 4H), 2.76-2.69 (m, 1H), 1.94-1.87 (m, 2H), 1.61-1.59 (m, 2H); ESI-MS m/z: calculated for 480.18, found 479.14 [M−H].sup.−.

Example 115

(169) Compound 115 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 115 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.12 (s, 1H), 8.43 (d, J=7.80 Hz, 1H), 8.13 (d, J=7.56 Hz, 1H), 7.93-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.71-7.70 (m, 2H), 7.54-7.53 (m, 2H), 7.32 (brs, 2H), 7.21-7.14 (m, 1H), 3.90-3.76 (m, 4H), 3.57-3.41 (m, 4H); ESI-MS m/z: calculated for 540.14, found 539.23 [M−H].sup.−.

Example 116

(170) Compound 116 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 116 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 10.21 (s, 1H), 8.42 (d, J=7.74 Hz, 1H), 8.13 (d, J=7.74 Hz, 1H), 7.93-7.90 (m, 1H), 7.88-7.86 (m, 1H), 7.44-7.42 (m, 2H), 7.32-7.30 (m, 2H), 7.17-7.09 (m, 3H), 3.81-3.27 (m, 8H); ESI-MS; m/z: calculated for 490.15, found 491.01 [M+H].sup.+.

Example 117

(171) Compound 117 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 117 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.33 (s, 1H), 8.44 (d, J=7.92 Hz, 1H), 8.13 (d, J=7.92 Hz, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.28-7.27 (m, 4H), 7.16-7.13 (m, 1H), 7.01 (t, 2H, J=8.58 Hz), 3.81 (brs, 2H), 3.51 (brs, 2H), 3.45-3.38 (m, 2H), 2.52 (brs, 2H), 2.42 (brs, 2H); ESI-MS m/z: calculated for 476.17, found 475.32 [M−H].sup.−.

Example 118

(172) Compound 118 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 118 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.51 (s, 1H), 8.44 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.91-7.87 (m, 2H), 7.31-7.30 (m, 2H), 7.16-7.15 (m, 1H), 3.77 (brs, 2H), 3.53 (brs, 2H), 3.00 (brs, 2H), 2.95 (brs, 2H); ESI-MS m/z calculated for: 368.13, found: 367.15 [M−H].sup.−.

Example 119

(173) Compound 119 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 119 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3) δ 9.26 (s, 1H), 8.62-8.56 (m, 1H), 8.45-8.44 (m, 1H), 8.15-8.12 (m, 1H), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.83-7.81 (m, 1H), 7.73 (brs, 1H), 7.39-7.28 (m, 3H), 7.21-7.13 (m, 1H), 3.93-3.72 (m, 6H), 3.55-3.49 (m, 2H); ESI-MS m/z calculated for: 437.15, found: 437.96 [M+H].sup.+.

Example 120

(174) Compound 120 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 120 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.36 (s, 1H), 8.44 (d, J=7.56 Hz, 1H), 8.14 (d, J=7.56 Hz, 1H), 7.94-7.91 (m, 1H), 7.90-7.87 (m, 1H), 7.32-7.31 (m, 2H), 7.19-7.16 (m, 1H), 4.62-4.56 (m, 1H), 4.00-3.82 (m, 5H), 3.70-3.46 (m, 5H), 2.39-2.34 (m, 1H), 2.06-2.00 (m, 2H), 1.94-1.90 (m, 1H); ESI-MS m/z: calculated for 466.17, found 467.1 [M+H].sup.+.

Example 121

(175) Compound 121 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 121 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.93 (s, 1H), 8.43 (d, J=7.68 Hz, 1H), 8.13 (d, J=7.86 Hz, 1H), 7.93-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.32-7.31 (m, 2H), 7.18-7.16 (m, 1H), 3.80-3.67 (m, 4H), 3.57-3.42 (m, 4H), 2.33-2.27 (m, 2H), 1.04 (brs, 1H), 0.59-0.58 (m, 2H), 0.19-0.15 (m, 2H); ESI-MS m/z: calculated for 450.17, found 473.07 [M+Na].sup.+.

