Phthalazinone derivatives and manufacturing process thereof

Abstract

The present invention relates to phthalazinone derivatives, including pharmaceutical compositions and for the preparation of phthalazinone derivatives. And more particularly the present invention provided a pharmaceutical composition of phthalazinone derivatives for inhibiting activity of the Poly(ADP-riboside) polymerase enzyme.

Claims

1. A compound represented by Formula I, .Iadd.a .Iaddend.racemic .Iadd.mixture thereof.Iaddend., .Iadd.an .Iaddend.enantiomer .Iadd.thereof.Iaddend., .Iadd.a .Iaddend.diastereoisomer thereof, or .Iadd.a .Iaddend.pharmaceutically acceptable salt thereof, ##STR00050## .[.In.]. .Iadd.wherein in .Iaddend.the present Formula I, n is 1 or 2, ##STR00051## .[.Wherein.]. .Iadd.wherein.Iaddend., when .[.the.]. R is ##STR00052## m is 0, 1 or 2, L is .[.oxygen,.]. methylene, carbonyl, .[.CONHCH.sub.2, NR.sup.c1CH.sub.2,.]. NR.sup.c2CO, NR.sup.c3, CONR.sup.c4 or CH.sub.2NR.sup.c5 .[.(especially, R.sup.c1.]., .Iadd.wherein .Iaddend.R.sup.c2, R.sup.c3, R.sup.c4 and R.sup.c5 is each independently .[.oxygen, C.sub.1-4alkylamine,.]. .Iadd.hydrogen, .Iaddend.C.sub.1-6 alkyl, .[.C.sub.1-6 alkoxy, halo C.sub.1-6 alkyl, C.sub.2-6 alkenyl,.]. C.sub.2-6 alkynyl, .Iadd.or .Iaddend.C.sub.3-8 cycloalkyl, R.sup.X is hydrogen, cyano, hydroxyl, trifluoromethyl, .[.C.sub.1-6 alkyl or C.sub.3-8 cycloalkyl.]. .Iadd.methyl, ethyl or cyclopropyl.Iaddend., R.sup.Y is hydrogen, .[.amide.]. .Iadd.dimethylamide.Iaddend., cyano, hydroxyl, trifluoromethyl, halo, .[.ester.]. .Iadd.ethylester.Iaddend., .[.C.sub.1-4 alkylamine, C.sub.1-6 alkyl, C.sub.1-6 methoxyalkyl or C.sub.2-6 alkynyl.]. .Iadd.dimethylamine, methyl, methoxymethyl or propargyl.Iaddend., Z is .[.unsubstituted,.]. C.sub.1-6 alkyl, C.sub.1-6 methoxyalkyl, .[.C.sub.2-6 alkenyl,.]. C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, .[.C.sub.3-8 cycloalkenyl,.]. C.sub.6-10 aromatic cycle or 3-8 membered heterocycle having 1-3 nitrogens, wherein, when .[.the.]. R is ##STR00053## p and q is each independently .[.from 1 to 3.]. .Iadd.1 or 2.Iaddend., W is CR.sup.d1R.sup.d2 or NR.sup.d3 .[.(especially.]., .Iadd.wherein .Iaddend.R.sup.d1, R.sup.d2 and R.sup.d3 is each independently hydrogen, fluoro or .[.C.sub.1-6 alkyl).]. .Iadd.methyl.Iaddend., wherein, when .[.the.]. R is ##STR00054## R.sup.1, R.sup.2 and R.sup.3 is each independently hydrogen.[.or C.sub.1-6 alkyl.]..Iadd., methyl, or ethyl.Iaddend..

.[.2. The compound according to claim 1, wherein, L is methylene, carbonyl, CONHCH.sub.2, NR.sup.c1CH.sub.2, NR.sup.c2CO, NR.sup.c3, CONR.sup.c4 or CH.sub.2NR.sup.c5 (especially, R.sup.c1, R.sup.c2, R.sup.c3, R.sup.c4 and R.sup.c5 is each independently hydrogen, C.sub.1-6alkyl, C.sub.2-6 alkynyl or C.sub.3-8 cycloalkyl), R.sup.X is hydrogen, cyano, hydroxyl, trifluoromethyl, methyl, ethyl or cyclopropyl, R.sup.Y is hydrogen, dimethylamide, cyano, hydroxyl, trifluoromethyl, halo, ethylester, dimethylamine, methyl, methoxymethyl or propargyl, Z is unsubstituted, C.sub.1-6 alkyl, C.sub.1-6 methoxyalkyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.6-10 aromatic cycle or 3-8 membered heterocycle having 1-3 nitrogens, p and q is each independently 1 or 2, W is CR.sup.d1R.sup.d2 or NR.sup.d3 (especially R.sup.d1, R.sup.d2 and R.sup.d3 is each independently hydrogen, fluoro or methyl), R.sup.1, R.sup.2 and R.sup.3 is each independently hydrogen, methyl or ethyl..].

.[.3. The compound according to claim 1, wherein, L is NR.sup.c1CH.sub.2, CONR.sup.c4 or CH.sub.2NR.sup.c5 (especially, R.sup.c1, R.sup.c4 and R.sup.c5 is each independently hydrogen, methyl, ethyl, propyl, propargyl or cyclopropyl), Z is ##STR00055## ##STR00056## ##STR00057## .].

.[.4. The compound according to claim 1, wherein, L is methylene or carbonyl, Z is ##STR00058## .].

5. The compound according to claim 1, wherein, L is .[.CONHCH.sub.2 or.]. NR.sup.c2CO.[.(especially.]., .Iadd.wherein .Iaddend.R.sup.c2 is hydrogen, methyl, ethyl or propyl.[.).]., Z is ##STR00059##

6. The compound according to claim 1, wherein, .[.the present R is ##STR00060## .]. .Iadd.R is .Iaddend. ##STR00061##

.[.7. The compound according to claim 1, wherein, the compound represented by Formula I is selected from the group Consisting of the following compounds: (R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (S)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-hydroxyazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(hydroxymethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide; N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)cyclopropanecarboxamide; (S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide; (R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide; N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide; (S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide; 3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione; (R)-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione; (R)-1-ethyl-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione; 4-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-carboxamide; 4-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (S)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(cyclohexylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(3-(3-(cyclopropylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(3-(3-(cyclobutylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(3-(3-(cyclopentylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(bis(cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(neopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-((2,2-dimethylcyclopentyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; ethyl 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopent-1-enecarboxylate; 4-(4-fluoro-3-(3-(pentan-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-((1-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(bicyclo[2.2.1]heptan-2-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(sec-butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-((dicyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((4-methylpentan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((3-hydroxybutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(pentan-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((1-(1-methyl cyclopropyl)ethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((3,3,3-trifluoro-2-methylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-(allylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(isopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((3-methylbut-2-en-1-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-((cyclopentylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((4,4,4-trifluorobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(pentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-((2-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(propylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (S)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (S)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (S)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-(cyclopropyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(cyclopropyl(ethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(cyclobutyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(cyclopentyl(prop-2-yn-1-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(3,3-difluoropyrrolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(4-fluoropiperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(pyrrolidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(piperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(phenylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(prop-2-yn-1-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (S)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((1-(hydroxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((1-methylcyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (S)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (S)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((1-(methoxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-(but-3-yn-1-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((2-methylallyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((3-hydroxy-2,2-dimethylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)methyl)cyclopropanecarbonitrile; 4-(4-fluoro-3-(3-((2,2,2-trifluoroethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (S)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopentanecarbonitrile; 1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile; 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)propanenitrile; 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)butanenitrile; 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)-3-methylbutanenitrile; 2-cyclopropyl-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)acetonitrile; 4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (S)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (S)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (S)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (S)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile; (R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)nicotinonitrile; (R)-4-(4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylnicotinamide; (R)-4-(3-(3-((5-bromopyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-(benzylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((3,3,3-trifluoropropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(3-([1,3′-bipyrrolidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-(piperidin-1-yl)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (R)-4-(4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-((tert-butylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((phenylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 1-((((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)methyl)amino)methyl)cyclopropanecarbonitrile; 1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)methyl)amino)cyclopropanecarbonitrile; 4-(3-(3-((cyclopropyl(prop-2-yn-1-yl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-((cyclopropyl(methyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-((cyclopropyl(ethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; 4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; 4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; 4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; 4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; 4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; 4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; 4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; 4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; (R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; 1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile hydrochloride; (R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; 4-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; 4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; 4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; 4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; 4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; 4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; 4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; 4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; and 4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride..].

.Iadd.8. A compound, a racemic mixture thereof, an enantiomer thereof, a diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following: 4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(3-(3-(cyclopropylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (R)-4-(3-(3-(cyclopentylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((-1-(trifluoromethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; and 4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one. .Iaddend.

.Iadd.9. The compound according to claim 8, wherein the compound is 4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof. .Iaddend.

.Iadd.10. The compound according to claim 8, wherein the compound is (R)-4-(3-(3-(cyclopropylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof. .Iaddend.

.Iadd.11. The compound according to claim 8, wherein the compound is (R)-4-(3-(3-(cyclopentylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof. .Iaddend.

.Iadd.12. The compound according to claim 8, wherein the compound is 4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof. .Iaddend.

.Iadd.13. The compound according to claim 8, wherein the compound is 4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof. .Iaddend.

.Iadd.14. The compound according to claim 8, wherein the compound is 4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof. .Iaddend.

.Iadd.15. The compound according to claim 8, wherein the compound is 4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof. .Iaddend.

.Iadd.16. The compound according to claim 8, wherein the compound is 4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof. .Iaddend.

.Iadd.17. The compound according to claim 8, wherein the compound is 4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof. .Iaddend.

.Iadd.18. The compound according to claim 8, wherein the compound is 4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof. .Iaddend.

.Iadd.19. The compound according to claim 8, wherein the compound is 4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof. .Iaddend.

.Iadd.20. The compound according to claim 8, wherein the compound is 4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride. .Iaddend.

.Iadd.21. The compound according to claim 8, wherein the compound is 4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride. .Iaddend.

.Iadd.22. The compound according to claim 8, wherein the compound is 4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride. .Iaddend.

.Iadd.23. The compound according to claim 8, wherein the compound is 4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride. .Iaddend.

.Iadd.24. The compound according to claim 8, wherein the compound is 4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride. .Iaddend.

.Iadd.25. The compound according to claim 8, wherein the compound is 4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride. .Iaddend.

.Iadd.26. The compound according to claim 8, wherein the compound is 4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride. .Iaddend.

.Iadd.27. The compound according to claim 8, wherein the compound is 4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride. .Iaddend.

.Iadd.28. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable excipient. .Iaddend.

.Iadd.29. A pharmaceutical composition comprising the compound of claim 16 and a pharmaceutically acceptable excipient. .Iaddend.

.Iadd.30. A pharmaceutical composition comprising the compound of claim 24 and a pharmaceutically acceptable excipient. .Iaddend.

.Iadd.31. A method of inhibiting growth of a tumor associated with cancer in a subject, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 28 to the subject. .Iaddend.

.Iadd.32. The method according to claim 31, wherein the cancer is caused by a defect of BRCA1, BRCA2, and ERG fusion gene. .Iaddend.

.Iadd.33. The method according to claim 32, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, lung cancer, colorectal cancer, brain tumor, prostate cancer and Ewings sarcoma. .Iaddend.

.Iadd.34. A method of inhibiting growth of a tumor associated with cancer in a subject, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 29 to the subject. .Iaddend.

.Iadd.35. The method according to claim 34, wherein the cancer is caused by a defect of BRCA1, BRCA2, and ERG fusion gene. .Iaddend.

.Iadd.36. The method according to claim 35, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, lung cancer, colorectal cancer, brain tumor, prostate cancer and Ewings sarcoma. .Iaddend.

.Iadd.37. A method of inhibiting growth of a tumor associated with cancer in a subject, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 30 to the subject. .Iaddend.

.Iadd.38. The method according to claim 37, wherein the cancer is caused by a defect of BRCA1, BRCA2, and ERG fusion gene. .Iaddend.

.Iadd.39. The method according to claim 38, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, lung cancer, colorectal cancer, brain tumor, prostate cancer and Ewings sarcoma. .Iaddend.

Description

EXAMPLE

Example 1

(R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-1)

Step 1: Preparation of ((R)-benzyl(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)carbamate

(1) 2-fluoro-5-formylbenzoic acid (220 mg, 0.91 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 384 mg, 1.01 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.52 mL, 2.98 mmol) was added to a solution of (R)-benzyl pyrrolidin-3-ylcarbamate (200 mg, 0.91 mmol) in DMF (5 mL) and stirred for 12 hours. The react ion mixture was concentrated in vacuum, added dichloromethane and washed sat. NH.sub.4Cl (ag) and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuum and purified using silica chromatography to give the intermediate compound (R)-benzyl (1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)carbamate (229 mg, 68%).

Step 2: Preparation of (R,Z)-benzyl(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)carbamate

(2) The intermediate compound (Step 1)(236 mg, 0.62 mmol) and triethylamine (0.12 mL, 0.81 mmol) was added to a solution of dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (220 mg, 0.91 mmol) in THF (1.7 mL) and stirred for 5 hours at 0° C. The reaction mixture was concentrated in vacuum then the white residue was slurried in water for 30 minutes, filtered, washed with water, hexane and ether, and dried to yield the intermediate compound (R,Z)-benzyl (1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)carbamate (164 mg, 59%).

Step 3: Preparation of (R)-benzyl(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)carbamate

(3) Hydrazine monohydrate (19 uL, 0.38 mmol) was added to a suspension of the intermediate compound (Step 2)(164 mg, 0.35 mmol) in water (1.5 mL) and stirred for 2 hours at 40° C. The reaction was cooled to room temperature and concentrated in vacuum. Water was added to the react ion mixture and the product was extracted into dichloromethane. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuum and purified using silica chromatography to give (R)-benzyl(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)carbamate (100 mg, 47%).

Step 4: Preparation of (R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(4) The intermediate compound (step 3)(100 mg, 0.20 mmol) and 10 wt. % Pd/C (10 mg) in methanol (30 mL) was hydrogenated at atmosphere for 6 h. The reaction mixture was filtered, evaporated in vacuum and purified using silica chromatography to afford the title compound (63 mg, 85%).

(5) .sup.1H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.50-7.44 (m, 1H), 7.40 (d, 1H), 7.21 (t, 1H), 4.37 (s, 2H), 3.79-3.67 (m, 1H), 3.59-3.33 (m, 3H), 3.29-3.06 (m, 3H).

Example 2

(S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-2)

Step 1: Preparation of (S)-benzyl(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)carbamate

(6) This compound was made using the procedure described for example 1 (Step 1). Thus, (S)-benzylpyrrolidine-3-ylcarbamate (150 mg, 0.68 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (114 mg, 0.68 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 335 mg, 0.88 mmol) and N,N-diisopropyl ethyl amine (DIPEA, 0.24 mL, 1.36 mmol) to afford the intermediate compound (S)-benzyl (1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)carbamate (156 mg, 62%).

Step 2: Preparation of (S,Z)-benzyl(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)carbamate

(7) This compound was made using the procedure described for example 1 (Step 2). Thus, this intermediate compound (Step 1) was reacted with dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (102 mg, 0.42 mmol) and triethyl amine (88 uL, 0.63 mmol) to afford the intermediate compound (S,Z)-benzyl (1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)carbamate (117 mg, 57%).

Step 3: Preparation of (S)-benzyl(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)carbamate

(8) This compound was made using the procedure described for example 1 (Step 3). Thus, this intermediate compound (Step 2) was reacted with hydrazine monohydrate (24 uL, 0.48 mmol) to afford the intermediate compound (S)-benzyl (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl) benzoyl)pyrrolidin-3-yl)carbamate (58 mg, 48%).

Step 4: Preparation of (S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(9) This compound was made using the procedure described for example 1 (Step 4). Thus, this intermediate compound (Step 3)(58 mg, 0.12 mmol) was reacted with 10 wt. Pd/C (6 mg) to afford the title compound (39 mg, 88%).

(10) .sup.1H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.50-7.44 (m, 1H), 7.40 (d, 1H), 7.21 (t, 1H), 4.37 (s, 2H), 3.79-3.67 (m, 1H), 3.59-3.33 (m, 3H), 3.29-3.06 (m, 3H).

Example 3

4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-3)

Step 1: Preparation of benzyl(1-(2-fluoro-5-formylbenzoyl)azetidin-3-yl)carbamate

(11) This compound was made using the procedure described for example 1 (Step 1). Thus, benzyl azetidine-3-ylcarbamate (500 mg, 2.42 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (408 mg, 2.42 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 1.20 g, 3.15 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.84 mL, 4.85 mmol) to affoed the intermediate compound benzyl (1-(2-fluoro-5-formylbenzoyl)azetidin-3-yl)carbamate (604 mg, 70%).

Step 2: Preparation of (Z)-benzyl(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)carbamate

(12) This compound was made using the procedure described for example 1 (Step 2). Thus, this intermediate compound (Step 1)(604 mg, 1.69 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (410 mg, 1.69 mmol) and triethylamine (0.35 mL, 2.54 mmol) to afford the intermediate compound (Z)-benzyl (1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)carbamate (497 mg, 62%).

Step 3: Preparation of benzyl(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)carbamate

(13) This compound was made using the procedure described for example 1 (Step 3). Thus, this intermediate compound (Step 2)(497 mg, 1.05 mmol) was reacted with hydrazine monohydrate (0.1 mL, 2.1 mmol) to afford the intermediate compound benzyl (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)carbamate (261 mg, 51%).

Step 4: Preparation of 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(14) This compound was made using the procedure described for example 1 (Step 4). Thus, this intermediate compound (Step 3)(261 mg, 0.54 mmol) was reacted with 10 wt. % Pd/C (30 mg) to afford the title compound (174 mg, 91%).

(15) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.27-8.25 (m, 1H), 7.97 (d, 1H), 7.91-7.81 (m, 2H), 7.48-7.44 (m, 1H), 7.41-7.39 (m, 1H), 7.21 (t, 1H), 4.33 (s, 2H), 4.15-4.10 (m, 2H), 3.66-3.59 (m, 3H).

Example 4

(R)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-4)

Step 1: Preparation of (R)-3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

(16) This compound was made using the procedure described for example 1 (Step 1). Thus, (R)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (300 mg, 1.49 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (250 mg, 1.49 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 734 mg, 1.93 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.52 mL, 2.97 mmol) to afford the intermediate compound (R)-3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (377 mg, 72%).

Step 2: Preparation of (R,Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

(17) This compound was made using the procedure described for example 1 (Step 2). Thus, this intermediate compound (Step 1)(377 mg, 1.07 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (260 mg, 1.07 mmol) and trietylamine (0.22 mL, 1.61 mmol) to afford the intermediate compound (R,Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyidene)isobenzofuran-1(3H)-one (300 mg, 60%).

Step 3: Preparation of ((R)-4-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(18) This compound was made using the procedure described for example 1 (Step 3). Thus, this intermediate compound (Step 2)(300 mg, 0.64 mmol) was reacted with hydrazine monohydrate (63 uL, 1.28 mmol) to afford the intermediate compound (R)-4-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (148 mg, 48%).

Step 4: Preparation of (R)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(19) The intermediate compound (step 3)(148 mg, 0.30 mmol) in THF (3 mL) cooled to 0° C. was added 1M solution of tetra-n-butylammonium fluoride in THF (TBAF, 0.60 mL, 0.60 mmol), and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuum, added dichloromethane and washed with sat. NH.sub.4Cl (ag) and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuum and purified using silica chromatography to afford the title compound (101 mg, 92%).

(20) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.25 (d, 1H), 7.98 (d, 1H), 7.87 (t, 1H), 7.82 (t, 1H), 7.51-7.45 (m, 1H), 7.40 (d, 1H), 7.21 (t, 1H), 4.37 (s, 2H), 3.79-3.65 (m, 2H), 3.59-3.28 (m, 5H).

Example 5

(S)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

Step 1: Preparation of (S)-3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

(21) This compound was made using the procedure described for example 1 (Step 1). Thus, (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (300 mg, 1.49 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (250 mg, 1.49 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 734 mg, 1.93 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.52 mL, 2.97 mmol) to afford the intermediate compound (S)-3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (377 mg, 72%).

Step 2: Preparation of (S,Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

(22) This compound was made using the procedure described for example 1 (Step 2). Thus, this intermediate compound (Step 1)(377 mg, 1.07 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (260 mg, 1.07 mmol) and trietylamine (0.22 mL, 1.61 mmol) to afford the intermediate compound (S,Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (300 mg, 60%).

Step 3: Preparation of (S)-4-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(23) This compound was made using the procedure described for example 1 (Step 3). Thus, this intermediate compound (Step 2)(300 mg, 0.64 mmol) was reacted with hydrazine monohydrate (63 uL, 1.28 mmol) to afford the intermediate compound (S)-4-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (148 mg, 48%).

Step 4: Preparation of (S)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(24) This compound was made using the procedure described for example 4 (Step 4). Thus, this intermediate compound (Step 3)(144 mg, 0.30 mmol) was reacted with a 1M solution of tetra-n-butylammonium fluoride in THF (TBAF, 0.60 mL, 0.60 mmol) to afford the title compound (101 mg, 92%).

(25) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.25 (d, 1H), 7.98 (d, 1H), 7.87 (t, 1H), 7.82 (t, 1H), 7.51-7.45 (m, 1H), 7.40 (d, 1H), 7.21 (t, 1H), 4.37 (s, 2H), 3.79-3.65 (m, 2H), 3.59-3.28 (m, 5H).

Example 6

4-(4-fluoro-3-(3-hydroxyazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-6)

Step 1: Preparation of 3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzaldehyde

(26) This compound was made using the procedure described for example 1 (Step 1). Thus, 3-((tert-butyldimethylsilyl)oxy)azetidine (300 mg, 1.60 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (269 mg, 1.60 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 789 mg, 2.08 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.56 mL, 3.20 mmol) to afford the intermediate compound 3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzaldehyde (378 mg, 70%).

Step 2: Preparation of (Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

(27) This compound was made using the procedure described for example 1 (Step 2). Thus, this intermediate compound (Step 1)(378 mg, 1.12 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (271 mg, 1.12 mmol) and trietylamine (0.23 mL, 1.68 mmol) to afford the intermediate compound (Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (284 mg, 56%).

Step 3: Preparation of 4-(3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(28) This compound was made using the procedure described for example 1 (Step 3). Thus, this intermediate compound (Step 2)(284 mg, 0.62 mmol) was reacted with hydrazine monohydrate (61 uL, 1.26 mmol) to afford the intermediate compound 4-(3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (149 mg, 51%).

Step 4: Preparation of 4-(4-fluoro-3-(3-hydroxyazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(29) This compound was made using the procedure described for example 4 (Step 4). Thus, this intermediate compound (Step 3)(149 mg, 0.32 mmol) was reacted with a 1M solution of tetra-n-butylammonium fluoride in THF (TBAF, 0.64 mL, 0.64 mmol) to afford the title compound (98 mg, 92%).

(30) .sup.1H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.27-8.26 (m, 1H), 7.96 (d, 1H), 7.91-7.81 (m, 2H), 7.48-7.45 (m, 1H), 7.41-7.39 (m, 1H), 7.20 (t, 1H), 4.33 (s, 2H), 4.15-4.11 (m, 3H), 3.66-3.58 (m, 2H).

Example 7

4-(4-fluoro-3-(3-(hydroxyethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-7)

Step 1: Preparation of 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde

(31) This compound was made using the procedure described for example 1 (Step 1). Thus, 3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine (300 mg, 1.60 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (269 mg, 1.60 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 789 mg, 2.08 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.56 mL, 3.20 mmol) to afford the intermediate compound 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde (378 mg, 72%).

Step 2: Preparation of (Z)-3-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

(32) This compound was made using the procedure described for example 1 (Step 2). Thus, this intermediate compound (Step 1)(378 mg, 1.12 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (271 mg, 1.12 mmol) and trietylamine (0.23 mL, 1.68 mmol) to afford the intermediate compound (Z)-3-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (284 mg, 56%).

Step 3: Preparation of 4-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(33) This compound was made using the procedure described for example 1 (Step 3). Thus, this intermediate compound (Step 2)(284 mg, 0.63 mmol) was reacted with hydrazine monohydrate (61 uL, 1.25 mmol) to afford the intermediate compound 4-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (149 mg, 51%).

Step 4: Preparation of 4-(4-fluoro-3-(3-(hydroxymethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(34) This compound was made using the procedure described for example 4 (Step 4). Thus, this intermediate compound (Step 3)(149 mg, 0.32 mmol) was reacted with a 1M solution of tetra-n-butylammonium fluoride in THF (TBAF, 0.64 mL, 0.64 mmol) to afford the title compound (98 mg, 92%).

(35) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.28-8.26 (m, 1H), 7.97 (d, 1H), 7.92-7.81 (m, 2H), 7.49-7.45 (m, 1H), 7.42-7.39 (m, 1H), 7.21 (t, 1H), 4.33 (s, 2H), 4.15-4.11 (m, 3H), 3.66-3.58 (m, 2H), 3.47 (m, 2H).

Example 8

(R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide; (I-8)

Step 1: Preparation of (R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide

(36) Cyclopropanecarboxylic acid (20 uL, 0.28 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 66 mg, 0.42 mmol) and 4-(Dimethylamino)pyridine (DMAP, 68 mg, 0.56 mmol) was added to a solution of (R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 1)(100 mg, 0.28 mmol) in dichloromethane (1.5 mL) and stirred for 12 hours. The reaction mixture was concentrated in vacuum, added dichloromethane and washed sat. NH.sub.4Cl (ag) and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuum and purified using silica chromatography to afford title compound (83 mg, 68%).

(37) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.36 (d, 1H), 8.46 (m, 1H), 7.79 (m, 2H), 7.71 (m, 1H), 7.35 (m, 1H), 7.32 (m, 1H), 7.04 (q, 1H), 5.89 (m, 1H), 4.60 (q, 0.3H), 4.45 (q, 0.7H), 4.26 (d, 2H), 3.82 (m, 1H), 3.65 (m, 1H), 3.51 (m, 1H), 3.40 (m, 1H), 3.18 (m, 1H), 2.28 (m, 2H), 1.61 (m, 1H), 0.98 (m, 11H), 0.96 (m, 2H), 0.74 (m, 2H).

