PHTHALAZINE DERIVATIVES

This application claims the benefit of U.S. Provisional Application Serial No. 60/865,947, filed November 15, 2006 and U.S. Provisional Application Serial No. 60/913,593, filed April 24, 2007, the entire disclosures of each of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to novel phthalazine derivatives and, more particularly, to phthalazine derivatives that are useful as protein kinase inhibitors. The invention also relates to methods of preparing the compounds, compositions containing the compounds, and methods of treatment using the compounds.

BACKGROUND OF THE INVENTION

Protein kinase is an enzyme that can modify the functioning of other proteins by changing enzyme activity, cellular location or protein association. Kinases are known to regulate cellular pathways, especially those involved in signal transduction (i.e., the transmission of signals within the cell).

Hundreds of protein kinases have been identified in the human genome. Protein kinase cell signalling has been implicated in numerous human diseases, including cancer, cardiovascular disease, diabetes, inflammation, arthritis, and Alzheimer's disease. See e.g., Tortora et al., Clin. Cancer Research, Vol. 8, 303-304, 2002; Inagaki et al., Circulation, 111: 44-50, 2005; Koya et al., Diabetes, Vol. 47, 1998; Choi et al., J. Cell Science, 119 (7), 1329-1340. 2006.

Compounds that inhibit one or more protein kinases have been investigated for the treatment of various disorders. For example, the inhibition of protein kinase S6K1 has been implicated in diabetes, insulin sensitivity, insulin resistance, obesity, angiogenesis and cancer. See, e.g., Um, et al., Nature, 431, 485, 2004; International Publication No. WO 2005/019829. Consequently, there is continued interest in the development of compounds that act as protein kinase inhibitors.

SUMMARY OF THE INVENTION

The present invention relates to novel phthalazine derivatives and, more particularly, to phthalazine derivatives that are useful as protein kinase inhibitors. The

invention also relates to methods of preparing the compounds, compositions containing the compounds, and methods of treatment using the compounds.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention relates to compounds of formula I:

wherein

R ¹ and R ² are each independently hydrogen, carboxyl, alkyl, alkenyl, alkynyl, aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle, acyl, alkoxy, alkythio, arylthio, or alkoxycarbonyl, wherein, if present, the aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, or alkylheterocycle may be substituted by one or more halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine or alkylthio and combinations thereof;

R ³ is hydrogen, halogen, hydroxy, cyano, amino, carboxyl, alkyl, alkenyl, alkynyl, aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle, acyl, alkoxy, alkythio, arylthio, -alkylene-NR ^a R ^b , -C(O)R ^a , -

C(O)NR ^a R ^b , -C(O)OR ³ , -C(S)NR ^a R ^b , -C(S)R ³ , -C(O)SR ³ , NO ₂ , NH ₂ , -NR ³ C(O)R ^b , - NR ^a R ^b , -NR ^a OR ^b , -NR ^a C(S)R ^b , -NR ³ C(0)NR ^b R ^c , -NR ^a C(S)NR ^b R ^c , -NR ³ (C00R ^b ), - NR ³ S(O) ₂ NRV, -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -OR ^a , -OC(O)R ³ , -0NR ^a R ^b , -0C(0)NR ^a R ^b , -SR ³ , -S(O) ₂ R ³ , or -S(O) ₂ NR ^a R ^b , wherein R ³ , R ^b and R ^c are each independently hydrogen, halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle, acyl, alkoxy, alkythio, arylthio, or alkoxycarbonyl, wherein, if present, the aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, or alkylheterocycle may be substituted by one or more halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine or alkylthio and combinations thereof; and

R ⁴ and R ⁵ are each independently hydrogen, carboxyl, alkyl, alkenyl, alkynyl, aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle, acyl,

alkoxy, alkythio, arylthio, or alkoxycarbonyl, wherein, if present, the aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, or alkylheterocycle may be substituted by one or more halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine, alkylthio, -C(O)NR ^d -alkylheterocycle (in which R ^d is H or alkyl), O- alkylheterocycle, or combinations thereof, and pharmaceutically acceptable salts or solvates (e.g., hydrates) thereof, or solvates of pharmaceutically acceptable salts thereof, provided that when R ³ is heterocycle, said heterocycle is other than 4-hydroxy-l- piperidinyl. In one embodiment, R ³ is other than piperidinyl.

In a further embodiment, the present invention relates to compounds of formula I wherein:

R ¹ and R ² are each independently hydrogen, alkyl, alkenyl or alkylaryl, wherein, if present, the alkylaryl may be substituted by one or more halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine or alkylthio and combinations thereof;

R ³ is hydrogen, halogen or cyano;

R ⁴ and R ⁵ are each independently hydrogen or aryl, wherein, if present, the aryl may be substituted by one or more halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine, alkylthio, -C(O)NR ^d -alkylheterocycle (in which R is H or alkyl), O-alkylheterocycle, or combinations thereof,

In certain embodiments, the present invention provides compounds of formula I wherein:

R ¹ and R ² are each independently hydrogen, alkyl (e.g., methyl), alkenyl (e.g., - CH ₂ -CH=CH ₂ ) or alkylaryl (e.g., benzyl);

R ³ is hydrogen, halogen (e.g., Cl, I) or cyano; and

R ⁴ and R ⁵ are each independently hydrogen or aryl (e.g., phenyl), wherein, if present, the aryl may be substituted by one or more halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine or alkylthio and combinations thereof.

In certain embodiments, when R ⁴ and/or R ⁵ are aryl, the aryl (e.g., phenyl) may be substituted by one or more alkyl, alkoxy, and combinations thereof (e.g., trifluoromethylphenyl, methoxyphenyl, such as 3- trifiuoromethylphenyl, 3- methoxyphenyl) . In additional embodiments, one of R ⁴ and R ⁵ is H and the other is phenyl, trifluoromethylphenyl or methoxyphenyl.

In one embodiment, the compounds of formula I do not include 4-(3-Chloro-4- methoxybenzyl)aminophthalazines.

In another embodiment, R ¹ and R ² are not both hydrogen. According to another embodiment, the compound of formula I is not 4-[[(3- chloro-4-methoxyphenyl)methyl] amino]- 1 -(4-hydroxy- 1 -piperidinyl)-6- phthalazinecarboxamide or 4- [ [(3 -chloro-4-methoxyphenyl)methyl] amino] - 1 -(4-hydroxy- l-piperidinyl)-N,N-dimethyl-6-phthalazinecarboxamide, or a pharmaceutically acceptable salt thereof.. In a compound and/or method aspect, the present invention includes compounds of formula I chosen from:

I) l-Allylamino-4-chloro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)- amide,

3) l-Methylamino-4-chloro-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide,

5) l-benzylamino-4-chloro-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide,

7) 4-Cyano-l-methylamino-phthalazine-6-carboxylic acid (3-trifiuoromethyl- phenyl)-amide, 9) l-Benzylamino-4-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)- amide,

I 1) l-Benzylamino-phthalazine-ό-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 12) 4-Cyano-l-benzylamino-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide, 13) l-Benzylamino-4-chloro-phthalazine-6-carboxylic acid phenylamide,

15) l-Benzylamino-4-chloro-phthalazine-6-carboxylic acid (3-methoxy-phenyl)- amide, and

17) l-Dimethylamino-4-chloro-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide, wherein free base forms listed above can also be in the form of a pharmaceutically acceptable salt, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate), wherein a compound listed above (in a free base form or solvate thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. In another aspect, the present invention relates to compounds of formula II:

wherein

R ⁶ and R ⁷ are each independently hydrogen, carboxyl, alkyl, alkenyl, alkynyl, aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle, acyl, alkoxy, alkythio, arylthio, or alkoxycarbonyl, wherein, if present, the aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, or alkylheterocycle may be substituted by one or more halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine or alkylthio and combinations thereof;

R ⁸ is hydrogen, halogen, hydroxy, cyano, amino, carboxyl, alkyl, alkenyl, alkynyl, aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle, acyl, alkoxy, alkythio, arylthio, -alkylene-NR ^a R ^b , -C(O)R ^a , - C(O)NR ^a R ^b , -C(O)OR ³ , -C(S)NR ^a R ^b , -C(S)R ³ , -C(O)SR ³ , NO ₂ , NH ₂ , -NR ^a C(0)R ^b , -

NR ^a R ^b , -NR ^a OR ^b , -NR ^a C(S)R ^b , -NR ^a C(O)NR ^b R ^c , -NR ^a C(S)NR ^b R ^c , -NR ^a (COOR ^b ), - NR ^a S(O) ₂ NR ^b R ^c , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -OR ^a , -OC(O)R ³ , -ONR ^a R ^b , -OC(O)NR ^a R ^b , -SR ^a , -S(O) ₂ R ³ , or -S(O) ₂ NR ³ R ^b , wherein R ³ , R ^b and R ^c are each independently hydrogen, halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkynyl, aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle, acyl, alkoxy, alkythio, arylthio, or alkoxycarbonyl, wherein, if present, the aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, or alkylheterocycle may be substituted by one or more halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine or alkylthio and combinations thereof; and R ⁹ and R ¹⁰ are each independently hydrogen, carboxyl, alkyl, alkenyl, alkynyl, aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle, acyl, alkoxy, alkythio, arylthio, or alkoxycarbonyl, wherein, if present, the aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, or alkylheterocycle may be substituted by one or more halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine, alkylthio, -C(O)NR ^d -alkylheterocycle (in which R ^d is H or alkyl), O- alkylheterocycle, or combinations thereof, and pharmaceutically acceptable salts or solvates (e.g., hydrates) thereof, or solvates of pharmaceutically acceptable salts thereof, provided that when R ⁸ is heterocycle, said heterocycle is other than 4-hydroxy-l- piperidinyl.

In one embodiment, R ⁸ is other than piperidinyl.

In a further embodiment, the present invention relates to compounds of formula II wherein:

R ⁶ and R ⁷ are each independently hydrogen, alkyl, alkenyl or alkylaryl, wherein, if present, the alkylaryl may be substituted by one or more halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine or alkylthio and combinations thereof;

R ⁸ is hydrogen, halogen or cyano; and

R ⁹ and R ¹⁰ each independently represents hydrogen or aryl, wherein, if present, the aryl may be substituted by one or more halogen, hydroxy, cyano, nitro, amino,

carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine, alkylthio, -C(O)NR ^d - alkylheterocycle (in which R ^d is H or alkyl), O-alkylheterocycle, or combinations thereof,

In certain embodiments, the present invention provides compounds of formula II wherein: R ⁶ and R ⁷ are each independently hydrogen, alkyl (e.g., methyl), alkenyl (e.g., -

CH2-CH=CH ₂ ) or alkylaryl (e.g., benzyl);

R ⁸ is hydrogen, halogen (e.g., Cl, I) or cyano; and

R ⁹ and R ¹⁰ each independently represent hydrogen or aryl (e.g., phenyl), wherein, if present, the aryl may be substituted by a halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine or alkylthio.

In certain embodiments, when R ⁹ and/or R ¹⁰ are aryl, the aryl (e.g., phenyl) may be substituted by alkyl or alkoxy (e.g., trifluoromethylphenyl, methoxyphenyl, such as 3- trifluoromethylphenyl , 3 -methoxyphenyl) .

In additional embodiments, one of R ⁹ and R ¹⁰ is H and the other is phenyl, trifluoromethylphenyl or methoxyphenyl.

In one embodiment, the compounds of formula II do not include 4-(3-Chloro-4- methoxybenzyl)aminophthalazines.

In another embodiment, R ⁶ and R ⁷ are not both hydrogen.

According to another embodiment, the compound of formula II is not 4-[[(3-chloro-4- methoxyphenyl)methyl] amino]- 1 -(4-hydroxy- 1 -piperidinyl)-6-phthalazinecarboxamide or 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-l-(4-hydroxy-l-p iperidinyl)-N,N- dimethyl-6-phthalazinecarboxamide, or a pharmaceutically acceptable salt thereof.

In a compound and/or method aspect, the present invention includes compounds of formula II chosen from: 2) 4-Allylamino-l-chloro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)- amide,

4) 4-Methylamino-l-chloro-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide,

6) 4-benzylamino-l-chloro-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide,

8) l-Cyano-4-methylamino-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl) -amide,

10) 4-Benzylamino-l-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)- amide, 14) 4-Benzylamino- 1 -chloro-phthalazine-ό-carboxylic acid phenylamide,

16) 4-Benzylamino- l-chloro-phthalazine-6-carboxylic acid (3-methoxy-phenyl)- amide,

18) 4-Dimethylamino- 1 -chloro-phthalazine-β-carboxylic acid (3 -trifluoromethyl- phenyl)-amide, 21) l-Cyano-4-dimethylamino-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide, and

22) 4-Cyano-l-dimethylamino-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide, wherein free base forms listed above can also be in the form of a pharmaceutically acceptable salt, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate), wherein a compound listed above (in a free base form or solvate thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

According to a further aspect, the present invention relates to compounds of formula III:

wherein

X is hydrogen, halogen, alkyl, aryl, heteroaryl, cyano or alkoxy;

R' is hydrogen, alkyl (e.g., methyl), -C(O)R _x , -SO ₂ R _x or -P(O)(OR _X ) ₂ , where R _x is hydrogen or alkyl;

R and R are each independently hydrogen, halogen, hydroxy, cyano, amino, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle, acyl, alkoxy, alkythio, arylthio, -alkylene-NR ^a R ^b , C(O)R ³ , -C(0)NR ^a R ^b , -alkylene-C(O)NR ^a R ^b , -C(O)OR ³ , -C(S)NR ^a R ^b , -C(S)R ³ , -C(O)SR ³ , NO ₂ , NH ₂ , - NR ^a C(0)R ^b , -NR ³ R ^b , -NR ³ 0R ^b , -NR ³ C(S)R ^b , -NR ^a C(0)NR ^b R ^c , -NR ^a C(S)NR ^b R ^c , - NR ³ (C00R ^b ), -NR ^a S(O) ₂ NR ^b R ^c , -NR ³ S(0)R ^b , -NR ^a S(O) ₂ R ^b , -OR ³ , -OC(O)R ³ , -0NR ^a R ^b , -0C(0)NR ³ R ^b , -SR ³ , -S(O) ₂ R ³ , or -S(O) ₂ NR ^a R ^b , wherein R ³ , R ^b and R ^c are each independently hydrogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, haloaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle, acyl, alkoxy, alkythio, arylthio, or alkoxycarbonyl, wherein, if present, an aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycle, or alkylheterocycle may be substituted by one or more halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine, alkylthio, -C(O)NR ^d -alkylheterocycle (in which R ^d is H or alkyl), O- alkylheterocycle, alkylheterocycle, aryl, heteroaryl, heterocycle, aryloxy, alkylamino, dialkylamino, aminoalkyl, -O-alkylene-0-, -alkylene-O-, -O-alkylene-0-alkylene-, -alkylene-O-alkyl, -NR ^e C(0)R ^f , -NR ^e (alkylene-NR ^e R ^f ), -NR ^e (alkylheterocycle), -O- alkylene-NR ^e R ^f (in which R ^e and R ^f are independently hydrogen or alkyl, e.g., methyl), or combinations thereof; wherein at least one of R ¹¹ or R ¹² is -alkylene-C(O)NR ³ R ^b , -alkyl ene-NR ³ R ^b , -C(0)NR ^a R ^b , -NR ^a C(0)R ^b or -NR ³ R ^b ; and pharmaceutically acceptable salts or solvates (e.g., hydrates) thereof, or solvates of pharmaceutically acceptable salts thereof. provided that said compound is not:

N-(3,4-dihydro-4-oxo-6-phthalazinyl)-2-methyl-2-propenami de,

N-( 1 ,2-dihydro- 1 -oxo-6-phthalazinyl)-2-methyl-2-propenamide, 7- (cyclohexylamino)-6-(phenylamino)- 1 (2H)-phthalazinone,

6,7-bis(phenylamino)- 1 (2H)-phthalazinone, 6-amino-7-chloro- 1 (2H)-phthalazinone, or a pharmaceutically acceptable salt thereof.