Example 122

(176) Compound 122 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 122 was obtained as a white solid. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.72 (s, 1H), 8.44 (d, J=7.26 Hz, 1H), 8.13 (d, 1H, J=7.80 Hz), 7.93-7.91 (m, 1H), 7.89-7.87 (m, 1H), 7.32-7.31 (m, 2H), 7.19-7.16 (m, 1H), 3.84-3.73 (m, 3H), 3.66 (brs, 1H), 3.59 (brs, 1H), 3.52 (brs, 1H), 3.47-3.40 (m, 2H), 2.41-2.34 (m, 2H), 1.86 (brs, 2H), 1.64-1.55 (m, 7H); ESI-MS m/z: calculated for 478.20, found 501.11 [M+Na].sup.+.

Example 123

(177) Compound 123 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 123 was obtained as a white solid. .sup.1H NMR (600 MHZ, DMSO-d.sub.6): δ11.97 (s, 1H), 8.26 (d, J=7.80 Hz, 1H), 8.11 (d, J=7.92 Hz, 1H), 8.01-7.99 (m, 1H), 7.96-7.94 (m, 1H), 7.46-7.41 (m, 2H), 7.38 (t, 1H, J=8.88 Hz), 3.63-3.57 (m, 6H), 3.27-3.26 (m, 2H), 2.19 (s, 3H), 0.82-0.80 (m, 2H), 0.65-0.63 (m, 2H); ESI-MS m/z: calculated for 465.1, found 488.14 [M+Na].sup.+.

Example 124

(178) Compound 124 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 124 was obtained as a white solid. .sup.1H NMR (600 MHZ, DMSO-d.sub.6): δ11.96 (s, 1H), 8.26 (d, J=7.92 Hz, 1H), 8.10 (d, J=7.80 Hz, 1H), 8.01-7.99 (m, 1H), 7.96-7.94 (m, 1H), 7.46-7.41 (m, 2H), 7.38 (t, 1H, J=8.85 Hz), 3.62-3.55 (m, 6H), 3.28-3.25 (m, 2H), 2.14 (s, 6H), 0.84-0.83 (m, 2H), 0.72-0.70 (m, 2H); ESI-MS m/z: calculated for 479.2, found 502.12 [M+Na].sup.+.

Example 125

(179) Compound 125 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 125 was obtained as a white solid. .sup.1H NMR (600 MHZ, DMSO-d.sub.6): δ11.97 (s, 1H), 8.26 (d, J=7.62 Hz, 1H), 8.11 (d, J=8.10 Hz, 1H), 8.01-7.99 (m, 1H), 7.96-7.94 (m, 1H), 7.45-7.36 (m, 3H), 3.64-3.56 (m, 6H), 3.26-3.20 (m, 2H), 0.85-0.81 (m, 2H), 0.76 (brs, 1H), 0.63-0.62 (m, 1H); ESI-MS m/z: calculated for 451.45, found 450.56 [M−H].sup.−.

Example 126

(180) Compound 126 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 126 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.97 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 8.11-8.09 (m, 1H), 8.01-7.98 (m, 1H), 7.96-7.93 (m, 1H), 7.45-7.40 (m, 2H), 7.37-7.35 (m, 1H), 3.62-3.55 (m, 4H), 3.52-3.47 (m, 2H), 3.27-3.19 (m, 2H), 2.36-2.21 (m, 4H), 2.15 (s, 3H), 2.11 (s, 3H), 1.62-1.57 (m, 1H), 1.53-1.48 (m, 1H); ESI-MS m/z: calculated for 493.2, found 515.98 [M+Na].sup.+.

Example 127

(181) Compound 127 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 127 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 8.36 (d, J=7.8 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.02-8.00 (m, 1H), 7.97-7.94 (m, 1H), 7.44-7.41 (m, 1H), 7.40-7.38 (m, 2H), 3.82-3.80 (m, 2H), 3.68-3.66 (m, 2H), 3.60-3.58 (m, 2H), 3.46-2.44 (m, 2H), 3.45 (s, 3H), 2.68-2.63 (m, 2H), 2.05-2.02 (m, 3H), 1.73-1.68 (m, 1H); ESI-MS m/z: calculated for 479.20, found 480.25 [M+H].sup.+.