Example 9

N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)cyclopropanecarboxamide; (I-9)

Step 1: Preparation of N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)cyclopropanecarboxamide

(38) This compound was made using the procedure described for example 8 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(100 mg, 0.28 mmol) was reacted with cyclopropanecarboxylic acid (20 uL, 0.28 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 66 mg, 0.42 mmol) and 4-(Dimethylamino)pyridine (DMAP, 68 mg, 0.56 mmol) to afford the title compound (78 mg, 62%).

(39) .sup.1H-NMR (MeOD, 400 MHz): δ 8.39 (dd, 1H), 7.94 (dd, 1H), 7.85-7.80 (m, 2H), 7.52-7.45 (m, 2H), 7.17-7.12 (m, 1H), 4.63-4.53 (m, 1H), 4.44-4.37 (m, 3H), 4.30-4.21 (m, 1H), 4.01-3.89 (m, 2H), 1.59-1.52 (m, 1H), 0.92-0.78 (m, 4H).

Example 10

(S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide; (I-10)

Step 1: Preparation of (S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide

(40) This compound was made using the procedure described for example 8 (Step 1). Thus, (S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 2)(100 mg, 0.28 mmol) was reacted with cyclopropanecarboxylic acid (20 uL, 0.28 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 66 mg, 0.42 mmol) and 4-(Dimethylamino)pyridine (DMAP, 68 mg, 0.56 mmol) to afford the title compound (77 mg, 65%).

(41) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 9.55 (s, 0.6H), 9.52 (s, 0.6H), 8.46 (d, 1H), 7.82-7.71 (m, 3H), 7.38-7.26 (m, 2H), 7.04 (q, 1H), 5.75 (m, 1H), 4.60 (m, 0.4H), 4.42 (m, 0.6H), 4.28 (s, 0.8H), 4.27 (s, 1.2H), 3.92-3.64 (m, 2.4H), 3.56-3.33 (m, 1H), 3.17 (dd, 0.6H), 2.33-2.16 (m, 1H), 1.93 (m, 1H), 1.32 (m, 1H), 0.96 (m, 2H), 0.75 (m, 2H).

Example 11

(R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide; (I-11)

Step 1: Preparation of (R)—N-(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide

(42) 2-fluoro-5-formylbenzoic acid (350 mg, 2.08 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 1.02 g, 2.79 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.72 mL, 4.16 mmol) was added to a solution of (R)—N-methyl-N-(pyrrolidin-3-yl)cyclopropanecarboxamide (350 mg, 2.08 mmol) in DMF (5 mL) and stirred for 12 hours. The react ion mixture was concentrated in vacuum, added dichloromethane and washed sat. NH.sub.4Cl (ag) and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuum and purified using silica chromatography to afford the intermediate compound (R)—N-(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide (470 mg, 72%). (R)-benzyl(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)carbamate (229 mg, 68%).

Step 2: Preparation of (R,Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide

(43) Trietylamine (0.38 mL, 2.21 mmol) was added drop-wide to a solution of the intermediate compound (Step 1)(470 mg, 1.48 mmol) and dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (357 mg, 1.48 mmol) in THF (1.7 mL) and stirred for 5 hours at 0° C. The reaction mixture was concentrated in vacuum then the white residue was slurried in water for 30 minutes, filtered, washed with water, hexane and ether, and dried to afford the intermediate compound (R,Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide (398 mg, 62%).

Step 3: Preparation of (R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide

(44) Hydrazine monohydrate (90 uL, 1.83 mmol) was added to a suspension of the intermediate compound (Step 2)(398 mg, 0.92 mmol) in ethanol (1.5 mL) and stirred at 40° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuum. Water was added to the react ion mixture and the product was extracted into dichloromethane. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuum and purified using silica chromatography to afford the title compound (184 mg, 45%).

(45) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 5.35 (q, 0.7H), 4.78 (q, 0.3H), 3.65 (m, 1H), 3.51 (m, 1H), 3.40 (m, 1H), 3.01 (s, 3H), 2.28 (m, 2H), 1.61 (m, 1H), 0.98 (m, 1H), 0.96 (m, 2H), 0.74 (m, 2H).

Example 12

N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)azetidin-3-yl)-N-ethylcyclopropanecarboxamide; (I-12)

Step 1: Preparation of N-(1-(2-fluoro-5-formylbenzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide

(46) This compound was made using the procedure described for example 11 (Step 1). Thus, N-(azetidin-3-yl)-N-methylcyclopropanecarboxamide (200 mg, 1.30 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (218 mg, 1.30 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 640 mg, 1.68 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.45 mL, 2.59 mmol) to afford the intermediate compound N-(1-(2-fluoro-5-formylbenzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide (256 mg, 65%).

Step 2: Preparation of (Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide

(47) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(256 mg, 0.84 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (204 mg, 0.84 mmol) and trietylamine (0.17 mL, 1.26 mmol) to afford the intermediate compound (Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide (202 mg, 57%).

Step 3: Preparation of N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide

(48) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(202 mg, 0.48 mmol) was reacted with hydrazine monohydrate (46 uL, 0.96 mmol) to afford the title compound (106 mg, 51%).

(49) .sup.1H-NMR (MeOD, 400 MHz): δ 8.39 (dd, 1H), 7.94 (dd, 1H), 7.85-7.80 (m, 2H), 7.52-7.45 (m, 2H), 7.17-7.12 (m, 1H), 4.63-4.53 (m, 1H), 4.44-4.37 (m, 3H), 4.30-4.21 (m, 1H), 4.01-3.89 (m, 2H), 3.26 (s, 3H), 1.59-1.52 (m, 1H), 0.92-0.78 (m, 4H).

Example 13

(S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide; (I-13)

Step 1: Preparation of (S)—N-(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide

(50) This compound was made using the procedure described for example 11 (Step 1). Thus, (S)—N-methyl-N-(pyrrolidin-3-yl)cyclopropanecarboxamide (350 mg, 2.08 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (349 mg, 2.08 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 1.02 mg, 2.70 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.72 mL, 4.16 mmol) to afford the intermediate compound (S)—N-(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide (470 mg, 71%).

Step 2: Preparation of (S,Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide

(51) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(470 mg, 1.48 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (357 mg, 1.48 mmol) and trietylamine (0.31 mL, 2.12 mmol) to afford the intermediate compound (S,Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide (397 mg, 62%).

Step 3: Preparation of (S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide

(52) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(397 mg, 0.92 mmol) was reacted with hydrazine monohydrate (90 uL, 1.83 mmol) to afford the title compound (185 mg, 45%).

(53) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.13 (s, 0.5H), 9.97 (s, 0.5H), 8.46 (s, 1H), 7.81-7.70 (m, 3H), 7.37 (m, 1H), 7.30 (m, 1H), 7.03 (q, 1H), 5.34 (m, 0.5H), 5.13 (m, 0.5H), 4.27 (d, 2H), 3.88 (m, 0.5H), 3.78 (m, 0.5H), 3.66-3.34 (m, 3H), 3.20-3.14 (m, 3.5H), 2.98-2.82 (m, 0.5H), 2.20-2.06 (m, 1H), 1.78-1.65 (m, 1H), 1.06-0.92 (m, 2H), 0.81 (m, 2H).

Example 14

3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione; (I-14)

Step 1: Preparation of 3-(3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzaldehyde

(54) This compound was made using the procedure described for example 11 (Step 1). Thus, 3-(azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione (150 mg, 0.82 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (137 mg, 0.82 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 403 mg, 1.06 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.29 mL, 1.63 mmol) to afford the intermediate compound 3-(3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzaldehyde (152 mg, 56%).

Step 2: Preparation of (Z)-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione

(55) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(152 mg, 0.45 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (111 mg, 0.45 mmol) and trietylamine (96 uL, 0.68 mmol) to afford the intermediate compound (Z)-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione (89 mg, 43%).

Step 3: Preparation of 3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione

(56) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(89 mg, 0.19 mmol) was reacted with hydrazine monohydrate (20 uL, 0.39 mmol) to afford the title compound (47 mg, 51%).

(57) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36-8.35 (m, 1H), 7.92 (t, 1H), 7.98 (d, 1H), 7.90-7.82 (m, 2H), 7.48-7.43 (m, 2H), 7.22 (t, 1H), 4.34 (s, 2H), 4.07-4.03 (m, 1H), 3.94 (t, 1H), 3.85-3.76 (m, 2H), 3.27-3.23 (m, 1H), 1.32 (s, 6H).

Example 15

(R)-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione; (I-15)

Step 1: Preparation of (R)-3-(3-(2,5-dioxoimidazolidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

(58) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)-3-(pyrrolidin-3-yl)imidazolidine-2,4-dione (150 mg, 0.88 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (149 mg, 0.88 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 437 mg, 1.15 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.31 mL, 1.77 mmol) to afford the intermediate compound (R)-3-(3-(2,5-dioxoimidazolidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (158 mg, 56%).

Step 2: Preparation of (R,Z)-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione

(59) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(158 mg, 0.50 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (120 mg, 0.50 mmol) and trietylamine (58 uL, 0.42 mmol) to afford the intermediate compound (R,Z)-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione (93 mg, 43%).

Step 3: Preparation of (R)-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione

(60) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(93 mg, 0.21 mmol) was reacted with hydrazine monohydrate (21 uL, 0.43 mmol) to afford the title compound (54 mg, 56%).

(61) .sup.1H-NMR (MeOD, 400 MHz): δ 8.35-8.32 (m, 1H), 7.91 (t, 1H), 7.86-7.77 (m, 2H), 7.47-7.38 (m, 2H), 7.16-7.10 (m, 1H), 4.80-4.58 (m, 1H), 4.35 (d, 2H), 3.98-3.94 (m, 2H), 3.68-3.60 (m, 1H), 3.51-3.45 (m, 2H), 2.50-2.32 (m, 1H), 2.24-2.12 (m, 2H).

Example 16

(R)-1-ethyl-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione; (I-16)

Step 1: Preparation of (R)-3-(3-(3-ethyl-2,5-dioxoimidazolidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

(62) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)-1-ethyl-3-(pyrrolidin-3-yl)imidazolidine-2,4-dione (200 mg, 1.01 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (170 mg, 1.01 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 500 mg, 1.31 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.35 mL, 2.02 mmol) to afford the intermediate compound (R)-3-(3-(3-ethyl-2,5-dioxoimidazolidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (197 mg, 56%).

Step 2: Preparation of (R,Z)-1-ethyl-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione

(63) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(197 mg, 0.56 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (137 mg, 0.56 mmol) and trietylamine (0.12 mL, 0.85 mmol) to afford the intermediate compound (R,Z)-1-ethyl-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione (134 mg, 51%).

Step 3: Preparation of (R)-1-ethyl-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione

(64) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(134 mg, 0.29 mmol) was reacted with hydrazine monohydrate (28 uL, 0.58 mmol) to afford the title compound (66 mg, 48%).

(65) .sup.1H-NMR (MeOD, 400 MHz): δ 8.37-8.34 (m, 1H), 7.92 (t, 1H), 7.87-7.80 (m, 2H), 7.49-7.43 (m, 1H), 7.41-7.39 (m, 1H), 7.17-7.11 (m, 1H), 4.78-4.59 (m, 1H), 4.37 (d, 2H), 3.94 (s, 2H), 3.87 (d, 2H), 3.84-3.79 (m, 1H), 3.67-3.60 (m, 1H), 3.47-3.35 (m, 2H), 2.59-2.44 (m, 1H), 2.19 (d, 2H), 1.20-1.13 (m, 3H).

Example 17

4-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-17)

Step 1: Preparation of 4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzaldehyde

(66) This compound was made using the procedure described for example 11 (Step 1). Thus, azetidin-3-yl(4-fluoropiperidin-1-yl)methanone (200 mg, 1.07 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (180 mg, 1.07 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 529 mg, 1.40 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.37 mL, 2.14 mmol) to afford the intermediate compound 4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzaldehyde (216 mg, 60%).

Step 2: Preparation of (Z)-3-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

(67) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(261 mg, 0.64 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (156 mg, 0.64 mmol) and trietylamine (0.13 mL, 0.96 mmol) to afford the intermediate compound (Z)-3-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (140 mg, 48%).

Step 3: Preparation of 4-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(68) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(140 mg, 0.31 mmol) was reacted with hydrazine monohydrate (30 uL, 0.62 mmol) to afford the title compound (76 mg, 53%).

(69) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.95 (d, 1H), 7.79-7.90 (m, 2H), 7.45-7.60 (m, 2H), 7.15 (t, 1H), 4.37 (s, 2H), 4.32 (d, 1H), 4.15-4.27 (m, 3H), 3.70-3.88 (m, 2H), 3.41-3.62 (m, 2H), 3.27-3.36 (m, 2H), 1.76-1.94 (m, 4H).

Example 18

4-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-18)

Step 1: Preparation of 3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde

(70) This compound was made using the procedure described for example 11 (Step 1). Thus, azetidin-3-yl(3,3-difluoroazetidin-1-yl)methanone (200 mg, 1.14 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (190 mg, 1.14 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 560 mg, 1.47 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.41 mL, 2.27 mmol) to afford the intermediate compound 3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde (222 mg, 60%).

Step 2: Preparation of (Z)-3-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

(71) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(222 mg, 0.68 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (164 mg, 0.68 mmol) and trietylamine (0.14 mL, 1.02 mmol) to afford the intermediate (Z)-3-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (145 mg, 48%).

Step 3: Preparation of 4-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(72) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(145 mg, 0.33 mmol) was reacted with hydrazine monohydrate (31 uL, 0.65 mmol) to afford the title compound (79 mg, 53%).

(73) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.94 (d, 1H), 7.79-7.89 (m, 2H), 7.46-7.58 (m, 2H), 7.14 (t, 1H), 4.46-4.64 (m, 2H), 4.25-4.40 (m, 5H), 4.05-4.23 (m, 3H), 3.51-3.59 (m, 1H).

Example 19

4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-19)

Step 1: Preparation of 3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde

(74) This compound was made using the procedure described for example 11 (Step 1). Thus, azetidin-3-yl(3,3-difluoropyrrolidin-1-yl)methanone (200 mg, 1.05 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (176 mg, 1.05 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 518 mg, 1.05 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.37 mL, 1.37 mmol) to afford the intermediate compound 3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde (214 mg, 60%).

Step 2: Preparation of (Z)-3-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

(75) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(214 mg, 0.63 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (152 mg, 0.63 mmol) and trietylamine (0.13 mL, 0.94 mmol) to afford the intermediate compound (Z)-3-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (138 mg, 48%).

Step 3: Preparation of 4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(76) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(138 mg, 0.31 mmol) was reacted with hydrazine monohydrate (30 uL, 0.62 mmol) to afford the title compound (75 mg, 53%).

(77) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.95 (d, 1 Hz), 7.80-7.90 (m, 2H), 7.45-7.54 (m, 2H), 7.15 (t, 1H), 4.38 (s, 2H), 4.29-4.36 (m, 2H), 4.16-4.28 (m, 3H), 3.58-3.85 (m, 4H), 2.36-2.51 (m, 2H).

Example 20

4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-20)

Step 1: Preparation of 3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

(78) This compound was made using the procedure described for example 11 (Step 1). Thus, (3,3-difluoropyrrolidin-1-yl)(pyrrolidin-3-yl)methanone (210 mg, 1.03 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (172 mg, 1.03 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 507 mg, 1.33 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.36 mL, 2.05 mmol) to afford the intermediate compound 3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (218 mg, 60%).

Step 2: Preparation of (Z)-3-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

(79) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(218 mg, 0.62 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (149 mg, 0.62 mmol) and trietylamine (0.13 mL, 0.93 mmol) to afford the intermediate compound (Z)-3-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (139 mg, 48%).

Step 3: Preparation of 4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(80) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(139 mg, 0.30 mmol) was reacted with hydrazine monohydrate (29 uL, 0.59 mmol) to afford the title compound (76 mg, 53%).

(81) .sup.1H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.26 (d, 1H), 7.98 (d, 1H), 7.90 (t, 1H), 7.86-7.80 (m, 1H), 7.46-7.37 (m, 2H), 7.22 (t, 1H), 4.33 (s, 2H), 4.08-3.98 (m, 1H), 3.79-3.67 (m, 2H), 3.64-3.42 (m, 3H), 3.32-3.16 (m, 2H), 2.49-2.32 (m, 2H), 2.23-2.04 (m, 1H), 1.97-1.87 (m, 1H), 1.18 (t, 1H).

Example 21

(R)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)pyrrolidine-3-carboxamide; (I-21)

Step 1: Preparation of (R)—N-(cyclopropylmethyl)-1-(2-fluoro-5-formylbenzoyl)pyrrolidine-3-carboxamide

(82) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)—N-(cyclopropylmethyl)pyrrolidine-3-carboxamide (300 mg, 1.78 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (299 mg, 1.78 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 879 mg, 2.32 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.63 mL, 3.57 mmol) to afford the intermediate compound (R)—N-(cyclopropylmethyl)-1-(2-fluoro-5-formylbenzoyl)pyrrolidine-3-carboxamide (266 mg, 47%).

Step 2: Preparation of (R,Z)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidine-3-carboxamide

(83) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(266 mg, 0.84 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (203 mg, 0.84 mmol) and trietylamine (0.18 mL, 1.26 mmol) to afford the intermediate compound (R,Z)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidine-3-carboxamide (186 mg, 51%).

Step 3: Preparation of (R)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-carboxamide

(84) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(186 mg, 0.43 mmol) was reacted with hydrazine monohydrate (42 uL, 0.85 mmol) to afford the title compound (84 mg, 44%).

(85) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36-8.34 (m, 1H), 7.93 (t, 1H), 7.88-7.78 (m, 2H), 7.47-7.39 (m, 2H), 7.14 (t, 1H), 4.37 (s, 2H), 3.82-3.53 (m, 2H), 3.49-3.33 (m, 2H), 3.12-2.96 (m, 3H), 2.22-1.96 (m, 2H), 0.99-0.88 (m, 1H), 0.52-0.44 (m, 2H), 2.24-2.02 (m, 2H).

Example 22

4-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-22)

Step 1: Preparation of 4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzaldehyde

(86) This compound was made using the procedure described for example 11 (Step 1). Thus, azetidin-3-yl(pyrrolidin-1-yl)methanone (200 mg, 1.30 mmol) was 2-fluoro-5-formyl benzoic acid (218 mg, 1.30 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 639 mg, 1.69 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.45 mL, 2.59 mmol) to afford the intermediate 4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzaldehyde (244 mg, 62%).

Step 2: Preparation of (Z)-3-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

(87) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(244 mg, 0.80 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (194 mg, 0.80 mmol) and trietylamine (0.17 mL, 1.21 mmol) to afford the intermediate compound (Z)-3-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (172 mg, 51%).

Step 3: Preparation of 4-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(88) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(172 mg, 0.42 mmol) was reacted with hydrazine monohydrate (40 uL, 0.82 mmol) to afford the title compound (97 mg, 55%).

(89) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.37 (m, 1H), 7.24 (d, 1H), 7.80-7.90 (m, 2H), 7.49 (m, 2H), 7.14 (t, 1H), 4.37 (s, 2H), 4.32 (t, 1H), 4.22 (m, 3H), 3.71 (m, 1H), 3.44 (m, 2H), 3.30-3.44 (m, 2H), 1.86-1.97 (m, 4H).

Example 23

(R)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-23)

Step 1: Preparation of (R)-3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde

(90) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)-azetidin-3-yl(3-(dimethylamino)pyrrolidin-1-yl)methanone (200 mg, 1.05 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (176 mg, 2.05 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 515 mg, 1.36 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.52 mL, 2.98 mmol) to afford the intermediate compound (R)-3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde (150 mg, 42%).

Step 2: Preparation of (R,Z)-3-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

(91) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(150 mg, 0.44 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (106 mg, 0.44 mmol) and trietylamine (92 uL, 0.65 mmol) to afford the intermediate compound (R,Z)-3-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (102 mg, 51%).

Step 3: Preparation of (R)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(92) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(102 mg, 0.22 mmol) was reacted with hydrazine monohydrate (21 uL, 0.45 mmol) to afford the title compound (53 mg, 50%).

(93) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (m, 1H), 7.94-7.92 (m, 1H), 7.89-7.80 (m, 2H), 7.56-7.39 (m, 2H), 7.16 (t, 1H), 4.36 (s, 2H), 4.20-4.03 (m, 2H), 3.96-3.80 (m, 2H), 3.67 (m, 1H), 3.44 (t, 2H), 3.39-3.32 (m, 2H), 2.98-2.90 (m, 1H), 2.10 (s, 6H), 1.82-1.80 (m, 2H).

Example 24

(S)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-24)

Step 1: Preparation of (S)-3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde

(94) This compound was made using the procedure described for example 11 (Step 1). Thus, (S)-azetidin-3-yl(3-(dimethylamino)pyrrolidin-1-yl)methanone (200 mg, 1.05 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (176 mg, 2.05 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 515 mg, 1.36 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.52 mL, 2.98 mmol) to afford the intermediate compound (S)-3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde (150 mg, 42%).

Step 2: Preparation of (S,Z)-3-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

(95) This compound was made using the procedure described for example 11 (Step 2). Thus, this intermediate compound (Step 1)(150 mg, 0.44 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (106 mg, 0.44 mmol) and trietylamine (92 uL, 0.65 mmol) to afford the intermediate compound (S,Z)-3-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one (102 mg, 51%).

Step 3: Preparation of (S)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(96) This compound was made using the procedure described for example 11 (Step 3). Thus, this intermediate compound (Step 2)(102 mg, 0.22 mmol) was reacted with hydrazine monohydrate (21 uL, 0.45 mmol) to afford the title compound (53 mg, 50%).

(97) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (m, 1H), 7.94-7.92 (m, 1H), 7.89-7.80 (m, 2H), 7.56-7.39 (m, 2H), 7.16 (t, 1H), 4.36 (s, 2H), 4.20-4.03 (m, 2H), 3.96-3.80 (m, 2H), 3.67 (m, 1H), 3.44 (t, 2H), 3.39-3.32 (m, 2H), 2.98-2.90 (m, 1H), 2.10 (s, 6H), 1.82-1.80 (m, 2H).

Example 25

4-(3-(3-(cyclobutyl amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-25)

Step 1: Preparation of 4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(98) Cyclobutanone (42 uL, 0.57 mmol) was added to a solution of 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(100 mg, 0.28 mmol) in 1,2-dichloroethane (2 mL) and stirred for 30 min then acetic acid (32 uL, 0.56 mmol) and triacetoxyborohydride (118 mg, 0.56 mmol) was added to the reaction mixture at 0° C. and stirred for 12 hours. The reaction mixture was concentrated in vacuum, added 2N NaOH(aq) and extracted into dichloromethane. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuum and purified using silica chromatography to afford the title compound (82 mg, 72%).

(99) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.50-7.21 (m, 2H), 7.21 (t, 1H), 4.33 (s, 2H), 4.10 (t, 1H), 3.97 (t, 1H), 3.67-3.51 (m, 3H), 3.08 (m, 1H), 2.76 (m, 1H), 1.99 (t, 2H), 1.69-1.46 (m, 4H).

Example 26

4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-26)

Step 1: Preparation of 4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(100) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with (1-ethoxycyclopropoxy)trimethylsilane(51 uL, 0.57 mmol) and sodium triacetoxyborohydride (248 mg, 1.17 mmol) to afford the title compound (152 mg, 68%).

(101) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.93 (d, 1H), 7.79-7.89 (m, 2H), 7.48-7.54 (m, 1H), 7.42 (d, 1H), 7.15 (t, 1H), 4.00-4.05 (m, 2H), 3.75-3.80 (m, 2H), 3.34-3.39 (m, 1H), 3.12 (s, 2H), 1.32-1.36 (m, 1H), 0.64-0.72 (m, 2H), 0.41-0.46 (m, 2H).

Example 27

4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-27)

Step 1: Preparation of 4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(102) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with cyclopentanone (51 uL, 0.57 mmol) and sodium triacetoxyborohydride (248 mg, 1.178 mmol) to afford the title compound (240 mg, 66%).

(103) .sup.1H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.44-7.50 (m, 1H), 7.40 (d, 1H), 7.21 (t, 1H), 4.33 (s, 2H), 4.13 (t, 1H), 4.00 (t, 1H), 3.54-3.70 (m, 3H), 2.82-2.91 (m, 1H), 1.52-1.67 (m, 4H), 1.43 (brs, 2H), 1.10-1.27 (m, 2H).

Example 28

4-(3-(3-(cyclohexylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-28)

Step 1: Preparation of 4-(3-(3-(cyclohexylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(104) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with cyclohexanone (59 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (203 mg, 82%).

(105) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H), 7.91-7.81 (m, 2H), 7.49-7.45 (m, 1H), 7.41-7.39 (m, 1H), 7.21 (t, 1H), 4.33 (s, 2H), 4.16-3.98 (m, 2H), 3.67-3.58 (m, 3H), 2.33-2.26 (m, 1H), 1.72-1.61 (m, 4H), 1.52 (d, 1H), 1.23-1.06 (m, 3H), 1.00-0.90 (m, 2H).

Example 29

(R)-4-(3-(3-(cyclopropylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-29)

Step 1: Preparation of (R)-4-(3-(3-(cyclopropylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(106) This compound was made using the procedure described for example 25 (Step 1). Thus, (R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 1)(200 mg, 0.54 mmol) was reacted with (1-ethoxycyclopropoxy)tri methylsilane(49 uL, 0.54 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (142 mg, 65%).

(107) .sup.1H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.27-8.25 (m, 1H), 7.97 (d, 1H), 7.89-7.82 (m, 2H), 7.44-7.33 (m, 2H), 7.22 (t, 1H), 4.32 (s, 2H), 3.29-3.23 (m, 2H), 3.15-2.99 (m, 1H), 2.06-1.73 (m, 3H), 1.24 (s, 1H), 0.39-0.13 (m, 4H).