In one embodiment, R' is hydrogen or alkyl (e.g., methyl).

In additional embodiments R ¹¹ and/or R ¹² are other than OR ^a where R ^a is alkyl (e.g., methyl). In additional embodiments, (i) when R' and X are hydrogen and one of R ¹¹ and R ¹² is NR ^a C(O)R ^b , then R ^b is not -C(=CH2)CH3, (ii) when R' and X are hydrogen and one of R ¹¹ and R ¹² is -NHC ₆ H ₅ , then the other of R ¹¹ and R ¹² is not -NHC ₆ H ₅ or - NH(cyclohexyl), (iii) when R' and X are hydrogen and one of R ¹¹ and R ¹² is -NH ₂ , then the other of R ¹ ' and R ¹² is not halogen.

According to another embodiment, the present invention relates to compounds of formula III wherein:

X is hydrogen, halogen, alkyl (e.g., methyl), aryl, heteroaryl, cyano or alkoxy;

R' is hydrogen or alkyl (e.g., methyl);

R ¹¹ and R ¹² are each independently hydrogen, -alkylene-NR ^a R ^b , -C(O)NR ^a R ^b ,

-alkylene-C(O)NR > ^aa rR>b ^D , -NR ³ C(O)R ⁰ or -NR a ³ τR>b".; wherein R ^a , R and R ^c are each independently hydrogen, alkyl, aryl, alkylaryl, alkylheteroaryl or alkylheterocycle, wherein, if present, an aryl, alkylaryl, alkylheteroaryl or alkylheterocycle may be substituted by one or more halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine, alkylthio, -C(O)NR ^d -alkylheterocycle (in which R ^d is H or alkyl), O-alkylheterocycle, alkylheterocycle, aryl, heteroaryl, heterocycle, aryloxy, alkylamino, dialkylamino, aminoalkyl, -O-alkylene-0-, -alkylene-O-, -O- alkylene-O-alkylene-, -alkylene-O-alkyl, -NR ^e C(O)R ^f , -NR ^e (alkylene-NR ^e R ^f ), - NR ^e (alkylheterocycle), -O-alkylene-NR ^e R ^f , (in which R ^e and R ^f are independently hydrogen or alkyl, e.g., methyl), or combinations thereof.

In one embodiment, one of R ¹¹ and R ¹² is hydrogen and the other of R ¹¹ and R ¹² is -alkylene-NR ^a R ^b , -C(O)NR ³ R ^b , -alkylene-C(O)NR ^a R ^b , -NR ^a C(O)R ^b or -NR ^a R ^b .

One of ordinary skill in the art will readily appreciate that some compounds of formula III may exist in different tautomeric forms, e.g., as shown below:

These two forms of formula III are used interchangeably herein, and both are encompassed within the present invention.

In certain embodiments, the present invention provides compounds of III wherein:

X represents hydrogen, halogen (e.g., Cl), alkyl (e.g., methyl), aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl);

R ¹¹ and R ¹² each independently represent hydrogen, -C(O)NR ^a R ^b , -NR ^a C(O)R ^b , or -NR ^a R ^b , wherein each R ^a and R ^b independently represents hydrogen, aryl, heteroaryl or alkylaryl, wherein, if present, the aryl, heteroaryl or alkylaryl may be substituted by a halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamine, alkylthio, -C(O)NR ^d -alkylheterocycle (in which R ^d is H or alkyl), or O- alkylheterocycle. For example, the aryl or alkylaryl may be substituted by a halogen, alkoxy, -C(O)NR ^d -alkylheterocycle (in which R ^d is H or alkyl), or O-alkylheterocycle.

In additional embodiments, the compounds of formula III are represented by subformulas Ilia - IHj, in which R is -alkylene- (e.g., -CH ₂ -, -CH ₂ CH ₂ -):

In one embodiment, the compound of formula III is represented by formulas Ilia and IHb. In another embodiment, the compound of formula III is represented by formulas IHc and IHd. In another embodiment, the compound of formula III is represented by formulas HIe and IHf. In another embodiment, the compound of formula III is represented by formulas HIg and IHh. In another embodiment, the compound of formula III is represented by formulas IHi and IHj. In further embodiments, the compound of formula III is represented by formulas IHa-IIIf. In other embodiments, the compound of formula III is represented by formulas Ilia, IHb and IHe.

In certain embodiments, the compound is represented by formula Ilia -IHj in which X is hydrogen, halogen (e.g., Cl), alkyl (e.g., methyl), aryl (e.g., phenyl), alkoxy (e.g., methoxy), cyano or heteroaryl (e.g., pyridyl); R' is hydrogen or alkyl (e.g., methyl), R is alkylene (e.g., -CH ₂ - or -CH ₂ CH ₂ -) and R ^a and R ^b are each independently hydrogen, alkyl (e.g., methyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridinyl), alkylaryl (e.g., benzyl, phenethyl), alkylheterocycle (e.g., morpholinylethyl, piperidinylethyl) or alkylheteroaryl (e.g., furanylmethyl). Where present, any aryl, heteroaryl or heterocycle group may be optionally substituted.

In certain embodiments, the compound is represented by formula Ilia or IHb in which X is halogen (e.g., Cl), alkyl (e.g., methyl), aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl) and R ^a and R ^b each independently represent hydrogen, aryl (e.g., phenyl), heteroaryl (e.g., pyridinyl)or alkylaryl (e.g., benzyl). Where present, any aryl, arylalkyl or heteroaryl group may be optionally substituted.

In additional embodiments, the compound is represented by formula Ilia or IIIb in which one of R ^a and R ^b is hydrogen or alkyl (e.g.. methyl) and the other is phenyl, hydroxybiphenyl, trifluoromethylphenyl, bis(trifluoromethyl)phenyl, difluorophenyl, fluoro(trifluoromethyl)phenyl, fluoro(methyl)phenyl, trifluoromethylpyridyl, methyl(trifluoromethyl)phenyl, methoxybenzyl, trifiuoromethylbenzyl, (trifluoromethyl)(morpholinyl)phenyl, (piperidinylmethyl)phenyl, furanylphenyl, methylphenyl, difluoromethoxyphenyl, trifluoromethoxyphenyl, chloro(dimethylarninoethoxyphenyl)phenyl (e.g., 4-chloro-3'-(2- dimethylaminoethoxy)biphenyl-3-yl), or (ethoxymethyl)(methyl)- (pyrrolidinylethylamino)phenyl (e.g., 5-ethoxymethyl-2-methyl-3-(2-pyrrolidin-l- yl)ethylamino)phenyl). In certain embodiments, the compound is represented by formula IIIc or IHd in which X is halogen (e.g., Cl) and R ^a and R ^b are each independently hydrogen or aryl. Where present, any aryl group may be optionally substituted. For example, the aryl may be substituted by alkyl or alkoxy (e.g., trifluoromethylphenyl, methoxyphenyl).

In certain embodiments, the compound is represented by formula HIe or IHf in which X is halogen (e.g., Cl) or alkyl (e.g., methyl) and R ^a and R ^b are each independently hydrogen, alkyl (e.g., methyl), aryl (e.g., phenyl), alkylheteroaryl (e.g., pyridinylmethyl),

heteoraryl (e.g., furanyl) or alkylaryl (e.g., benzyl, phenethyl). Where present, any aryl, alkylheteroaryl, alkylaryl or heteroaryl group may be optionally substituted.

For example, any aryl, alkylheteroaryl, alkylaryl or heteroaryl group present may be optionally substituted by alkyl (e.g., methyl, trifluoromethyl), halogen (e.g., F, Cl), alkoxy (e.g., methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy), hydroxyl, amino, alkylamino, dialkylamino (e.g., -N(CH ₃ ) ₂ ), aminoalkyl (e.g., CH ₂ N(CH ₃ ) ₂ ), aryloxy (e.g., OC ₆ H ₅ ), heteroaryloxy (e.g., pyrazinyloxy, methylpyrazinyloxy), -O-alkylheterocycle (e.g., O-morpholinylethyl), -O-aminoalkyl (e.g., -OCH ₂ CH ₂ N(CH ₃ ) ₂ ), NH-aminoalkyl (e.g., NHCH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ , NHCH ₂ CH ₂ N(CH ₃ ) ₂ ), NHalkylheterocycle (e.g., NH- morpholinylethyl), -C(O)NH-alkylheterocycle (e.g., -C(O)NHpyrrolidinylethyl), - OCH ₂ CH ₂ O-, -OCH ₂ CH ₂ -, -OCH ₂ CH ₂ CH ₂ O-, -OCH ₂ OCH ₂ -, NHC(O)alkyl (e.g., - NHC(O)CH ₃ ), optionally substituted aryl (e.g., phenyl), heteroaryl (e.g., pyrazolyl, pyridinyl, thiophenyl, pyrrolyl, imidazolyl, triazolyl), heterocycle (e.g., piperidinyl, methylpiperidinyl, aminopiperidinyl, moφholinyl, piperazinyl, methylpiperazinyl, diazepanyl, methyldiazepanyl, pyrrolidinyl, hexahydropyrrol[3,4-c]pyrrolyl, perhydrodiazepanyl), alkylheterocycle (e.g., piperidinylmethyl, morpholinylmethyl, moφholinylethyl, pyrrolidinylmethyl) and combinations thereof.

In additional embodiments, the compound is represented by formula HIe or IHf in which one of R ^a and R ^b is hydrogen or alkyl (e.g., methyl) and the other is benzyl, trifluoromethylbenzyl (e.g., 2-trifluromethylbenzyl, 3-trifluoromethylbenzyl), dichlorobenzyl (e.g., 2,4-dichlorophenyl, 2,5-dichlorobenzyl, 3,5-dichlorobenzyl), chlorobenzyl (e.g., 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl), methoxybenzyl (e.g., 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl), fluorobenzyl (e.g., 3- fluorobenzyl), difluorobenzyl (e.g., 2,3-difluorobenzyl, 2,5-difluorobenzyl, 3,4- difluorophenyl, 3,5-difluorobenzyl), methylbenzyl (e.g., 3-methylbenzyl), trifluoromethylphenyl (e.g., 3-trifluoromethylphenyl), phenethyl, (morpholinylethoxy)benzyl (e.g., 3-(2-morpholin-4-yl-ethoxy)benzyl, 2-(2-morpholin-4- yl-ethoxy)benzyl), (pyrrolidinylethylamido)benzyl (e.g.,-CH ₂ -C ₆ H ₄ -C(O)NH-CH ₂ CH ₂ - pyrrolidinyl), (piperidinylmethyl)benzyl (e.g., 2-piperi din- 1-ylmethyl -benzyl, 3- piperidin-1-ylmethylbenzyl), piperidinylbenzyl, chlorofluorobenzyl (e.g., 2-chloro-6- fluorobenzyl), (pyrazolyl)benzyl (e.g., 2-pyrazol-l-ylbenzyl, 3-pyrazol-l-ylbenzyl),

(pyridinyl)benzyl (e.g., 2-pyridin-3-ylbenzyl, (thiophenyl)benzyl (e.g., 2-thiophen-2- ylbenzyl, 3-thiophen-2-ylbenzyl, 3-thiophen-3-ylbenzyl), (furanyl)benzyl (e.g., 2-furan- 2-ylbenzyl, 3-furan-2-ylbenzyl), (piperazinyl)benzyl (e.g., 2-piperazinylbenzyl), (methylpiperazinyl)benzyl (e.g., 2-(4-methylpiperazin-l-yl)benzyl, 3-(4-methylpiperazin- l-yl)benzyl, 2-(3-methylpiperazin-l-yl)benzyl), (morpholinylmethyl)benzyl (e.g., 2- morpholin-4-ylmethyl-benzyl, 3-morpholin-4-ylmethylbenzyl), (phenoxy)benzyl (e.g., 2- phenoxybenzyl), dihydrobenzodioxinylmethyl (e.g., 2,3-dihydro-benzo[l,4]dioxin-5- ylmethyl), dihydrobenzofuranylmethyl (e.g., 2,3-dihydro-benzofuran-5-ylmethyl), (fluoro)(trifluoromethyl)benzyl (e.g., 2-fluoro-5-trifluoromethylbenzyl), (methyl)(chloro)benzyl (e.g., 5-chloro-2-methylbenzyl), (chloro)(trifluoromethyl)benzyl (e.g., 2-chloro-5-trifluoromethylbenzyl), (fluoro)(trifluoromethyl)benzyl (e.g., 2-fluoro-3- trifluoromethylbenzyl), (chloro)(phenoxy)benzyl (e.g., 2-chloro-6-phenoxybenzyl), dimethylbenzyl (e.g., 2,3-dimethylbenzyl, 3,4-dimethylbenzyl, 2,5-dimethylbenzyl), (morpholinyl)benzyl (e.g., 3-morpholin-4-ylbenzyl), dihydrobenzodioxepinylmethyl (e.g., 3,4-dihydro-2H-benzo[b][l,4]dioxepin-6-ylmethyl), fluoro(benzodioxinylmethyl (e.g., 6-fluoro-4H-benzo[l,3]dioxin-8-ylmethyl), (methyl)(phenyl)furanylmethyl (e.g., 5- methyl-2-phenyl-furan-3-ylmethyl), trifluoromethoxybenzyl (e.g., 2- trifluoromethoxybenzyl, 3 -trifluoromethoxybenzyl, 4-trifluoromethoxybenzyl), difluoromethoxybenzyl (e.g., 2-difluoromethoxybenzyl, 3-difluoromethoxybenzyl), dimethoxybenzyl (e.g., 3,5-dimethoxybenzyl, 2,3-dimethoxybenzyl, 2,5- dimethoxybenzyl), hydroxybenzyl (e.g., 3-hydroxybenzyl), (CH ₃ C(O)NH)benzyl, biphenylmethyl (e.g., biphenyl-3-ylmethyl), dimethylminobenzyl (e.g., 3- dimethylaminobenzyl), isopropoxybenzyl (e.g., 3-isopropoxybenzyl), (pyrrolyl)benzyl (e.g., 2-pyrrol-l-yl-benzyl, 3-pyrrol-l-yl-benzyl), pyridinylmethyl (e.g., pyridin-3- ylmethyl, pyridin-2-ylmethyl), (imidazolyl)benzyl (e.g., 2-imidazol-l-yl -benzyl),

(triazolyl)benzyl (e.g., 2-[l,2,4]triazol-l-yl-benzyl), (methylpiperidinylmethyl)benzyl (e.g., 3-(4-methyl-piperidin-l-ylmethyl)benzyl), (dimethylaminopropylamino)benzyl (e.g., 3-(3-dimethylamino-propylamino)benzyl), (morpholinylethylamino)benzyl (e.g., 3- (2-morpholin-4-yl-ethylamino)benzyl), (methyldiazepanyl)benzyl (e.g., (3-(4-methyl- [l,4]diazepam-l-yl)benzyl), (dimethylaminomethyl)benzyl (e.g., 3- dimethylaminomethyl-benzyl), (dimethylaminoethylamino)benzyl (e.g., 3-(2-

dimethylamino-ethylamino)benzyl), (pyrrolidinylmethyl)benzyl (e.g., 3-pyrrolidin-l- ylmethylbenzyl), (pyrrolidinyl)benzyl (e.g., 2-pyrrolidin-l-ylbenzyl, 3-pyrrolidin-l- ylbenzyl), (pyrrolidinyl)pyridinylmethyl (e.g., 6-pyrrolidin-l-yl-pyridin-2-ylmethyl), (morpholinyl)benzyl (e.g., 2-moφholin-4-ylbenzyl), pyrazinyloxybenzyl (e.g., 3-(6- methyl-pyrazin-2-yloxy)benzyl), dihydropyridooxazinylmethyl (e.g., 3-methyl-3,4- dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-ylmethyl), hexahydropyrrolo[3,4-c]pyrrolyl- benzyl (e.g., 2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-ylbenzyl), (perhydrodiazepinyl)benzyl (e.g., 2-perhydro-l,4-diazepin-l-ylbenzyl), (piperazinyl)(trifluoromethyl)benzyl (e.g., 2- piperazin-l-yl-5-trifluoromethylbenzyl), (piperazinyl(methoxy)benzyl (e.g., 5-methoxy- 2-piperazin-l-ylbenzyl), aminopiperidinylbenzyl (e.g., 4-amino-piperidin-l-ylbenzyl) or (fluoro)piperazinylbenzyl (e.g., 5-fluoro-2-piperazin-l-ylbenzyl).