Example 128

(182) Compound 128 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 128 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 11.97 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 8.11-8.09 (m, 1H), 8.01-7.98 (m, 1H), 7.96-7.93 (m, 1H), 7.45-7.43 (m, 1H), 7.41-7.36 (m, 2H), 3.63-3.52 (m, 3H), 3.51-3.41 (m, 4H), 3.36-3.32 (m, 1H), 2.73-2.54 (m, 1H), 2.23-2.10 (m, 1H), 1.83-1.70 (m, 2H), 1.64-1.57 (m, 1H), 1.54-1.43 (m, 1H); ESI-MS m/z: calculated for 465.2, found 487.77 [M+Na].sup.+.

Example 129

(183) Compound 129 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 129 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 8.36 (d, J=7.2 Hz, 1H), 8.20 (d, J=7.2 Hz, 1H), 8.02-7.99 (m, 1H), 7.96-7.94 (m, 1H), 7.44-7.43 (m, 1H), 7.40-7.38 (m, 1H), 7.32-7.29 (m, 1H), 3.82 (brs, 4H), 3.73 (brs, 2H), 3.47 (brs, 2H), 3.42 (brs, 1H), 3.02 (brs, 1H), 2.70 (s, 3H), 2.38-2.34 (m, 1H), 2.23 (brs, 1H), 2.10 (brs, 1H), 2.02-1.97 (m, 1H), 1.52 (s, 3H); ESI-MS m/z: calculated for 493.2, found 491.96 [M−H].sup.−.

Example 130

(184) Compound 130 of the present invention was prepared according to Scheme 4. The synthetic method was similar with Example 7. Compound 130 was obtained as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): δ 8.37 (d, J=7.2 Hz, 1H), 8.21 (d, J=7.2 Hz, 1H), 8.03-8.00 (m, 1H), 7.97-7.95 (m, 1H), 7.46-7.42 (m, 1H), 7.41-7.38 (m, 1H), 7.33-7.29 (m, 1H), 3.88-3.82 (m, 2H), 3.81-3.77 (m, 2H), 3.75-3.69 (m, 2H), 3.55-3.50 (m, 2H), 2.35-2.22 (m, 2H), 2.08-2.00 (m, 2H), 1.65 (s, 3H), 1.61-1.58 (m, 2H); ESI-MS m/z: calculated for 479.2, found 479.93 [M+H].sup.+.

BIOLOGICAL EVALUATION

Test Example 1: Screening Assay for Poly (ADP-Ribose) Polymerase (PARP-1) Inhibition

(185) The following in vitro screening assay is used to evaluate the PARP-1 inhibiting effect of the compounds of present invention.

(186) Principle

(187) PARP-1 can catalyze the NAD-dependent addition of poly (ADP-ribose) to adjacent nuclear proteins such as histone. The activity of PARP was determined by detecting biotin coupled ADP-ribose that attaches to histone using chemiluminiscence method with HT Universal Chemiluminescent PARP Assay Kit With Histone-coated Strip Wells purchased from TREVIGEN. The positive control compound was AZD-2281 purchased from SelleckChem.

(188) Method

(189) The kit is based on ELISA. 10 μl sample/well, 15 μl PARP enzyme/well and PARP cocktail 25 μl/well with a total volume of 50 μl/well were added into a 96-well plate coated with histone. Meanwhile, blank control (without enzyme and sample) and negative control (without sample) were set. The plate was incubated at room temperature for 60 min; washed with 1×PBS (+0.1% TritonX-100) for twice; Strep-HRP 50 μl/well was added and incubated at room temperature for 60 min; and then washed with 1×PBS (+0.1% TritonX-100) for twice, chemiluminescence substrate 100 μl/well was added for measurement. The inhibition rate was calculated according to the value of chemiluminiscence intensity RLU (relative light unit), inhibition rate=[1−(RLU sample−RLU blank)/(RLU negative−RLU blank)]×100%. Each sample was gradiently diluted into eight concentrations, each concentration was set in a single well, IC.sub.50 values were calculated using 4 Parameter Logistic Model in XLfit software according to the inhibition rate of samples. The results were shown in the following Table 1.