Example 30

(R)-4-(3-(3-(cyclobutylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-30)

Step 1: Preparation of (R)-4-(3-(3-(cyclobutylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(108) This compound was made using the procedure described for example 25 (Step 1). Thus, (R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 1)(200 mg, 0.54 mmol) was reacted with cyclobutanone (41 uL, 0.54 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (163 mg, 72%).

(109) .sup.1H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.44-7.50 (m, 1H), 7.40 (d, 1H), 7.21 (t, 1H), 4.37 (s, 2H), 3.79-3.67 (m, 1H), 3.59-3.33 (m, 3H), 3.29-3.06 (m, 3H), 2.76 (m, 1H), 1.99 (t, 2H), 1.69-1.46 (m, 4H).

Example 31

(R)-4-(3-(3-(cyclopentylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-31)

Step 1: Preparation of (R)-4-(3-(3-(cyclopentylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(110) This compound was made using the procedure described for example 25 (Step 1). Thus, (R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 1)(200 mg, 0.54 mmol) was reacted with cyclopentanone (48 uL, 0.54 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (190 mg, 81%).

(111) .sup.1H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.44-7.50 (m, 1H), 7.40 (d, 1H), 7.21 (t, 1H), 4.37 (s, 2H), 3.79-3.67 (m, 1H), 3.59-3.33 (m, 3H), 3.29-3.06 (m, 3H), 2.82-2.91 (m, 1H), 1.52-1.67 (m, 4H), 1.43 (brs, 2H), 1.10-1.27 (m, 2H).

Example 32

4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-32)

Step 1: Preparation of 4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(112) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with acetone (42 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (123 mg, 55%).

(113) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.27-8.25 (m, 1H), 7.97 (d, 1H), 7.91-7.81 (m, 2H), 7.48-7.44 (m, 1H), 7.41-7.39 (m, 1H), 7.21 (t, 1H), 4.33 (s, 2H), 4.15-4.10 (m, 2H), 3.66-3.59 (m, 3H), 3.17 (d, 1H), 2.68-2.61 (m, 1H), 0.92-0.83 (m, 6H).

Example 33

4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-33)

Step 1: Preparation of 4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(114) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with cyclopropanecarbaldehyde (42 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (153 mg, 66%).

(115) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.28-7.97 (m, 2H), 7.91-7.81 (m, 2H), 7.48-7.40 (m, 2H), 7.22 (m, 1H), 4.33 (s, 2H), 4.13-3.98 (m, 2H), 3.70-3.56 (m, 3H), 2.29 (m, 2H), 0.83-0.72 (m, 1H), 0.37-0.32 (m, 2H), 0.06 (m, 2H).

Example 34

4-(3-(3-(bis(cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-34)

Step 1: Preparation of 4-(3-(3-(bis(cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(116) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with cyclopropanecarbaldehyde (84 uL, 1.14 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (116 mg, 43%).

(117) .sup.1H-NMR (DMSO, 400 MHz): δ 12.57 (s, 1H), 8.23 (m, 1H), 7.97-7.77 (m, 3H), 7.47-7.36 (m, 2H), 7.18 (m, 1H), 4.29 (s, 2H), 3.99 (m, 1H), 3.88-3.58 (m, 4H), 2.38-2.31 (m, 4H), 0.77 (m, 2H), 0.38 (s, 2H), 0.36 (s, 2H), 0.01 (s, 4H).

Example 35

4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-35)

Step 1: Preparation of 4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(118) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with isobutyraldehyde (52 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (194 mg, 83%).

(119) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.93 (m, 1H), 7.89-7.82 (m, 2H), 7.51-7.49 (m, 1H), 7.45-7.43 (m, 1H), 7.15 (t, 1H), 4.38 (s, 2H), 4.28-4.26 (m, 1H), 4.16-4.12 (m, 1H), 3.88-3.84 (m, 1H), 3.79-3.75 (m, 1H), 3.66-3.64 (m, 1H), 2.31-2.28 (m, 2H), 1.71-1.68 (m, 1H), 0.91 (dd, 6H).

Example 36

4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-36)

Step 1: Preparation of 4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(120) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with 1-hydroxypropan-2-one (39 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (82 mg, 35%).

(121) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36-8.34 (m, 1H), 7.94-7.92 (m, 1H), 7.88-7.81 (m, 2H), 7.50-7.49 (m, 1H), 7.46-7.44 (m, 1H), 7.16-7.11 (m, 1H), 4.36 (s, 2H), 4.35-4.33 (m, 1H), 4.20-4.17 (m, 1H), 3.90-3.3.83 (m, 3H), 3.46-3.43 (m, 1H), 3.39-3.36 (m, 1H), 2.77-2.75 (m, 1H), 1.95 (s, 1H), 1.02 (q, 3H).

Example 37

4-(4-fluoro-3-(3-(neopentyl amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-37)

Step 1: Preparation of 4-(4-fluoro-3-(3-(neopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(122) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with pivalaldehyde (62 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (185 mg, 77%).

(123) .sup.1H-NMR (MeOD, 400 MHz): δ 8.34 (m, 1H), 7.92-7.78 (m, 3H), 7.50-7.43 (m, 2H), 7.13 (t, 1H), 4.35 (s, 2H), 4.29-4.10 (m, 2H), 3.88-3.75 (m, 2H), 3.62 (m, 1H), 2.23 (m, 2H), 0.91 (s, 9H).

Example 38

4-(3-(3-((2,2-dimethylcyclopentyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-38)

Step 1: Preparation of 4-(3-(3-((2,2-dimethylcyclopentyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(124) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with 2,2-dimethylcyclopentanone (72 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (99 mg, 39%).

(125) .sup.1H-NMR (MeOD, 400 MHz): δ 8.35 (m, 1H), 7.93-7.79 (m, 3H), 7.51-7.42 (m, 2H), 7.14 (t, 1H), 4.36 (s, 2H), 4.30-4.10 (m, 2H), 3.90-3.68 (m, 3H), 2.43 (m, 1H), 1.95-1.82 (m, 1H), 1.68-1.28 (m, 5H), 1.01 (d, 3H), 0.84 (s, 3H).

Example 39

ethyl 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopent-1-enecarboxylate; (I-39)

Step 1: Preparation of ethyl 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopent-1-enecarboxylate

(126) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with ethyl 2-oxocyclopentanecarboxylate (85 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (64 mg, 23%).

(127) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 11.44 (s, 1H), 8.48 (m, 1H), 7.80-7.73 (m, 3H), 7.55 (m, 1H), 7.34-7.28 (m, 1H), 7.01 (t, 1H), 4.50 (t, 1H), 4.39-4.27 (m, 4H), 4.15 (m, 2H), 4.01 (m, 2H), 2.52-2.38 (m, 4H), 1.86-1.80 (m, 2H), 1.28 (t, 3H).

Example 40

4-(4-fluoro-3-(3-(pentan-3-yl amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-40)

Step 1: Preparation of 4-(4-fluoro-3-(3-(pentan-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(128) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with pentan-3-one (48 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (46 mg, 19%).

(129) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 11.32 (br, 1H), 8.47 (m, 1H), 7.77-7.72 (m, 3H), 7.51 (m, 1H), 7.32-7.31 (m, 1H), 7.00 (t, 1H), 4.39 (m, 1H), 4.29 (s, 2H), 4.17 (m, 1H), 3.85-3.74 (m, 3H), 2.36 (m, 1H), 2.06 (br, 1H), 1.38 (m, 4H), 0.87 (dd, 6H).

Example 41

4-(4-fluoro-3-(3-((3-ethylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-41)

Step 1: Preparation of 4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(130) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with 3-methylbutan-2-one (61 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (125 mg, 52%).

(131) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 11.22 (s, 1H), 8.50-8.45 (m, 1H), 7.79-7.71 (m, 3H), 7.52-7.50 (m, 1H), 7.33-7.29 (m, 1H), 7.01 (t, 1H), 4.38 (m, 1H), 4.29 (s, 2H), 4.21-4.13 (m, 1H), 3.86-3.72 (m, 3H), 2.50-2.40 (m, 1H), 1.66-1.55 (m, 1H), 0.94-0.84 (m, 9H).

Example 42

4-(3-(3-((1-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-42)

Step 1: Preparation of 4-(3-(3-((1-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(132) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with 1-cyclopropylethanone (56 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (239 mg, 43%).

(133) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 11.18 (s, 1H), 8.49-8.47 (m, 1H), 7.79-7.72 (m, 3H), 7.52-7.50 (m, 1H), 7.33-7.29 (m, 1H), 7.01 (t, 1H), 4.40 (m, 1H), 4.29 (s, 2H), 3.79 (m, 1H), 1.93 (br, 1H), 1.83 (m, 1H), 1.14 (m, 3H), 0.70-0.40 (m, 3H), 0.15-0.04 (m, 2H).

Example 43

4-(3-(3-(bicyclo[2.2.1]heptan-2-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-43)

Step 1: Preparation of 4-(3-(3-(bicyclo[2.2.1]heptan-2-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(134) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with norcamphor (62 mg, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (48 mg, 19%).

(135) .sup.1H-NMR (MeOD, 400 MHz): δ 8.37 (d, 1H), 7.92 (d, 1H), 7.82-7.88 (m, 2H), 7.48-7.50 (m, 1H), 7.41-7.43 (m, 1H), 7.14 (t, 1H), 4.38 (s, 2H), 4.28-4.37 (m, 1H), 4.09-4.26 (m, 1H), 3.70-3.91 (m, 2H), 3.61-3.69 (m, 1H), 2.88-2.95 (m, 1H), 2.14-2.23 (m, 2H), 1.73-1.94 (m, 2H), 1.48-1.71 (m, 2H), 1.22-1.40 (m, 4H).

Example 44

4-(3-(3-(sec-butyl amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-44)

Step 1: Preparation of 4-(3-(3-(sec-butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(136) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with butan-2-one (51 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (74 mg, 32%).

(137) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.58 (s, 1H), 8.49-8.45 (m, 1H), 7.80-7.71 (m, 3H), 7.52-7.49 (dd, 1H), 7.33-7.30 (m, 1H), 7.01 (t, 1H), 4.44-4.35 (m, 1H), 4.28 (s, 2H), 4.22-4.14 (m, 1H), 3.86-3.73 (m, 3H), 2.59-2.52 (m, 1H), 1.48-1.24 (m, 3H), 1.02-0.98 (m, 3H), 0.91-0.86 (m, 3H).

Example 45

4-(3-(3-((dicyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-45)

Step 1: Preparation of 4-(3-(3-((dicyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(138) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with dicyclopropylmethanone (43 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (28 mg, 11%).

(139) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.63 (s, 1H), 8.50-8.45 (m, 1H), 7.87-7.71 (m, 3H), 7.52-7.50 (m, 1H), 7.33-7.31 (m, 1H), 7.01 (t, 1H), 4.41-4.37 (m, 1H), 4.28 (s, 2H), 4.20-4.16 (m, 1H), 3.99-3.93 (m, 1H), 3.89-3.76 (m, 2H), 1.74 (br, 1H), 1.08 (t, 1H), 0.85-0.77 (m, 2H), 0.54-0.42 (m, 4H), 0.24-0.18 (m, 2H), 0.08-0.04 (m, 2H).

Example 46

4-(4-fluoro-3-(3-((4-ethylpentan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-46)

Step 1: Preparation of 4-(4-fluoro-3-(3-((4-methylpentan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(140) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with 4-methylpentan-2-one (57 mg, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (104 mg, 42%).

(141) .sup.1H-NMR (MeOD, 400 MHz): δ 8.37-8.35 (m, 1H), 7.95-7.92 (m, 1H), 7.87-7.82 (m, 2H), 7.51-7.49 (m, 1H), 7.45-7.43 (m, 1H), 7.16 (q, 1H), 4.37 (s, 2H), 4.34-4.32 (m, 1H), 4.19-4.17 (m, 1H), 3.84-3.82 (m, 3H), 2.78-2.76 (m, 1H), 1.71-1.68 (m, 1H), 1.32-1.27 (m, 2H), 1.03-0.99 (m, 3H), 0.92-0.86 (m, 6H).

Example 47

4-(4-fluoro-3-(3-((3-hydroxybutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-47)

Step 1: Preparation of 4-(4-fluoro-3-(3-((3-hydroxybutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(142) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with 3-hydroxybutan-2-one (49 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (60 mg, 25%).

(143) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.36 (m, 1H), 7.94-7.92 (m, 1H), 7.88-7.80 (m, 2H), 7.52-7.49 (m, 1H), 7.46-7.44 (m, 1H), 7.16-7.11 (m, 1H), 4.37 (s, 2H), 4.35-4.32 (m, 1H), 4.19-4.16 (m, 1H), 3.91-3.89 (m, 3H), 2.04-1.99 (m, 2H), 1.15-1.12 (m, 3H), 0.12-0.95 (m, 3H).

Example 48

4-(4-fluoro-3-(3-(pentan-2-yl amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-48)

Step 1: Preparation of 4-(4-fluoro-3-(3-(pentan-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(144) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with pentan-2-one (49 mg, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (113 mg, 51%).

(145) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.55 (s, 1H), 8.49-8.45 (m, 1H), 7.80-7.71 (m, 3H), 7.50 (d, 1H), 7.33-7.29 (m, 1H), 7.01 (t, 1H), 4.42-4.36 (m, 1H), 4.21-4.11 (m, 1H), 3.85-3.72 (m, 3H), 2.66-2.59 (m, 1H), 1.40-1.25 (m, 5H), 1.02-0.98 (m, 3H), 0.92-0.88 (m, 3H).

Example 49

4-(4-fluoro-3-(3-((1-(1-methylcyclopropyl)ethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-49)

Step 1: Preparation of 4-(4-fluoro-3-(3-((1-(1-methylcyclopropyl)ethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(146) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with 1-(1-methylcyclopropyl)ethanone (63 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (37 mg, 16%).

(147) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.22 (s, 1H), 8.48-8.45 (m, 1H), 7.78-7.71 (m, 3H), 7.50-7.49 (m, 1H), 7.33-7.29 (m, 1H), 7.02 (t, 1H), 4.40-4.34 (m, 1H), 4.27 (s, 2H), 4.15 (t, 1H), 3.84-3.73 (m, 3H), 1.85-1.79 (m, 1H), 1.41 (br, 1H), 1.10-1.07 (dd, 3H), 0.97-0.95 (d, 3H).

Example 50

4-(4-fluoro-3-(3-((3,3,3-tri fluoro-2-ethylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-50)

Step 1: Preparation of 4-(4-fluoro-3-(3-((3,3,3-trifluoro-2-methylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(148) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with 3,3,3-trifluoro-2-methylpropanal (0.1 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (137 mg, 52%).

(149) .sup.1H-NMR (MeOD, 400 MHz): δ 8.26 (d, 1H), 7.72-7.84 (m, 3H), 7.33-7.41 (m, 2H), 7.04 (t, 1H), 4.28 (s, 2H), 4.18 (t, 1H), 4.02-4.05 (m, 1H), 3.71-3.76 (m, 1H), 3.63-3.67 (m, 1H), 3.54-3.58 (m, 1H), 2.65-2.70 (m, 1H), 2.32-2.38 (m, 2H), 1.05-1.07 (m, 3H).

Example 51

4-(3-(3-(allyl amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-51)

Step 1: Preparation of 4-(3-(3-(allylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(150) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with acrylaldehyde (38 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (147 mg, 66%).

(151) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.02 (s, 1H), 8.40-8.38 (m, 1H), 7.72-7.64 (m, 3H), 7.44-7.42 (m, 1H), 7.25-7.22 (m, 1H), 6.97-6.93 (m, 1H), 5.79 (m, 1H), 5.13-5.03 (m, 2H), 4.30-4.27 (m, 1H), 4.20 (s, 2H), 4.10-4.08 (m, 1H), 3.83-3.79 (m, 1H), 3.72-3.65 (m, 2H), 3.14 (d, 2H).

Example 52

4-(4-fluoro-3-(3-(isopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-52)

Step 1: Preparation of 4-(4-fluoro-3-(3-(isopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(152) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with 3-methylbutanal (61 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (190 mg, 79%).

(153) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.14 (s, 1H), 8.47-8.45 (m, 1H), 7.79-7.71 (m, 3H), 7.50 (m, 1H), 7.33-7.29 (m, 1H), 7.02 (t, 1H), 4.36 (t, 1H), 4.27 (s, 2H), 4.18 (t, 1H), 3.88-3.68 (m, 3H), 2.56 (m, 2H), 1.62 (m, 1H), 1.51 (br, 1H), 1.38-1.35 (m, 2H), 0.90-0.88 (dd, 6H).

Example 53

4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-53)

Step 1: Preparation of 4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(154) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with butyraldehyde (51 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (198 mg, 85%).

(155) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.28 (s, 1H), 8.40-8.38 (m, 1H), 7.72-7.66 (m, 1H), 7.44-7.41 (m, 1H), 7.24-7.22 (m, 1H), 6.97-6.92 (m, 1H), 4.30-4.27 (m, 1H), 4.20 (s, 2H), 4.11-4.09 (m, 1H), 3.81-3.79 (m, 1H), 3.72-3.70 (m, 1H), 3.64-3.62 (m, 1H), 2.50-2.46 (m, 2H), 2.02 (s, 1H), 1.40-1.37 (m, 2H), 1.30-1.24 (m, 2H), 0.86-0.80 (m, 5H).

Example 54

4-(4-fluoro-3-(3-((3-ethylbut-2-en-1-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-54)

Step 1: Preparation of 4-(4-fluoro-3-(3-((3-methylbut-2-en-1-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(156) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with 3-methylbut-2-enal (55 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (146 mg, 61%).

(157) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.79-7.94 (m, 3H), 7.43-7.51 (m, 2H), 7.13 (t, 1H), 5.19 (brs, 1H), 4.37 (s, 2H), 4.26 (t, 1H), 4.13 (t, 1H), 3.83-3.87 (m, 1H), 3.74-3.78 (m, 1H), 3.63-3.66 (m, 1H), 3.11 (d, 2H), 1.71 (s, 3H), 1.64 (s, 3H).

Example 55

4-(3-(3-((cyclopentylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-55)

Step 1: Preparation of 4-(3-(3-((cyclopentylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(158) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with cyclopentanecarbaldehyde (61 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (178 mg, 72%).

(159) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.36 (m, 1H), 7.94-7.93 (m, 1H), 7.89-7.82 (m, 2H), 7.51-7.43 (m, 2H), 7.17-7.12 (m, 1H), 4.38 (s, 2H), 4.29-4.28 (m, 1H), 4.15-4.13 (m, 1H), 3.88-3.87 (m, 1H), 3.79-3.77 (m, 1H), 3.66-3.64 (m, 1H), 2.45-2.42 (m, 2H), 1.98-1.95 (m, 1H), 1.81-1.79 (m, 2H), 1.65-1.56 (m, 4H), 1.18-1.16 (m, 2H).

Example 56

4-(4-fluoro-3-(3-((4,4,4-trifluorobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2)-one; (I-56)

Step 1: Preparation of 4-(4-fluoro-3-(3-((4,4,4-trifluorobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(160) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with 4,4,4-trifluorobutanol (72 mg, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (111 mg, 42%).

(161) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.92 (m, 1H), 7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.17-7.12 (m, 1H), 4.37 (s, 2H), 4.30-4.28 (m, 1H), 4.16-4.14 (m, 1H), 3.86-3.83 (m, 1H), 3.78-3.76 (m, 1H), 3.68-3.66 (m, 1H), 2.58-2.55 (m, 2H), 2.24-2.17 (m, 2H), 1.74-1.68 (m, 2H).

Example 57

4-(4-fluoro-3-(3-(pentyl amino)azetidine-1-carbonyl) benzyl)phthalazin-1(2H)-one; (I-57)

Step 1: Preparation of 4-(4-fluoro-3-(3-(pentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(162) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with pentanal (61 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (200 mg, 83%).

(163) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.94-7.92 (m, 1H), 7.89-7.82 (m, 2H), 7.51-7.49 (m, 1H), 7.45-7.43 (m, 1H), 7.17-7.12 (m, 1H), 4.37 (s, 2H), 4.30-4.28 (m, 1H), 4.17-4.15 (m, 1H), 3.88-3.86 (m, 1H), 3.80-3.78 (m, 1H), 3.69-3.67 (m, 1H), 2.53-2.49 (m, 2H), 1.51-1.47 (m, 2H), 1.35-1.29 (m, 4H), 0.91 (t, 3H).

Example 58

4-(3-(3-((2-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-58)

Step 1: Preparation of 4-(3-(3-((2-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(164) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with 2-cyclopropylacetaldehyde (48 mg, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (240 mg, 69%).

(165) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.36 (m, 1H, 7.95-7.93 (m, 1H), 7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.17-7.15 (m, 1H), 4.38 (s, 2H), 4.30-4.29 (m, 1H), 4.15-4.14 (m, 1H), 3.87-3.86 (m, 1H), 3.78-3.77 (m, 1H), 3.68-3.66 (m, 1H), 2.60-2.56 (m, 2H), 1.39-1.34 (m, 2H), 0.72-0.71 (m, 1H), 0.46-0.42 (m, 2H), 0.06-0.04 (m, 2H).

Example 59

4-(4-fluoro-3-(3-(propyl amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-59)

Step 1: Preparation of 4-(4-fluoro-3-(3-(propylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(166) This compound was made using the procedure described for example 25 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 0.57 mmol) was reacted with propionaldehyde (42 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound (191 mg, 85%).

(167) .sup.1H-NMR (MeOD, 400 MHz): δ 10.39 (s, 1H), 8.47-8.45 (m, 1H), 7.80-7.72 (m, 3H), 7.51-7.48 (m, 1H), 7.33-7.29 (m, 1H), 7.04-6.99 (m, 1H), 4.39-4.34 (m, 1H), 4.27 (s, 2H), 4.19-4.17 (m, 1H), 3.89-3.85 (m, 1H), 3.81-3.77 (m, 1H), 3.71-3.70 (m, 1H), 2.55-2.50 (m, 2H), 1.52-1.47 (m, 2H), 0.94-0.91 (m, 3H).

Example 60

4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-60)

Step 1: Preparation of 4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(168) isonicotinaldehyde (26 uL, 0.28 mmol) was added to a solution of 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(100 mg, 0.28 mmol) in 1,2-dichloroethane (1.1 mL) and stirred for 30 min then acetic acid (31 uL, 0.54 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) was added to the reaction mixture at 0° C. and stirred for 12 hours. The reaction mixture was concentrated in vacuum, added 2N NaOH(aq) and extracted into dichloromethane. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuum and purified using silica chromatography to afford the intermediate compound 4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (108 mg, 87%).

Step 2: Preparation of 4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(169) K.sub.2CO.sub.3 (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48 mmol) was added to a solution of the intermediate compound (Step 1)(108 mg, 0.24 mmol) in DMF (1.5 mL) and stirred for 3 hours. The reaction mixture was concentrated in vacuum, added dichloromethane and washed sat. NH.sub.4Cl (aq) and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuum and purified using silica chromatography to afford the title compound (99 mg, 91%).

(170) .sup.1H-NMR (MeOD, 400 MHz): δ 8.47 (d, 2H), 8.36 (d, 2H), 7.94 (d, 1H), 7.78-7.91 (m, 2H), 7.40-7.55 (m, 3H), 7.15 (t, 1H), 4.38 (s, 2H), 4.18-4.25 (m, 1H), 3.97-4.14 (m, 2H), 3.80-3.90 (m, 1H), 3.42-3.54 (m, 3H), 2.08 (s, 3H).

Example 61

(R)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-61)

Step 1: Preparation of (R)-4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(171) This compound was made using the procedure described for example 60 (Step 1). Thus, (R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 1)(100 mg, 0.28 mmol) was reacted with isonicotinaldehyde (26 uL, 0.28 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) to afford the intermediate compound (R)-4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (106 mg, 83%).

Step 2: Preparation of (R)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(172) This compound was made using the procedure described for example 60 (Step 2). Thus, this intermediate compound (Step 1)(106 mg, 0.23 mmol) was reacted with K.sub.2CO.sub.3 (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48 mmol) to afford the title compound (98 mg, 91%).

(173) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.51-8.47 (m, 2H), 8.26 (t, 1H), 7.97 (m, 1H), 7.92-7.78 (m, 2H), 7.45-7.33 (m, 3H), 7.24 (m, 2H), 4.32 (s, 2H), 3.76 (m, 1H), 3.51 (m, 3H), 3.30 (s, 2H), 3.08 (m, 1H), 1.92 (s, 3H), 1.81 (m, 2H),

Example 62

(S)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-62)

Step 1: Preparation of (S)-4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(174) This compound was made using the procedure described for example 60 (Step 1). Thus, (S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 2)(100 mg, 0.23 mmol) was reacted with isonicotinaldehyde (33 uL, 0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) to afford the intermediate compound (S)-4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (106 mg, 83%).

Step 2: Preparation of (S)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(175) This compound was made using the procedure described for example 60 (Step 2). Thus, this intermediate compound (Step 1)(106 mg, 0.24 mmol) was reacted with K.sub.2CO.sub.3 (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48 mmol) to afford the title compound (98 mg, 91%).

(176) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.51-8.47 (m, 2H), 8.26 (t, 1H), 7.97 (m, 1H), 7.92-7.78 (m, 2H), 7.45-7.33 (m, 3H), 7.24 (m, 2H), 4.32 (s, 2H), 3.76 (m, 1H), 3.51 (m, 3H), 3.30 (s, 2H), 3.08 (m, 1H), 1.92 (s, 3H), 1.81 (m, 2H), 1.19 (m, 1H).

Example 63

(S)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-63)

Step 1: Preparation of (S)-4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(177) This compound was made using the procedure described for example 60 (Step 1). Thus, (S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 2)(100 mg, 0.23 mmol) was reacted with picolinaldehyde (33 uL, 0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) to afford the intermediate compound (S)-4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (85 mg, 81%).

Step 2: Preparation of (S)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(178) This compound was made using the procedure described for example 60 (Step 2). Thus, this intermediate compound (Step 1)(85 mg, 0.19 mmol) was reacted with K.sub.2CO.sub.3 (51 mg, 0.37 mmol) and iodomethane (23 uL, 0.37 mmol) to afford the title compound (79 mg, 88%).