In certain embodiments, the compound is represented by formula IHg or IIIh in which X is halogen (e.g., Cl), R is alkylene (e.g., -CH ₂ -) and R ^a and Rb are each independently hydrogen or aryl, wherein the aryl may be substituted. For example, one of R ^a and R ^b is hydrogen and the other is (dimethylaminoethyl)methylamino)phenyl (e.g., 2- dimethylaminoethyl)methylamino)phenyl.

In certain embodiments, the compound is represented by formula IHi or IHj in which X is halogen (e.g., Cl), R is alkylene (e.g., -CH ₂ CH ₂ -) and R ^a and R ^b are each independently hydrogen or aryl, wherein the aryl may be substituted. For example, one of R ^a and R ^b is hydrogen and the other is (dimethylaminoethyl)methylamino)phenyl (e.g., 2- dimethylaminoethyl)methylamino)phenyl.

In a further compound and/or method aspect, the present invention includes compounds of formula III chosen from:

19) 1 -Methoxy-4-chloro-phthalazine-6-carboxylic acid (3 -trifluoromethyl-phenyl)- amide,

20) 4-Methoxy-l-chloro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)- amide,

23) 4-Chloro-7-(3-trifluoromethyl-benzylamino)-phthalazin-l-ol

24) 4-chloro-6-(3-trifluoromethyl-benzylamino)-phthalazin- 1 -ol, 27) l-Chloro-4-hydroxy-phthalazine-6-carboxylic acid (3-trifiuoromethyl-phenyl)- amide,

28) l-chloro^-hydroxy-phthalazine-ό-carboxylic acid (4-trifluoromethyl-phenyl) amide,

29) 4-chloro-l-hydroxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-phenyl) amide, 30) l-Chloro-4-hydroxy-phthalazine-6-carboxylic acid phenylamide,

31) 4-Chloro- 1 -hydroxy-phthalazine-6-carboxylic acid phenylamide,

32) l-Chloro-4-hydroxy-phthalazine-6-carboxylic acid (2-methyl-3-trifluoromethyl- phenyl) amide,

33) 4-chloro-l-hydroxy-phthalazine-6-carboxylic acid (2-methyl-3-trifluoromethyl- phenyl) amide,

34) l-chloro-4-hydroxy-phthalazine-6-carboxylic acid (2,5-difluoro-phenyl) amide,

35) 4-chloro-l-hydroxy-phthalazine-6-carboxylic acid (2,5-difluoro-phenyl) amide,

36) l-chloro-4-hydroxy-phthalazine-6-carboxylic acid (2-fluoro-5-trifluoromethyl- phenyl) amide, 37) 4-chloro-l-hydroxy-phthalazine-6-carboxylic acid (2-fluoro-5-trifluoromethyl - phenyl) amide,

38) l-chloro^-hydroxy-phthalazine-ό-carboxylic acid (2-fluoro-5-methyl-phenyl) amide,

39) 4-chloro-l-hydroxy-phthalazine-6-carboxylic acid (2-fluoro-5 -methyl -phenyl) amide,

40) 4-Chloro- 1 -hydroxy-phthalazine-6-carboxylic acid (3 -trifluoromethyl-phenyl)- amide,

41) 1 -Iodo-4-hydroxy-phthalazine-6-carboxylic acid (3 -trifluoromethyl-phenyl)- amide, 42) 4-Iodo-l-hydroxy-phthalazine-6-carboxylic acid (3 -trifluoromethyl -phenylamide,

43) l-Hydroxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide,

44) l-hydroxy-4-phenyl-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)- amide, 45) l-hydroxy-4-pyridin-2-yl-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide,

46) 4-hydroxy-l-methoxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-pyridin-2- yl)-amide,

47) l-hydroxy-4-methoxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-pyridin-2- yl)-amide, 48) 6- { [(2,4-Dichlorophenyl)methyl]amino} ^-chloro^H-phthalazin- 1 -one,

49) 7- { [(2,4-dichlorophenyl)methyl]amino} -4-chloro-2H-phthalazin- 1 -one,

50) 6- { [(4-Chlorophenyl)methyl] amino} -4-chloro-2H-phthalazin- 1 -one,

51) 7- { [(4-Chlorophenyl)methyl]amino } ^-chloro^H-phthalazin- 1 -one,

52) 6- { [(3-Methoxyphenyl)methyl]amino} -4-chloro-2H-phthalazin- 1 -one, 53) 7-{[(3 -Methoxyphenyl)methyl] amino } -4-chloro-2H-phthalazin- 1 -one,

54) 6- { [(3 ,4-Difluorophenyl)methyl]amino} -4-chloro-2H-phthalazin- 1 -one,

55) 7- { [(3 ,4-Difluorophenyl)methyl] amino} -4-chloro-2H-phthalazin- 1 -one,

56) 6- { [(3-Methylphenyl)methyl]amino} -4-chloro-2H-phthalazin- 1 -one,

57) 7- { [(3-Methylphenyl)methyl]amino} -4-chloro-2H-phthalazin- 1 -one, 58) 6- { [(2-Methoxyphenyl)methyl]amino} -4-chloro-2H-phthalazin- 1 -one,

59) 7- { [(2-Methoxyphenyl)methyl]amino} -4-chloro-2H-phthalazin- 1 -one,

60) 6-(4-Methoxy-benzylamino)-2H-phthalazin- 1 -one,

61) 6-Benzylamino-4-chloro-2H-phthalazin-l-one

62) 7-Benzylamino-4-chloro-2H-phthalazin- 1 -one, 63) 4-Chloro-6-(3-trifluoromethyl-phenylamino)-2H-phthalazin-l-o ne,

64) 4-Chloro-7-(3-trifluoromethyl-phenylamino)-2H-phthalazin-l-o ne,

65) 4-Chloro-6-phenethylamino-2H-phthalazin- 1 -one,

66) 4-Chloro-7-phenethylamino-2H-phthalazin- 1 -one,

67) 4-[(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-ylamino)-methyl] -N-(2-pyrrolidin- l-yl-ethyl)-benzamide,

68) 4-[(l-Chloro-4-oxo-3,4-dihydro-phthalazin-6-ylamino)-methyl] -N-(2-pyrrolidin-

1 -yl-ethyl)-benzamide,

69) 3-[(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-ylamino)-methyl] -N-(2-pyrrolidin- 1 -yl-ethyl)-benzamide, 70) 3-[(l-Chloro-4-oxo-3,4-dihydro-phthalazin-6-ylamino)-methyl] -N-(2-pyrrolidin- 1 -yl-ethyl)-benzamide,

71 ) N-(4-Chloro- 1 -oxo- 1 ,2-dihydro-phthalazin-6-yl)-3 -trifluoromethyl-benzamide,

72) N-(I -Chloro-4-oxo-3, 4-dihydro-phthalazin-6-yl)-3 -trifluoromethyl-benzamide,

73) 4-Chloro-6-[3-(2-morpholin-4-yl-ethoxy)-benzylamino]-phthala zin-l-ol,

74) 4-Chloro-7-[3-(2-morpholin-4-yl-ethoxy)-benzylamino]-phthala zin-l-ol, 75) 4-Methyl-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide,

76) 4-M ethyl- 1 -oxo- l,2-dihydro-phthalazine-6-carboxylic acid 3-trifluoromethyl- benzylamide,

77) 4-Methyl-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid 3-methoxy- benzylamide,

78) 4-Chloro-6-(3-piperidin-l-ylmethyl-benzylamino)-2H-phthalazi n-l- one,

79) 4-Chloro-6-[2-(2-morpholin-4-yl-ethoxy)-benzylamino]-2H-phth alazin- 1 -one,

80) 6-(Benzyl-methyl-amino)-4-chloro-2H-phthalazin- 1 -one,

81) 4-Chloro-6-(2,5-dichloro-benzylamino)-2H-phthalazin- 1 -one, 82) 4-Chloro-6-(2-methyl-benzylamino)-2H-phthalazin-l-one,

83) 4-Chloro-6-(2-chloro-6-fluoro-benzylamino)-2H-phthalazin- 1 -one,

84) 4-Chloro-6-(2-pyrazol- 1 -yl-benzylamino)-2H-phthalazin- 1 -one,

85) 4-Chloro-6-(3-pyrazol-l-yl-benzylamino)-2H-phthalazin-l-one,

86) 4-Chloro-6-(2-pyridin-3-yl-benzylamino)-2H-phthalazin- 1 -one, 87) 4-Chloro-6-(2-piperidin- 1 -yl-benzylamino)-2H-phthalazin- 1 -one,

88) 4-Chloro-6-(2-thiophen-2-yl-benzylamino)-2H-phthalazin-l-one ,

89) 4-Chloro-6-(3-thiophen-2-yl-benzylamino)-2H-phthalazin-l-one ,

90) 4-Chloro-6-(2-furan-2-yl-benzylamino)-2H-phthalazin- 1 -one,

91) 4-Chloro-6-[3-(4-methyl-piperazin-l-yl)-benzylamino]-2H-phth alazin-l-one, 92) 4-Chloro-6-(2-morpholin-4-ylmethyl-benzylamino)-2H-phthalazi n- 1 -one,

93) 4-Chloro-6-(3-thiophen-3-yl-benzylamino)-2H-phthalazin-l-one ,

94) 4-Chloro-6-[2-(4-methyl-piperazin- 1 -yl)-benzylamino]-2H-phthalazin- 1 -one,

95) 4-Chloro-6-(2-phenoxy-benzylamino)-2H-phthalazin- 1 -one,

96) 4-Chloro-6-[(2,3 -dihydro-benzo[ 1 ,4]dioxin-5-ylmethyl)-amino]-2H-phthalazin- 1 - one,

97) 4-Chloro-6-[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-2H-ph thalazin-l-one,

98) 4-Chloro-6-(2-piperazin- 1 -yl-benzylamino)-2H-phthalazin- 1 -one,

99) 4-Chloro-6-(2-fluoro-5-trifluoromethyl-benzylamino)-2H-phtha lazin- 1 -one,

100) 4-Chloro-6-(5-chloro-2-methyl-benzylamino)-2H-phthalazin- 1 -one,

101) 4-Chloro-6-(2-chloro-5 -trifluoromethyl-benzylamino)-2H-phthalazin- 1 -one, 102) 4-Chloro-6-(2-chloro-3 -trifluoromethyl-benzylamino)-2H-phthalazin- 1 -one,

103) 4-Chloro-6-(2-chloro-6-phenoxy-benzylamino)-2H-phthalazin- 1 -one,

104) 4-Chloro-6-(2,5-dimethyl-benzylamino)-2H-phthalazin-l-one,

105) 4-Chloro-6-(3-morpholin-4-yl-benzylamino)-2H-phthalazin-l-on e,

106) 4-Chloro-6-(2,3-dimethyl-benzylamino)-2H-phthalazin-l-one, 107) 4-Chloro-6-[(3 ,4-dihydro-2H-benzo[&] [ 1 ,4]dioxepin-6-ylmethyl)-amino]-2H- phthalazin- 1 -one,

108) 4-Chloro-6-(3-furan-2-yl-benzylamino)-2H-phthalazin-l-one,

109) 4-Chloro-6-[(6-fluoro-4H-benzo[ 1 ,3]dioxin-8-ylmethyl)-amino]-2H-phthalazin- 1 - one, 110) 4-Chloro-6-[(5-methyl-2-phenyl-furan-3-ylmethyl)-amino]-2H-p hthalazin-l-one,

111) 1 -Chloro-4-oxo-3 ,4-dihydro-phthalazine-6-carboxylic acid (3 -difluoromethoxy- phenyl)-amide,

112) 4-Chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3-difluoromethoxy- phenyl)-amide, 113) 4-Chloro-7-(3-fluoro-benzylamino)-2H-phthalazin-l-one

114) 4-Chloro-6-(3-fluoro-benzylamino)-2H-phthalazin-l-one,

115) 4-Chloro-7-(3-trifluoromethoxy-benzylamino)-2H-phthalazin- 1 -one

116) 4-Chloro-6-(3-trifluoromethoxy-benzylamino)-2H-phthalazin-l- one,

117) 4-Chloro-6-(3-chloro-benzylamino)-2H-phthalazin-l-one, 118) 4-Chloro-6-(2-trifluoromethyl-benzylamino)-2H-phthalazin-l-o ne,

119) 4-Chloro-6-(3 ,5-dimethoxy-benzylamino)-2H-phthalazin- 1 -one,

120) 4-Chloro-6-(3 -hydroxy-benzylamino)-2H-phthalazin- 1 -one,

121) 4-Chloro-6-(3 ,5-difluoro-benzylamino)-2η-phthalazin- 1 -one,

122) 4-Chloro-6-(2,5-difluoro-benzylamino)-2H-phthalazin-l-one, 123) N- {3-[(4-Chloro- 1 -oxo- 1 ,2-dihydro-phthalazin-6-ylamino)-methyl]-phenyl}- acetamide,

124) 4-Chloro-6-(3,5-dichloro-benzylamino)-2H-phthalazin-l-one,

125) 6-[(Biphenyl-3-ylmethyl)-amino]-4-chloro-2H-phthalazin-l-one ,

127) 4-Chloro-6-(3 -difluoromethoxy-benzylaniino)-2H-phthalazin- 1 -one,

128) 4-Chloro-6-(2,3-difluoro-benzylamino)-2H-phthalazin- 1 -one, 129) 4-Chloro-6-(2-chloro-benzylamino)-2H-phthalazin-l-one,

130) 4-Chloro-6-(3 ,4-dimethyl-benzylamino)-2H-phthalazin- 1 -one,

131) 4-Chloro-6-(3-dimethylamino-benzylamino)-2H-phthalazin-l-one ,

132) 4-Chloro-6-(3 -isopropoxy-benzylamino)-2H-phthalazin- 1 -one,

133) 4-Chloro-6-(2 -pyrrol- 1 -yl-benzylamino)-2H-phthalazin- 1 -one, 134) 6-(4-tert-Butoxy-benzylamino)-4-chloro-2H-phthalazin- 1 -one,

135) 4-Chloro-6-[(pyridin-3 -ylmethyl)-amino] -2H-phthalazin- 1 -one,

136) 4-Chloro-6-(2,3-dimethoxy-benzylamino)-2H-phthalazin-l-one,

137) 4-Chloro-6-(2 , 5 -dimethoxy-benzylamino)-2H-phthalazin- 1 -one,

138) 4-Chloro-6-[(pyridin-2-ylmethyl)-arnino] -2H-phthalazin- 1 -one, 139) 4-Chloro-6-(2-trifluoromethoxy-benzylamino)-2H-phthalazin- 1 -one,

140) 4-Chloro-6-(2-difluoromethoxy-benzylamino)-2H-phthalazin- 1 -one,

141) 4-Chloro-6-(2-imidazol- 1 -yl-benzylamino)-2H-phthalazin- 1 -one,

143) 4-Chloro-6-(2-[l,2,4]triazol-l-yl-benzylamino)-2H-phthalazin -l-one,

144) 4-Chloro-6-(3-morpholin-4-ylmethyl-benzylamino)-2H-phthalazi n- 1 -one, 145) 4-Chloro-6-(3 -pyrrol- l-yl-benzylamino)-2H-phthalazin-l -one,

146) 4-Chloro-6-[3 -(4-methyl-piperidin- 1 -ylmethyl)-benzylamino] -2H-phthalazin- 1 - one,

150) 4-Chloro-6-[3-(3-dimethylamino-propylamino)-benzylamino]-2H- phthalazin-l- one, 151) 4-Chloro-6-[3-(2-morpholin-4-yl-ethylamino)-benzylamino]-2η -phthalazin- 1 - one,