(190) TABLE-US-00002 TABLE 1 Compound No. IC.sub.50 (PARP-1)/μM AZD-2281 0.012 61 0.008 85 0.009 88 0.015 99 0.017 100 0.03 107 0.013 124 0.006 126 0.007

Test Example 2 Cell Proliferation Inhibition Assay

(191) The following in vitro assay was used to evaluate the inhibiting effect of the compounds of present invention for the proliferation of BRCA-mutant (or deficient) human prostatic cancer cell line DU-145, lung adenocarcinoma cell line SW-1271, as well as breast cancer cell lines MDA-MB-436 and MDA-MB-361.

(192) Principle

(193) This assay was used to study the effect of PARP-1 inhibitor alone for tumor suppression. Breast cancer susceptibility genes BRCA1 and BRCA2 play an important role in homologous recombination DNA repair. BRCA-mutant (or deficient) cells represent homologous recombination repair defect, if PARP-mediated DNA repair is inhibited at the same time, DNA damage in cells may be increased, resulting in chromatin abnormality or even cell death.

(194) BRCA-mutant (or deficient) human prostatic cancer cell line DU-145, lung adenocarcinoma cell line SW-1271, as well as breast cancer cell lines MDA-MB-436 and MDA-MB-361 were selected for the assay, PARP inhibitor was used alone to evaluate its damage effect on cells. The inhibition effect of the compound was expressed by IC.sub.50.

(195) Method

(196) Prostatic cancer cell line DU-145 grown in EMEM supplement with 10% FBS was seeded in 96 well tissue culture plates (2000 cells/well). Lung adenocarcinoma cell line SW-1271 grown in L15 supplement with 10% FBS was seeded in 96 well tissue culture plates (4000 cells/well), and breast cancer cell line MDA-MB-361 grown in L15 supplement with 20% FBS was seeded in 96 well tissue culture plates (4000 cells/well). Test compounds (10 mM stock solution in DMSO) and reference compound staurosporine (1 mM stock solution in DMSO) were diluted by DMSO for 200 times to obtain the desired final concentration. 0.5 ul compound dilutions were directly added to the cells in 96 well plates, and the cells were incubated at 37° C. for 5 days. HPE control wells were added 1 uM staurosporine dilution, while ZPE wells were added 0.5% DMSO. After 5 days plates were equilibrated to room temperature and 50 ul of Cell Titer-Glo Reagent (Promega) was added to the culture wells. The plates were agitated briefly and luminescence signal was measured with Envision (PerkinElmer). The percent inhibition of the signal was calculated as (Day5−Day5.sub.HPE)/(Day5.sub.ZPE−Day5.sub.HPE)*100%. IC.sub.50 values were calculated with Prism software (Graph Pad, San Diego, Calif., USA) for both test compounds and reference compound staurosporine. The results were shown in Table 2 below.

(197) TABLE-US-00003 TABLE 2 IC.sub.50/μM Compound No. DU-145 SW-1271 MD-MBA-361 AZD-2281 65 17.4 >10 85 3.7 1.5 2.4 107 1.3 0.77 1.9 124 2.7 1.6 — 126 1.9 1.1 4.0 Note: “—” indicates “no detection test was conducted”.

(198) Breast cancer cell line MDA-MB-436 in good growth condition seeded in 96-well plates (5000 cells/well or 3000 cells/well), and cultured overnight in an incubator at 37° C., 5% CO.sub.2 with saturated humidity. On the next day, samples with a series of concentration gradients were added and cultured for another six days. SRB method was used to detect the samples' inhibiton on cell growth and calculate their growth inhibition rate. 4 Parameter Logistic Model in Xlfit software was used to calculate IC.sub.50, and the results were shown in Table 3 below.