(179) .sup.1H-NMR (MeOD, 400 MHz): δ 10.82 (s, 0.4H), 10.40 (s, 0.6H), 8.62 (dd, 1H), 8.46 (m, 1H), 7.75 (m, 3H), 7.52 (m, 1H), 7.37 (m, 2H), 7.17 (m, 1H), 7.0 (m, 1H), 4.15 (s, 2H), 3.96 (m, 1H), 3.89 (m, 1H), 3.74 (d, 1H), 3.63 (m, 2H), 3.46 (m, 1H), 3.41 (m, 1H), 2.21 (s, 2H), 1.93 (m, 3H).

Example 64

(R)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-64)

Step 1: Preparation of (R)-4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(180) This compound was made using the procedure described for example 60 (Step 1). Thus, (R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 1)(100 mg, 0.23 mmol) was reacted with picolinaldehyde (33 uL, 0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) to afford the intermediate compound (R)-4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (85 mg, 81%).

Step 2: Preparation of (R)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(181) This compound was made using the procedure described for example 60 (Step 2). Thus, this intermediate compound (Step 1)(85 mg, 0.19 mmol) was reacted with K.sub.2CO.sub.3 (51 mg, 0.37 mmol) and iodomethane (23 uL, 0.37 mmol) to afford the title compound (79 mg, 88%).

(182) .sup.1H-NMR (MeOD, 400 MHz): δ 10.82 (s, 0.4H), 10.40 (s, 0.6H), 8.62 (dd, 1H), 8.46 (m, 1H), 7.75 (m, 3H), 7.52 (m, 1H), 7.37 (m, 2H), 7.17 (m, 1H), 7.0 (m, 1H), 4.15 (s, 2H), 3.96 (m, 1H), 3.89 (m, 1H), 3.74 (d, 1H), 3.63 (m, 2H), 3.46 (m, 1H), 3.41 (m, 1H), 2.21 (s, 2H), 1.93 (m, 3H).

Example 65

4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-65)

Step 1: Preparation of 4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(183) This compound was made using the procedure described for example 60 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(100 mg, 0.28 mmol) was reacted with picolinaldehyde (26 uL, 0.28 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) to afford the intermediate compound 4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (108 mg, 87%).

Step 2: Preparation of 4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(184) This compound was made using the procedure described for example 60 (Step 2). Thus, this intermediate compound (Step 1)(108 mg, 0.24 mmol) was reacted with K.sub.2CO.sub.3 (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48 mmol) to afford the title compound (99 mg, 91%).

(185) .sup.1H-NMR (MeOD, 400 MHz): δ 8.47 (d, 1H), 8.35 (d, 1H), 7.94 (d, 1H), 7.78-7.89 (m, 3H), 7.43-7.54 (m, 3H), 7.30-7.35 (m, 1H), 7.14 (t, 1H), 4.38 (s, 2H), 4.17-4.22 (m, 1H), 3.95-4.06 (m, 2H), 3.87-3.94 (m, 1H), 3.57 (s, 2H), 3.44-3.51 (m, 1H), 2.18 (s, 3H).

Example 66

4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-66)

Step 1: Preparation of 4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(186) This compound was made using the procedure described for example 60 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(100 mg, 0.28 mmol) was reacted with nicotinaldehyde (26 uL, 0.28 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) to afford the intermediate compound 4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (108 mg, 87%).

Step 2: Preparation of 4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(187) This compound was made using the procedure described for example 60 (Step 2). Thus, this intermediate compound (Step 1)(108 mg, 0.24 mmol) was reacted with K.sub.2CO.sub.3 (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48 mmol) to afford the title compound (99 mg, 91%).

(188) .sup.1H-NMR (MeOD, 400 MHz): δ 8.43-8.51 (m, 2H), 8.36 (d, 1H), 7.94 (d, 1H), 7.79-7.90 (m, 3H), 7.48-7.53 (m, 1H), 7.39-7.48 (m, 2H), 7.15 (t, 1H), 4.38 (s, 2H), 4.18-4.25 (m, 1H), 3.96-4.10 (m, 2H), 3.89-3.96 (m, 1H), 3.39-3.56 (m, 2H), 2.06 (s, 3H).

Example 67

(S)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-67)

Step 1: Preparation of (S)-4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(189) This compound was made using the procedure described for example 60 (Step 1). Thus, (S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 2)(100 mg, 0.23 mmol) was reacted with nicotinaldehyde (26 uL, 0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) to afford the intermediate compound (S)-4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (86 mg, 82%).

Step 2: Preparation of (S)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(190) This compound was made using the procedure described for example 60 (Step 2). Thus, this intermediate compound (Step 1)(86 mg, 0.19 mmol) was reacted with K.sub.2CO.sub.3 (52 mg, 0.38 mmol) and iodomethane (24 uL, 0.38 mmol) to afford the title compound (98 mg, 91%).

(191) .sup.1H-NMR (MeOD, 400 MHz): δ 10.36 (s, 0.4H), 10.01 (s, 0.6H), 8.46 (m, 3H), 7.73 (m, 3H), 7.40 (m, 1H), 7.38 (m, 3H), 7.04 (m, 1H), 4.27 (s, 2H), 3.89 (m, 1H), 3.67 (m, 3H), 3.47 (m, 3H), 3.12 (m, 1H), 2.13 (m, 5H), 1.87 (m, 1H).

Example 68

(R)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-68)

Step 1: Preparation of (R)-4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(192) This compound was made using the procedure described for example 60 (Step 1). Thus, (R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 1)(100 mg, 0.23 mmol) was reacted with nicotinaldehyde (26 uL, 0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) to afford the intermediate compound (R)-4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (86 mg, 82%).

Step 2: Preparation of (R)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(193) This compound was made using the procedure described for example 60 (Step 2). Thus, this intermediate compound (Step 1)(86 mg, 0.19 mmol) was reacted with K.sub.2CO.sub.3 (52 mg, 0.38 mmol) and iodomethane (24 uL, 0.38 mmol) to afford the title compound (98 mg, 91%).

(194) .sup.1H-NMR (MeOD, 400 MHz): δ 10.36 (s, 0.4H), 10.01 (s, 0.6H), 8.46 (m, 3H), 7.73 (m, 3H), 7.40 (m, 1H), 7.38 (m, 3H), 7.04 (m, 1H), 4.27 (s, 2H), 3.89 (m, 1H), 3.67 (m, 3H), 3.47 (m, 3H), 3.12 (m, 1H), 2.13 (m, 3H), 1.87 (m, 1H).

Example 69

4-(3-(3-(cyclopropyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-69)

Step 1: Preparation of 4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(195) This compound was made using the procedure described for example 60 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(100 mg, 0.23 mmol) was reacted with (1-ethoxycyclopropoxy)trimethylsilane(46 uL, 0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) to afford the intermediate compound 4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (58 mg, 71%).

Step 2: Preparation of 4-(3-(3-(cyclopropyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(196) This compound was made using the procedure described for example 60 (Step 2). Thus, this intermediate compound (Step 1)(58 mg, 0.16 mmol) was reacted with K.sub.2CO.sub.3 (44 mg, 0.32 mmol) and iodomethane (33 uL, 0.32 mmol) to afford the title compound (62 mg, 95%).

(197) .sup.1H-NMR (MeOD, 400 MHz): δ 8.32-8.39 (d, 1H), 7.89-7.95 (d, 1H), 7.78-7.88 (m, 2H), 7.46-7.53 (m, 1H), 7.39-7.45 (m, 1H), 7.14 (t, 1H), 4.37 (s, 2H), 4.14-4.22 (m, 1H), 4.05-4.13 (m, 2H), 3.98-4.03 (m, 2H), 3.54-3.63 (m, 1H), 2.26 (s, 3H), 0.34-0.56 (m, 4H).

Example 70

4-(3-(3-(cyclopropyl(ethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-70)

Step 1: Preparation of 4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(198) This compound was made using the procedure described for example 60 (Step 1) to afford the intermediate compound 4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (58 mg, 71%).

Step 2: Preparation of 4-(3-(3-(cyclopropyl(ethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(199) This compound was made using the procedure described for example 60 (Step 2). Thus, this intermediate compound (Step 1)(58 mg, 0.16 mmol) was reacted with K.sub.2CO.sub.3 (44 mg, 0.32 mmol) and iodoethane (33 uL, 0.32 mmol) to afford the title compound (58 mg, 91%).

(200) .sup.1H-NMR (MeOD, 400 MHz): δ 8.32-8.40 (m, 1H), 7.90-7.95 (m, 1H), 7.77-7.89 (m, 2H), 7.46-7.54 (m, 1H), 7.30-7.45 (m, 1H), 7.14 (t, 1H), 4.36 (s, 2H), 3.95-4.24 (m, 4H), 3.73-3.84 (m, 1H), 2.60-2.71 (m, 2H), 1.68-1.78 (m, 1H), 1.19-1.26 (m, 1H), 1.01-1.10 (m, 3H), 0.35-0.58 (m, 4H).

Example 71

4-(3-(3-(cyclobutyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-71)

Step 1: Preparation of 4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(201) This compound was made using the procedure described for example 60 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(100 mg, 0.23 mmol) was reacted with cyclobutanone (17 uL, 0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) to afford the intermediate compound 4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (84 mg, 90%).

Step 2: Preparation of 4-(3-(3-(cyclobutyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(202) This compound was made using the procedure described for example 60 (Step 2). Thus, this intermediate compound (Step 1)(84 mg, 0.21 mmol) was reacted with K.sub.2CO.sub.3 (57 mg, 0.41 mmol) and iodomethane (25 uL, 0.41 mmol) to afford the title compound (82 mg, 93%).

(203) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.93 (d, 1H), 7.79-7.89 (m, 2H), 7.48-7.54 (m, 1H), 7.42 (d, 1H), 7.15 (t, 1H), 4.37 (s, 2H), 4.08-4.18 (m, 1H), 3.98-4.04 (m, 1H), 3.89-3.99 (m, 2H), 3.35-3.43 (m, 1H), 2.80-2.90 (m, 1H), 2.06 (s, 3H), 1.81-1.97 (m, 4H), 1.59-1.72 (m, 2H).

Example 72

4-(3-(3-(cyclopentyl(prop-2-yn-1-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-72)

Step 1: Preparation of 4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(204) This compound was made using the procedure described for example 60 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(100 mg, 0.23 mmol) was reacted with cyclopentanone (20 uL, 0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) to afford the intermediate compound 4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (74 mg, 77%).

Step 2: Preparation of 4-(3-(3-(cyclopentyl(prop-2-yn-1-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(205) This compound was made using the procedure described for example 60 (Step 2). Thus, this intermediate compound (Step 1)(74 mg, 0.18 mmol) was reacted with K.sub.2CO.sub.3 (49 mg, 0.35 mmol) and 1N solution of propargyl bromide in toluene (0.35 mL, 0.35 mmol) to afford the title compound (67 mg, 81%).

(206) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.32 (s, 1H), 8.48-8.46 (m, 1H), 7.80-7.71 (m, 3H), 7.51-7.48 (m, 1H), 7.33-7.29 (m, 1H), 7.01 (t, 1H), 4.29-4.25 (m, 3H), 4.12-3.99 (m, 3H), 3.81-3.74 (m, 1H), 3.52-3.39 (m, 2H), 2.96-2.89 (m, 1H), 2.16 (m, 1H), 1.83-1.51 (m, 6H), 1.41-1.30 (m, 2H)

Example 73

4-(3-(3-(3,3-difluoropyrrolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-73)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(207) 4-(4-fluoro-3-(3-hydroxyazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (example 6)(200 mg, 0.57 mmol) was dissolved in dichloromethane (2.5 mL) and 1,4-dioxane (1 mL). Dess-Mart in periodinane (DMP, 484 mg, 1.14 mmol) was added at 0° C., after stirring at room temperature for 12 h. The reaction mixture added dichloromethane and washed with aqueous sodium hydroxide and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuum to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (162 mg, 81%).

Step 2: Preparation of 4-(3-(3-(3,3-difluoropyrrolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(208) 3,3-difluoropyrrolidine (43 uL, 0.46 mmol) was added to a solution of the intermediate compound (Step 1)(162 mg, 0.46 mmol) in 1,2-dichloroethane/methanol (2 mL/1 mL) and stirred for 30 min then acetic acid (31 uL, 0.54 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) was added to the reaction mixture at 0° C. and stirred for 12 hours. The reaction mixture was concentrated in vacuum, added 2N NaOH(aq) and extracted into dichloromethane. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuum and purified using silica chromatography to afford the title compound (134 mg, 66%).

(209) .sup.1H-NMR (DMSO, 400 MHz): δ 12.62 (s, 1H), 8.26 (d, 1H), 7.99 (d, 1H), 7.90 (t, 1H), 7.84 (t, 1H), 7.45 (d, 2H), 7.23 (t, 1H), 4.33 (s, 2H), 4.11 (m, 1H), 4.07-0.03 (m, 1H), 3.96 (t, 1H), 3.89-3.85 (m, 1H), 3.81-3.78 (m, 1H), 2.90 (t, 2H), 2.69-2.65 (m, 2H), 2.30-2.19 (m, 2H).

Example 74

(210) 4-(4-fluoro-3-(3-(4-fluoropiperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-74)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(211) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-(4-fluoropiperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(212) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 4-fluoropiperidine (43 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (145 mg, 72%).

(213) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.26 (d, 1H), 7.99 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.48-7.42 (m, 2H), 7.22 (t, 1H), 4.78-4.60 (m, 1H), 4.33 (s, 2H), 4.05-4.01 (m, 1H), 3.91 (t, 1H), 3.81-3.77 (m, 1H), 3.74-3.70 (m, 1H), 2.41-2.31 (m, 2H), 2.25-2.12 (m, 2H), 1.91-1.77 (m, 2H), 1.75-1.64 (m, 2H).

Example 75

4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-75)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(214) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(215) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with azetidine (28 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (113 mg, 74%).

(216) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.26 (d, 1H), 7.78 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.45 (m, 2H), 7.22 (t, 1H), 4.33 (d, 2H), 4.11 (m, 1H), 3.97 (t, 1H), 3.87 (t, 1H), 3.68 (m, 1H), 3.60 (t, 1H), 3.10 (m, 4H), 1.95 (t, 2H).

Example 76

4-(4-fluoro-3-(3-(pyrrolidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-76)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(217) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-(pyrrolidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(218) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with pyrrolidine (38 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (159 mg, 85%).

(219) .sup.1H-NMR (MeOD, 400 MHz): δ 8.37-8.35 (m, 1H), 7.94 (d, 1H), 7.98 (d, 1H), 7.92-7.82 (m, 2H), 7.48-7.42 (m, 2H), 7.22 (t, 1H), 4.34 (s, 2H), 4.07-4.03 (m, 1H), 3.94 (t, 1H), 3.85-3.81 (m, 1H), 3.76-3.73 (m, 1H), 3.27-3.23 (m, 1H), 2.38 (d, 4H), 1.69 (s, 4H).

Example 77

4-(4-fluoro-3-(3-(piperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-77)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(220) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-(piperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(221) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with piperidine (43 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (162 mg, 85%).

(222) .sup.1H-NMR (DMSO, 400 MHz): δ 12.62 (s, 1H), 8.25 (d, 1H), 8.01 (d, 1H), 7.88 (t, 1H), 7.82 (t, 1H), 7.48-7.39 (m, 2H), 7.21 (t, 1H), 4.33 (s, 2H), 4.10-4.08 (m, 1H), 3.95 (t, 1H), 3.85 (t, 1H), 3.69-3.65 (m, 1H), 3.61-3.55 (m, 1H), 2.42 (t, 4H), 1.55-1.49 (m, 6H).

Example 78

4-(4-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-78)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(223) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(224) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 1-methylpiperazine (50 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (90 mg, 45%).

(225) .sup.1H-NMR (MeOD, 400 MHz): δ 8.37-8.35 (m, 1H), 7.95-7.93 (m, 1H), 7.89-7.81 (m, 2H), 7.57-7.40 (m, 2H), 7.15 (t, 1H), 4.38 (s, 2H), 4.21-4.02 (m, 2H), 3.97-3.82 (m, 2H), 3.65 (m, 1H), 2.94-2.80 (m, 6H), 2.59 (s, 3H).

Example 79

4-(4-fluoro-3-(3-(phenylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-79)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(226) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-(phenylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(227) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with aniline (42 uL, 0.46 mmol), titanium(IV) epoxide (Ti[OCH.sub.2(CH.sub.3).sub.4], 96 mL, 46 mmol) and sodium triacetoxyborohydride (227 mg, 1.0 mmol) to afford the title compound (43 mg, 22%).

(228) .sup.1H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.25 (d, 1H), 7.97 (d, 1H), 7.89 (t, 1H), 7.82 (t, 1H), 7.41 (m, 1H), 7.33 (m, 1H), 7.23 (t, 1H), 7.06 (t, 2H), 6.59 (d, 2H), 6.51 (t, 1H), 4.38 (m, 1H), 4.33 (s, 2H), 4.28-4.19 (m, 2H), 3.80 (dd, 1H), 3.70 (m, 1H).

Example 80

4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-80)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(229) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(230) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 1-(trifluoromethyl)cyclopropylamine (74 mg, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (51 mg, 24%).

(231) .sup.1H-NMR (MeOD, 400 MHz): δ 8.25 (d, 1H), 7.83 (d, 1H), 7.71-7.76 (m, 2H), 7.33-7.39 (m, 1H), 7.31-7.40 (m, 1H), 7.03 (t, 1H), 4.25 (s, 2H), 4.20-4.26 (m, 1H), 4.01-4.06 (m, 1H), 3.66-3.80 (m, 3H), 0.97-0.99 (m, 2H), 0.81-0.83 (m, 2H).

Example 81

4-(4-fluoro-3-(3-(prop-2-yn-1-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-81)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(232) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-(prop-2-yn-1-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(233) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with propargylamine (29 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (134 mg, 66%).

(234) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.40 (s, 1H), 8.48-8.46 (m, 1H), 7.79-7.71 (m, 3H), 7.52-7.50 (m, 1H), 7.32-7.30 (m, 1H), 7.02 (t, 1H), 4.43-4.38 (m, 1H), 4.28 (s, 2H), 4.23-4.20 (m, 1H), 4.00-3.93 (m, 1H), 3.88-3.85 (m, 2H), 3.42 (q, 2H), 2.21 (m, 1H).

Example 82

(S)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-82)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(235) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of (S)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(236) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with (S)-1-methoxypropane-2-amine (48 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (125 mg, 64%).

(237) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.93 (m, 1H), 7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.14 (t, 1H), 4.38 (s, 2H), 4.12-4.10 (m, 1H), 4.18-4.15 (m, 1H), 3.84-3.77 (m, 3H), 3.22-3.19 (m, 1H), 2.89-2.87 (m, 1H), 2.03 (s, 3H), 1.00 (t, 3H).

Example 83

(R)-4-(4-fluoro-3-(3-((1-ethoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-83)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(238) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of (R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(239) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with (R)-1-methoxypropane-2-amine (48 uL, 0.4 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (125 mg, 64%).

(240) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.93 (m, 1H), 7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.14 (t, 1H), 4.38 (s, 2H), 4.12-4.10 (m, 1H), 4.18-4.15 (m, 1H), 3.84-3.77 (m, 3H), 3.22-3.19 (m, 1H), 2.89-2.87 (m, 1H), 2.03 (s, 3H), 1.00 (t, 3H).

Example 84

4-(4-fluoro-3-(3-((1-(hydroxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-84)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(241) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-((1-(hydroxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(242) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with (1-aminocyclopropyl)methanol (40 mg, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (84 mg, 43%).

(243) .sup.1H-NMR (MeOD, 400 MHz): δ 8.35-8.34 (m, 1H), 7.95-7.82 (m, 3H), 7.51-7.44 (m, 2H), 7.13 (t, 1H), 4.37-4.33 (m, 3H), 4.19-4.17 (m, 1H), 3.90-3.86 (m, 3H), 1.29-1.27 (m, 1H), 0.57-0.54 (m, 2H), 0.52-0.50 (m, 2H).

Example 85

4-(4-fluoro-3-(3-((1-methylcyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-85)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(244) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-((1-methylcyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(245) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 1-methylcyclopropanamine (43 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (35 mg, 19%).

(246) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.93 (d, 1H), 7.80-7.86 (m, 2H), 7.42-7.52 (m, 2H), 7.14 (t, 1H), 4.32-4.37 (m, 3H), 4.16 (t, 1H), 3.78-3.88 (m, 3H), 1.29 (s, 3H), 0.51-0.57 (m, 2H, 0.33-0.39 (m, 2H).

Example 86

(R)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-86)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(247) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of (R)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(248) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with (R)-3,3-dimethylbutan-2-amine (55 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (110 mg, 55%).

(249) .sup.1H-NMR (MeOD, 400 MHz): δ 8.39 (d, 1H), 7.87-8.38 (m, 3H), 7.43-7.53 (m, 2H), 7.17 (t, 1H), 4.41 (s, 2H), 4.28-4.40 (m, 1H), 4.09-4.18 (m, 1H), 3.71-3.90 (m, 3H), 2.17-2.27 (m, 1H), 0.94-0.98 (m, 12H).

Example 87

(S)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-87)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(250) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of (S)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(251) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with (S)-3,3-dimethylbutan-2-amine (55 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (110 mg, 55%).

(252) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.28 (d, 1H), 8.48-8.46 (m, 1H), 7.79-7.70 (m, 3H), 7.50 (d, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.43-4.32 (m, 1H), 4.27 (s, 2H), 4.21-4.09 (m, 1H), 3.84-3.70 (m, 3H), 2.26-2.14 (m, 1H), 0.96-0.90 (m, 3H), 0.88-0.86 (dd, 9H).

Example 88

(R)-4-(4-fluoro-3-(3-((3-ethylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-88)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(253) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of (R)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(254) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with (R)-3-methylbutan-2-amine (53 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (113 mg, 58%).

(255) .sup.1H-NMR (MeOD, 400 MHz): δ 8.39 (d, 1H), 7.83-8.38 (m, 3H), 7.44-7.52 (m, 2H), 7.17 (t, 1H), 4.63 (brs, 2H), 4.40 (s, 2H), 3.76-3.86 (m, 3H), 2.44-2.46 (m, 1H), 1.64-1.67 (m, 1H), 0.86-0.96 (m, 9H).

Example 89

(S)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-89)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(256) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of (S)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(257) This compound was made using the procedure described for example 73 (Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with (S)-3-methylbutan-2-amine (53 uL, 0.46 mmol) and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (113 mg, 58%).

(258) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.61 (s, 1H), 8.48-8.46 (m, 1H), 7.80-7.71 (m, 3H), 7.53-7.47 (m, 1H), 7.32-7.30 (m, 1H), 7.01 (t, 1H), 4.38 (m, 1H), 4.28 (s, 2H), 4.15 (m, 1H), 3.84-3.71 (m, 3H), 2.45 (m, 1H), 1.59 (m, 1H), 0.94-0.83 (m, 9H).

Example 90

4-(4-fluoro-3-(3-((1-(methoxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-90)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(259) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-((1-(methoxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(260) This compound was made using the procedure described for example 73 (Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 1-(methoxymethyl)cyclopropanamine (46 mg, 0.46 mmol), and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (78 mg, 39%)

(261) .sup.1H-NMR (MeOD, 400 MHz): δ 8.37-8.35 (m, 1H), 7.95-7.93 (m, 1H), 7.89-7.82 (m, 2H), 7.50-7.43 (m, 2H), 7.16-7.13 (m, 1H), 4.37 (s, 2H), 7.36-7.33 (m, 1H), 7.15-7.14 (m, 1H), 3.87-3.82 (m, 3H), 3.31 (s, 3H), 1.29 (br, 2H), 0.60-0.59 (m, 2H), 0.53-0.51 (m, 2H).

Example 91

4-(3-(3-(but-3-yn-1-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-91)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(262) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(3-(3-(but-3-yn-1-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(263) This compound was made using the procedure described for example 73 (Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with but-3-yn-1-amine (38 uL, 0.46 mmol), and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (145 mg, 78%).

(264) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.94-7.82 (m, 3H), 7.52-7.43 (m, 2H), 7.17-7.14 (m, 1H), 4.37 (s, 2H), 4.32-4.29 (m, 1H), 4.15-4.13 (m, 1H), 3.88-3.69 (m, 3H), 2.69-2.66 (m, 2H), 2.34-2.31 (m, 3H).

Example 92

4-(4-fluoro-3-(3-((2-ethylallyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-92)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(265) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-((2-methylallyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(266) This compound was made using the procedure described for example 73 (Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 2-methylprop-2-en-1-amine (35 uL, 0.46 mmol), and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (83 mg, 45%).

(267) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38 (d, 1H), 8.36 (d, 1H), 7.81-7.95 (m, 2H), 7.44-7.50 (m, 1H), 7.11-7.17 (m, 1H), 4.38 (brs, 2H), 4.26-4.30 (m, 1H), 4.11-4.13 (m, 1H), 3.85-3.88 (m, 1H), 3.76-3.78 (m, 1H), 3.66-3.69 (m, 1H), 3.34 (s, 2H), 3.08 (s, 2H), 1.25 (s, 3H).

Example 93

4-(4-fluoro-3-(3-((3-hydroxy-2,2-dimethylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-93)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(268) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-((3-hydroxy-2,2-dimethylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(269) This compound was made using the procedure described for example 73 (Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 3-amino-2,2-dimethylpropan-1-ol (47 mg, 0.46 mmol), and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (24 mg, 12%).

(270) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 11.53 (br, 1H), 8.46 (m, 1H), 7.78-7.72 (m, 3H), 7.51-7.49 (m, 1H), 7.34-7.29 (m, 1H), 7.01 (t, 1H), 4.36-4.32 (m, 3H), 4.18-4.10 (m, 1H), 3.90-3.78 (m, 2H), 3.67 (m, 1H), 2.53-2.45 (m, 5H), 0.93 (s, 3H), 0.91 (s, 3H).

Example 94

1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)azetidin-3-yl)amino)methyl)cyclopropanecarbonitrile; (I-94)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(271) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)methyl)cyclopropanecarbonitrile

(272) This compound was made using the procedure described for example 73 (Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 1-(aminomethyl)cyclopropanecarbonitrile (44 mg, 0.46 mmol), and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (91 mg, 46%).