152) 4-Chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3-piperidin-l- ylmethyl-phenyl)-amide,

153) 4-Chloro-6-[3-(4-methyl-[l,4]diazepan-l-yl)-benzylamino]-2H- phthalazin-l-one, 154) l-Chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (2-morpholin-4-yl-5- trifluoromethyl-phenyl)-amide,

155) 4-Chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (2-morpholin-4-yl-5- trifluoromethyl-phenyl)-amide,

156) 1 -chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (3-furan-2-yl-phenyl)- amide, 157) 4-chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3-furan-2-yl-phenyl)- amide,

158) 4-Chloro-6-(3 -dimethylaminomethyl-benzylamino)-2H-phthalazin- 1 -one,

159) 4-Chloro-6- [3 -(2-dimethylamino-ethylamino)-benzylamino] -2H-phthalazin- 1 - one, 160) l-Chloro^-oxo-S^-dihydro-phthalazine-ό-carboxylic acid m-tolylamide,

161) 4-Chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid m-tolylamide,

162) l-Chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethoxy- phenyl)-amide,

163) 4-Chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethoxy- phenyl)-amide,

164) l-Chloro-S-methyM-oxo-S^-dihydro-phthalazine-ό-carboxylic acid (3- trifluoromethyl-phenyl)-amide,

165) 4-Chloro-2-methyl-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide, 166) l-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid [5-ethoxymethyl-2- methyl-3 -(2-pyrrolidin- 1 -yl-ethylamino)-phenyl] -amide,

167) 4-chloro- 1 -oxo- 1 ,2-dihydro-phthalazine-6-carboxylic acid [5-ethoxy methyl-2- methyl-3-(2-pyrrolidin-l-yl-ethylamino)-phenyl]-amide,

168) 1 -Oxo- 1 ,2-dihydro-phthalazine-6-carboxylic acid [5-ethoxymethyl-2-methyl-3- (2-pyrrolidin- 1 -yl-ethylamino)-phenyl]-amide,

169) l-Chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid 3-trifluoromethyl- benzylamide,

170) 4-Chloro- 1 -oxo- 1 ,2-dihydro-phthalazine-6-carboxylic acid 3 -trifluoromethyl- benzylamide, 171) N-(4-Chloro- 1 -oxo- 1 ,2-dihydro-phthalazin-6-yl)-3 -methoxy-benzamide,

174) 2-(4-Chloro- 1 -oxo- 1 ,2-dihydro-phthalazin-6-yl)-N- {2-[(2-dimethylamino-ethyl)- methyl-amino] -phenyl } -acetamide,

175) 2-( 1 -Chloro-4-oxo-3 ,4-dihydro-phthalazin-6-yl)-N- {2-[(2-dimethylamino-ethyl)- methyl-aminoj-phenyl} -acetamide, 176) 4-Chloro-6-(2- {2-[(2-dimethylamino-ethyl)-methyl-amino]-phenylamino} -ethyl)- 2H-phthalazin- 1 -one,

177) 4-Chloro-7-(2- {2-[(2-dimethylamino-ethyl)-methyl-amino]-phenylamino} -ethyl)- 2H-phthalazin- 1 -one,

178) 4-Chloro- 1 -hydroxy-phthalazine-6-carboxylic acid [4-chloro-3 '-(2- dimethylamino-ethoxy) -biphenyl-3 -yl] -amide,

179) l-Chloro-4-hydroxy-phthalazine-6-carboxylic acid [4-chloro-3'-(2- dimethylamino-ethoxy)-biphenyl-3-yl]-amide,

180) 4-Chloro- 1 -hydroxy-phthalazine-ό-carboxylic acid (3'-hydroxy-biphenyl-3-yl)- amide, 181) l-Chloro-4-hydroxy-phthalazine-6-carboxylic acid (3'-hydroxy-biphenyl-3-yl)- amide,

182) 4-Chloro- 6-(3-pyrrolidin- 1 -ylmethyl-benzylamino)-2η-phthalazin- 1 -one,

183) 4-Chloro-6-(3 -pyrrolidin- 1 -yl-benzylamino)-2H-phthalazin- 1 -one,

184) 4-Chloro-6-[(6-pyrrolidin- 1 -yl-pyridin-2-ylmethyl)-amino]-2H-phthalazin- 1 -one, 185) 4-Chloro-6-(2 -pyrrolidin- 1 -yl-benzylamino)-2H-phmalazin- 1 -one,

186) 4-Chloro-6-(2-morpholin-4-yl-benzylamino)-4a,8a-dihydro-2H-p hthalazin- 1 -one,

187) 4-Chloro-6- {methyl-[3-(6-methyl-pyrazin-2-yloxy)-benzyl]-amino} -4a,8a- dihydro-2H-phthalazin- 1 -one,

188) 4-Chloro-6-[methyl-(4-methyl-3,4-dihydro-2H-pyrido[3,2-έ][l ,4]oxazin-7- ylmethyl)-amino]-4a,8a-dihydro-2H-phthalazin- 1 -one,

189) 4-Chloro-6-[2-((R)-3-methyl-piperazin-l-yl)-benzyl amino]-4a,8a-dihydro-2H- phthalazin- 1 -one,

190) 4-Chloro-6-[2-(hexahydro-pyrrolo[3 ,4-c]pyrrol-2-yl)-benzylamino]-2H- phthalazin-1-one, 191) 4-Chloro-6-(2-perhydro- 1 ,4-diazepin- 1 -yl-benzylamino)-2H-phthalazin- 1 -one,

192) 4-Chloro-6-(2-piperazin- 1 -yl-5-trifluoromethyl-benzylamino)-2H-phthalazin- 1 - one,

193) 4-Chloro-6-(5-methoxy-2-piperazin- 1 -yl-benzylamino)-2H-phthalazin- 1 -one,

194) 6-[2-(4-Amino-piperidin- 1 -yl)-benzylamino]-4-chloro-2H-phthalazin- 1 -one, and 195) 4-Chloro-6-(5-fluoro-2-piperazin- 1 -yl-benzylamino)-2η-phthalazin- 1 -one, wherein free base forms listed above can also be in the form of a pharmaceutically acceptable salt, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate), wherein a compound listed above (in a free base form or solvate thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

In a further compound and/or method aspect, the present invention includes compounds of formula III chosen from:

4-Chloro- 1 -hydroxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide sodium salt, 4-Chloro-6-[(pyridin-3-ylmethyl)-amino]-2H-phthalazin- 1-one hydro formate,

4-Chloro-6-[3-(3-dimethylamino-propylamino)-benzylamino]- 2H-phthalazin-l-one hydroformate,

4-Chloro-6-[3-(2-morpholin-4-yl-ethylamino)-benzylamino]- 2η-phthalazin-l-one hydroformate, 4-Chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3-piperidin-l-ylmethyl- phenyl) -amide hydroformate,

4-Chloro-6-[3-(4-methyl-[ 1 ,4]diazepan- 1 -yl)-benzylamino]-2H-phthalazin- 1 -one hydroformate,

4-Chloro-6-(3-dimethylaminomethyl-benzylamino)-2H-phthala zin- 1 -one hydroformate, 4-Chloro-6-[3-(2-dimethylamino-ethylamino)-benzylamino]-2H-p hthalazin-l-one hydroformate,

l-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid [5-ethoxymethyl-2-methyl-3- (2-pyrrolidin- 1 -yl-ethylamino)-phenyl]-amide hydroformate,

4-chloro-l-oxo-l,2-dihydro-ρhthalazine-6-carboxylic acid [5-ethoxy methyl-2-methyl-3- (2-pyrrolidin- 1 -yl-ethylamino)-phenyl]-amide hydroformate, wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

In another aspect, the present invention relates to compound of formula IV:

wherein R , 13 is hydrogen, halogen, alkyl (e.g., methyl), aryl, heteroaryl, cyano or alkoxy;

R ¹⁴ is hydrogen, alkyl (e.g., methyl), -C(O)R _x , -SO ₂ R _y or -P(O)(OR _y ) ₂ , where R _y is hydrogen or alkyl; and

R ¹⁵ is hydrogen, alkyl, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteraryl, alkylheterocycle or aminoalkyl; wherein an aryl, heteroaryl, heterocycle, alkylaryl, alkylheteraryl, alkylheterocycle may be optionally substituted by halogen, alkyl, alkenyl, alkynyl, cyano, nitro, amino, alkylamino, dialkylamino, hydroxyl, carboxyl, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle, alkylalkoxy, or NR ^x (alkylheterocycle) where R ^x is hydrogen or alkyl (e.g., methyl). For example, the aryl, heteroaryl, heterocycle, alkylaryl, alkylheteraryl, alkylheterocycle may be optionally substituted by alkyl (e.g., methyl), alkylalkoxy (e.g., ethoxymethyl) or NR ^x (alkylheterocycle) (e.g., pyrrolidinylethylamino).

In one embodiment, R ¹⁴ is hydrogen or alkyl (e.g., methyl). In one embodiment, R ¹³ is halogen, R ¹⁴ is hydrogen and R ¹⁵ is aryl, heteroaryl, alkylheterocycle, or alkylamino. For example, R ¹⁵ is phenyl, trifluoromethylphenyl (e.g., 3-trifluoromethylphenyl), (pyrrolidinylethylamino)phenyl (e.g., 3-(2-pyrrolidin-l-yl- ethylamino)phenyl), (ethoxymethyl)(methyl)(pyrrolidinylethylamino)phenyl (e.g., 5-

ethoxymethyl-2-methyl-3-(2-pyrrolidin- 1 -yl-ethylamino)ρhenyl), pyrazinyl, morpholinyl ethyl (e.g., 2-morpholin-4-yl-ethyl) or dimethylaminopropyl (e.g., 3- dimethylaminopropyl) .

One of ordinary skill in the art will readily appreciate that some compounds of formula IV may exist in different tautomeric forms, e.g., in a similar manner to the compounds of formula III, as described above. These two forms of formula IV are used interchangeably herein, and both are encompassed within the present invention.

In a compound and/or method aspect, the present invention includes compounds of formula IV chosen from: 126) 4-Chloro-6-(4-phenyl-piperazin- 1 -yl)-2H-phthalazin- 1 -one,

142) 4-Chloro-6-[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -2H-phthalazin- 1 -one,

147) 4-Chloro-6-(2,3,5,6-tetrahydro-[l,2']bipyrazinyl-4-yl)-2H-ph thalazin-l-one,

148) 4-Chloro-6-[4-(2-morpholin-4-yl-ethyl)-piperazin-l-yl]-2H-ph thalazin-l-one,

149) 4-Chloro-6-[4-(3-dimethylamino-propyl)-piperazin- 1 -yl]-2H-phthalazin- 1 -one, and

172) 4-Chloro-6-{4-[3-(2-pyrrolidin-l-yl-ethylamino)-phenyl]-pipe razin-l-yl}-2H- phthalazin-1-one,

173) 4-Chloro-6-{4-[5-ethoxymethyl-2-methyl-3-(2-pyrrolidin-l-yl- ethylamino)- phenyl] -piperazin- 1 -yl } -2H-phthalazin- 1 -one, wherein free base forms listed above can also be in the form of a pharmaceutically acceptable salt, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate), wherein a compound listed above (in a free base form or solvate thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. In a further compound and/or method aspect, the present invention includes compounds of formula IV chosen from:

4-Chloro-6-[4-(2-morpholin-4-yl-ethyl)-piperazin-l-yl]-2H -phthalazin-l-one hydroformate,

4-Chloro-6-[4-(3-dimethylamino-propyl)-piperazin-l-yl]-2H -phthalazin-l-one hydroformate, 4-Chloro-6- {4-[3-(2-pyrrolidin- l-yl-ethylamino)-phenyl]-piperazin- 1 -yl} -2H-phthalazin-

1-one hydroformate, and

4-Chloro-6- {4-[5-ethoxymethyl-2-methyl-3-(2-pyrrolidin- 1 -yl-ethylamino)-phenyl]- piperazin- 1 -yl } -2H-phthalazin- 1 -one hydroformate, wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

In a further compound and/or method aspect, the present invention includes compounds chosen from:

178) 4-Chloro-l-hydroxy-phthalazine-6-carboxylic acid [4-chloro-3'-(2- dimethylamino-ethoxy)-biphenyl-3 -yl]-amide,

180) 4-Chloro-l-hydroxy-phthalazine-6-carboxylic acid (3'-hydroxy-biphenyl-3-yl)- amide,

98) 4-Chloro-6-(2-piperazin- 1 -yl-benzylamino)-2η-phthalazin- 1 -one,

95) 4-Chloro-6-(2-phenoxy-benzylamino)-2H-phthalazin- 1 -one, 89) 4-Chloro-6-(3-thiophen-2-yl-benzylamino)-2H-phthalazin-l-one ,

92) 4-Chloro-6-(2-morpholin-4-ylmethyl-benzylamino)-2H-phthalazi n- 1 -one,

93) 4-Chloro-6-(3-thiophen-3-yl-benzylamino)-2H-phthalazin-l-one , 88) 4-Chloro-6-(2-thiophen-2-yl-benzylamino)-2H-phthalazin- 1 -one, 87) 4-Chloro-6-(2-piperidin- 1 -yl-benzylamino)-2H-phthalazin- 1 -one, 86) 4-Chloro-6-(2-pyridin-3-yl-benzylamino)-2H-phthalazin-l-one, 84) 4-Chloro-6-(2-pyrazol- 1 -yl-benzylamino)-2H-phthalazin- 1 -one, 145) 4-Chloro-6-(3 -pyrrol- 1 -yl-benzylamino)-2H-phthalazin- 1 -one, 112) 4-Chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3-difluoromethoxy- phenyl)-amide, 23) 4-Chloro-7-(3-trifluoromethyl-benzylamino)-phthalazin-l-ol, and

26) 4-Chloro- 1 -hydroxy-phthalazine-ό-carboxylic acid (3 -trifiuoromethyl-phenyl)- amide, wherein free base forms listed above can also be in the form of a pharmaceutically acceptable salt, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate), wherein a compound listed above (in a free base form or solvate thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof,) can also be in the form of a polymorph, and wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

As used herein the term "halogen" means F, Cl, Br, and I.

The term "alkyl" means a substituted or unsubstituted saturated hydrocarbon radical which may be straight-chain or branched-chain and contains about 1 to about 20 carbon atoms, for instance 1 to 12 carbon atoms, such as 1 to 8 carbon atoms, e.g., 1 to 4 carbon atoms. Suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Other examples of suitable alkyl groups include, but are not limited to, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4- methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl, and the like.

Substituted alkyl groups are alkyl groups as described above which are substituted in one or more positions by, e.g., halogen, hydroxyl, amino, carboxy, and cyano, and combinations thereof (e.g., CF ₃ , CHF ₂ ).

The term "alkenyl" means a substituted or unsubstituted hydrocarbon radical which may be straight-chain or branched-chain, which contains one or more carbon- carbon double bonds, and which may comprise about 1 to about 20 carbon atoms, such as 1 to 12 carbon atoms, for instance 1 to 6 carbon atoms. Suitable alkenyl groups include ethenyl, propenyl, butenyl, etc.

Substituted alkenyl groups are alkenyl groups as described above which are substituted in one or more positions by, e.g., halogen, hydroxyl, amino, carboxy, cyano, and combinations thereof.

The term "alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1- methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

The term "alkynyl" means a substituted or unsubstituted aliphatic hydrocarbon radical which may be straight-chain or branched-chain and which contains one or more carbon-carbon triple bonds. Preferably the alkynyl group contains 2 to 15 carbon atoms, such as 2 to 12 carbon atoms, e.g., 2 to 8 carbon atoms. Suitable alkynyl groups include ethynyl, propynyl, butynyl, etc.

Substituted alkynyl groups are alkynyl groups as described above which are substituted in one or more positions by, e.g., halogen, hydroxyl, amino, carboxy, cyano, and combinations thereof.

The term "alkylcycloalkyl" means a cycloalkyl-alkyl- group, where cycloalkyl and alkyl are as described above.