(199) TABLE-US-00004 TABLE 3 Compound No. IC.sub.50 (MDA-MB-436)/μM AZD-2281 4.38 49 4.21 61 1.98 85 3.35 88 3.28 99 2.63 100 4.12 107 3.17 124 3.70 130 3.85

(200) The results showed that the inhibitory activities of the representative compounds of the present application against BRCA-mutant (or deficient) human prostatic cancer cell line DU-145, lung adenocarcinoma cell line SW-1271, and breast cancer cell line MDA-MB-361 were significantly superior to the positive control AZD-2281.

Test Example 3 Solubility Test

(201) To absorb the compound in the intestinal after oral administration, solid or suspension dosage forms must be disintegrated, dissolved and diffused onto the surfaces of intestinal epithelial cells before entering circulatory system. Compounds with high solubility could increase its concentration on the epithelial cell surface and facilitate intestinal to absorb more molecules in unit time and surface area Insoluble compounds could lead to incomplete absorption, resulting in lower bioavailability when administered orally (see Drug Metabolism and Disposition, 1998, 26, 152-163; Journal of Medicinal Chemistry, 2001, 44, 1313-1333).

(202) Principle

(203) In this test, excess amount of test sample was added into pH=7.4 phosphate buffer. Ultrasonic was performed for 30 min until the drug no longer dissolved. The solution was continuously shaked for 24 hours at a constant temperature of 25° C. to achieve a thermodynamic equilibrium of compound, and then the solution was filtrated to get filtrate. Quantitative analysis of compound in filtrate using external standard method is performed according to “Appendix VD High Performance Liquid Chromatography, Part II of Pharmacopeia 2010,” and the sample thermohynamic solubility in pH=7.4 phosphate buffer was determined.

(204) Method

(205) Solubility test of AZD-2281

(206) Chromatographic Conditions

(207) Agilent 1200 LC, Phenomen C18 column (4.6 mm*150 mm, 0.4 μm), mobile phase: methanol:water (60:40), flow rate: 1 mL/min, column temperature: 25° C., wave length: 230 nm, injection volume: 10 μL

(208) Preparation of Test Solution

(209) About 30 mg test compound was put in a 10 mL volumetric flask, about 8 mL pH=7.4 phosphate buffer was added and ultrasonic was performed for 30 min, and the solution was shaked for 24 hours in a shaker at a constant temperature of 25° C. The solution was settled for half an hour under 25° C., filtered with 0.45 μm hydrophilic filter. The filtrate was used as test sample.

(210) Preparation of Standard Solution

(211) Standard compound AZD-2281 was put in a volumetric flask and dissolved in the mobile phase. Standard stock solutions with different concentrations as shown in Table 4 were prepared. The solutions were injected to measure the peak area. The retention time of AZD-2281 was about 8.5 min. The peak area was regressed against concentration to get a regression equation y=29.66x+302.82 (r=0.9997), and the linear range is 52.45˜83.92 g/mL (see FIG. 1).

(212) TABLE-US-00005 TABLE 4 Concentration (μg/mL) 52.45 83.92 104.9 239.75 239.75 Area 1765.2 2821.4 3586.6 7261.7 14568

(213) The test solution was injected for three times according to the above chromatographic conditions. The peak area was measured to calculate the corresponding concentration.

(214) The procedures for testing the solubility of other compounds were similar with compound AZD-2281. The solubility results are shown in the following Table 5.

(215) TABLE-US-00006 TABLE 5 Mobile Phase Retention Water Solubility Example No. (methanol:water) Time (min) (PH = 7.4)/μg/mL AZD-2281 60:40 8.5 531 55 60:40 7.6 602 79 65:35 8.4 650 100 55:45 8.3 660 124 55:35 8.5 1440 125 50:50 8.7 671 127 55:45 8.2 630

(216) The results showed that the representative compounds of the present invention had better water solubility relative to AZD-2281. In particular, the water solubility of Compound 124 was enhanced by almost twice.

Test Example 4 Pharmacokinetic Test

(217) The following tests were used to study and evaluate the pharmacokinetic properties of the compounds of the present invention.

(218) Principle

(219) Male SD rats were used as experimental animals in this test. After tail intravenous administration of Compound 124 and control compound AZD-2281, venous blood was collected at different time points. LC-MS/MS method was used to test blood drug concentration, and Winnonlin 6.1 software was used to calculate pharmacokinetic parameters to study and evaluate the pharmacokinetic properties.