(273) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38 (dd, 1H), 8.00 (d, 1H), 7.83-7.92 (m, 2H), 7.54-7.62 (m, 2H), 7.14 (t, 1H), 4.41 (s, 2H), 4.28-4.36 (m, 1H), 4.14-4.18 (m, 1H), 3.71-3.81 (m, 3H), 1.35 (s, 4H).

Example 95

4-(4-fluoro-3-(3-((2,2,2-tri fluoroethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-95)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(274) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of 4-(4-fluoro-3-(3-((2,2,2-trifluoroethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(275) This compound was made using the procedure described for example 73 (Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with 2,2,2-trifluoroethaneamine (36 uL, 0.46 mmol), and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound (200 mg, 60%).

(276) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.92 (m, 1H), 7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.17-7.12 (m, 1H), 4.37 (s, 2H), 4.30-4.28 (m, 1H), 4.16-4.14 (m, 1H), 3.86-3.83 (m, 1H), 3.78-3.76 (m, 1H), 3.68-3.66 (m, 1H), 2.90-2.83 (m, 2H).

Example 96

(R)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-96)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(277) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of (R)-tert-butyl-3-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)amino)pyrrolidin-1-carboxylate

(278) The intermediate compound (Step 1, 162 mg, 0.46 mmol) was added to a solution of (R)-tert-butyl-3-aminopyrrolidin-1-carboxylate (25 uL, 0.46 mmol) in dichloromethane (3 mL), methanol (1 mL) and stirred for 30 min then acetic acid (36 uL, 0.69 mmol) and sodium triacetoxyborohydride (144 mg, 0.69 mmol) was added to the reaction mixture at 0° C. and stirred for 12 hours. The reaction mixture was concentrated in vacuo, added 2N NaOH(aq) and extracted into dichloromethane. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuo and purified using silica chromatography to afford (R)-tert-butyl-3-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)amino)pyrrolidin-1-carboxylate (122 mg, 43%).

Step 3: Preparation of (R)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(279) The intermediate compound (Step 2)(122 mg, 0.20 mmol) in dichloromethane (4 mL) cooled to 0° C. was added 1.0 N HCl solution (0.40 mL, 0.40 mmol), and the mixture was stirred at room temperature for 3 h. The react ion mixture was concentrated in vacuo, added dichloromethane and washed with 2N NaOH(aq) and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuo and purified using silica chromatography to afford the title compound (76 mg, 90%).

(280) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.36 (m, 1H), 7.95-7.83 (m, 3H), 7.54 (m, 1H), 7.44-7.42 (m, 1H), 7.25 (t, 1H), 4.38 (s, 2H), 4.35-4.33 (m, 1H), 4.19-4.17 (m, 1H), 3.78-3.77 (m, 1H), 3.74-3.71 (m, 2H), 3.36-3.21 (m, 2H), 3.17-3.08 (m, 2H), 2.09-1.99 (m, 1H), 1.82-1.79 (m, 1H), 1.28 (s, 1H).

Example 97

(S)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-97)

Step 1: Preparation of 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(281) This compound was made using the procedure described for example 73 (Step 1) to afford the intermediate compound 4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81 mg, 162%).

Step 2: Preparation of (S)-tert-butyl-3-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)amino)pyrrolidin-1-carboxylate

(282) This compound was made using the procedure described for example 96 (Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol) was reacted with (S)-tertbutyl-3-aminopyrrolidin-1-carboxylate (25 uL, 0.46 mmol), and sodium triacetoxyborohydride (144 mg, 0.69 mmol) to afford the title compound (122 mg, 43%).

Step 3: Preparation of (S)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(283) This compound was made using the procedure described for example 96 (Step 3). Thus, the intermediate compound (Step 2)(122 mg, 0.20 mmol) was reacted with 1.0 N HCl solution (0.40 mL, 0.40 mmol)) to afford the title compound (76 mg, 90%).

(284) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.36 (m, 1H), 7.95-7.83 (m, 3H), 7.54 (m, 1H), 7.44-7.42 (m, 1H), 7.25 (t, 1H), 4.38 (s, 2H), 4.35-4.33 (m, 1H), 4.19-4.17 (m, 1H), 3.78-3.77 (m, 1H), 3.74-3.71 (m, 2H), 3.36-3.21 (m, 2H), 3.17-3.08 (m, 2H), 2.09-1.99 (m, 1H), 1.82-1.79 (m, 1H), 1.28 (s, 1H).

Example 98

1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)azetidin-3-yl)amino)cyclopentanecarbonitrile; (I-98)

Step 1: Preparation of 1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopentanecarbonitrile

(285) Cyclopentanone (79 uL, 1.17 mmol) was added to a solution of 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (200 mg, 1.17 mmol) in 1,2-dichloroethane (6 mL) and stirred for 30 min then acetic acid (67 uL, 1.17 mmol) and trimethylsilyl cyanide (0.30 mL, 2.34 mmol) was added to the reaction mixture at 0° C. and stirred for 12 hours. The reaction mixture was concentrated in vacuo, added 2N NaOH(aq) and extracted into dichloromethane. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuo and purified using silica chromatography to afford the title compound (328 mg, 63%).

(286) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (m, 1H), 7.93-7.79 (m, 3H), 7.51-7.43 (m, 2H), 7.14 (t, 1H), 4.43-4.39 (m, 1H), 4.36 (s, 2H), 4.25 (m, 1H), 3.96-3.91 (m, 3H), 2.10-2.02 (m, 2H), 1.86-1.76 (m, 6H).

Example 99

1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile; (I-99)

Step 1: Preparation of 1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile

(287) This compound was made using the procedure described for example 98 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 1.17 mmol) was reacted with cyclobutanone (87 uL, 1.17 mmol), trimethylsilyl cyanide (0.30 mL, 2.34 mmol) to afford the title compound (293 mg, 58%).

(288) .sup.1H-NMR (MeOD, 400 MHz): δ 8.35 (m, 1H), 7.92-7.78 (m, 3H), 7.50-7.43 (m, 2H), 7.13 (t, 1H), 4.41-4.39 (m, 1H), 4.36 (s, 2H), 4.23 (m, 1H), 3.98-3.92 (m, 2H), 3.85-3.78 (m, 1H), 2.48-2.41 (m, 2H), 2.20-2.02 (m, 2H).

Example 100

2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)propanenitrile; (I-100)

Step 1: Preparation of 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)propanenitrile

(289) This compound was made using the procedure described for example 98 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 1.17 mmol) was reacted with acetaldehyde (70 uL, 1.17 mmol), trimethylsilyl cyanide (0.30 mL, 2.34 mmol) to afford the title compound (336 mg, 71%).

(290) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (m, 1H), 7.94-7.79 (m, 3H), 7.50-7.44 (m, 2H), 7.14 (t, 1H), 4.41-4.17 (m, 4H), 4.00-3.93 (m, 1H), 3.89-3.66 (m, 3H), 1.42 (d, 3H).

Example 101

2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)butanenitrile; (I-101)

Step 1: Preparation of 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)butanenitrile

(291) This compound was made using the procedure described for example 98 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3, 200 mg, 1.17 mmol) was reacted with propionaldehyde (84 uL, 1.17 mmol), trimethylsilyl cyanide (0.30 mL, 2.34 mmol) to afford the title compound (294 mg, 60%).

(292) .sup.1H-NMR (MeOD, 400 MHz): δ 8.35 (m, 1H), 7.94-7.80 (m, 3H), 7.49-7.44 (m, 2H), 7.14 (t, 1H), 4.40-4.16 (m, 4H), 4.00-3.91 (m, 1H), 3.88-3.76 (m, 2H), 3.61-3.50 (m, 1H), 1.79-1.68 (m, 2H), 1.08-1.01 (m, 3H).

Example 102

2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)-3-ethylbutanenitrile; (I-102)

Step 1: Preparation of 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)-3-methylbutanenitrile

(293) This compound was made using the procedure described for example 98 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 1.17 mmol) was reacted with isobutylaldehyde (0.1 mL, 1.17 mmol), trimethylsilyl cyanide (0.30 mL, 2.34 mmol) to afford the title compound (294 mg, 58%).

(294) .sup.1H-NMR (MeOD, 400 MHz): δ 8.34 (m, 1H), 7.92-7.78 (m, 3H), 7.49-7.44 (m, 2H), 7.13 (t, 1H), 4.39-4.15 (m, 4H), 4.02-3.96 (m, 1H), 3.88-3.76 (m, 2H), 3.46-3.39 (dd, 1H), 1.93 (m, 1H), 1.04-0.87 (m, 6H).

Example 103

2-cyclopropyl-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)acetonitrile; (I-103)

Step 1: Preparation of 2-cyclopropyl-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)acetonitrile

(295) This compound was made using the procedure described for example 98 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 1.17 mmol) was reacted with cyclopropancabaldehyde (79 uL, 1.17 mmol), trimethylsilyl cyanide (0.30 mL, 2.34 mmol) to afford the title compound (409 mg, 81%).

(296) .sup.1H-NMR (MeOD, 400 MHz): δ 8.35 (m, 1H), 7.93-7.78 (m, 3H), 7.50-7.44 (m, 2H), 7.13 (t, 1H), 4.40-4.17 (m, 4H), 4.01-3.79 (m, 3H), 3.42-3.37 (dd, 1H), 1.17 (m, 1H), 0.65-0.42 (m, 4H).

Example 104

4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-104)

Step 1: Preparation of 4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(297) This compound was made using the procedure described for example 98 (Step 1). Thus, 4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 3)(200 mg, 1.17 mmol) was reacted with cyclobutanone (79 uL, 1.17 mmol), trifluoromethyltrimethylsilane (0.30 mL, 2.34 mmol) to afford the title compound (328 mg, 63%).

(298) .sup.1H-NMR (MeOD, 400 MHz): δ 8.26 (d, 1H), 7.72-7.84 (m, 3H), 7.34-7.41 (m, 2H), 7.04 (t, 1H), 7.71-7.76 (m, 2H), 7.33-7.39 (m, 1H), 7.31-7.40 (m, 1H), 7.03 (t, 1H), 4.25 (s, 2H), 4.20-4.26 (m, 1H), 4.01-4.06 (m, 1H), 3.66-3.80 (m, 3H), 0.97-0.99 (m, 2H), 0.81-0.83 (m, 2H).

Example 105

(S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-105)

Step 1: Preparation of (S)-4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde

(299) This compound was made using the procedure described for example 11 (Step 1). Thus, (S)—N-methyl-N-(pyrrolidin-3-yl)pyrimidine-2-amine (200 mg, 1.12 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (188 mg, 1.12 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 553 mg, 1.46 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.40 mL, 2.24 mmol) to afford (S)-4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde (154 mg, 43%).

Step 2: Preparation of (S,Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

(300) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(154 mg, 0.47 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (114 mg, 0.47 mmol), triethylamine (98 uL, 0.47 mmol) to afford intermediate compound (S,Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (107 mg, 51%).

Step 3: Preparation of (S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one)

(301) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(107 mg, 0.24 mmol) was reacted with hydrazine monohydrate (23 uL, 0.48 mmol) to afford title compound (55 mg, 50%).

(302) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 9.96 (d, 1H), 8.45 (m, 1H), 8.43 (dd, 2H), 7.75 (m, 3H), 7.39 (m, 1H), 7.31 (m, 1H), 7.02 (m, 1H), 6.52 (q, 1H), 5.53 (m, 1H), 4.26 (d, 2H), 3.93 (m, 1H), 3.66 (m, 1H), 3.44 (m, 1H), 3.27 (m, 1H), 3.10 (s, 1.3H), 3.04 (s, 1.7H), 2.21 (m, 1H), 2.06 (m, 1H).

Example 106

(S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-106)

Step 1: Preparation of (S)-4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde

(303) This compound was made using the procedure described for example 11 (Step 1). Thus, (S)—N-ethyl-N-(pyrrolidin-3-yl)pyrimidine-2-amine (200 mg, 1.12 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (175 mg, 1.04 mmol), O-(benzotriazole-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU, 512 mg, 1.35 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.36 mL, 2.08 mmol) to afford (S)-4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde (149 mg, 42%).

Step 2: Preparation of (S,Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

(304) This compound was made using the procedure described for example 11 (Step 2). Thus, intermediate compound (Step 1)(149 mg, 0.43 mmol) was dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphate (105 mg, 0.43 mmol), triethylamine (92 uL, 0.66 mmol) to afford (S,Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (102 mg, 51%).

Step 3: Preparation of (S)-4-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(305) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(102 mg, 0.22 mmol) was reacted with hydrazine monohydrate (21 uL, 0.45 mmol) to afford title compound (53 mg, 50%).

(306) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.63 (d, 1H), 8.49 (m, 1H), 8.32 (dd, 2H), 7.73 (m, 3H), 7.39 (m, 1H), 7.28 (m, 1H), 7.02 (m, 1H), 6.50 (m, 1H), 5.13 (dt, 1H), 4.29 (d, 2H), 3.95 (m, 1H), 3.58 (m, 2H), 3.46 (m, 2H), 3.27 (m, 1H), 2.23 (m, 1H), 2.09 (m, 1H), 1.93 (dt, 3H).

Example 107

4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-107)

Step 1: Preparation of 4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzaldehyde

(307) This compound was made using the procedure described for example 11 (Step 1). Thus, N-(azetidin-3-yl)-N-methylpyrimidine-2-amine (200 mg, 1.12 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (204 mg, 1.22 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, HBTU, 600 mg, 1.58 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.42 mL, 2.44 mmol) to afford 4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzaldehyde (149 mg, 42%).

Step 2: Preparation of (Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

(308) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(202 mg, 0.65 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (156 mg, 0.65 mmol), triethylamine (0.13 mL, 0.96 mmol) to afford intermediate compound (Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (169 mg, 61%).

Step 3: Preparation of 4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(309) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(169 mg, 0.39 mmol) was reacted with hydrazine monohydrate (38 uL, 0.79 mmol) to afford title compound (89 mg, 51%).

(310) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.53 (dd, 1H), 8.31 (d, 2H), 7.80-7.70 (m, 3H), 7.54 (dd, 1H), 7.34-7.30 (m, 1H), 7.10-7.03 (m, 1H), 6.55 (t, 1H), 5.48-5.41 (m, 1H), 4.52-4.45 (m, 1H), 4.39-4.27 (m, 4H), 4.23-4.12 (m, 1H), 3.21 (s, 3H).

Example 108

4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-108)

Step 1: Preparation of 4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzaldehyde

(311) This compound was made using the procedure described for example 11 (Step 1). Thus, N-(azetidin-3-yl)-N-ethylpyrimidine-2-amine (200 mg, 1.12 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (188 mg, 1.12 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 553 mg, 1.45 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.39 mL, 2.24 mmol) to afford 4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzaldehyde (195 mg, 53%).

Step 2: Preparation of (Z)-3-(4-fluoro-3-(3-(methyl (pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

(312) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(195 mg, 0.59 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (144 mg, 0.59 mmol), triethylamine (0.12 mL, 0.89 mmol) to afford intermediate compound (Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzylidene) isobenzofuran-1(3H)-one (161 mg, 61%).

Step 3: Preparation of 4-(4-fluoro-3-(3-(methyl(pyrimidin-2-.SUB.y.l)amino)azetidine-1-carbonyl)benzyl) phthalazin-1(2H)-one

(313) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(161 mg, 0.36 mmol) was reacted with hydrazine monohydrate (36 uL, 0.73 mmol) to afford title compound (84 mg, 51%).

(314) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.53 (dd, 1H), 8.31 (d, 2H), 7.80-7.70 (m, 3H), 7.54 (dd, 1H), 7.34-7.30 (m, 1H), 7.10-7.03 (m, 1H), 6.55 (t, 1H), 5.09-5.01 (m, 1H), 4.55-4.46 (m, 1H), 4.44-4.28 (m, 4H), 4.20-4.13 (m, 1H), 3.82-3.63 (m, 2H), 1.18 (t, 3H).

Example 109

4-(4-fluoro-3-(3-(pyrimidin-2-yl amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-109)

Step 1: Preparation of 4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzaldehyde

(315) This compound was made using the procedure described for example 11 (Step 1). Thus, N-(azetidin-3-yl)-pyrimidine-2-amine (220 mg, 1.46 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (246 mg, 1.46 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 722 mg, 1.90 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.51 mL, 2.93 mmol) to afford 4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzaldehyde (233 mg, 53%).

Step 2: Preparation of (Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

(316) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(233 mg, 0.78 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (188 mg, 0.78 mmol), triethylamine (0.16 mL, 1.16 mmol) to afford intermediate compound (Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (197 mg, 61%).

Step 3: Preparation of 4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(317) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(197 mg, 0.47 mmol) was reacted with hydrazine monohydrate (46 uL, 0.95 mmol) to afford title compound (104 mg, 51%).

(318) .sup.1H-NMR (DMSO, 400 MHz): δ 7.45 (d, 2H), 7.41 (d, 1H), 7.14 (d, 1H), 7.06-6.96 (m, 3H), 6.63-6.62 (m, 2H), 6.40-6.35 (m, 1H), 5.80 (t, 1H), 3.78-3.70 (m, 1H), 3.49-3.44 (m, 3H), 3.40-3.36 (m, 1H), 3.12-3.08 (m, 1H), 3.05-3.01 (m, 1H).

Example 110

(S)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-110)

Step 1: Preparation of (S)-4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde

(319) This compound was made using the procedure described for example 11 (Step 1). Thus, (S)—N-(pyrrolidin-3-yl)pyrimidine-2-amine (300 mg, 1.82 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (307 mg, 1.82 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 900 mg, 2.38 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.64 mL, 3.65 mmol) to afford (S)-4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde (252 mg, 44%).

Step 2: Preparation of (S,Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

(320) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(252 mg, 0.80 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (195 mg, 0.80 mmol), triethylamine (0.17 mL, 1.20 mmol) to afford intermediate compound (S,Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (138 mg, 40%).

Step 3: Preparation of (S)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(321) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(138 mg, 0.32 mmol) was reacted with hydrazine monohydrate (32 uL, 0.65 mmol) to afford title compound (73 mg, 51%).

(322) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.74 (d, 1H), 8.46 (m, 1H), 8.32 (dd, 2H), 7.73 (m, 3H), 7.40 (m, 1H), 7.28 (m, 1H), 7.01 (q, 1H), 6.60 (m, 1H), 5.60 (m, 1H), 4.60 (m, 1H), 4.27 (d, 2H), 4.03 (dd, 0.4H), 3.84 (m, 0.6H), 3.73 (m, 1H), 3.49 (m, 1H), 3.41 (m, 1H), 3.25 (m, 1H), 2.28 (m, 1H), 1.95 (m, 1H).

Example 111

(S)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-111)

Step 1: Preparation of (S)-3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

(323) This compound was made using the procedure described for example 11 (Step 1). Thus, (S)-6-chloro-N-methyl-N-(pyrrolidin-3-yl)pyridazin-3-amine (120 mg, 0.71 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (118 mg, 0.71 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 348 mg, 0.91 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.25 mL, 1.41 mmol) to afford (S)-3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (115 mg, 45%).

Step 2: Preparation of (S,Z)-3-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

(324) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(115 mg, 0.31 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (77 mg, 0.31 mmol), triethylamine (66 uL, 0.48 mmol) to afford intermediate compound (S,Z)-3-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one (85 mg, 56%).

Step 3: Preparation of (S)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(325) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(85 mg, 0.18 mmol) was reacted with hydrazine monohydrate (17 uL, 0.36 mmol) to afford title compound (46 mg, 52%).

(326) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.68 (d, 1H), 8.45 (m, 1H), 7.76 (m, 3H), 7.37 (m, 1H), 7.28 (m, 1H), 6.83 (d, 1H), 7.05 (q, 1H), 6.83 (q, 1H), 5.57 (m, 0.4H), 5.39 (m, 0.6H), 4.29 (d, 2H), 3.92 (m, 1H), 3.66 (m, 2H), 3.50 (m, 1H), 3.26 (m, 1H), 2.91 (s, 1.5H), 2.96 (s, 1.5H), 2.24 (m, 2H).

Example 112

(S)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenz yl)phthalazin-1(2H)-one; (I-112)

Step 1: Preparation of (S)-3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

(327) This compound was made using the procedure described for example 11 (Step 1). Thus, (S)-6-chloro-N-(pyrrolidin-3-yl)pyridazin-3-amine (200 mg, 1.01 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (169 mg, 1.01 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 496 mg, 1.31 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.35 mL, 2.01 mmol) to afford (S)-3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (158 mg, 45%).

Step 2: Preparation of (S,Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluoro benzylidene) isofuran-1(3H)-one

(328) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(158 mg, 0.45 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroi sobenzofuran-1-yl)phosphonate (109 mg, 0.45 mmol), triethylamine (95 uL, 0.68 mmol) to afford intermediate compound (S,Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one (117 mg, 56%).

Step 3: Preparation of (S)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(329) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(117 mg, 0.25 mmol) was reacted with hydrazine monohydrate (25 uL, 0.50 mmol) to afford title compound (64 mg, 52%).

(330) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.83 (d, 1H), 8.41 (m, 1H), 7.72 (m, 3H), 7.35 (m, 1H), 7.02 (m, 2H), 6.67 (dd, 1H), 5.37 (m, 1H), 4.57 (m, 1H), 4.27 (dd, 2H), 3.77 (m, 1H), 3.43 (m, 2H), 3.23 (m, 2H), 2.02 (m, 1H).

Example 113

(S)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-113)

Step 1: Preparation of (S)-4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde

(331) This compound was made using the procedure described for example 11 (Step 1). Thus, (S)—N-methyl-N-(pyrrolidin-3-yl)pyridazin-3-amine (200 mg, 1.22 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (204 mg, 1.22 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 600 mg, 1.58 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.42 mL, 2.43 mmol) to afford (S)-4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde (172 mg, 45%).

Step 2: Preparation of (S,Z)-3-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

(332) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(172 mg, 0.55 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (132 mg, 0.55 mmol), triethylamine (0.12 mL, 0.55 mmol) to afford intermediate compound (S,Z)-3-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (132 mg, 56%).

Step 3: Preparation of (S)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(333) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(132 mg, 0.31 mmol) was reacted with hydrazine monohydrate (30 uL, 0.61 mmol) to afford title compound (71 mg, 52%).

(334) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.68 (d, 1H), 8.6 (m, 1H), 8.45 (m, 1H), 7.75 (m, 3H), 7.37 (m, 2H), 7.20 (m, 1H), 7.04 (m, 1H), 6.67 (dd, 1H), 4.65 (m, 2H), 4.27 (d, 2H), 3.91 (m, 2H), 3.48 (m, 1H), 3.22 (m, 1H), 2.40 (m, 1H), 2.02 (m, 1H).

Example 114

4-(3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2)-one; (I-114)

Step 1: Preparation of 3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde

(335) This compound was made using the procedure described for example 11 (Step 1). Thus, N-(azetidin-3-yl)-6-chloropyridazin-3-amine (200 mg, 1.08 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (182 mg, 1.08 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 534 mg, 1.40 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.38 mL, 2.17 mmol) to afford 3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde (184 mg, 51%).

Step 2: Preparation of (Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

(336) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(184 mg, 0.55 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (133 mg, 0.55 mmol), triethylamine (0.12 mL, 0.83 mmol) to afford intermediate compound (Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenz ylidene)isofuran-1(3H)-one (146 mg, 59%).

Step 3: Preparation of 4-(3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(337) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(146 mg, 0.33 mmol) was reacted with hydrazine monohydrate (32 uL, 0.66 mmol) to afford title compound (82 mg, 54%).

(338) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.16 (s, 1H), 8.47-8.42 (m, 1H), 7.79-7.67 (m, 4H), 7.47 (dd, 1H), 7.35-7.31 (m, 1H), 7.18 (d, 1H), 7.04-6.99 (m, 1H), 6.72 (d, 1H), 5.29-5.25 (m, 1H), 4.87-4.73 (m, 1H), 4.65-4.59 (m, 1H), 4.47-4.43 (m, 1H), 4.31-4.26 (m, 3H), 4.09-4.05 (m, 1H), 3.92-3.88 (m, 1H).

Example 115

4-(3-(3-((6-chloropyridazin-3-yl)(ethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl) phthalazin-1(2H)-one; (I-115)

Step 1: Preparation of 3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde

(339) This compound was made using the procedure described for example 11 (Step 1). Thus, N-(azetidin-3-yl)-6-chloro-N-methylpyridazin-3-amine (200 mg, 1.00 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (169 mg, 1.00 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 496 mg, 1.31 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.35 mL, 2.01 mmol) to afford 3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde (179 mg, 51%).

Step 2: Preparation of (Z)-3-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzylidene) isofuran-1(3H)-one

(340) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(179 mg, 0.51 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroi sobenzofuran-1-yl)phosphonate (124 mg, 0.51 mmol), triethylamine (0.11 mL, 0.77 mmol) to afford intermediate compound (Z)-3-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one (140 mg, 59%).

Step 3: Preparation of 4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(341) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(140 mg, 0.30 mmol) was reacted with hydrazine monohydrate (30 uL, 0.60 mmol) to afford title compound (78 mg, 54%).

(342) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.16 (s, 1H), 8.47-8.42 (m, 1H), 7.79-7.67 (m, 4H), 7.47 (dd, 1H), 7.35-7.31 (m, 1H), 7.18 (d, 1H), 7.04-6.99 (m, 1H), 6.72 (d, 1H), 5.21-5.15 (m, 1H), 4.87-4.73 (m, 1H), 4.65-4.59 (m, 1H), 4.47-4.43 (m, 1H), 4.31-4.26 (m, 3H), 4.09-4.05 (m, 1H), 3.92-3.88 (m, 1H), 3.06 (s, 3H).

Example 116

4-(3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-116)

Step 1: Preparation of 3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde

(343) This compound was made using the procedure described for example 11 (Step 1). Thus, N-(azetidin-3-yl)-N-cyclobutylpyrimidine-2-amine (500 mg, 2.44 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (411 mg, 2.44 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 1.2 g, 3.18 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.86 mL, 4.89 mmol) to afford 3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde (442 mg, 51%).