The term "amino" means -NH ₂ .

The term "alkylamino" means -NH(alkyl), wherein alkyl is as described above. The term "dialkylamino" means -N(alkyl) ₂ , wherein alkyl is as described above.

The term "alkylsulfonyl" means an -SO ₂ -alkyl group, wherein alkyl is as described above.

The term "alkylsulfinyl" means an -SO-alkyl group, wherein alkyl is as described above. The term "aryl" means a substituted or unsubstituted aromatic monocyclic or bicyclic ring system comprising about 5 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl and indenyl.

Substituted aryl groups include the above-described aryl groups which are substituted one or more times by, for example, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle,

halogen, hydroxyl, cyano, alkoxy, arylaoxy, cycloalkyloxy, alkoxycarbonyl, carboxyl, amino, alkylamino, dialkylamino, -SH, thioalkyl, alkylsulfonyl, alkylsulfmyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, aroyl, acyl, and combinations thereof. The term "arylsulfonyl" means an -SO ₂ -aryl group, wherein aryl is as described above.

The term "arylsulfinyl" means an-SO-aryl group, wherein aryl is as described above.

The term "carboxyl" means -C(O)OH. The term "cycloalkyl" means a monocyclic, bicyclic or tricyclic nonaromatic saturated hydrocarbon radical having 3 to 10 carbon atoms, such as 3 to 8 carbon atoms, for example, 3 to 6 carbon atoms. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, 1-decalin, adamant- 1-yl, and adamant-2-yl. Other suitable cycloalkyl groups include, but are not limited to, spiropentyl, bicyclo[2.1.OJpentyl, bicyclo[3.1.Ojhexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl, spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, and spiro[3.5]nonyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be substituted, for example, by one or more halogens and/or alkyl groups. The term "heteroaryl" means a substituted or unsubstituted aromatic monocyclic or multicyclic ring system comprising 5 to about 10 ring atoms, preferably 5 or 6 ring atoms, wherein at least one of the ring atoms is an N, O or S atom. Suitable heteroaryl groups include, but are not limited to furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, naphthyridinyl and the like. Substituted heteroaryl groups include the above-described heteroaryl groups which are substituted one or more times by, for example, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle, halogen, hydroxyl, cyano, alkoxy, arylaoxy, cycloalkyloxy, alkoxycarbonyl, carboxyl, amino, alkylamino, dialkylamino, -SH, thioalkyl, alkylsulfonyl, alkylsulfmyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, aroyl, acyl, and combinations thereof.

The term "heterocycle" means a substituted or unsubstituted non-aromatic mono- or multicyclic ring system comprising 3 to 10 atoms, preferably 5 or 6 atoms, wherein at least one of the ring atoms is an N, O or S atom. Suitable heterocyle groups include, but are not limited to tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, and the like

Substituted heterocycle groups include the above-described heterocycle groups which are substituted one or more times by, for example, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycle, alkylheterocycle, halogen, hydroxyl, cyano, alkoxy, arylaoxy, cycloalkyloxy, alkoxycarbonyl, carboxyl, amino, alkylamino, dialkylamino, -SH, thioalkyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, aroyl, acyl, and combinations thereof.

The term "aroyl" means an aryl-C(O)-, in which the aryl group is as previously described. Suitable aroyl groups include, but are not limited to, benzoyl and 1- naphthoyl.

The term "acyl" means an HC(O)-, alkyl-C(O)-, or cycloalkyl-C(O)-, in which the alkyl and cycloalkyl groups are as previously described.

The term "alkoxy" means alkyl-O- groups and in which the alkyl portion is in accordance with the previous discussion. Suitable alkoxy groups include, but are not limited to, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, pentoxy, hexoxy, heptoxy, octoxy, and the like. For example, the alkoxy can be methoxy, difluromethoxy, trifluoromethoxy or ethoxy.

The term "alkylaryl" refers to an aryl-alkyl-radical in which the aryl and alkyl portions are in accordance with the previous descriptions. Suitable examples include, but are not limited to, benzyl, 1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl, phenpentyl, and napthylmethyl

The term "alkylheterocycle" refers to a heterocycle-alkyl-group wherein the heterocycle and alkyl portions are in accordance with the previous discussions. The term "alkylheteroaryl" refers to a heteroaryl-alkyl-group wherein the heteroaryl and alkyl portions are in accordance with the previous discussions. Suitable

examples include, but are not limited to, pyridylmethyl, thiazolylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl, and isoquinolinylmethyl

The term "aryloxy" means an aryl-O- group, in which the aryl group is as previously described. The term "alkylaryloxy" means aryl-alkyl-O-, in which the aryl and alkyl groups are as previously described.

The term "alkylthio" means an alkyl-S- group, in which the alkyl group is as previously described.

The term "arylthio" means an aryl-S- group, in which the aryl group is as previously described.

The term "alkoxycarbonyl" means an alkyl-O-CO- group, in which the alkyl group is as previously described.

The term "aminoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -NRR' where R is hydrogen, alkyl, or -COR ^a where R ^a is alkyl, and R' is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or haloalkyl, e.g, aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, 1,3-diaminopropyl, dimethylaminoethyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, and the like. The term "amidoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -(CO)NRR ¹ where R is hydrogen, alkyl, or -COR ^a where R ^a is alkyl, and R' is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or haloalkyl, e.g, CH ₂ CONH ₂ , CH ₂ CONHalkyl (e.g., CH ₂ CONHCH ₃ ), CH ₂ CONH(alkyl) ₂ (e.g., CH ₂ CON(CH ₃ ) ₂ ), and the like.

The term aminosulfinyl" means a -SONRR' radical where R is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl and R' is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl as defined above, e.g., - SONH ₂ , methylaminosulfϊnyl, 2-dimethylaminosuliϊnyl, and the like.

The term "aminosulfonyl" means a -SO ₂ NRR' radical where R is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl and R' is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl as defined above, e.g., - SO ₂ NH ₂ , methylaminosulfonyl, 2-dimethylaminosulfonyl, and the like.

The term "aryloxycarbonyl" means an aryl-O-C(O)- group, in which the aryl group is as previously described.

In another aspect, the present invention relates to methods for preparing the compounds of formulas I-IV. The compounds of the present invention may be prepared by conventional methods, known to one or ordinary skill in the art. For example, some of the processes that can be used are given in the general reaction schemes outlined below. Modifications to these exemplary reaction schemes will be readily apparent to those skilled in the art upon reading the present disclosure and examples which follow. All starting materials are commercially available or can be conventionally prepared from known starting materials, unless otherwise indicated. 1,2,4-benzene tricarboxylic anhydride, 4-nitrophthalic anhydride and 4-bromophthalic anhydride are commercially available from Sigma Aldrich (St. Louis, MO).

For example, as outlined in Scheme I, 1,2,4-benzene tricarboxylic anhydride 1 may be reacted with hydrazine in a suitable solvent, e.g., ethanol, isopropyl alcohol, or n- methyl-2-pyrrolidinone, to produce dihydroxy-phthalazine 2. Compound 2 may then be reacted with SOCl ₂ and POCl ₃ to produce a trichloride intermediate that is reacted immediately with an amine XjX ₂ NH (where X ¹ and X ² are , e.g., hydrogen, alkyl, aryl, etc.) to produce an amide compound 3. Compound 3 may then be reacted with NaI and HI in a suitable solvent, e.g., acetone, to produce a di-iodo compound 4. Compound 4 may then be further reacted with a suitable nucleophile in a suitable solvent to form a mixture of the two correspondent regioisomers 5 and 6. Replacement of any remaining iodine atoms may be achieved using standard nucleophilic substitution and/or transition metal reactions known to one of skill in the art, for example, Stille and Suzuki type reactions. A chlorine atom in compound 3 may also be directly replaced with a suitable nucleophile (where, for example, Y is HNRiR ₂ or NaOR) by reacting compound 3 with

the nucleophile in a suitable solvent to form a mixture of the two correspondent regioisomers 7 and 8.

It will be readily apparent to those skilled in the art upon reading the present disclosure that numerous amines and hydroxyl derivatives may be chosen and may be used to produce compounds that are within the scope of the present invention.

Scheme I

The synthesis of phthalazine derivatives of general formulas 13-20 may be achieved as outlined in Scheme II. In general, a mixture of 4-nitrophthalic anhydride 9 and hydrazine may be refluxed in a suitable solvent, e.g., isopropyl alcohol, to provide 6- amino-phthalazine-l,4-diol 10 in almost quantitative yield. Compound 10 may then be treated with phosphorus oxychloride and N,N-diisopropylethylamine to form 1 ,4- dichloro-phthalazin-6-ylamine 11. Reduction of compound 11 with a suitable reducing agent, e.g., iron, may be used to produce the amino derivative 12. Alkylation or acylation of the amino group of compound 12 using A-B-X (where, for example, A is alkyl, aryl, arylalkyl, arylheteroalkyl, B is absent, CO, SO ₂ , and X is a suitable leaving group, such as, Cl, Br, I, OTosyl, etc.) may be used to provide the dichloro derivative of general formula 13. Treatment of compound 13 with a nucleophile of general formula R ¹ R ² NH affords two isomers of general formulas 17 and 18. Alternatively, compound 13 may be treated with NaI and HI in, e.g., acetone to obtain the di-iodo derivative 14. Compound 14 may then be reacted with an appropriate nucleophile (e.g., of general formula

R R NH) to produce compounds 15 and 16. Compounds 15 and 16 may then be treated with CuCN to produce the corresponding cyano derivatives 19 and 20.

Scheme II

The synthesis of phthalazine derivatives of general formulas 25-26 may be achieved as outlined in Scheme III. In general, a mixture of 4-bromophthalic anhydride and hydrazine may be refluxed in a suitable solvent, e.g., isopropyl alcohol, to provide 6- bromo-phthalazine-l,4-diol 21 in almost quantitative yield. Compound 21 may then be treated with phosphorus oxychloride to form 1 ,4-dichloro-6-bromo phthalazine 22. Treatment of compound 22 with a suitable nucleophile (where, for example, Y is NR]R ₂ or NaOR) affords two isomers of general formulas 23 and 24. Displacement of the bromine atom with a suitable amino or alcohol derivative A-B-X (where, for example, A is alkyl, aryl, arylalkyl, arylheteroalkyl, B is absent, CO, and X is OH, NH ₂ ), using a suitable Pd complex derivative in the presence of a base like sodium tert-butoxide in a suitable solvent, affords the desired 6-amino or 6-alkoxy phthalazine derivatives of general formula 25-26.

Scheme III

The selective synthesis of phthalazine derivatives of general formulas 30 may be undertaken as outlined in Scheme IV. Treatment of bromo di ester 27 with the desired anhidride in presence of zinc and cobalt bromide affords the desired intermediate 28. Saponification using a suitable base followed by treatment with hydrazine gives the desired phthalazine intermediate that may be refluxed in thionyl chloride to provide intermediate 29 in good yield. Reaction of this acid chloride 29 derivative with the desired amino group ^R ¹³ NH in presence of a suitable base and solvent affords the desired product of general formula 30.

Scheme IV

One of ordinary skill in the art will recognize that compounds of formulas I-IV can exist in different tautomeric and geometrical isomeric forms. All of these compounds, including cis isomers, trans isomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers, substantially pure, and pure enantiomers, are within the scope of the present invention. Substantially pure enantiomers contain no more than 5% w/w of the corresponding opposite enantiomer, preferably no more than 2%, most preferably no more than 1%.

The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, are also useful. The optically active compounds of formulas I-IV can likewise be obtained by utilizing optically active starting materials in chiral synthesis processes under reaction conditions which do not cause racemization. In addition, one of ordinary skill in the art will recognize that the compounds can be used in different enriched isotopic forms, e.g., enriched in the content of ² H, ³ H, ¹¹ C, ¹³ C and/or ¹⁴ C. In one particular embodiment, the compounds are deuterated. Such deuterated forms can be made the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the efficacy and increase the duration of action of drugs.

Deuterium substituted compounds can be synthesized using various methods such as described in, for example, Dean, Dennis C; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] (2000), 110 pp. CAN 133:68895 AN 2000:473538 CAPLUS; Kabalka, George W.; Varma, Rajender S. The synthesis of radiolabeled compounds via organometallic intermediates. Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRAB ISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981), 64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN 1981:476229 CAPLUS.

Where applicable, the present invention also relates to useful forms of the compounds as disclosed herein, such as base free forms, and pharmaceutically acceptable salts or prodrugs of all the compounds of the present invention for which salts or prodrugs can be prepared. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts can be prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.

The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides,

hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3- phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates. For example, the pharmaceutically acceptable salt can be a hydrochloride, a hydrobromide, a hydroformate, a maleate or a sodium salt.

Preferably, the salts formed are pharmaceutically acceptable for administration to mammals. However, pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, for isolating the compound as a salt and then converting the salt back to the free base compound by treatment with an alkaline reagent. The free base can then, if desired, be converted to a pharmaceutically acceptable acid addition salt. One of ordinary skill in the art will also recognize that some of the compounds of formulas I-IV can exist in different polymorphic forms. As known in the art, polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species. A polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state. Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds. One of ordinary skill in the art will further recognize that compounds of formulas

I-IV can exist in different solvate forms. Solvates of the compounds of the invention may also form when solvent molecules are incorporated into the crystalline lattice structure of the compound molecule during the crystallization process.

The term "prodrug" means a compound that is a drug precursor which upon administration to a subject undergoes chemical conversion by metabolic or chemical processes to yield a compound of the present invention. Such prodrugs are considered to be within the scope of this invention.

The compounds of the invention can be administered alone or as an active ingredient of a formulation. Thus, the present invention also includes pharmaceutical compositions of compounds of formulas I-IV, containing, for example, one or more pharmaceutically acceptable carriers.

Numerous standard references are available that describe procedures for preparing various formulations suitable for administering the compounds according to the invention. Examples of potential formulations and preparations are contained, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).

Administration of the compounds of the present invention may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intraveneously, intramuscularly, intrasternally and by infusion) by inhalation, rectally, vaginally, topically and by ocular administration.

Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.

Various liquid oral dosage forms can also be used for administering compounds of the inventions, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms can also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration can be in

the form of a pessary, tampon, cream, gel, past foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art.

For topical administration the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose.

Topical administration may also involve transdermal administration via means such as transdermal patches.

Aerosol formulations suitable for administering via inhalation also can be made.

For example, for treatment of disorders of the respiratory tract, the compounds according to the invention can be administered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions. The aerosol formulation can be placed into a pressurized acceptable propellant.

According to other embodiments, methods for treating a condition that responds to a protein kinase inhibitor are provided. In certain embodiments, the compounds of the present invention may be useful as serine/threonine protein kinase inhibitors. For example, the compounds of the present invention may be useful as S6 Kinase 1 (S6K1) and/or S6 Kinase 2 (S6K2) inhibitors. In other embodiments, the compounds of the present invention may be useful as Rho Kinase, PIM, and/or Polo-Like Kinase (PLK) inhibitors. For example, some embodiments provide methods of treating a condition that responds to a kinase inhibitor comprising administering to a patient in need thereof an effective amount of a compound of the present invention.

In exemplary embodiments, the present invention provides methods of treatment of conditions related to cancer, the endocrine system, the cardiovascular system, inflammation, hematological disorders, metabolic disorders, immune disorders and neurological disorders. For example, the present invention provides methods of treatment of diseases and conditions such as, but not limited to, tumors, metastases, breast cancer, lung cancer, melanoma, colorectal cancer, bladder cancer, ovarian cancer, prostate cancer, renal cancer, squamous cell cancer, glioblastoma, pancreatic cancer, Kaposi's sarcoma, multiple myeloma, leukemia, diabetes, diabetic retinopathy, insulin resistance, Type II diabetes, non insulin dependent diabetes mellitus, obesity, transplant

rejection, multiple sclerosis, IBS, Crohn's disease, ulcerative colitis, renal disease, cachexia, septic shock, lupus, psoriasis, dermatitis, eczema, COPD, asthma, arthritic, osteoarthritis, rheumatoid arthritis, AIDS, depression, Alzheimer's disease, Parkinson's disease, ocular disease, macular degeneration, glaucoma, apoptosis, ischaemic disease, stroke, neural injury, myocardial infarction, angina, acute or congestive heart failure, hypertension, nephropathy, electrolyte abnormality, and vasospasm.