(220) Method

(221) 1. Experimental Animals

(222) 12 male SD rats weighed 180-260 g, purchased from Vital River Laboratory Animal Technology Co., Ltd.

(223) 2. Preparation of Drugs

(224) 2.1 Preparation of AZD-2281

(225) 15.55 mg AZD-2281 was precisely weighed and added into 0.259 mL DMSO and 4.924 mL hydroxypropyl-β-cyclodextrin (30%, w/v) solvents, filtered through 0.22 μm PTFE membrane to obtain a colorless clear solution with a final concentration of 3 mg/mL. 50 μL solution was pipetted into a 1.5 mL EP tube.

(226) 2.2 Preparation of Compound 124

(227) 15.1 mg Compound 124 was precisely weighed and added into 0.252 mL DMSO and 4.781 mL hydroxypropyl-β-cyclodextrin (30%, w/v) solvents, and then filtered through 0.22 μm PTFE membrane to obtain a colorless clear solution with a final concentration of 3 mg/mL. 50 μL solution was pipetted into a 1.5 mL EP tube.

(228) The volume ratio of DMSO and hydroxypropyl-β-cyclodextrin (30%, w/v) was 5:95. All of the above solutions were freshly prepared prior to use.

(229) 3. Dosing

(230) 12 male SD rats were fasted overnight with free access to water, and were fed four hours after dosing.

(231) The rats were divided into two groups (6 rats in each group), and were dosed with 15 mg/kg Compound 124 and 15 mg/kg AZD-2281 by tail vein injection, respectively.

(232) 4. Sample Collection

(233) 0.2 mL blood was collected through jugular vein before dosing and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after the dosing, respectively, and put into heparinized tubes. The samples were centrifuged for 10 min at 5500 rpm to separate plasma, and stored at −30° C.

(234) 5. Sample Treatment and Test

(235) 5.1 Compound 124 Plasma Sample

(236) An aliquot of 20 μL of plasma sample was added with 200 μL acetonitrile (containing 5.00 ng/mL verapamil and 50.0 ng/mL glibenclamide as internal standards). The mixture was vortexed for 4 min, and then centrifuged at 3700 rpm for 18 min. An aliquot of 70 μL supernatant was added into 70 μL water, and then vortexed for 4 min. Finally, 10 μL of the mixture was injected into the LC-MS/MS system for analysis.

(237) 5.2 AZD-2281 Plasma Sample

(238) An aliquot of 30 μL of plasma sample was added with 150 μL acetonitrile (containing 5.00 ng/mL verapamil and 50.0 ng/mL glibenclamide as internal standards). The mixture was vortexed for 5 min, and then centrifuged at 3700 rpm for 18 min. An aliquot of 70 μL supernatant was added into 70 μL water, and then vortexed for 5 min. Finally, 10 μL of the mixture was injected into the LC-MS/MS system for analysis.

(239) 6. Pharmacokinetic Parameters

(240) Winnonlin 6.1 software was used to calculate pharmacokinetic parameters. The calculation results were shown in Table 6 as follows.

(241) TABLE-US-00007 TABLE 6 AUC.sub.0-t CL Vdss (ng .Math. h .Math. MRT t.sub.1/2 (mL .Math. kg.sup.−1 .Math. (L .Math. Compound No. mL.sup.−1) (h) (h) min.sup.−1) kg.sup.−1) 124 10059 0.374 3.08 28.0 0.665 AZD-2281 6436 0.330 0.682 39.1 0.766

(242) The results showed that AZD-2281 had low exposure and poor metabolic stability, and the pharmacokinetic properties of Compound 124 were significantly superior to AZD-2281.

(243) The preparation, activities, dissolution characteristics, and pharmacokinetic properties of the representative compounds of the present invention were explained in details in the preparation examples and test examples above. The compounds of the present invention can be synthesized by conventional methods. Compared with AZD-2281, which represents the optimal activity, the representative compounds of the present invention demonstrated better activities, solubilities and pharmacokinetic properties.