Step 2: Preparation of (Z)-3-(3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

(344) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(442 mg, 1.24 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (302 mg, 1.24 mmol), triethylamine (0.26 mL, 1.87 mmol) to afford intermediate compound (Z)-3-(3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one (288 mg, 49%).

Step 3: Preparation of 4-(3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(345) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(288 mg, 0.62 mmol) was reacted with hydrazine monohydrate (60 uL, 1.22 mmol) to afford title compound (124 mg, 42%).

(346) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.46-8.44 (m, 1H), 8.28 (d, 2H), 7.75-7.72 (m, 3H), 7.52-7.49 (m, 1H), 7.36-7.28 (m, 1H), 7.04-6.99 (m, 1H), 6.55 (t, 1H), 4.97-4.90 (m, 1H), 4.82-4.74 (m, 1H), 4.66-4.62 (m, 1H), 4.47-4.43 (m, 1H), 4.31-4.26 (m, 3H), 4.17-4.13 (m, 1H), 2.25-2.01 (m, 5H).

Example 117

4-(4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-117)

Step 1: Preparation of 4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzaldehyde

(347) This compound was made using the procedure described for example 11 (Step 1). Thus, N-(azetidin-3-yl)pyridazin-3-amine (200 mg, 1.33 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (224 mg, 1.33 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 656 mg, 1.73 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.46 mL, 2.66 mmol) to afford 4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzaldehyde (203 mg, 51%).

Step 2: Preparation of (Z)-3-(4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

(348) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(203 mg, 0.68 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (164 mg, 0.68 mmol), triethylamine (0.14 mL, 1.02 mmol) to afford intermediate compound (Z)-3-(4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (172 mg, 61%).

Step 3: Preparation of 4-(4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(349) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(172 mg, 0.41 mmol) was reacted with hydrazine monohydrate (40 uL, 0.82 mmol) to afford title compound (93 mg, 52%).

(350) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.86 (s, 1H), 8.58-8.57 (m, 1H), 8.44 (d, 1H), 7.78-7.69 (m, 3H), 7.48-7.46 (m, 1H), 7.35-7.31 (m, 1H), 7.18-7.15 (m, 1H), 7.00 (t, 1H), 6.70 (d, 1H), 5.68 (brs, 1H), 4.81-4.74 (m, 1H), 4.61-4.42 (m, 2H), 4.26 (s, 2H), 4.11-4.07 (m, 1H), 3.93-3.90 (m, 1H).

Example 118

(R)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl) phthalazin-1(2H)-one; (I-118)

Step 1: Preparation of (R)-3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

(351) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)-6-chloro-N-(pyrrolidin-3-yl)pyridazin-3-amine (200 mg, 1.00 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (169 mg, 1.00 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 496 mg, 1.31 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.35 mL, 2.01 mmol) to afford (R)-3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (179 mg, 51%).

Step 2: Preparation of (R,Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

(352) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(179 mg, 0.51 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (124 mg, 0.51 mmol), triethylamine (0.1 mL, 0.77 mmol) to afford intermediate compound (R,Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one (146 mg, 61%).

Step 3: Preparation of (R)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(353) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(146 mg, 0.31 mmol) was reacted with hydrazine monohydrate (30 uL, 0.31 mmol) to afford title compound (78 mg, 52%).

(354) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.85 (s, 0.6H), 10.61 (s, 0.4H), 8.43 (m, 1H), 7.79-7.66 (m, 3.5H), 7.32 (m, 1.5H), 7.15-6.98 (m, 2H), 6.69 (d, 0.4H), 6.58 (d, 0.6H), 5.37 (t, 1H), 4.65 (m, 0.4H), 4.58 (m, 0.6H), 4.26 (d, 2H), 3.99-3.83 (m, 1H), 3.79-3.66 (m, 2H), 3.43 (m, 0.5H), 3.25 (dd, 0.5H), 2.32 (m, 1H), 2.04 (m, 1H).

Example 119

(R)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-119)

Step 1: Preparation of (R)-3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

(355) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)-6-chloro-N-methyl-N-(pyrrolidin-3-yl)pyridazin-3-amine (200 mg, 0.94 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (158 mg, 0.94 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 463 mg, 1.22 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.33 mL, 1.88 mmol) to afford (R)-3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (174 mg, 51%).

Step 2: Preparation of (R,Z)-3-(3-(3-((6-chloropyridazin-3-yl)methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene) isofuran-1(3H)-one

(356) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(174 mg, 0.48 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (116 mg, 0.48 mmol), triethylamine (0.1 mL, 0.72 mmol) to afford intermediate compound (R,Z)-3-(3-(3-((6-chloropyridazin-3-yl)methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one (140 mg, 61%).

Step 3: Preparation of (R)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl) phthalazin-1(2H)-one

(357) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(140 mg, 0.29 mmol) was reacted with hydrazine monohydrate (29 uL, 0.59 mmol) to afford title compound (74 mg, 52%).

(358) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.42 (s, 0.6H), 10.29 (s, 0.4H), 8.46 (m, 1H), 7.81-7.70 (m, 3H), 7.38 (m, 1H), 7.34-7.24 (m, 1H), 7.22 (d, 1H), 7.03 (m, 1H), 6.82 (dd, 1H), 5.58 (m, 0.5H), 5.41 (m, 0.5H), 4.29 (s, 0.8H), 4.28 (s, 1.2H), 3.92 (m, 1H), 3.74-3.61 (m, 2H), 3.44 (m, 0.5H), 3.26 (dd, 0.5H), 2.99 (s, 1.2H), 2.94 (s, 1.8H), 2.32-2.04 (m, 2H).

Example 120

(R)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-120)

Step 1: Preparation of (R)-4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde

(359) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)—N-(pyrrolidin-3-yl)pyrimidine-2-amine (200 mg, 1.22 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (205 mg, 1.22 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 600 mg, 1.58 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.42 mL, 2.44 mmol) to afford (R)-4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde (195 mg, 51%).

Step 2: Preparation of (R,Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

(360) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(195 mg, 0.62 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (150 mg, 0.62 mmol), triethylamine (0.13 mL, 0.94 mmol) to afford intermediate compound (R,Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1 (3H)-one (163 mg, 61%).

Step 3: Preparation of (R)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(361) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(163 mg, 0.38 mmol) was reacted with hydrazine monohydrate (37 uL, 0.76 mmol) to afford title compound (88 mg, 52%).

(362) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.73 (s, 0.6H), 10.51 (s, 0.4H), 8.42 (s, 1H), 8.30 (dd, 2H), 7.78-7.68 (m, 3H), 7.41 (m, 1H), 7.28 (m, 1H), 7.03 (q, 1H), 6.59 (m, 1H), 5.57 (dd, 1H), 4.63 (m, 0.4H), 4.53 (m, 0.6H), 4.27 (s, 0.8H), 4.26 (s, 1.2H), 4.02 (dd, 0.4H), 3.88-3.68 (m, 1.6H), 3.62 (dd, 0.4H), 3.52-3.40 (m, 1H), 3.26 (d, 0.6H), 2.37-2.24 (m, 1H), 2.08-1.95 (m, 1H).

Example 121

(R)-4-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-121)

Step 1: Preparation of (R)-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

(363) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)—N-ethyl-N-(pyrrolidin-3-yl)pyrimidine-2-amine (220 mg, 1.14 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (158 mg, 0.94 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 564 mg, 1.49 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.40 mL, 2.29 mmol) to afford (R)-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (200 mg, 51%).

Step 2: Preparation of (R,Z)-3-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

(364) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(200 mg, 0.58 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (141 mg, 0.58 mmol), triethylamine (0.12 mL, 0.87 mmol) to afford intermediate compound (R,Z)-3-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one (163 mg, 61%).

Step 3: Preparation of (R)-4-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(365) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(163 mg, 0.36 mmol) was reacted with hydrazine monohydrate (34 uL, 0.72 mmol) to afford title compound (87 mg, 52%).

(366) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.43 (s, 0.5H), 10.38 (s, 0.5H), 8.47 (m, 1H), 8.30 (m, 2H), 7.81-7.68 (m, 3H), 7.39 (dd, 1H), 7.28 (m, 1H), 7.03 (m, 1H), 6.51 (m, 1H), 5.37-5.18 (m, 1H), 4.29 (s, 0.8H), 4.27 (s, 1.2H), 4.02-3.90 (m, 1H), 3.67-3.53 (m, 2H), 3.52-3.37 (m, 2.5H), 3.27 (t, 0.5H), 2.22 (m, 1H), 2.13 (m, 1H), 1.22 (t, 1.5H), 1.16 (t, 1.5H).

Example 122

(R)-4-(4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-122)

Step 1: Preparation of (R)-4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzaldehyde

(367) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)—N-(pyrrolidin-3-yl)pyridazin-3-amine (200 mg, 1.34 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (225 mg, 1.34 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 660 mg, 1.74 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.47 mL, 2.68 mmol) to afford (R)-4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzaldehyde (214 mg, 51%).

Step 2: Preparation of (R,Z)-3-(4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

(368) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(214 mg, 0.68 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (165 mg, 0.68 mmol), triethylamine (0.14 mL, 1.02 mmol) to afford intermediate compound (R,Z)-3-(4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1 (3H)-one (179 mg, 61%).

Step 3: Preparation of (R)-4-(4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(369) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(179 mg, 0.42 mmol) was reacted with hydrazine monohydrate (41 uL, 0.84 mmol) to afford title compound (97 mg, 52%).

(370) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.88 (s, 0.6H), 10.49 (s, 0.4H), 8.58 (m, 1H), 8.44 (m, 1H), 7.74 (m, 3H), 7.39-7.25 (m, 2H), 7.17 (m, 1H), 7.02 (m, 1H), 6.71 (d, 0.4H), 6.63 (d, 0.6H), 5.30 (m, 0.4H), 5.00 (m, 0.6H), 4.28 (s, 0.8H), 4.26 (s, 1.2H), 4.02 (m, 0.6H), 3.87 (m, 1.4H), 3.79-3.64 (m, 1H), 3.52-3.42 (m, 0.5H), 3.25 (m, 0.5H), 2.43-2.26 (m, 1H), 2.07 (m, 1H).

Example 123

(R)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl) phthalazin-1(2H)-one; (I-123)

Step 1: Preparation of (R)-4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde

(371) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)—N-methyl-N-(pyrrolidin-3-yl)pyridazin-3-amine (200 mg, 1.12 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (188 mg, 1.12 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 553 mg, 1.46 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.39 mL, 2.24 mmol) to afford (R)-4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde (187 mg, 51%).

Step 2: Preparation of (R,Z)-3-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

(372) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(187 mg, 0.57 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (138 mg, 0.57 mmol), triethylamine (0.12 mL, 0.86 mmol) to afford intermediate compound (R,Z)-3-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (155 mg, 61%).

Step 3: Preparation of (R)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(373) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(155 mg, 0.35 mmol) was reacted with hydrazine monohydrate (34 uL, 0.70 mmol) to afford title compound (83 mg, 52%).

(374) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.70 (s, 0.6H), 10.25 (s, 0.4H), 8.61 (m, 1H), 8.46 (m, 1H), 7.81-7.70 (m, 3H), 7.39 (m, 1H), 7.33-7.21 (m, 2H), 7.08-6.97 (m, 1H), 6.81 (m, 1H), 5.74 (m, 0.4H), 5.52 (m, 0.6H), 4.29 (s, 0.8H), 4.27 (s, 1.2H), 3.92 (m, 1H), 3.75-3.63 (m, 2H), 3.52-3.39 (m, 0.4H), 3.24 (dd, 0.6H), 2.99 (s, 1.2H), 2.94 (s, 1.8H), 2.25 (m, 1H), 2.08 (m, 1H).

Example 124

(R)-4-(4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-124)

Step 1: Preparation of (R)-4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde

(375) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)—N-(pyrrolidine-3-yl)thiazol-2-amine (200 mg, 1.18 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (198 mg, 1.18 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 582 mg, 1.54 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.42 mL, 2.36 mmol) to afford (R)-4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde (170 m g, 45%).

Step 2: Preparation of (R,Z)-3-(4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

(376) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(170 mg, 0.53 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (128 mg, 0.53 mmol), triethylamine (0.11 mL, 0.80 mmol) to afford intermediate compound (R,Z)-3-(4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzylidene) isofuran-1(3H)-one (125 mg, 54%).

Step 3: Preparation of (R)-4-(4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(377) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(125 mg, 0.29 mmol) was reacted with hydrazine monohydrate (28 uL, 0.57 mmol) to afford title compound (67 mg, 52%).

(378) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (m, 1H), 7.85 (m, 3H), 7.39 (m, 2H), 7.15 (m, 1H), 6.96 (dd, 1H), 6.58 (dd, 1H), 4.41 (m, 2H), 3.71 (m, 3H), 3.40 (m, 1H), 3.21 (m, 1H), 2.29 (m, 1H), 2.04 (m, 1H).

Example 125

(R)-4-(3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl) phthalazin-1(2H)-one; (I-125)

Step 1: Preparation of (R)-3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

(379) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)-5-ethynyl-N-(pyrrolidin-3-yl)pyrimidine-2-amine (230 mg, 1.22 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (205 mg, 1.22 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 602 mg, 1.59 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.43 mL, 2.44 mmol) to afford (R)-3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (210 mg, 51%).

Step 2: Preparation of (R,Z)-3-(3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

(380) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 2)(210 mg, 0.62 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (150 mg, 0.62 mmol), triethylamine (0.13 mL, 0.93 mmol) to afford intermediate compound (R,Z)-3-(3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one (164 mg, 58%).

Step 3: Preparation of (R)-4-(3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(381) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(164 mg, 0.36 mmol) was reacted with hydrazine monohydrate (36 uL, 0.72 mmol) to afford title compound (103 mg, 61%).

(382) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.10-0.93 (dd, 1H), 8.41-8.38 (m, 3H), 7.78-7.68 (m, 3H), 7.41-7.37 (m, 1H), 7.32-7.27 (m, 1H), 7.04-7.02 (m, 1H), 5.48-5.44 (m, 1H), 4.66-4.51 (m, 1H), 4.27 (s, 2H), 4.03 (m, 0.5H), 3.85-3.39 (m, 3H), 3.28-3.26 (m, 0.5H), 3.19 (m, 2H), 2.40-2.23 (m, 1H), 2.17-1.93 (m, 1H).

Example 126

(R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)pyrrolidin-3-yl) amino)pyrimidine-5-carbonitrile; (I-126)

Step 1: Preparation of (R)-2-((1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile

(383) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)-2-(pyrrolidin-3-ylamino)pyrimidine-5-carbonitrile (230 mg, 1.22 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (205 mg, 1.22 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 602 mg, 1.59 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.43 mL, 2.44 mmol) to afford (R)-3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (210 mg, 51%).

Step 2: Preparation of (R,Z)-2-((1-(2-fluoro-5-((3-oxoisofuran-1(3H)-ylidene)methyl)benzol)pyrrolidin-3-yl) amino)pyrimidine-5-carbonitrile

(384) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(210 mg, 0.63 mol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (150 mg, 0.63 mmol), triethylamine (0.13 mL, 0.93 mmol) to afford intermediate compound (R,Z)-2-((1-(2-fluoro-5-((3-oxoisofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile (164 mg, 58%).

Step 3: Preparation of (R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl) amino)pyrimidine-5-carbonitrile

(385) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(164 mg, 0.36 mmol) was reacted with hydrazine monohydrate (164 mg, 0.36 mmol) to afford title compound (103 mg, 61%).

(386) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 9.93-9.81 (m, 1H), 8.50-8.43 (m, 2H), 7.79-7.62 (m, 3H), 7.41-7.27 (m, 3H), 7.07-6.99 (m, 1H), 5.83-5.76 (m, 1H), 4.71-4.55 (m, 1H), 4.27 (d, 2H), 4.05-4.00 (m, 0.5H), 3.88-3.62 (m, 2H), 3.52-3.44 (m, 1H), 3.29-3.25 (m, 0.5H), 2.42-2.28 (m, 1H), 2.09-1.96 (m, 1H).

Example 127

(R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)pyrrolidin-3-yl) amino)nicotinonitrile; (I-127)

Step 1: Preparation of (R)-2-((1-(2-fluoro-5-formylbenzoyl)pyrrolidine-3-yl)amino)nicotinonitrile

(387) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)-2-(pyrrolidin-3-ylamino)nicotinonitrile (300 mg, 1.59 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (205 mg, 1.22 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 785 mg, 2.07 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.55 mL, 3.18 mmol) to afford (R)-2-((1-(2-fluoro-5-formylbenzoyl)pyrrolidine-3-yl)amino)nicotinonitrile (275 mg, 51%).

Step 2: Preparation of (R,Z)-2-((1-(2-fluoro-5-((3-oxoisofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidine-3-yl) amino)nicotinonitrile

(388) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(275 mg, 0.81 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (196 mg, 0.81 mmol), triethylamine (1.7 mL, 1.22 mmol) to afford intermediate compound (R,Z)-2-((1-(2-fluoro-5-((3-oxoisofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidine-3-yl)amino)nicotinonitrile (155 mg, 42%).

Step 3: Preparation of (R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl) amino)nicotinonitrile

(389) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(155 mg, 0.34 mmol) was reacted with hydrazine monohydrate (34 uL, 0.68 mmol) to afford title compound (78 mg, 49%).

(390) .sup.1H-NMR (DMSO, 400 MHz): δ 12.59 (d, 1H), 8.28 (m, 2H), 7.85 (m, 4H), 7.38 (m, 2H), 7.22 (m, 2H), 6.72 (m, 1H), 4.57 (m, 1H), 4.32 (d, 2H), 3.75 (m, 1H), 3.46 (m, 2H), 3.21 (m, 1H), 2.10 (m, 2H).

Example 128

(R)-4-(4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-128)

Step 1: Preparation of (R)-4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde

(391) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)—N-(pyrrolidin-3-yl)pyridine-2-amine (250 mg, 0.92 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (154 mg, 0.92 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 453 mg, 1.19 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.32 mL, 1.83 mmol) to afford (R)-4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde (178 m g, 62%).

Step 2: Preparation of (R,Z)-3-(4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

(392) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(178 mg, 0.57 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (138 mg, 0.57 mmol), triethylamine (0.12 mL, 0.85 mmol) to afford intermediate compound (R,Z)-3-(4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene) isofuran-1(3H)-one (144 mg, 59%).

Step 3: Preparation of (R)-4-(4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(393) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(144 mg, 0.34 mmol) was reacted with hydrazine monohydrate (33 uL, 0.67 mmol) to afford title compound (91 mg, 61%).

(394) .sup.1H-NMR (MeOD, 400 MHz): δ 8.35-8.31 (m, 1H), 7.95-7.93 (m, 1H), 7.88-7.81 (m, 2H), 7.76-7.73 (m, 1H), 7.45-7.39 (m, 3H), 7.34-7.32 (m, 1H), 7.15-7.08 (m, 2H), 4.67-4.30 (m, 1H), 4.38-4.31 (d, 2H), 3.98-3.12 (m, 5H), 2.35-2.19 (m, 1H), 2.06-1.88 (m, 1H).

Example 129

(R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl) amino)-N,N-dimethylnicotinamide; (I-129)

Step 1: Preparation of (R)-2-((1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylnicotinamide

(395) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)—N,N-dimethyl-2-(pyrrolidin-3-ylamino)nicotinamide (320 mg, 1.36 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (300 mg, 1.36 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 673 mg, 1.77 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.48 mL, 2.73 mmol) to afford (R)-2-((1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylnicotinamide (220 mg, 42%).

Step 2: Preparation of (R,Z)-2-((1-(2-fluoro-5-((3-oxoisofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl) amino)-N,N-dimethylnicotinamide

(396) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(220 mg, 0.57 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (139 mg, 0.57 mmol), triethylamine (0.2 mL, 0.86 mmol) to afford intermediate compound (R,Z)-2-((1-(2-fluoro-5-((3-oxoisofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylnicotinamide (109 mg, 38%).

Step 3: Preparation of (R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl) amino)-N,N-dimethylnicotinamide

(397) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(109 mg, 0.22 mmol) was reacted with hydrazine monohydrate (22 uL, 0.44 mmol) to afford title compound (39 mg, 35%).

(398) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (m, 1H), 7.88 (m, 4H), 7.44 (m, 3H), 7.13 (m, 1H), 6.69 (m, 1H), 4.56 (m, 1H), 4.36 (d, 2H), 3.85 (m, 1H), 3.55 (m, 2H), 3.21 (m, 1H), 3.02 (s, 6H), 2.30 (m, 1H), 2.07 (m, 1H).

Example 130

(R)-4-(3-(3-((5-bromopyridin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-130)

Step 1: Preparation of (R)-3-(3-((5-bromopyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

(399) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)-5-bromo-N-(pyrrolidin-3-yl)pyrimidine-2-amine (320 mg, 1.32 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (221 mg, 1.32 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 649 mg, 1.71 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.46 mL, 2.63 mmol) to afford (R)-3-(3-((5-bromopyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde (274 mg, 53%).

Step 2: Preparation of (R,Z)-3-(4-fluoro-3-(3-((5-bromopyrimidin-2-yl)aminopyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

(400) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(274 mg, 0.70 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (169 mg, 0.70 mmol), triethylamine (0.15 mL, 1.04 mmol) to afford intermediate compound (R,Z)-3-(4-fluoro-3-(3-((5-bromopyrimidin-2-yl)aminopyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (217 mg, 61%).

Step 3: Preparation of (R)-4-(4-fluoro-3-(3-((5-bromopyrimidin-2-yl)aminopyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(401) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(217 mg, 0.43 mmol) was reacted with hydrazine monohydrate (45 uL, 0.86 mmol) to afford title compound (131 mg, 59%).

(402) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 9.93-9.81 (m, 1H), 8.50-8.43 (m, 2H), 7.79-7.62 (m, 3H), 7.41-7.27 (m, 3H), 7.07-6.99 (m, 1H), 5.83-5.76 (m, 1H), 4.71-4.55 (m, 1H), 4.27 (d, 2H), 4.05-4.00 (m, 0.5H), 3.88-3.62 (m, 2H), 3.52-3.44 (m, 1H), 3.29-3.25 (m, 0.5H), 2.42-2.28 (m, 1H), 2.09-1.96 (m, 1H).

Example 131

(R)-4-(4-fluoro-3-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl) benzyl)phthalazin-1(2H)-one; (I-131)

Step 1: Preparation of (R)-4-fluoro-3-(3-((5-(trifluoromethylpyridin-2-yl)aminopyrrolidine-1-carbonyl)benzaldehyde

(403) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)—N-(pyrrolidin-3-yl)-5-(trifluoromethyl-2-amine (200 mg, 0.86 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (145 mg, 0.86 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 426 mg, 1.12 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.31 mL, 1.72 mmol) to afford (R)-4-fluoro-3-(3-((5-(trifluoromethylpyridin-2-yl)aminopyrrolidine-1-carbonyl)benzaldehyde (174 mg, 53%).

Step 2: Preparation of (R,Z)-3-(4-fluoro-3-(3-((5-(trifluoromethylpyridin-2-yl)amino)pyrrolidine-1-carbonyl) benzylidene)isofuran-1(3H)-one

(404) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(174 mg, 0.46 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (111 mg, 0.46 mmol), triethylamine (96 uL, 0.69 mmol) to afford intermediate compound R,Z)-3-(4-fluoro-3-(3-((5-(trifluoromethylpyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (139 mg, 61%).

Step 3: Preparation of (R)-4-(4-fluoro-3-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(405) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(139 mg, 0.28 mmol) was reacted with hydrazine monohydrate (28 uL, 0.56 mmol) to afford title compound (85 mg, 59%).

(406) .sup.1H-NMR (DMSO, 400 MHz): δ 12.59 (d, 1H), 8.29 (m, 2H), 7.85 (m, 3H), 7.62 (m, 2H), 7.39 (m, 2H), 7.20 (m, 1H), 6.58 (m, 1H), 4.38 (m, 1H), 4.32 (d, 2H), 3.75 (m, 1H), 3.47 (m, 2H), 3.21 (m, 1H), 2.20 (m, 1H), 1.92 (m, 1H).

Example 132

(R)-4-(4-fluoro-3-(3-((4-(trifluoroethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl) benzyl)phthalazin-1(2H)-one; (I-132)

Step 1: Preparation of (R)-4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde

(407) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)—N-(pyrrolidin-3-yl)-4-(trifluoromethyl)pyridine-2-amine (200 mg, 0.86 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (145 mg, 0.86 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 426 mg, 1.12 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.31 mL, 1.72 mmol) to afford (R)-4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde (174 mg, 53%).

Step 2: Preparation of (R,Z)-3-(4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

(408) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(174 mg, 0.46 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (111 mg, 0.46 mmol), triethylamine (96 uL, 0.69 mmol) to afford intermediate compound (R,Z)-3-(4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (139 mg, 61%).

Step 3: Preparation of (R)-4-(4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(409) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(139 mg, 0.28 mmol) was reacted with hydrazine monohydrate (28 uL, 0.56 mmol) to afford title compound (85 mg, 59%).

(410) .sup.1H-NMR (DMSO, 400 MHz): δ 12.59 (d, 1H), 8.29 (m, 2H), 7.85 (m, 3H), 7.62 (m, 2H), 7.39 (m, 2H), 7.20 (m, 1H), 6.58 (m, 1H), 4.38 (m, 1H), 4.32 (d, 2H), 3.75 (m, 1H), 3.47 (m, 2H), 3.21 (m, 1H), 2.20 (m, 1H), 1.92 (m, 1H).

Example 133

4-(3-(3-(benzylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; I-133

Step 1: Preparation of 4-(3-(3-(benzylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(411) Benzyl bromide (0.10 mL, 0.86 mmol) and K.sub.2CO.sub.3 (119 mg, 0.86 mmol) was added to a suspension of the example 3 product (150 mg, 0.43 mmol) in dimethylformamide (DMF, 8 mL) and stirred for 8 hours at 80° C. The reaction was cooled to room temperature and concentrated in vacuo, added dichloromethane and washed a solution of sodium bicarbonate and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuo and purified using silica chromatography to afford title compound (86 mg, 45%).