In certain embodiments, the present invention provides methods of treating cancer and/or metabolic disorders. For example, in one embodiment, the present invention provides methods of treating cancer. In another embodiment, the present invention provides methods of treating obesity. In a further embodiment, the present invention provides methods of treating type II diabetes.

The term "treating" means to relieve, alleviate, delay, reduce, reverse, improve or prevent at least one symptom of a condition in a subject. The term "treating" may also mean to arrest, delay the onset {i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a condition. The compounds of the present invention may be administered as a mono-therapy or administered as part of a combination therapy. For example, one or more of the compounds of the present invention may be co-administered or used in combination with one or more additional therapies known in the art. An "effective amount" means the amount of a compound of formula I- IV that, when administered to a patient (e.g., a mammal) for treating a disease, is sufficient to effect such treatment for the disease, or an amount of a compound of formulas I-IV that is sufficient for inhibiting serine/threonine protein kinases (such as, e.g., S6K1 and/or S6K2) to achieve the objectives of the invention. The "effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.

A subject or patient in whom administration of the therapeutic compound is an effective therapeutic regimen for a disease or disorder is preferably a human, but can be any animal, including a laboratory animal in the context of a clinical trial or screening or activity experiment. Thus, as can be readily appreciated by one of ordinary skill in the art, the methods, compounds and compositions of the present invention are particularly

suited to administration to any animal, particularly a mammal, and including, but by no means limited to, humans, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals (whether in the wild or in a zoological garden), research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc., i.e., for veterinary medical use.

In some embodiments, the compounds of the present invention are administered as a mono-therapy. In other embodiments, the compounds of the present invention are administered as part of a combination therapy. For example, a compound of formulas I- IV may be used in combination with other drugs or therapies that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of formulas I-IV are useful. In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of formulas I-IV. When a compound of formulas I-IV is used contemporaneously with one or more other drugs, a pharmaceutical unit dosage form containing such other drugs in addition to the compound of formulas I-IV may be employed. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of formula I-IV.

The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention in any way as many variations and equivalents that are encompassed by the present invention will become apparent to those skilled in the art upon reading the present disclosure.

EXAMPLES

Examples 1 and 2: Synthesis of l-AHylamino-^chloro-phthalazine-ό-carboxylic acid (3-trifluoromethyl-phenyl)-amide and 4-Allylamino-l -chloro-phthalazine-6- carboxylic acid (3-trifluoromethyI-phenyl)-amide

A mixture of 1,2,4 benzenetricarboxylic anhydride (5 g, 0.026 mol) and anhydrous hydrazine (1.67 g, 0.052 mol) in isopropyl alcohol (50 mL) was refluxed for 5 hours. The resulting mixture was neutralized with concentrated HCl and stirred at room temperature for an additional 1 hour. The mixture was filtered and the white residue washed with isopropyl alcohol to provide l,4-dihydroxy-phthalazine-6-carboxylic acid (5.1g, 95%) as a white solid.

A mixture of l^-dihydroxy-phthalazine-ό-carboxylic acid (2 g, 9.7 mmol) in thionyl chloride (20 mL) was refluxed for 3 hours. Phosphorous oxychloride (20 mL) was added and the resulting solution stirred at reflux for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess of chloride. The crude residue was dissolved in DMF (100 mL) and cooled to 0 ⁰ C. A solution of 3-(trifluoromethyl)aniline (2.34 g, 14.6 mmol) and Et ₃ N (2.9 g, 29.1 mmol) in DMF (50 mL) was added dropwise. The solution was stirred at 0 ⁰ C for 1 hour. The solution was then diluted with ether (200 mL) and washed with water (2 x), saturated solution OfNH ₄ Cl (1 x), brine (1 x), dried and concentrated under reduced pressure. The crude mixture was purified by chromatography using EtOAc/hexane to provide 1,4- dichloro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (1.0 g, 30%). A mixture of 1 ,4-dichloro-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide (900 mg, 2.33 mmol), allylamine (134 mg, 2.35 mmol), and Et ₃ N (263 mg, 2.6 mmol) in 5 mL of DMF was heated at 65-7O ⁰ C for 15 hours. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 x 50 mL). Combined extracts were washed with water (2 x 50 mL), saturated solution OfNaHCO ₃ (1 x 50 mL), brine (1 x 50 mL), and concentrated under reduced pressure. The crude mixture containing the two isomers was purified by chromatography using EtOAc/hexane. The following two compounds were obtained:

l-Allylamino-4-chloro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)- amide (270 mg, 28.5%), m/z (M+H)=408, ¹ H NMR (500 MHz, d6-DMSO, ppm): 10.93 (lH,s); 8.90 (lH,s); 8.48-7.50 (7H, m); 6.26 (IH, m); 5.32-5.14 (2H, dd); 4.24 (2H, m); and 4-Allylamino-l-chloro-phthalazine-6-carboxylic acid (3-trifiuoromethyl-phenyl)- amide (520 mg, 54.8%), m/z (M+H)=408, ¹ H NMR (500MHz, d6-DMSO): δ 10.95 (lH,s); 8.60-7.50 (8H, m); 6.26 (IH, m); 5.30-5.10 (2H, dd); 4.22 (2H, m). Examples 3 and 4: Synthesis of l-Methylamino-^-chloro-phthalazine-o-carboxylic acid (3-trifluoromethyl-phenyl)-amide and 4-Methylamino-l-chIoro-phthalazine-6- carboxylic acid (3-trifluoromethyl-phenyl)-amide

The experimental procedure for Examples 3 and 4 is analogous to the procedure for Examples 1 and 2. In preparing Examples 3 and 4, methyl amine rather than allylamine is reacted with l,4-dichloro-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide. Accordingly, the following two compounds were obtained: 1- Methylammo-4-chloro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (12 mg, 6.1%), m/z (M+H)=381, ¹ H NMR (500MHz, d6-DMSO): δ 9.85 (lH,s); 8.75 (IH, s); 8.45-7.25 (7H, m); 6.60 (IH, m); 3.16 (3H, d); and 4-Methylamino-l-chloro- phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (80 mg, 40.5%), m/z (M+H)=381, ¹ H NMR (500MHz, d6-DMSO): δ 10.5 (lH,s); 8.64 (IH, s); 8.36-7.28 (8H, m); 3.12 (3H,d).

Examples 5 and 6: Synthesis of l-benzylamino^-chloro-phthalazine-o-carboxylic acid (3-trifluoromethyl-phenyl)-amide and 4-benzylamino-l-chloro-phthalazine-6- carboxylic acid (3-trifluoromethyl-phenyl)-amide

The experimental procedure for Examples 5 and 6 is analogous to the procedure for Examples 1 and 2. In preparing Examples 5 and 6, benzylamine rather than allylamine is reacted with l,4-dichloro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)- amide. Accordingly, the following two compounds were obtained: l-Benzylamino-4- chloro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (11 mg, 3.1%), m/z (M+H)=457, ¹ H NMR (500MHz, d6-DMSO): δ 9.30 (lH,s); 8.78-6.86 (12H, m); 6.61 (IH, s); 4.55 (2H,d); and 4-Benzylamino-l-chloro-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (23 mg, 6.5%), m/z (M+H)=457, ¹ H NMR (500MHz, d6- DMSO): δ 9.42 (lH,s); 8.34-7.20 (12H, m); 5.77 (IH, s); 4.72 (2H,d). Examples 7 and 8: Synthesis of ^Cyano-l-methylamino-phthalazine-ό-carboxylic acid (3-trifluoromethyl-phenyl)-amide and l-Cyano-4-methylamino-phthalazine-6- carboxylic acid (3-trifluoromethyl-phenyl)-amide

To a solution of l^-dichloro-phthalazine-δ-carboxylic acid (3-trifluoromethyl- phenyl)-amide (3.3 g, 8.55 mmol) in acetone (100 mL) were added NaI (6.44 g, 42.96 mmol) and HI (few drops). The solution was refluxed for 1 hour then concentrated under vacuum and purified by chromatography (hexanes/EtOAc) to provide 1,4-di-iodo- phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (4.01g, 82.5 %) as a colored solid.

To a solution of l,4-di-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide (200 mg, 0.35 mmol) in THF was added a solution of methyl amine in THF (2 mL, 2 M solution). The solution was stirred at room temperature for 40 hours

then concentrated under vacuum. The crude mixture was diluted with pyridine (10 mL) and CuCN was added (94 mg, 1.05 mmol). The solution was refluxed for 30 minutes then concentrated under vacuum. Flash chromatography (EtOAc/hexane) was used to obtain the two desired compounds: l-Cyano-4-methylamino-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (20 mg, white solid), ¹ H-NMR (DMSO-d6) δ: 3.18 (d, 3H), 7.52 (d, IH), 7.66 (t, IH), 8.08 (d, IH), 8.26 (s, IH), 8.4-8.55 (m, 3H), 8.72 (m, IH), 11.06 (s, IH); and 4-Cyano-l-methylamino-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (6 mg, colored solid) ¹ H-NMR (OMSO-d6) δ: 3.18 (d, 3H), 7.52 (d, IH), 7.66 (t, IH), 8.08 (d, 2H), 8.24 (s, IH), 8.49(dd, IH), 8.81 (m, IH), 8.94 (s, lH)10.95 (s, IH).

Examples 9 and 10: Synthesis of l-Benzylamino^-iodo-phthalazine-ό-carboxylic acid (3-trifluoromethyl-phenyl)-amide and 4-Benzylamino-l-iodo-phthalazine-6- carboxylic acid (3-trifluoromethyl-phenyl)-amide

To a solution of l,4-di-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl)-amide (2.0 g, 3.52 mmol) in THF (15 mL) was added benzylamine (0.77 mL, 7.03 mmol). The solution was stirred at room temperature overnight then concentrated under vacuum. Chromatography (hexanes/EtOAc) was used to obtain: l-Benzylamino-4- iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide ¹ H-NMR (DMSO- d6) δ: 4.75 (d, 2H), 7.24 (t, IH), 7.33 (t, 2H), 7.41 (d, 2H), 7.52 (d, IH), 7.65 (t, IH), 8.09 (d, IH), 8.27 (s, IH), 8.36 (s, IH), 8.42 (t, IH), 8.48 (m, 2H), 11.0 (s, IH). m/z (M+l) 549.03; and 4-Benzylamino-l-iodo-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide ¹ H-NMR (DMSO-d6) δ: 4.79 (d, 2H), 7.23 (t, IH), 7.32 (t, 2H), 7.42 (d, 2H), 7.50 (d, IH), 7.65 (t, IH), 7.97 (d, IH), 8.07 (d, IH), 8.24 (s, IH), 8.41 (m, IH), 8.49 (t, IH), 8.90 (s, IH), 10.91 (s, IH).

Example 11: Synthesis of l-Benzylamino-phthalazine-ό-carboxylic acid (3- trifluoromethyl-phenyl)-amide

A mixture of l-benzylaniino-4-iodo-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (24 mg, 0.04 mmol), MeOH (5 mL) and 10% wet Pd/C (catalytic) was evacuated and flushed (3 x) with hydrogen. The mixture was stirred under hydrogen for 5 hours. The mixture was filtered through celite, rinsed with MeOH and concentrated under vacuum. Chromatography (hexanes/EtOAc) was used to obtain 1- Benzylamino-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (9 mg, 50 %) as a solid, ¹ H-NMR (CDCl ₃ ) δ: 4.80 (bs, 2H), 7.35 (m, 7H), 8.10 (m, 3H), 8.30 (bs, 2H), 8.80 (bs, IH). m/z (M+ 1) 423.23.

Example 12: Synthesis of 4-Cyano-l-benzylamino-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide

To a solution of l-benzylamino-4-iodo-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (62 mg, 0.11 mmol) in pyridine was added CuCN (30 mg, 0.34 mmol). The solution was heated to 90 ⁰ C for 1 hour, then concentrated under vacuum. Flash chromatography (hexanes/EtOAc) was used to obtain 4-Cyano-l- benzylamino-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (25 mg, 50 %) as a yellow solid. ¹ H-NMR (DMSO-d6) δ: 4.94 (d, 2H), 7.26 (m, IH), 7.34 (t, 2H), 7.43 (d, 2H), 7.52 (d, IH), 7.66 (t, IH), 8.10 (d, IH), 8.26 (s, IH), 8.52 (m, 2H), 8.65 (d, IH), 9.21 (t, IH), 11.0 (s, IH).

Examples 13 and 14: Synthesis of l-Benzylamino^-chloro-phthalazine-ό-carboxylic acid phenylamide and 4-Benzylamino-l-chloro-phthalazine-6-carboxylic acid phenylamide.

A mixture of 1 ^-dihydroxy-phthalazine-ό-carboxylic acid (2 g, 9.7 mmol) in thionyl chloride (20 mL) was refluxed for 3 hours. Phosphorous oxychloride (20 mL) was added and the resulting solution stirred at reflux for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess of chloride.

The crude residue was dissolved in DMF (50 mL) and cooled to 0 ⁰ C. A solution of aniline (1.3 mL, 14.6 mmol) and Et ₃ N (5.4 mL, 38.8 mmol) in DMF (20 mL) was added dropwise. The solution was stirred at 0 ⁰ C for 1 hour, then diluted with ether (200 mL) and washed with water (2 x), saturated solution OfNH ₄ Cl (1 x), brine (1 x), dried and concentrated under reduced pressure. The crude mixture was purified by chromatography using EtOAc/hexane to provide 1 ,4-dichloro-phthalazine-6-carboxylic acid phenylamide (0.34g, 11%), ¹ H-NMR (DMSO-d6) δ: 7.18 (t, IH), 7.38-7.46 (m, 2H), 7.81 (d, 2H), 8.50 (d, IH), 8.71 (dd, IH), 8.85 (d, IH), 10.88 (s, IH). A mixture of 1 ^-dichloro-phthalazine-ό-carboxylic acid phenylamide (340 mg,

1.07 mmol), benzylamine (0.175 mL, 1.61 mmol), and Et ₃ N (0.30 mL, 2.14 mmol) in 5 mL of DMF was heated at 65-7O ⁰ C for 15 hours. After cooling to room temperature, reaction mixture was poured in water (500 mL) and extracted with EtOAc (2 x 25 mL). Combined extracts were washed with water (2 x 50 mL), saturated solution OfNaHCO ₃ (50 mL), brine (50 mL), and concentrated under reduced pressure. The crude mixture containing the two isomers was purified by chromatography using EtOAc/hexane. The following two compounds were obtained: 4-Benzylamino-l-chloro-phthalazine-6- carboxylic acid phenylamide (50 mg), ¹ H-NMR (OMSO-d6) δ: 4.68 (d, 2H), 6.25 (bs, IH), 7.02-7.20 (m, 6H), 7.28-7.34 (m, 2H), 7.58 (d, 2H), 8.13 (d, IH), 8.33 (d, IH), 8.60 (s, IH), 8.85 (s, IH); and l-Benzylammo^-chloro-phthalazine-ό-carboxylic acid phenylamide (25 mg), ¹ H-NMR (DMSO-λJ) δ: 4.81 (s, 2H), 7.06-7.14 (m, 2H), 7.19-

7.24 (m, IH), 7.25-7.34 (m, 4H), 7.41 (d, 2H), 7.75 (d, 2H), 8.20 (d, IH), 8.33 (dd, IH), 8.61 (d, IH), 9.98 (s, IH).

Examples 15 and 16: Synthesis of l-Benzylamino-φchloro-phthalazine-ό-carboxylic acid (3-methoxy-phenyl)-amide and 4-Benzylamino-l-chloro-phthalazine-6- carboxylic acid (3-methoxy-phenyl)-amide.

A mixture of l^-dihydroxy-phthalazine-ό-carboxylic acid (2 g, 9.7 mmol) in thionyl chloride (20 mL) was refluxed for 3 hours. Phosphorous oxychloride (20 mL) was added and the resulting solution stirred at reflux for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess of chloride.