(412) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.17 (s, 1H), 8.47-8.46 (m, 1H), 7.82-7.72 (m, 3H), 7.54-7.50 (m, 1H), 7.37-7.31 (m, 5H), 7.06-7.01 (m, 1H), 4.37-4.32 (m, 1H), 4.29 (s, 2H), 4.19-4.16 (m, 1H), 3.89-3.73 (m, 5H).

Example 134

4-(4-fluoro-3-(3-((3,3,3-tri fluoropropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-134)

Step 1: Preparation of 4-(4-fluoro-3-(3-((3,3,3-trifluoropropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(413) This compound was made using the procedure described for example 133 (Step 1). Thus, 4-(3-(3-aminoazetidin-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (150 mg, 0.43 mmol) was reacted with 3-bromo-1,1,1-trifluoropropan (0.25 mL, 0.86 mmol), K.sub.2CO.sub.3 (119 mg, 0.86 mmol) to afford title compound (98 mg, 51%).

(414) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.92 (m, 1H), 7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.17-7.12 (m, 1H), 4.37 (s, 2H), 4.30-4.28 (m, 1H), 4.16-4.14 (m, 1H), 3.86-3.83 (m, 1H), 3.78-3.76 (m, 1H), 3.68-3.66 (m, 1H), 2.48-2.42 (m, 2H), 1.92-1.85 (m, 2H).

Example 135

(R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-135)

Step 1: Preparation of (S)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl) pyrrolidine-3-ylmethansulfonate

(415) The example 5 intermediate compound (S)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1 (2H)-one (539 mg, 1.25 mmol) in dichloromethane (7 mL) cooled to 0° C. was added triethylamine (0.1 mL, 1.50 mmol), methanesulfonyl chloride (MsCl, 0.11 mL, 1.38 mmol), and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo, added dichloromethane and washed with aqueous sodium bicarbonate and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuo to afford (S)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-ylmethanesulfonate (434 mg, 78%).

Step 2: Preparation of (R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(416) The intermediate compound (Step 1)(434 mg, 0.97 mmol) in dimethylformamide (DMF, 5 mL) was added azetidine (0.20 mL, 2.93 mmol), Li.sub.2CO.sub.3 (216 mg, 2.93 mmol) and the mixture was stirred at 80° C. for 16 h. The reaction mixture was concentrated in vacuo, added dichloromethane and washed with aqueous ammonium chloride and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuo and purified using silica chromatography to afford the title compound (117 mg, 45%).

(417) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.26 (d, 1H), 7.96 (t, 1H), 7.91-7.80 (m, 2H), 7.46-7.35 (m, 1H), 7.25-7.18 (m, 1H), 4.33 (s, 2H), 3.73-3.58 (m, 1H), 3.44-3.39 (m, 1H), 3.27-3.19 (m, 1H), 3.13-3.08 (m, 1H), 2.98 (t, 1H), 2.86 (d, 1H), 2.77-2.61 (m, 1H), 2.16 (t, 2H), 2.03 (t, 2H), 1.77-1.62 (m, 2H).

Example 136

(R)-4-(3-([1,3′-bipyrrolidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-136)

Step 1: Preparation of (S)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl) pyrrolidine-3-ylmethansulfonate

(418) The intermediate compound (S)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-yl-methansulfonate was made using the procedure described for example 135 (Step 1) in a yield of 78% (434 mg).

Step 2: Preparation of (R)-4-(3-([1,3′-bipyrrolidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(419) This compound was made using the procedure described for example 135 (Step 2). Thus, the intermediate compound (Step 1)(434 mg, 0.97 mmol) was reacted with pyrrolidine (0.22 mL, 2.93 mmol), Li.sub.2CO.sub.3 (216 mg, 2.93 mmol) to afford title compound (130 mg, 32%).

(420) .sup.1H-NMR (MeOD, 400 MHz): δ 8.35 (d, 1H), 7.93 (d, 1H), 7.90-7.79 (m, 2H), 7.54-7.44 (m, 1H), 7.42-7.37 (m, 1H), 7.18-7.11 (m, 1H), 4.37 (s, 2H), 3.85-3.74 (m, 1H), 2.65 (t, 2H), 2.57-2.50 (m, 1H), 2.40 (t, 1H), 2.23-2.07 (m, 1H), 1.97-1.90 (m, 1H), 1.85 (m, 2H), 1.76 (m, 2H).

Example 137

(R)-4-(4-fluoro-3-(3-(piperidin-1-yl)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-137)

Step 1: Preparation of (S)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl) pyrrolidine-3-ylmethansulfonate

(421) The intermediate compound (S)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-yl-methansulfonate was made using the procedure described for example 135 (Step 1) in a yield of 78% (434 mg).

Step 2: Preparation of (R)-4-(4-fluoro-3-(3-(piperidin-1-yl)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(422) This compound was made using the procedure described for example 135 (Step 2). Thus, the intermediate compound (Step 1)(434 mg, 0.97 mmol) was reacted with piperidine (0.10 mL, 2.93 mmol), Li.sub.2CO.sub.3 (216 mg, 2.93 mmol) to afford title compound (88 mg, 21%).

(423) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H), 7.91-7.80 (m, 2H), 7.46-7.39 (m, 1H), 7.38-7.35 (m, 1H), 7.25-7.19 (m, 1H), 4.32 (s, 2H), 3.75-3.59 (m, 1H), 3.39-3.36 (m, 0.5H), 3.29-3.12 (m, 2H), 2.97 (t, 0.5H), 2.83-2.71 (m, 1H), 2.42-2.28 (m, 3H), 2.15-1.98 (m, 2H), 1.73-1.63 (m, 1H), 1.51-1.29 (m, 6H).

Example 138

(R)-4-(4-fluoro-3-(3-(p-tolyl amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-138)

Step 1: Preparation of (R)-4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzaldehyde

(424) This compound was made using the procedure described for example 11 (Step 1). Thus, (R)-4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzaldehyde (200 mg, 1.13 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (190 mg, 1.13 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 559 mg, 1.48 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.40 mL, 2.27 mmol) to afford (R)-4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzaldehyde (230 mg, 62%).

Step 2: Preparation of (R,Z)-3-(4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

(425) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(230 mg, 0.70 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (170 mg, 0.70 mmol), triethylamine (0.15 mL, 1.10 mmol) to afford intermediate compound (R,Z)-3-(4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (190 mg, 61%).

Step 3: Preparation of (R)-4-(4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(426) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(190 mg, 0.43 mmol) was reacted with hydrazine monohydrate (42 uL, 0.86 mmol) to afford title compound (129 mg, 66%).

(427) .sup.1H-NMR (DMSO, 400 MHz): δ 12.59 (d, 1H), 8.26 (m, 1H), 7.85 (m, 3H), 7.60 (m, 1H), 7.36 (m, 1H), 7.20 (m, 1H), 6.88 (dd, 2H), 6.48 (dd, 2H), 5.60 (m, 1H), 4.32 (d, 2H), 3.91 (m, 2H), 3.52 (m, 2H), 3.11 (m, 1H), 2.14 (m, 1H), 2.12 (s, 3H), 1.90 (m, 1H).

Example 139

(R)-4-(4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-139)

Step 1: Preparation of (R)-4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzaldehyde

(428) This compound was made using the procedure described for example 11 (Step 1). Thus, (R) N-phenylpyrrolidine-3-amine (200 mg, 1.23 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (207 mg, 1.23 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 607 mg, 1.60 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.43 mL, 2.46 mmol) to afford (R)-4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzaldehyde (238 mg, 62%).

Step 2: Preparation of (R,Z)-3-(4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

(429) This compound was made using the procedure described for example 11 (Step 2). Thus, the intermediate compound (Step 1)(238 mg, 0.76 mmol) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (185 mg, 0.76 mmol), triethylamine (0.16 mL, 1.14 mmol) to afford intermediate compound (R,Z)-3-(4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (200 mg, 61%).

Step 3: Preparation of (R)-4-(4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(430) This compound was made using the procedure described for example 11 (Step 3). Thus, the intermediate compound (Step 2)(200 mg, 0.47 mmol) was reacted with hydrazine monohydrate (46 uL, 0.94 mmol) to afford title compound (136 mg, 66%).

(431) .sup.1H-NMR (MeOD, 400 MHz): δ 8.39-8.34 (m, 1H), 7.97-7.70 (m, 3H), 7.50-7.33 (m, 2H), 7.19-7.07 (m, 3H), 6.70-6.57 (m, 3H), 4.40 (s, 1H), 4.33 (s, 1H), 4.17-4.05 (m, 1H), 3.95-3.79 (m, 1H), 3.72-3.47 (m, 2H), 3.41-3.16 (m, 1H), 2.37-2.20 (m, 1H), 2.09-1.91 (m, 1H).

Example 140

4-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-140)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate

(432) The intermediate compound (example 7) 4-(4-fluoro-3-(3-(hydroxymethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (460 mg, 1.25 mmol) in dichloromethane (7 mL) cooled to 0° C. was added triethylamine (0.1 mL, 1.50 mmol), methanesulfonyl chloride (MsCl, 0.11 mL, 1.38 mmol), and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo, added dichloromethane and washed with aqueous sodium bicarbonate and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuo to afford (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate (417 mg, 75%).

Step 2: Preparation of 4-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(433) The intermediate compound (Step 1)(417 mg, 0.94 mmol) in 1,4-dioxane (5 mL) was added pyrrolidine (0.27 mL, 4.00 mmol) and the mixture was stirred at 80° C. for 16 h. The reaction mixture was concentrated in vacuo, added dichloromethane and washed with aqueous ammonium chloride and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuo and purified using silica chromatography to afford the title compound (138 mg, 35%).

(434) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 9.85 (s, 1H), 8.46-8.44 (m, 1H), 7.78-7.70 (m, 3H), 7.49-7.47 (m, 1H), 7.32-7.27 (m, 1H), 7.03-6.98 (m, 1H), 4.29-4.24 (m, 3H), 4.14-4.10 (t, 1H), 3.85-3.77 (m, 2H), 2.91-2.64 (m, 3H), 2.48 (s, 4H), 1.77 (s, 4H).

Example 141

4-(4-fluoro-3-(3-(piperidin-1-ylethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-141)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethanesulfonate

(435) The intermediate compound (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate was made using the procedure described for example 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of 4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(436) This compound was made using the procedure described for example 140 (Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol) was reacted with piperidine (0.44 mL, 4.00 mmol) to afford title compound (138 mg, 35%).

(437) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 9.94 (s, 1H), 8.46 (m, 1H), 7.78-7.70 (m, 3H), 7.50-7.48 (m, 1H), 7.31-7.27 (m, 1H), 7.01 (t, 1H), 4.27-4.23 (t, 1H), 4.26 (s, 2H), 7.13-4.09 (t, 1H), 3.83-3.70 (m, 2H), 2.88-2.84 (m, 1H), 2.57-2.55 (m, 2H), 2.32 (s, 4H), 1.54 (s, 4H), 1.42 (s, 2H).

Example 142

4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-142)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl) methylmethansulfonate

(438) The intermediate compound (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl) methyl methansulfonate was made using the procedure described for example 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of 4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(439) This compound was made using the procedure described for example 140 (Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol) was reacted with azetidine (0.28 mL, 4.00 mmol) to afford title compound (154 mg, 41%).

(440) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.94 (d, 1H), 7.84 (m, 2H), 7.50 (m, 2H), 7.13 (t, 1H), 4.38 (s, 2H), 4.19 (t, 1H), 4.09 (m, 1H), 3.74 (m, 2H), 3.30 (m, 4H), 2.69 (m, 3H), 2.14 (t, 2H).

Example 143

4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-143)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl) methyl methansulfonate

(441) The intermediate compound (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate was made using the procedure described for example 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of 4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(442) This compound was made using the procedure described for example 140 (Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol) was reacted with cyclopropylamine (0.28 mL, 4.00 mmol) to afford title compound (206 mg, 54%).

(443) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.03 (s, 1H), 8.47-8.45 (m, 1H), 7.80-7.71 (m, 3H), 7.52-7.48 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.27 (s, 2H), 4.26-4.22 (m, 1H), 4.10 (t, 1H), 3.85-3.81 (m, 1H), 3.73-3.70 (m, 1H), 2.99-2.88 (m, 2H), 2.81-2.72 (m, 1H), 2.07 (m, 1H), 1.57 (br, 1H), 0.45-0.41 (m, 2H), 0.29-0.26 (m, 2H).

Example 144

4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-144)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl) methyl methansulfonate

(444) The intermediate compound (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl) methyl methansulfonate was made using the procedure described for example 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of 4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(445) This compound was made using the procedure described for example 140 (Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol) was reacted with isopropylamine (0.34 mL, 4.00 mmol) to afford title compound (234 mg, 61%).

(446) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.20 (br, 1H), 8.47-8.45 (m, 1H), 7.80-7.70 (m, 3H), 7.51-7.49 (dd, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.27 (s, 2H), 4.28-4.23 (m, 1H), 4.12 (t, 1H), 3.84-3.81 (dd, 1H), 3.75-3.71 (dd, 1H), 2.88-2.69 (m, 4H), 1.05-1.03 (dd, 6H).

Example 145

4-(3-(3-(((cyclopropylmethyl)amino)ethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-145)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate

(447) The intermediate compound (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate was made using the procedure described for example 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of 4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(448) This compound was made using the procedure described for example 140 (Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol) was reacted with cyclopropylmethylamine (0.34 mL, 4.00 mmol) to afford title compound (189 mg, 48%).

(449) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.36 (br, 1H), 8.47-8.45 (m, 1H), 7.80-7.71 (m, 3H), 7.51-7.49 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.27-4.24 (m, 3H), 4.13 (t, 1H), 3.86-3.75 (m, 2H), 2.94-2.75 (m, 3H), 2.48-2.46 (dd, 2H), 1.61 (br, 1H), 0.95-0.91 (m, 1H), 0.51-0.46 (m, 2H), 0.12-0.09 (m, 2H).

Example 146

4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-146)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate

(450) The intermediate compound (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate was made using the procedure described for example 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of 4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(451) This compound was made using the procedure described for example 140 (Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol) was reacted with 2-methylpropan-1-amine (0.40 mL, 4.00 mmol) to afford title compound (207 mg, 52%).

(452) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.69 (br, 1H), 8.47-8.45 (m, 1H), 7.80-7.71 (m, 3H), 7.50-7.48 (m, 1H), 7.32-7.28 (m, 1H), 7.00 (t, 1H), 4.27-4.23 (m, 3H), 4.14 (t, 1H), 3.86-3.78 (m, 2H), 2.93-2.78 (m, 3H), 2.45 (s, 1H), 2.44 (s, 1H), 1.81-1.71 (m, 1H), 0.91 (s, 3H), 0.89 (s, 3H).

Example 147

4-(3-(3-((tert-butylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-147)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate

(453) The intermediate compound (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate was made using the procedure described for example 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of 4-(3-(3-((tert-butylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(454) This compound was made using the procedure described for example 140 (Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol) was reacted with 2-methylpropan-2-amine (0.42 mL, 4.00 mmol) to afford title compound (71 mg, 18%).

(455) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.49 (br, 1H), 8.47-8.45 (m, 1H), 7.80-7.72 (m, 3H), 7.52-7.48 (m, 1H), 7.31-7.28 (m, 1H), 7.01 (t, 1H), 4.27-4.22 (m, 3H), 4.14 (t, 1H), 2.90-2.75 (m, 3H), 1.14 (s, 9H).

Example 148

4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-148)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate

(456) The intermediate compound (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate was made using the procedure described for example 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of 4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(457) This compound was made using the procedure described for example 140 (Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol) was reacted with cyclobutylamine (0.43 mL, 4.00 mmol) to afford title compound (138 mg, 35%).

(458) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.33 (br, 1H), 8.47-8.45 (m, 1H), 7.80-7.71 (m, 3H), 7.50-7.48 (m, 1H), 7.31-7.28 (m, 1H), 7.00 (t, 1H), 4.27-4.22 (m, 3H), 4.11 (t, 1H), 3.83-3.72 (m, 2H), 3.23 (m, 1H), 2.83-2.72 (m, 3H), 2.23-2.17 (m, 2H), 1.71-1.62 (m, 5H).

Example 149

4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-149)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl) methyl methansulfonate

(459) The intermediate compound (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate was made using the procedure described for example 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of 4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(460) This compound was made using the procedure described for example 140 (Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol) was reacted with propargylamine (0.27 mL, 4.00 mmol) to afford title compound (163 mg, 43%).

(461) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.61 (s, 1H), 8.48-8.46 (m, 1H), 7.80-7.71 (m, 3H), 7.51-7.49 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.28-4.24 (m, 3H), 4.12 (t, 1H), 3.88-3.76 (m, 2H), 3.43 (m, 2H), 3.00-2.87 (m, 2H), 2.78-2.72 (m, 1H), 2.27-2.23 (m, 1H), 1.45 (br, 1H).

Example 150

4-(4-fluoro-3-(3-((phenylamino)ethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-150)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate

(462) The intermediate compound (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate was made using the procedure described for example 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of 4-(4-fluoro-3-(3-((phenylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

(463) This compound was made using the procedure described for example 140 (Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol) was reacted with aniline (0.36 mL, 4.00 mmol) to afford title compound (45 mg, 11%).

(464) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 11.25 (s, 1H), 8.48-8.46 (m, 1H), 7.77-7.70 (m, 3H), 7.51-7.49 (dd, 1H), 7.33-7.29 (m, 1H), 7.17 (t, 2H), 7.00 (t, 1H), 6.72 (t, 1H), 6.59 (m, 2H), 4.31-4.27 (m, 3H), 4.17-4.09 (m, 1H), 3.39-3.78 (m, 2H), 3.41-3.31 (m, 2H), 2.95-2.89 (m, 1H).

Example 151

1-((((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl) methyl)amino)methyl)cyclopropanecarbonitrile; (I-151)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate

(465) The intermediate compound (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate was made using the procedure described for example 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of 1-((((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)methyl)amino)methyl)cyclopropanecarbonitrile

(466) This compound was made using the procedure described for example 140 (Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol) was reacted with 1-(aminomethyl)cyclopropanecarbonitrile (384 mg, 4.00 mmol) to afford title compound (121 mg, 29%).

(467) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.82-7.95 (m, 3H), 7.44-7.46 (m, 2H), 7.13 (t, 1H), 4.37 (s, 2H), 4.21 (t, 1H), 4.10 (t, 1H), 3.74-3.85 (m, 2H), 2.80-2.87 (m, 3H), 2.68-2.70 (m, 2H), 1.20 (s, 2H), 0.95 (s, 2H).

Example 152

1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl) methyl)amino)cyclopropanecarbonitrile; (I-152)

Step 1: Preparation of (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate

(468) The intermediate compound (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate was made using the procedure described for example 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of 1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)methyl)amino)cyclopropanecarbonitrile

(469) This compound was made using the procedure described for example 140 (Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol) was reacted with 1-aminocyclopropanecarbonitrile (474 mg, 4.00 mmol) to afford title compound (44 mg, 11%).

(470) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.39 (s, 1H), 8.48-8.46 (m, 1H), 7.77-7.72 (m, 3H), 7.53-7.49 (m, 1H), 7.35-7.29 (m, 1H), 7.02 (t, 1H), 4.28 (s, 2H), 4.27-4.09 (m, 2H), 3.86-3.69 (m, 2H), 2.75 (m, 1H), 1.90 (m, 1H), 1.64 (s, 2H), 1.23 (m, 2H), 1.00 (m, 2H).

Example 153

4-(3-(3-((cyclopropyl(prop-2-yn-1-yl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-153)

Step 1: Preparation of 4-(3-(3-((cyclopropyl(prop-2-yn-1-yl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(471) 4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (example 144) (126 mg, 0.52 mmol) in dimethylformamide (DMF, 3 mL) was added Na.sub.2CO.sub.3 (63 mg, 1.56 mmol), 3-bromoprop-1-yn (0.16 mL, 2.60 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo, added dichloromethane and washed with aqueous ammonium chloride and water. The combined organic layers were dried over MgSO.sub.4, filtered, evaporated in vacuo and purified using silica chromatography to afford the title compound (190 mg, 82%).

(472) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 11.08 (s, 1H), 8.49-8.47 (m, 1H), 7.79-7.71 (m, 3H), 7.51-7.49 (m, 1H), 7.32-7.29 (m, 1H), 7.01 (t, 1H), 4.29 (s, 2H), 4.26-4.05 (m, 2H), 3.83-3.68 (m, 2H), 3.40 (m, 2H), 2.96-2.87 (m, 3H), 2.23 (m, 1H), 1.98-1.95 (m, 1H), 0.53-0.48 (m, 2H), 0.34-0.31 (m, 2H).

Example 154

4-(3-(3-((cyclopropyl(methyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-154)

Step 1: Preparation of 4-(3-(3-((cyclopropyl(methyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(473) This compound was made using the procedure described for example 153 (Step 1). Thus, the intermediate compound (example 144) 4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)-phthalazin-1(2H)-one (150 mg, 0.34 mmol) was reacted with Na.sub.2CO.sub.3 (78 mg, 0.74 mmol) and methyl iodide (46 uL, 0.74 mmol) to afford the title compound (121 mg, 85%).

(474) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.91 (s, 1H), 8.49-8.47 (m, 1H), 7.79-7.71 (m, 3H), 7.51-7.49 (m, 1H), 7.32-7.28 (m, 1H), 7.00 (t, 1H), 4.28 (s, 2H), 4.26-4.04 (m, 2H), 3.81-3.66 (m, 2H), 2.96-2.87 (m, 1H), 2.81-2.74 (m, 3H), 1.03 (m, 1H), 0.49-0.41 (m, 2H), 0.34-0.26 (m, 2H).

Example 155

4-(3-(3-((cyclopropyl(ethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-155)

Step 1: Preparation of 4-(3-(3-((cyclopropyl(ethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

(475) This compound was made using the procedure described for example 153 (Step 1). Thus, the intermediate compound (example 144) 4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)-phthalazin-1(2H)-one (150 mg, 0.34 mmol) was reacted with Na.sub.2CO.sub.3 (78 mg, 0.74 mmol) and ethyl iodide (49 uL, 0.74 mmol) to afford the title compound (113 mg, 77%).

(476) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.60 (s, 1H), 8.48-8.46 (m, 1H), 7.79-7.71 (m, 3H), 7.51-7.49 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.28 (s, 2H), 4.26-4.04 (m, 2H), 3.81-3.66 (m, 2H), 2.96-2.87 (m, 1H), 2.81-2.74 (m, 2H), 2.65-2.60 (m, 2H), 1.64 (m, 1H), 1.03 (m, 1H), 0.49-0.41 (m, 2H), 0.34-0.26 (m, 2H).

Example 156

4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; (I-156)

Step 1: Preparation of 4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride

(477) The intermediate compound (example 25) 4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (100 mg, 0.25 mmol) in dichloromethane (3 mL) cooled to 0° C. was added 1N solution of hydrochloric acid (0.50 mL, 0.50 mmol). After stirring at room temperature for 1 h, the solvents were evaporated to afford title compound (102 mg, 93%).

(478) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 9.23 (d, 2H), 8.26 (d, 1H), 7.97 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.50-7.21 (m, 2H), 7.21 (t, 1H), 4.33 (s, 2H), 4.10 (t, 1H), 3.97 (t, 1H), 3.67-3.51 (m, 3H), 3.08 (m, 1H), 2.76 (m, 1H), 1.99 (t, 2H), 1.69-1.46 (m, 4H).

Example 157

4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; (I-157)

Step 1: Preparation of 4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride

(479) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 26) 4-(3-(3-(cyclopropylcyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (100 mg, 0.25 mmol) was reacted with 1N solution of hydrochloric acid (0.50 mL, 0.50 mmol) to afford the title compound (97 mg, 91%).

(480) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.93 (d, 1H), 7.79-7.89 (m, 2H), 7.48-7.54 (m, 1H), 7.42 (d, 1H), 7.15 (t, 1H), 4.00-4.05 (m, 2H), 3.75-3.80 (m, 2H), 3.34-3.39 (m, 1H), 3.12 (s, 2H), 1.32-1.36 (m, 1H), 0.64-0.72 (m, 2H), 0.41-0.46 (m, 2H).

Example 158

4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; (I-158)

Step 1: Preparation of 4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride

(481) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 27) 4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (117 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid (0.48 mL, 0.48 mmol) to afford the title compound (99 mg, 90%).

(482) .sup.1H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 9.23 (d, 2H), 8.26 (d, 1H), 7.97 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.44-7.50 (m, 1H), 7.40 (d, 1H), 7.21 (t, 1H), 4.33 (s, 2H), 4.13 (t, 1H), 4.00 (t, 1H), 3.54-3.70 (m, 3H), 2.82-2.91 (m, 1H), 1.52-1.67 (m, 4H), 1.43 (brs, 2H), 1.10-1.27 (m, 2H).

Example 159

4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; (I-159)

Step 1: Preparation of 4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride

(483) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 32) 4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (100 mg, 0.25 mmol) was reacted with 1N solution of hydrochloric acid (0.50 mL, 0.50 mmol) to afford the title compound (102 mg, 95%).

(484) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 9.23 (d, 2H), 8.27-8.25 (m, 1H), 7.97 (d, 1H), 7.91-7.81 (m, 2H), 7.48-7.44 (m, 1H), 7.41-7.39 (m, 1H), 7.21 (t, 1H), 4.33 (s, 2H), 4.15-4.10 (m, 2H), 3.66-3.59 (m, 3H), 3.17 (d, 1H), 2.68-2.61 (m, 1H), 0.92-0.83 (m, 6H).

Example 160

4-(3-(3-((cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; (I-160)

Step 1: Preparation of 4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride

(485) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 33) 4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (100 mg, 0.25 mmol) was reacted with 1N solution of hydrochloric acid (0.50 mL, 0.50 mmol) to afford the title compound (98 mg, 89%).

(486) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 9.23 (d, 2H), 8.28-7.97 (m, 2H), 7.91-7.81 (m, 2H), 7.48-7.40 (m, 2H), 7.22 (m, 1H), 4.33 (s, 2H), 4.13-3.98 (m, 2H), 3.70-3.56 (m, 3H), 2.29 (m, 2H), 0.83-0.72 (m, 1H), 0.37-0.32 (m, 2H), 0.06 (m, 2H).