The crude residue was dissolved in DMF (50 mL) and cooled to 0 ⁰ C. A solution of m-anisidine (1.63 mL, 14.6 mmol) and Et ₃ N (5.4 mL, 38.8 mmol) in DMF (20 mL) was added dropwise. The solution was stirred at 0 ⁰ C for 1 hour, then diluted with ether (200 mL) and washed with water (2 x), saturated solution OfNH ₄ Cl (1 x), brine (1 x), dried and concentrated under reduced pressure. The crude mixture was purified by chromatography using EtOAc/hexane to provide l,4-dichloro-phthalazine-6-carboxylic acid (3-methoxy-phenyl)-amide (0.62g), ¹ H-NMR (DMSO-d6) δ: 3.79 (s, 3H), 6.76 (dd, IH), 7.31 (t, IH), 7.38-7.42 (m, IH), 7.49 (t, IH), 8.50 (d, IH), 8.70 (dd, IH), 8.84 (d, IH), 10.85 (s, IH).

A mixture of 1, 4-dichloro-phthalazine-6-carboxylic acid (3-methoxy-phenyl)- amide (620 mg, 1.07 mmol), benzylamine (0.30 mL, 2.69 mmol), and Et ₃ N (0.50 mL, 3.58 mmol) in 7 mL of DMF was heated at 65-7O ⁰ C for 15 hours. After cooling to room temperature, reaction mixture was poured in water (500 mL) and extracted with EtOAc (2 x 25 mL). Combined extracts were washed with water (2 x 50 mL), saturated solution of NaHCO ₃ (50 mL), brine (50 mL), and concentrated under reduced pressure. The crude

mixture containing the two isomers was purified by chromatography using EtOAc/hexane. The following two compounds were obtained: 4-benzylamino-l-chloro- phthalazine-6-carboxylic acid (3-methoxy-phenyl)-amide phenylamide (80 mg), H- NMR (CDCl ₃ ) δ: 2.55 (bs, 2H), 3.76 (s, 3H), 4.79 (d, 2H), 6.63-6.68 (m, IH), 7.03 (t, IH), 7.14-7.24 (m, 4H), 7.33-7.38 (m, 3H), 8.11 (d, IH), 8.83 (d, IH), 9.58 (s, IH); and l-Benzylamino-4-chloro-phthalazine-6-carboxylic acid (3 -methoxy-phenyl) -phenylamide (30 mg), ¹ H-NMR (DMSO-J ₆ ) δ: 3.88 (s, 3H), 4.92 (s, 2H), 6.48 (bs, IH), 6.77 (dt, IH), 7.30-7.36 (m, 4H), 7.36-7.42 (m, 2H), 7.49-7.52 (m, 2H), 7.55 (s, IH), 8.14 (d, IH), 8.41 (dd, IH), 8.68 (d, IH), 9.44 (s, IH). Examples 17 and 18: Synthesis of l-Dimethylamino^-chloro-phthalazine-ό- carboxylic acid (3-trifluoromethyl-phenyl)-amide and 4-Dimethylamino-l-chloro- phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide.

A mixture of 1 ^-dichloro-phthalazine-ό-carboxylic acid (3-trifluoromethyl- phenyl)-amide (0.30 g, 0.782 mmol), dimethylamine (0.78 mL, 1.56 mmol, 2 M solution in THF) and 8 mL of DMF was heated to 80 - 85 ⁰ C for 1 hour. The reaction was poured onto water, the solids filtered and washed with water. Chromatography (EtOAc/hexane) was used to obtain the following compounds: l-Dimethylamino-4-chloro-phthalazine-6- carboxylic acid (3-trifluoromethyl-phenyl)-amide (22 mg, 7.1 %, yellow solid), ¹ H-NMR (CDCl ₃ ) δ: 3.17 (s, 6H), 7.40 (m, IH), 7.44 (t, IH), 8.04-8.14 (m, 3H), 8.34 (dd, IH), 8.42 (s, IH), 9.62 (s, IH). m/z (M+l) 395.20; and 4-Dimethylamino-l-chloro- phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (177 mg, 57.3 %, white solid), ¹ H-NMR (CDCl ₃ ) δ: 3.19 (s, 6H), 7.36 (m, IH), 7.46 (t, IH), 8.06-8.10 (m, 2H), 8.18 (d, IH), 8.39 (dd, IH), 8.66 (s, IH), 10.13 (bs, IH). m/z (M+l) 395.20. Examples 19 and 20: Synthesis of l-Methoxy^-chloro-phthalazine-θ-carboxylic acid (3-trifluoromethyl-phenyl)-amide and 4-Methoxy-l-chloro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide.

A mixture of 1 ^-dichloro-phthalazine-ό-carboxylic acid (3-trifluoromethyl- phenyl)-amide (0.327 g, 0.847 mmol), sodium methoxide (0.1 g, 1.85 mmol) and 8 mL of DMF was heated to 80 - 85°C for 7 hours and then concentrated. Chromatography (EtOAc/hexane) was used to obtain the following compounds as a mixture (0.138 g, 42.7 %, off white solid), ¹ H-NMR (CDCl ₃ ) δ: 4.25 (s, 6H), 7.38 (m, 2H), 7.47 (m, 2H), 8.02- 8.12 (m, 4H), 8.23 (d, IH), 8.26 (IH), 8.47 (dd, IH), 8.50 (dd, IH), 8.73 (s, IH), 8.79 (s, IH), 9.92 (bs, IH), 10.09 (bs, IH). m/z (M+l) 382.11.

Example 21: Synthesis of l-Cyano^-dimethylamino-phthalazine-ό-carboxylic acid (3-trifluoromethyl-phenyl)-amide

A mixture of 4-dimethylamino-l-iodo-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (85 mg, 0.175 mmol), pyridine (3 mL) and CuCN (46 mg, 0.514 mmol) was heated to 85 ⁰ C for 2h and concentrated. Column chromatography (Hexanes/EtOAc) afforded the desired compound (38 mg, 56.7 %) as a yellow solid. ¹ H- NMR (CDCl ₃ ) δ: 3.44 (s, 6H), 7.30-7.34 (m, IH), 7.42 (t, IH), 8.00-8.04 (m, 2H), 8.07 (d, IH), 8.66 (dd, IH), 8.78 (s, IH), 10.26 (bs, IH). m/z (M+l) 386.20. Example 22: Synthesis of φCyano-l-dimethylamino-phthalazine-θ-carboxylic acid (3-trifluoromethyl-phenyl)-amide

A mixture of l-dimethylamino-4-iodo-phthalazine-6-carboxylic acid (3- trifluoromethyl-ρhenyl)-amide (40 mg, 0.082 mmol), pyridine (3 niL) and CuCN (22 mg, 0.247 mmol) was heated to 85 ⁰ C for 2h and concentrated. Column chromatography (Hexanes/EtOAc) afforded the desired compound (14 mg, 44.2 %) as a yellow solid. ¹ H- NMR (CDCl ₃ ) δ: 3.45 (s, 6H), 7.40-7.44 (m, IH), 7.49 (t, IH), 8.01 (d, IH), 8.12 (s, IH), 8.23 (d, IH), 8.31 (s, IH), 8.38 (d, IH), 9.13 (s, IH). m/z (M+ 1) 386.20. Example 23 and 24: Synthesis of 4-chloro-7-(3-trifluoromethyl-benzylamino)- phthalazin-1-ol and 4-chloro-6-(3-trifluoromethyl-benzylamino)-phthalazin-l-ol

l,4-Dihydroxy-6-nitro-phthalazine

A mixture of 4-nitrophthalic anhydride (10.0 g, 51.78 mmol) and IPA (180 mL) was stirred by a mechanical stirrer. Anhydrous hydrazine (2.77 mL, 56.96 mmol) was added dropwise and the reaction heated to 85 ⁰ C for 5h. The reaction was cooled then acidified to pH 3 with cone. HCl. The solids were filtered and washed with IPA to afford the desired compound (7.76 g, 72 %) as a pale yellow solid. l,4-Dichloro-6-nitro-phthalazine

A mixture of 1 ,4-dihydroxy-6-nitro-phthalazine (7.75 g, 37.41 mmol), POCl ₃ (50 mL) and ¹ Pr ₂ EtN (8 mL) was heated to 85 ⁰ C for 3h, then concentrated. The residue was dissolved in CH ₂ Cl ₂ , and poured onto ice water. The solution was filtered through celite. The organic layer of the filtrate was separated, washed with saturated aqueous NaHCO ₃ , 2N HCl, brine and dried (Na ₂ SO ₄ ). Column chromatography (Hexanes/EtOAc) afforded the desired compound (1.26 g, 13.8 %) as a brown coloured solid. l,4-Dichloro-6-amino-phthalazine

A mixture of 1 ,4-dichloro-6-nitro-phthalazine (1.24 g, 5.09 mmol), EtOH (20 mL), saturated aqueous NH ₄ Cl (20 mL) and iron powder (1.42 g, 25.47 mmol) was heated to reflux for 4h then concentrated. The residue was taken up in EtOAc washed with saturated aqueous NaHCO ₃ , brine, dried (Na ₂ SO ₄ ) and concentrated. Column chromatography (Hexanes/EtOAc) afforded the desired product (0.33 g, 30 %) as a pale yellow solid. (l,4-Dichloro-phthalazin-6-yl)-(3-trifluoromethyl-benzyl)-am ine

A mixture of 1 ,4-dichloro-6-amino-phthalazine (33 mg, 0.154 mmol), K ₂ CO ₃ (79 mg, 0.57 mmol), DMF (5 mL) and 3-(trifluoromethyl)benzyl bromide (2.OmL, 0.17 mmol) were heated to 85 ⁰ C for 18h. The reaction was cooled, poured onto water and extracted with EtOAc. The combined organic layers were washed with H ₂ O, brine, dried (Na ₂ SO^ and concentrated. Column chromatography (Hexanes/EtOAc) afforded the desired product (15 mg, 26.3 %) as a yellow solid, m/z 372.08 (M+l). 4-chloro- 7-(3-trifluoromethyl-benzylamino)-phthalazin-l-ol and 4-chloro-6-(3- trifluoromethyl-benzylamino)-phthalazin-l-ol

A mixture of (l,4-Dichloro-phthalazin-6-yl)-(3-trifluoromethyl-benzyl)-am ine (39 mg, 0.105 mmol), 2N NaOH (0.52 mL, 1.05 mmol) and dioxane (3 mL) was heated to 85 ⁰ C for 64 hours. The reaction was diluted with water, acidified with cone. HCl to ~pH 4 and extracted with EtOAc (x3). The combined organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. Chromatography (Hex/EtOAc) afforded 4-chloro-7-(3- trifluoromethyl-benzylamino)-phthalazin-l-ol (13 mg), ¹ H NMR (600 MHz, CDCl ₃ ) δ: 4.36 (d, 2H), 6.25 (t, IH), 7.00 (dd, IH), 7.22 (d, IH), 7.28-7.42 (m, 3H), 7.46 (s, IH), 7.57 (d, IH), 11.49 (s, IH) ppm. m/z 354.08; and 4-chloro-6-(3-trifluoromethyl- benzylamino)-phthalazin-l-ol (8 mg), ¹ H NMR (500 MHz, CDCl ₃ ) δ: 4.36 (d, 2H), 6.28 (t, IH), 6.74 (d, IH), 6.92 (dd, IH), 7.32-7.46 (m, 3H), 7.51 (s, IH), 7.95 (d, IH), 11.60 (s, IH) ppm. m/z 354.08. Example 25: Synthesis of dimethyl-(6-phenylaminomethyl-phthalazin-l-yl)-amine

5-Bromo-3-hydroxy-2,3-dihydro-isoindol-l-one

A mixture of zinc powder (8.68 g, 132.7 mmol), copper (II) sulfate pentahydrate

(0.11 g, 0.44 mmol) and aqueous sodium hydroxide (135 mL, 2M solution) were cooled to 0 ⁰ C. Bromophthalimide (25 g, 110.6 mmol) was added in portions over 30 minutes, maintaining the temperature at 0 ⁰ C. The reaction was stirred at 0 ⁰ C for 30 minutes, and at room temperature for 3 h. The reaction was filtered, neutralized to pH 7 with concentrated HCl, diluted with EtOH, and then extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford the desired compound (15.75 g, 63 %) as a colourless solid.

6-Bromo-2H-phthalazin-l -one

A mixture of 5-bromo-3-hydroxy-2,3-dihydro-isoindol-l-one (15.75 g, 69.06 mmol) and hydrazine hydrate (70 mL, 1439.2 mmol) was heated at 95 ⁰ C for 5 h. The precipitate was filtered, washed with water and the crude material triturated with hot EtOAc to afford the product (7.25 g, 46.6 %) as a yellow solid.

6-Bromo-l-chloro-phthalazine

A mixture of 6-Bromo-2H-phthalazin-l-one (2.5g), phosphorous oxychloride (11 mL) and diisopropyl ethyl amine (2 mL) was stirred at RT for 30 min then at 90 ⁰ C for

3h. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate and washed with a saturated solution OfNaHCO ₃ , NH ₄ Cl, and brine to afford the desired compound (2.0 g). TLC λ/0.8 (EA/hexane 2/3).

(6-Bromo-phthalazin-l-yl)-dimethyl-amine

A solution of 6-bromo-l-chloro-phthalazine (2g) and dimethylamino (8 mL, 2M solution in THF) in DMF (30 mL) was stirred at 85 ⁰ C for 3h. The reaction was then diluted with ethyl acetate (100 mL) and washed with water (2 x 100 mL), and brine (100 mL). Column chromatography (Hexanes/EtOAc) afforded the desired product (1.0 g) as a brown solid. TLC Rf 0.3 (EA). ¹ H-NMR (CDCl ₃ ) δ: 3.21 (s, 6H),7.86 (dd, IH), 7.95 (d,

IH), 7.99 (d, IH), 8.99 (s, IH).

Dimethyl-(6-vinyl-phthalazin-l-yl)-amine A mixture of (6-bromo-phthalazin-l-yl)-dimethyl-amine (0.32 g, 1.27 mmol) and toluene (8 mL) was purged with N ₂ . Pd(PPh ₃ ) ₄ (0.4 g, 0.346 mmol) and tributyl vinyl

stannane (1.11 mL, 3.80 mmol) were added and the reaction heated to 85 ⁰ C for 4 h. The reaction was cooled, filtered through celite and rinsed with CH ₂ Cl ₂ . The organic layers were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated. Column chromatography (Hexanes/EtOAc) afforded the desired product (0.15 g, 59.3 %) as a white solid. l-Dimethylamino-phthalazine-6-carbaldehyde

A mixture of dimethyl-(6-vinyl-phthalazin- 1 -yl)-amine (0.15 g, 0.753 mmol), water (0.1 mL), THF (2.6 mL) and OsO ₄ (catalytic) were stirred at room temperature. Sodium periodate (0.497 g, 2.32 mmol) was added to the reaction in 3 portions and the reaction stirred at room temperature for 14 h. The reaction mixture was diluted with EtOAc, washed with water, aq. Na ₂ S ₂ O ₃ , brine, dried (Na ₂ SO ₄ ) and concentrated. Chromatography (40% Hexanes/EtOAc to 100% EtOAc to 10% MeOH/EtOAc) afforded the product (50 mg, 33.3 %) was a coloured solid. Dimethyl- (6-phenylaminomethyl-phthalazin-l-yl) -amine

A mixture of l-dimethylamino-phthalazine-6-carbaldehyde (25 mg, 0.13 mmol), aniline (14 μL, 0.15 mmol), THF (1 mL) and MgSO ₄ (43 mg, 0.357 mmol) were stirred at room temperature. To this mixture was added acetic acid (8 μL) followed by sodium cyanoboroahydride (13 mg, 0.207 mmol) and the reaction stirred for 15h. The reaction was diluted with CH ₂ Cl ₂ , washed with aq. NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated. Purification by prep. HPLC yielded the desired compound, m/z 279.22 (M+l). Examples 26 and 27: Synthesis of 4-Chloro-l-hydroxy-phthalazine-6-carboxyIic acid (3-trifluoromethyl-phenyl)-amide and 1 -Chloro^-hydroxy-phthalazine-β-carboxylic acid (3-trifluoromethyI-phenyl)-amide

A mixture of l^-dichloro-phthalazine-β-carboxylic acid (3-trifluoromethyl- phenyl)-amide (0.304 mg, 0.787 mmol), 2N NaOH (4 mL, 8.00 mmol) and dioxane (6 mL) was stirred at 45 ⁰ C for 6 h. The reaction mixture was diluted with water, acidified

with cone. HCl to ~pH 4 and extracted with EtOAc (x3). The combined organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to afforded 4-chloro-l-hydroxy- phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.112 g) as a white solid, ¹ H NMR (600 MHz, CDCl ₃ ) δ: 7.33 (d, IH), 7.43 (t, IH), 8.03 (s, IH), 8.06 (d, IH), 8.36 (dd, IH), 8.42 (d, IH), 8.56 (s, IH), 10.28 (s, IH), 11.9 (s, IH) ppm, ¹ H NMR (500 MHz, d ₆ -DMSO) δ: 7.52 (d, IH), 7.65 (t, IH), 8.08 (d, IH), 8.26 (s, IH), 8.43 (d, IH), 8.47 (dd, IH), 8.52 (s, IH), 11.02 (s, IH), 13.02 (s, IH) ppm. m/z 368.13; and 1- chloro^-hydroxy-phthalazine-δ-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.083 g) as a white SoHd ₁ ¹ H NMR (500 MHz, CDCl ₃ ) δ: 7.21 (d, IH), 7.32 (t, IH), 7.92 (d, IH), 7.97 (d, IH), 8.00 (s, IH), 8.38 (d, IH), 8.93 (s, IH), 10.42 (s, IH), 12.20 (s, IH) ppm. m/z 368.13.