Example 161

4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; (I-161)

Step 1: Preparation of 4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride

(487) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 35) 4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid (0.48 mL, 0.48 mmol) to afford the title compound (101 mg, 95%).

(488) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.93 (m, 1H), 7.89-7.82 (m, 2H), 7.51-7.49 (m, 1H), 7.45-7.43 (m, 1H), 7.15 (t, 1H), 4.38 (s, 2H), 4.28-4.26 (m, 1H), 4.16-4.12 (m, 1H), 3.88-3.84 (m, 1H), 3.79-3.75 (m, 1H), 3.66-3.64 (m, 1H), 2.31-2.28 (m, 2H), 1.71-1.68 (m, 1H), 0.91 (dd, 6H).

Example 162

4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2)-one hydrochloride; (I-162)

Step 1: Preparation of 4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride

(489) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 36) 4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid (0.48 mL, 0.48 mmol) to afford the title compound (91 mg, 85%).

(490) .sup.1H-NMR (MeOD, 400 MHz): δ 8.36-8.34 (m, 1H), 7.94-7.92 (m, 1H), 7.88-7.81 (m, 2H), 7.50-7.49 (m, 1H), 7.46-7.44 (m, 1H), 7.16-7.11 (m, 1H), 4.36 (s, 2H), 4.35-4.33 (m, 1H), 4.20-4.17 (m, 1H), 3.90-3.3.83 (m, 3H), 3.46-3.43 (m, 1H), 3.39-3.36 (m, 1H), 2.77-2.75 (m, 1H), 1.95 (s, 1H), 1.02 (q, 3H).

Example 163

4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; (I-163)

Step 1: Preparation of 4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride

(491) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 53) 4-(3-(3-(butylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid (0.48 mL, 0.48 mmol) to afford the title compound (104 mg, 98%).

(492) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.28 (s, 1H), 9.19 (d, 2H), 8.40-8.38 (m, 1H), 7.72-7.66 (m, 1H), 7.44-7.41 (m, 1H), 7.24-7.22 (m, 1H), 6.97-6.92 (m, 1H), 4.30-4.27 (m, 1H), 4.20 (s, 2H), 4.11-4.09 (m, 1H), 3.81-3.79 (m, 1H), 3.72-3.70 (m, 1H), 3.64-3.62 (m, 1H), 2.50-2.46 (m, 2H), 2.02 (s, 1H), 1.40-1.37 (m, 2H), 1.30-1.24 (m, 2H), 0.86-0.80 (m, 5H).

Example 164

4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; (I-164)

Step 1: Preparation of 4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride

(493) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 75) 4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (100 mg, 0.25 mmol) was reacted with 1N solution of hydrochloric acid (0.50 mL, 0.50 mmol) to afford the title compound (88 mg, 82%).

(494) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 9.23 (d, 2H), 8.26 (d, 1H), 7.78 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.45 (m, 2H), 7.22 (t, 1H), 4.33 (d, 2H), 4.11 (m, 1H), 3.97 (t, 1H), 3.87 (t, 1H), 3.68 (m, 1H), 3.60 (t, 1H), 3.10 (m, 4H), 1.95 (t, 2H).

Example 165

(R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; (I-165)

Step 1: Preparation of (R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride

(495) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 83) (R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (117 mg, 0.23 mmol) was reacted with 1N solution of hydrochloric acid (0.46 mL, 0.46 mmol) to afford the title compound (93 mg, 88%).

(496) .sup.1H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.93 (m, 1H), 7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.14 (t, 1H), 4.38 (s, 2H), 4.12-4.10 (m, 1H), 4.18-4.15 (m, 1H), 3.84-3.77 (m, 3H), 3.22-3.19 (m, 1H), 2.89-2.87 (m, 1H), 2.03 (s, 3H), 1.00 (t, 3H).

Example 166

1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl) amino)cyclobutanecarbonitrile hydrochloride; (I-166)

Step 1: Preparation of 1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrilehydrochloride

(497) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 99) 1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile (100 mg, 0.23 mmol) was reacted with 1N solution of hydrochloric acid (0.46 mL, 0.46 mmol) to afford the title compound (86 mg, 79%).

(498) .sup.1H-NMR (MeOD, 400 MHz): δ 8.35 (m, 1H), 7.92-7.78 (m, 3H), 7.50-7.43 (m, 2H), 7.13 (t, 1H), 4.41-4.39 (m, 1H), 4.36 (s, 2H), 4.23 (m, 1H), 3.98-3.92 (m, 2H), 3.85-3.78 (m, 1H), 2.48-2.41 (m, 2H), 2.20-2.02 (m, 2H).

Example 167

(R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; (I-167)

Step 1: Preparation of (R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride

(499) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 135) (R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid (0.48 mL, 0.48 mmol) to afford the title compound (99 mg, 93%).

(500) .sup.1H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 9.23 (d, 2H), 8.26 (d, 1H), 7.96 (t, 1H), 7.91-7.80 (m, 2H), 7.46-7.35 (m, 1H), 7.25-7.18 (m, 1H), 4.33 (s, 2H), 3.73-3.58 (m, 1H), 3.44-3.39 (m, 1H), 3.27-3.19 (m, 1H), 3.13-3.08 (m, 1H), 2.98 (t, 1H), 2.86 (d, 1H), 2.77-2.61 (m, 1H), 2.16 (t, 2H), 2.03 (t, 2H), 1.77-1.62 (m, 2H).

Example 168

4-(4-fluoro-3-(3-(pyrrolidin-1-ylethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; (I-168)

Step 1: Preparation of 4-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride

(501) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 140)-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (100 mg, 0.23 mmol) was reacted with 1N solution of hydrochloric acid (0.46 mL, 0.46 mmol) to afford the title compound (96 mg, 91%).

(502) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 9.85 (s, 1H), 9.19 (d, 2H), 8.46-8.44 (m, 1H), 7.78-7.70 (m, 3H), 7.49-7.47 (m, 1H), 7.32-7.27 (m, 1H), 7.03-6.98 (m, 1H), 4.29-4.24 (m, 3H), 4.14-4.10 (t, 1H), 3.85-3.77 (m, 2H), 2.91-2.64 (m, 3H), 2.48 (s, 4H), 1.77 (s, 4H).

Example 169

4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; (I-169)

Step 1: Preparation of 4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride

(503) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 142) 4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (100 mg, 0.23 mmol) was reacted with 1N solution of hydrochloric acid (0.46 mL, 0.46 mmol) to afford the title compound (105 mg, 97%).

(504) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 9.94 (s, 1H), 9.19 (d, 2H), 8.46 (m, 1H), 7.78-7.70 (m, 3H), 7.50-7.48 (m, 1H), 7.31-7.27 (m, 1H), 7.01 (t, 1H), 4.27-4.23 (t, 1H), 4.26 (s, 2H), 7.13-4.09 (t, 1H), 3.83-3.70 (m, 2H), 2.88-2.84 (m, 1H), 2.57-2.55 (m, 2H), 2.32 (s, 4H), 1.54 (s, 4H), 1.42 (s, 2H).

Example 170

4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; (I-170)

Step 1: Preparation of 4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride

(505) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 143) 4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid (0.48 mL, 0.48 mmol) to afford the title compound (101 mg, 95%).

(506) .sup.1H-NMR (400 MHz, MeOD): δ 8.36 (d, 1H), 7.94 (d, 1H), 7.84 (m, 2H), 7.50 (m, 2H), 7.13 (t, 1H), 4.38 (s, 2H), 4.19 (t, 1H), 4.09 (m, 1H), 3.74 (m, 2H), 3.30 (m, 4H), 2.69 (m, 3H), 2.14 (t, 2H).

Example 171

4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; (I-171)

Step 1: Preparation of 4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride

(507) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 25) 4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (100 mg, 0.25 mmol) was reacted with 1N solution of hydrochloric acid (0.50 mL, 0.50 mmol) to afford the title compound (99 mg, 91%).

(508) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.03 (s, 1H), 9.18 (d, 2H), 8.47-8.45 (m, 1H), 7.80-7.71 (m, 3H), 7.52-7.48 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.27 (s, 2H), 4.26-4.22 (m, 1H), 4.10 (t, 1H), 3.85-3.81 (m, 1H), 3.73-3.70 (m, 1H), 2.99-2.88 (m, 2H), 2.81-2.72 (m, 1H), 2.07 (m, 1H), 1.57 (br, 1H), 0.45-0.41 (m, 2H), 0.29-0.26 (m, 2H).

Example 172

4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; (I-172)

Step 1: Preparation of 4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride

(509) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 145) 4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid (0.48 mL, 0.48 mmol) to afford the title compound (95 mg, 89%).

(510) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.20 (br, 1H), 9.19 (d, 2H), 8.47-8.45 (m, 1H), 7.80-7.70 (m, 3H), 7.51-7.49 (dd, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.27 (s, 2H), 4.28-4.23 (m, 1H), 4.12 (t, 1H), 3.84-3.81 (dd, 1H), 3.75-3.71 (dd, 1H), 2.88-2.69 (m, 4H), 1.05-1.03 (dd, 6H).

Example 173

4-(3-(3-(((cyclopropyl)ethyl)amino)ethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; (I-173)

Step 1: Preparation of 4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride

(511) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 146) 4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (100 mg, 0.23 mmol) was reacted with 1N solution of hydrochloric acid (0.46 mL, 0.46 mmol) to afford the title compound (94 mg, 90%).

(512) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.36 (br, 1H), 9.18 (d, 2H), 8.47-8.45 (m, 1H), 7.80-7.71 (m, 3H), 7.51-7.49 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.27-4.24 (m, 3H), 4.13 (t, 1H), 3.86-3.75 (m, 2H), 2.94-2.75 (m, 3H), 2.48-2.46 (dd, 2H), 1.61 (br, 1H), 0.95-0.91 (m, 1H), 0.51-0.46 (m, 2H), 0.12-0.09 (m, 2H).

Example 174

4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; (I-174)

Step 1: Preparation of 4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride

(513) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 147) 4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (100 mg, 0.23 mmol) was reacted with 1N solution of hydrochloric acid (0.46 mL, 0.46 mmol) to afford the title compound (101 mg, 93%).

(514) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.69 (br, 1H), 9.20 (d, 2H), 8.47-8.45 (m, 1H), 7.80-7.71 (m, 3H), 7.50-7.48 (m, 1H), 7.32-7.28 (m, 1H), 7.00 (t, 1H), 4.27-4.23 (m, 3H), 4.14 (t, 1H), 3.86-3.78 (m, 2H), 2.93-2.78 (m, 3H), 2.45 (s, 1H), 2.44 (s, 1H), 1.81-1.71 (m, 1H), 0.91 (s, 3H), 0.89 (s, 3H).

Example 175

4-(3-(3-((cyclobutylamino)ethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; (I-175)

Step 1: Preparation of 4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride

(515) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 149) 4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid (0.48 mL, 0.48 mmol) to afford the title compound (99 mg, 91%).

(516) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.33 (br, 1H), 9.19 (d, 2H), 8.47-8.45 (m, 1H), 7.80-7.71 (m, 3H), 7.50-7.48 (m, 1H), 7.31-7.28 (m, 1H), 7.00 (t, 1H), 4.27-4.22 (m, 3H), 4.11 (t, 1H), 3.83-3.72 (m, 2H), 3.23 (m, 1H), 2.83-2.72 (m, 3H), 2.23-2.17 (m, 2H), 1.71-1.62 (m, 5H).

Example 176

4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride; (I-176)

Step 1: Preparation of 4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one hydrochloride

(517) This compound was made using the procedure described for example 156 (Step 1). Thus, the intermediate compound (example 150) 4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (100 mg, 0.25 mmol) was reacted with 1N solution of hydrochloric acid (0.50 mL, 0.50 mmol) to afford the title compound (96 mg, 88%).

(518) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 10.61 (s, 1H), 9.19 (d, 2H), 8.48-8.46 (m, 1H), 7.80-7.71 (m, 3H), 7.51-7.49 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.28-4.24 (m, 3H), 4.12 (t, 1H), 3.88-3.76 (m, 2H), 3.43 (m, 2H), 3.00-2.87 (m, 2H), 2.78-2.72 (m, 1H), 2.27-2.23 (m, 1H), 1.45 (br, 1H).

Experiment 1

In Vitro Test for Antitumoral Activity

(519) To ecaluate the in vitro test, the invented compounds (from I-1 to I-155) were determined as follows and showed table 1, 2, 3, 4 and 5.

(520) 1. Determination of Cellular PAR Levels

(521) Cellular PAR assay was performed to measure cellular PARP inhibitory activity of the compounds in the present invention. Hela human cervical cancer cells cultured in Minimum Essential Medium with Earle's Balanced Salts (MEM/EBSS) containing 10% FBS were seeded into 96-well cell culture plates, and incubated for 1 day at 37° C. under 5% CO.sub.2 atmosphere. After the invented compounds serially diluted in DMSO were added to each well, and then DNA damage was provoked by addition of H.sub.2O.sub.2 solution in H.sub.2O. Cellular PAR levels were determined and EC.sub.50 was calculated by using PAR antibody and detection solution.

(522) TABLE-US-00001 TABLE 1 EC.sub.50 Cellular PAR Compound [EC.sub.50, nM] WO2004080976A1 A Example 168 I-8 B I-9 B I-10 A I-11 B I-12 A I-13 A I-14 B I-15 C I-16 C I-17 A I-18 A I-19 A I-20 B I-21 B I-22 A I-23 C I-24 C I-25 A I-26 A I-27 A I-28 A I-29 B I-30 B I-31 A I-32 A I-33 A I-34 C I-35 A I-36 B I-37 A I-38 A I-39 B I-40 A I-41 A I-42 A I-43 A I-44 A I-45 A I-46 A I-47 B I-48 A I-49 A I-50 A I-51 A I-52 A I-53 A I-54 A I-55 A I-56 A I-57 A I-58 A I-59 A I-60 B I-61 A I-62 A I-63 B I-64 B I-65 B I-66 A I-67 B I-68 B I-69 A I-70 A I-71 A I-72 C I-73 A I-74 A I-75 A I-76 A I-77 A I-78 B I-79 A I-80 A I-81 A I-82 A I-83 A I-84 B I-85 A I-86 A I-87 B I-88 A I-89 A I-90 A I-91 A I-92 A I-93 B I-94 B I-95 A I-96 C I-97 C I-98 A I-99 A I-100 A I-101 A I-102 A I-103 B I-104 A I-105 A I-106 C I-107 A I-108 B I-109 A I-110 A I-111 B I-112 B I-113 B I-114 B I-115 B I-116 B I-118 B I-119 C I-120 A I-121 C I-122 B I-123 B I-124 B I-125 B I-126 A I-127 C I-128 A I-129 D I-130 A I-131 B I-132 A I-133 B I-134 B I-135 A I-136 A I-137 B I-138 B I-139 B I-140 A I-141 A I-142 A I-143 A I-144 A I-145 A I-146 A I-147 B I-148 A I-149 A I-150 B I-151 B I-152 D I-153 B I-154 A I-155 A Range A: EC.sub.50 ≤ 5 nM Range B: 5 nM < EC.sub.50 ≤ 50 nM Range C: 50 nM < EC.sub.50 ≤ 300 nM Range D: 300 nM < EC.sub.50 ≤ 1,000 nM Range E: EC.sub.50 > 1,000 nM

(523) According to the above table 1, the compounds in the present invent ion showed potent cellular PARP inhibitory activity in cellular PAR assay.

(524) 2. Cell Viability Assay (MDA-MB-436)

(525) Cell viability assay was performed by using MDA-MB-436 cell line to measure cytotoxicity of compounds in the present invention. MDA-MB-436 breast cancer cell line was seeded into 96-well plates at 37° C. under 5% CO.sub.2 atmosphere using DMEM/F12 (Gibco) containing 10% FBS (Hyclone). After 24 hr incubation, cells were treated with the invented compounds at various concentrations for 6 days. The medium was changed every 3 day. 6 days later, A fluorescence reagent was used to determine the IC.sub.50 values.

(526) TABLE-US-00002 TABLE 2 Compound IC.sub.50 Compound MDA-MB-436 [nM] WO2004080976A1 B Example 168 WO2004080976A1 B Example 168 I-14 C I-19 C I-22 C I-24 D I-25 B I-26 B I-27 A I-28 B I-29 D I-30 C I-31 B I-32 A I-33 A I-34 D I-35 A I-36 B I-37 B I-38 B I-39 D I-40 B I-41 A I-42 A I-43 B I-44 A I-45 B I-46 B I-48 A I-49 B I-50 C I-51 B I-52 A I-53 A I-54 B I-55 B I-56 D I-57 B I-58 B I-59 B I-61 C I-66 C I-69 C I-70 C I-71 C I-73 C I-74 B I-75 B I-76 B I-77 C I-78 D I-79 C I-80 A I-81 C I-82 B I-83 B I-84 C I-85 A I-86 B I-87 D I-88 A I-89 B I-90 C I-91 C I-92 B I-93 C I-94 D I-95 C I-96 D I-98 D I-99 B I-100 D I-101 D I-102 D I-103 D I-104 D I-109 D I-110 D I-111 D I-112 D I-113 D I-114 D I-115 D I-116 D I-118 D I-120 A I-121 D I-124 C I-125 A I-126 B I-128 B I-129 D I-130 A I-131 C I-132 A I-133 C I-134 C I-135 B I-136 B I-137 C I-138 D I-140 A I-141 B I-142 B I-143 A I-144 A I-145 B I-146 B I-147 D I-148 A I-149 A I-150 C I-151 D I-153 D I-154 D I-155 C Range A: IC.sub.50 ≤ 5 nM Range B: 5 nM < IC.sub.50 ≤ 50 nM Range C: 50 nM < IC.sub.50 ≤ 300 nM Range D: 300 nM < IC.sub.50 ≤ 1,000 nM Range E: IC.sub.50 > 1,000 nM

(527) According to the above table 2, the compounds in the present invent ion showed potent growth inhibition of cancer cells in cell cytotoxicity assay using MDA-MB-436 breast cancer cell line.

(528) 3. Cell Viability Assay (Capan-1)

(529) Cell viability assay was performed by using Capan-1 cell line to measure cytotoxicity of compounds in the present invention. Capan-1 pancreatic cancer cell line was seeded into 96-well plates at 37° C. under 5% CO atmosphere using IMDM (Sigma) containing 10% FBS (Hyclone). After 24 hr incubation, cells were treated with the invented compounds at various concentrations for 10 days. After 7-day incubation, the medium was changed. 10 days later, A fluorescence reagent was used to determine the IC.sub.50 values.

(530) TABLE-US-00003 TABLE 3 Compound IC.sub.50, Compound Capan-1 [nM] WO2004080976A1 D Example 168 WO2004080976A1 D Example 168 I-25 D I-26 D I-27 C I-28 D I-31 C I-32 C I-33 D I-35 D I-40 D I-36 D I-41 D I-42 D I-43 D I-44 D I-53 D I-80 C I-82 D I-83 D I-132 B I-140 D I-141 D I-142 D I-143 C I-146 D I-149 D I-99 D I-100 D Range A: IC.sub.50 ≤ 5 nM Range B: 5 nM < IC.sub.50 ≤ 50 nM Range C: 50 nM < IC.sub.50 ≤ 300 nM Range D: 300 nM < IC.sub.50 ≤ 1,000 nM Range E: IC.sub.50 > 1,000 nM

(531) According to the above table 3, the compounds in the present invent ion showed potent growth inhibition of cancer cells in cell cytotoxicity assay using Capan-1 pancreatic cancer cell line.

(532) 4. Cell Viability Assay (LNCap)

(533) Cell viability assay was performed by using LNCaP cell line to measure cytotoxicity of compounds in the present invention. LNCaP prostate cancer cell line was seeded into 96-well plates at 37° C. under 5% CO.sub.2 atmosphere using RPMI-1640 (Hyclone) containing 10% FBS (Hyclone). After 24 hr incubation, cells were treated with the invented compounds at various concentrations for 11 days. The medium was changed every 3 to 4 day. 11 days later, A fluorescence reagent was used to determine the IC.sub.50 values.

(534) TABLE-US-00004 TABLE 4 Compound IC.sub.50 Compound LNCap [nM] WO2004080976A1 E Example 168 I-27 C I-32 C I-33 D I-35 E I-53 E I-80 C I-83 E I-99 D I-114 B I-131 B I-146 E I-149 E Range A: IC.sub.50 ≤ 5 nM Range B: 5 nM < IC.sub.50 ≤ 50 nM Range C: 50 nM < IC.sub.50 ≤ 300 nM Range D: 300 nM < IC.sub.50 ≤ 1,000 nM Range E: IC.sub.50 > 1,000 nM

(535) According to the above table 4, the compounds in the present invent ion showed potent growth inhibition of cancer cells in cell cytotoxicity assay using LNCaP prostate cancer cell line.

(536) 5. Tankyrase-1 Enzyme Assay

(537) Tankyrase-1 enzyme assay was performed to determine Tankyrase-1 inhibitory activity of compounds in the present invention. The enzymatic reaction was conducted by coating the plate with substrates of tankyrase-1, and then the plate was washed. Compounds in the present invention serially diluted in DMSO were added to the reaction buffer activating tankyrase-1, and incubated for 1 hr at room temperature. After stopping the reaction, the plate was washed, and streptavidin-HRP was added to each well. IC.sub.50 calculated by adding chemiluminescent substrate and immediately reading the sample in a microplate reader (Biotek).

(538) TABLE-US-00005 TABLE 5 Compound IC50 Compound Tankyrase-1 [nM] WO2004080976A1 E Example 168 I-27 E I-32 E I-33 E I-99 D I-114 E I-130 C I-147 E I-150 E Range A: IC.sub.50 ≤ 5 nM Range B: 5 nM < IC.sub.50 ≤ 50 nM Range C: 50 nM < IC.sub.50 ≤ 300 nM Range D: 300 nM < IC.sub.50 ≤ 1,000 nM Range E: IC.sub.50 > 1,000 nM

(539) According to the above table 5, the compounds in the prevent invention exhibited strong inhibitory activity against tankyrase-1.

Experiment 2

In Vivo Test for Antitumoral Activity

(540) To evaluate the in vivo antitumoral efficacy, the invented compounds (I-80˜171) was determined as a result to follows.

(541) Capan-1 Human pancreatic cancer cells were established as subcutaneous xenografts by injection of 8×10.sup.6 cells into the flanks of adult female Balb/c nude mice. Mice with established tumors (160-250 mm.sup.3) were selected for study (n=6/treatment group). The test compounds were formulated in DW and administered orally (po) at a dose of 30˜200 mg/kg. The vehicle alone was administered to control groups. Animals were dosed 5 days per week (Monday through Friday) for 3 consecutive weeks.

(542) Animals were weighed and tumor size was determined twice weekly by caliper measurements, and tumor volumes were calculated (volume=[1×w.sup.2]/2 (mm.sup.3), where 1 and w refer to the larger and smaller dimensions collected at each measurement). The mean tumor volumes of each group were calculated. The change in mean treated tumor volume was divided by the change in mean control tumor volume, multiplied by 100 and subtracted from 100% to give the tumor growth inhibition for each group.

(543) TABLE-US-00006 TABLE 6 Compound Does Schedule % TGI WO2004080976A1 200 mg/kg po qd × 5 53.5 Example 168 I-80 100 mg/kg po qd × 5 75.9 I-80 200 mg/kg po qd × 5 103.9 I-159 100 mg/kg po qd × 5 59.4 I-159 200 mg/kg po qd × 5 69.4 I-158 100 mg/kg po qd × 5 44.9 I-158 200 mg/kg po qd × 5 80.9 I-160 100 mg/kg po qd × 5 55.8 I-160 200 mg/kg po qd × 5 88.2 I-171  30 mg/kg po qd × 5 42.1 I-171  60 mg/kg po qd × 5 69.7

(544) As can be seen from table 6, the selected compounds showed useful tumor growth inhibition.

Experiment 3

Mouse Pharmacokinetics

(545) To ecaluate the pharmacokinetics test, the invented compounds (from I-25 to I-1171) were determined as follows. Blood samples are collected at 15, 30, 60, 120, 240, 480, 1140 min. Quantification is by using a LC-MS/MS method specific to the selected compound. Pharmarcokinetics parameters are calculated using WinNonLinnon compartmental analysis software.

(546) TABLE-US-00007 TABLE 7 AUC Compound [min * ng/mL] WO2004080976A1 39,927 Example 168 I-25 49,858 I-26 200,772 I-27 28,302 I-30 31,280 I-33 61,268 I-35 135,283 I-53 74,937 I-75 28,516 I-80 121,308 I-83 34,044 I-99 35,139 I-120 30,582 I-135 9,175 I-140 17,724 I-141 11,588 I-142 5,325 I-143 40,367 I-146 65,532 I-148 28,290 I-149 10,138 I-159 28,302 I-160 135,283 I-161 61,268 I-171 40,367

(547) As can be seen from table 7, the selected compounds showed significant pharmacokinetics in Balb/c male mice.

Experiment 4

Solubility Test

(548) To evaluate the solubility, the invented compounds (I-159, I-161 and I-171) was determined as follows. The compounds was dissolve in water (1 mL, 10 mL and 100 mL) at 25° C. under an atmospheric pressure.

(549) TABLE-US-00008 TABLE 8 Solvent by volume for one Compound part of soluble by weight. WO2004080976A1 From 1000 to 10000 mL Very slightly example 168 soluble I-159 From 30 to 100 mL Sparingly soluble I-161 From 30 to 100 mL Sparingly soluble I-171 From 30 to 100 mL Sparingly soluble

(550) As can be seen form Table 8. The invented compounds showed significant solubility.

(551) It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

INDUSTRIAL APPLICABILITY

(552) The compounds of the present invention are highly active in the suppression of PARP, and according to its pharmaceutical compositions are expected to be useful for therapeutic applications which are improved by suppression of PARP activity, and cancer with mutated BRCA1, BRCA2 and ERG fusion gene in mono or combination treatment with radiation and with chemotherapy.