Examples 28 and 29: Synthesis of l-chloro^-hydroxy-phthalazine-β-carboxylic acid (4-trifluoromethyl-phenyl) amide and 4-chloro-l-hydroxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-phenyl) amide

A mixture of l,4-dihydroxy-phthalazine-6-carboxylic acid (0.6g, 2.91 mmol) in thionyl chloride (6 mL) was refluxed for 3 hours. Phosphorous oxychloride (6 mL) was added and the reaction refluxed for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (5 mL) and added dropwise to a 0 ⁰ C solution of 4-(trifluoromethyl) aniline (0.54 mL, 4.34 mmol), DMF (5 mL) and NEt ₃ (1.21 mL, 8.68 mmol). The reaction was stirred at 0 ⁰ C for Ih, diluted with water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with water (x3), sat. aq. NH ₄ Cl, brine and dried (Na ₂ SO ₄ ). Column chromatography (Hex/EtOAc) afforded l,4-dichloro-phthalazine-6-carboxylic acid (4-trifluoromethyl) amide (0.22 g). m/z 386.06.

A mixture of 1 ,4-dichloro-phthalazine-6-carboxylic acid (4-trifluoromethyl) amide (0.22 g, 0.57 mmol), 2N NaOH (2.8 mL, 5.70 mmol) and dioxane (10 mL) was

heated to 50 ⁰ C for 16 hours. The reaction was diluted with water, acidified with cone. HCl to ~pH 4 and extracted with EtOAc (x3). The combined organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. Chromatography (Hex/EtOAc) afforded 1- chloro-4-hydroxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-phenyl) amide (7.6 mg) as a white solid, ¹ H NMR (500 MHz, CDCl ₃ ) δ: 7.28 (d, 2H), 7.70 (d, 2H), 7.78 (d, IH), 8.21 (dd, IH), 8.75 (s, IH), 10.40 (s, IH), 12.35 (s, IH) ppm. m/z 368.19; and 4- chloro-l-hydroxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-phenyl) amide (46.86 mg) as a white solid, ¹ H NMR (600 MHz, CDCl ₃ ) δ: 7.42 (d, 2H), 7.80 (d, 2H), 8.22 (dd, IH), 8.29 (d, IH), 8.41 (s, IH), 10.37 (s, IH), 12.37 (s, IH) ppm. m/z 368.06. Examples 30 and 31: Synthesis of l-Chloro^-hydroxy-phthalazine-ό-carboxylic acid phenylamide and 4-ChIoro-l-hydroxy-phthalazine-6-carboxylic acid phenylamide

The experimental procedure for Examples 30 and 31 is analogous to the procedure for Examples 28 and 29. In preparing Examples 30 and 31, aniline rather than 4-(trifluoromethyl) aniline was used to form the desired amide. Accordingly, the following two compounds were obtained, which were separated by HPLC: l-chloro-4- hydroxy-phthalazine-6-carboxylic acid phenylamide (2.13 mg), m/z 300.22; and 4- chloro-l-hydroxy-phthalazine-6-carboxylic acid phenylamide (3.36 mg) ¹ H NMR (500 MHz, CDCl ₃ ) δ: 7.06 (t, IH), 7.25 (d, 2H), 7.59 (d, 2H), 8.24 (dd, IH), 8.35 (d, IH), 8.46 (s, IH) ppm. m/z 300.28.

Examples 32 and 33: Synthesis of l-chloro^-hydroxy-phthalazine-ό-carboxylic acid (2-methyl-3-trifluoromethyl-phenyl) amide and 4-chloro-l-hydroxy-phthalazine-6- carboxylic acid (2-methyl-3-trifiuoromethyl-phenyl) amide

The experimental procedure for Examples 32 and 33 is analogous to the procedure for Examples 28 and 29. In preparing Examples 32 and 33, 2-methyl-3- (trifluoromethyl) aniline rather than 4-(trifluoromethyl) aniline was used to form the desired amide. Accordingly, the following two compounds were obtained: l-chloro-4- hydroxy-phthalazine-6-carboxylic acid (2-methyl-3-trifluoromethyl -phenyl) amide (17 mg), ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.30 (s, 3H), 7.21 (t, IH), 7.44 (d, IH), 7.53 (d, IH), 7.97 (d, IH), 8.41 (dd, IH), 8.94 (s, IH), 9.84 (s, IH), 12.15 (s, IH) ppm. m/z 382.04; and 4-chloro-l-hydroxy-phthalazine-6-carboxylic acid (2-methyl-3-trifluoromethyl- phenyl) amide (50 mg), m/z 382.04.

Examples 34 and 35: Synthesis of l-chloro-^-hydroxy-phthalazine-β-carboxylic acid (2,5-difluoro-phenyl) amide and 4-chloro-l-hydroxy-phthalazine-6-carboxylic acid (2,5-difluoro-phenyl) amide

The experimental procedure for Examples 34 and 35 is analogous to the procedure for Examples 28 and 29. In preparing Examples 34 and 35, 2,5-difluoroaniline rather than 4-(trifluoromethyl) aniline was used to form the desired amide. Accordingly, the following two compounds were obtained: l-chloro-4-hydroxy-phthalazine-6- carboxylic acid (2,5-difluoro-phenyl) amide (9 mg), ¹ H NMR (500 MHz, CDCl ₃ ) δ: 6.70- 6.76 (m, IH), 6.94-7.01 (m, IH), 7.76-7.82 (m, IH), 7.96 (d, IH), 8.35 (dd, IH), 8.83 (s, IH), 9.75 (s, IH), 12.34 (s, IH) ppm. m/z 336.08; and 4-chloro-l-hydroxy-phthalazine-6- carboxylic acid (2,5-difluoro-phenyl -phenyl) amide (9 mg), ¹ H NMR (500 MHz, CDCl ₃ ) δ: 6.70-6.76 (m, IH), 6.94-67.02 (m, IH), 7.75-7.82 (m, IH), 8.23 (dd, IH), 8.35 (d, IH), 8.43 (s, IH), 9.60 (s, IH), 12.36 (s, IH) ppm. m/z 336.15.

Examples 36 and 37: Synthesis of l-chloro-4-hydroxy-phthalazine-6-carboxylic acid (2-fluoro-5-trifluoromethyl-phenyl) amide and 4-chloro-l-hydroxy-phthalazine-6- carboxylic acid (2-fluoro-5-trifluoromethyl -phenyl) amide

The experimental procedure for Examples 36 and 37 is analogous to the procedure for Examples 28 and 29. In preparing Examples 36 and 37, 2-fluoro-5- (trifluoromethyl) aniline rather than 4-(trifluoromethyl) aniline was used to form the desired amide. Accordingly, the following two compounds were obtained: l-chloro-4- hydroxy-phthalazine-6-carboxylic acid (2-fiuoro-5-trifluoromethyl-phenyl) amide (18 mg), ¹ H NMR (500 MHz, CDCl ₃ ) δ: 7.18 (t, IH), 7.32-7.37 (m, IH), 8.00 (d, IH), 8.28 (d, IH), 8.41 (dd, IH), 8.90 (s, IH), 9.81 (s, IH), 12.27 (s, IH) ppm. m/z 386.06; and 4- chloro-l-hydroxy-phthalazine-6-carboxylic acid (2-fluoro-5-trifluoromethyl -phenyl) amide (11 mg) ¹ H NMR (500 MHz, CDCl ₃ ) δ: 7.24 (t, IH), 7.39-7.44 (m, IH), 8.32 (dd, IH), 8.41 (d, IH), 8.46 (d, IH), 8.54 (s, IH), 9.60 (s, IH), 12.10 (s, IH) ppm. m/z 386.06. Examples 38 and 39: Synthesis of l-chloro^-hydroxy-phthalazine-ό-carboxylic acid (2-fluoro-5-methyl-phenyl) amide and 4-chloro-l-hydroxy-phthalazine-6-carboxylic acid (2-fluoro-5-methyl -phenyl) amide

The experimental procedure for Examples 38 and 39 is analogous to the procedure for Examples 28 and 29. In preparing Examples 38 and 39, 2-fluoro-5- methylaniline rather than 4-(trifluoromethyl) aniline was used to form the desired amide. Accordingly, the following two compounds were obtained: l-chloro-4-hydroxy- phthalazine-6-carboxylic acid (2-fluoro-5-methyl-phenyl) amide (8mg), ¹ H NMR (500 MHz, CDCl ₃ ) δ: 2.22 (s, 3H), 6.80-6.85 (m, IH), 6.88-6.92 (m, IH), 7.73 (d, IH), 7.96 (d, IH), 8.37 (dd, IH), 8.83 (d, IH), 9.28 (s, IH), 12.30 (s, IH) ppm. m/z 332.05; and 4- chloro-l-hydroxy-phthalazine-6-carboxylic acid (2-fiuoro-5-methyl -phenyl) amide (15 mg) ¹ H NMR (500 MHz, CDCl ₃ ) δ: 2.41 (s, 3H), 6.95-7.00 (m, IH), 7.05-7.10 (m, IH), 8.11 (s, IH), 8.26-8.33 (m, 2H), 8.53 (s, IH), 8.60 (d, IH), 9.92 (s, IH) ppm. m/z 332.05.

Example 40: Synthesis of 4-Chloro-l-hydroxy-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide sodium salt

A mixture of 4-chloro-l-hydroxy-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (38 mg, 0.103 mmol) and THF was stirred at room temperature. 60 % NaH (4 mg, 0.172 mmol) was added and the reaction stirred for 30 minutes (solids appeared). The reaction was concentrated to afford 4-chloro-l-hydroxy- phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide sodium salt (39 mg), ¹ H NMR (500 MHz, d _ό -DMSO) δ: 7.45 (d, IH), 7.60 (t, IH), 8.06 (d, IH), 8.26 (s, IH), 8.29 (d, IH), 8.35 (dd, IH), 8.42 (s, IH), 11.75 (bs, IH) ppm.

Example 41 and 42: Synthesis of l-Iodo^-hydroxy-phthalazine-ό-carboxylic acid (3- trifluoromethyl-phenyl)-amide and 4-Iodo-l-hydroxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide

A mixture of 1 ^-di-iodo-phthalazine-ό-carboxylic acid (3-trifluoromethyl- phenyl)-amide (0.15 g, 0.264 mmol), 2N NaOH (1.32 mL, 2.64 mmol) and dioxane (3 mL) was stirred at 50 ⁰ C for 16 h. The reaction mixture was diluted with water, acidified with cone. HCl to ~ pH 4 and extracted with EtOAc (x3). The combined organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to afford l-iodo-4-hydroxy- phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (27 mg), ¹ H NMR (600 MHz, CDCl ₃ ) δ: 7.20 (d, IH), 7.31 (t, IH), 7.72 (d, IH), 7.96 (d, IH), 8.00 (s, IH), 8.33 (dd, IH), 8.86 (s, IH), 10.40 (s, IH), 12.39 (s, IH) ppm. m/z 460.07; and 4-iodo-l- hydroxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (27 mg), ¹ H

NMR (500 MHz, CDCl ₃ ) δ: 7.27 (d, IH), 7.38 (t, IH), 8.00 (m, 2H), 8.24 (m, 2H), 8.30

(d, IH), 10.32 (s, IH), 12.34 (s, IH) ppm. m/z 460.07.

Example 43: Synthesis of l-Hydroxy-phthalazine-ό-carboxylic acid (3- trifluoromethyl-phenyl)-amide

A mixture of 4-chloro- 1 -hydroxy-phthalazine-ό-carboxylic acid (3- trifluoromethyl-phenyl)-amide (64 mg, 0.174 mmol) (example 25), MeOH (3 niL) and 10% wet Pd/C (catalytic) was evacuated and flushed (3x) with hydrogen. The mixture was stirred under hydrogen for 16 h. The mixture was filtered through celite, rinsed with MeOH and concentrated under vacuum. Chromatography (Hex/EtOAc) was used to obtain l-hydroxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (20 mg) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.35 (d, IH), 7.45 (t, IH), 8.03 (s, IH), 8.08 (d, IH), 8.19 (s, IH), 8.30-8.37 (m, 2H), 8.44 (d, IH), 10.05 (s, IH), 11.26 (s, IH) ppm. m/z 334.10. Example 44: Synthesis of l-hydroxy^-phenyl-phthalazine-ό-carboxylic acid (3- trifluoromethyl-phenyl)-amide

l-iodo-^methoxy-phthalazine-ό-carboxylic acid (3-trifluoromethyl-phenyl)-amide and 4- iodo-l-methoxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide A mixture of 1 ^-di-iodo-phthalazine-ό-carboxylic acid (3-trifluoromethyl- phenyl)-amide (0.59 g, 1.037 mmol), sodium methoxide (0.11 g, 2.036 mmol) in DMF (8 mL) was stirred at room temperature for 18 hours. The reaction was poured onto water, neutralized with 2N HCl. The product was extracted with EtOAc (x3), the combined organic extracts washed with water (x3), brine and dried (Na ₂ SO ₄ ). Chromatography

(Hex/EtOAc) afforded l-iodo-4-methoxy-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (134 mg), m/z 473.91; and 4-iodo-l-methoxy-phthalazine- 6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (132 mg), m/z 473.91. 1 -methoxy-^phenyl-phthalazine-ό-carboxylic acid (3-trifluoromethyl-phenyl)-amide A mixture of 4-iodo- 1 -methoxy-phthalazine-ό-carboxylic acid (3-trifluoromethyl- phenyl)-amide (0.123 g, 0.26 mmol), K ₂ CO ₃ (0.072g, 0.52 mmol), water (0.5 mL), toluene (3 mL), methanol (3 mL), phenylboronic acid (0.035 g, 0.286 mmol), Pd(PPh ₃ ) ₄ (0.09 g, 0.078 mmol) was heated to 65 ⁰ C for 1 hour. The reaction was cooled, filtered through celite, rinsed with methanol and concentrated. The residue was taken up in EtOAc, washed with sat. aq. NaHCO ₃ and dried (Na ₂ SO ₄ ). Chromatography (Hex/EtOAc) afforded l-methoxy-4-phenyl-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (89 mg), m/z 424.05. l-hydroxy^-phenyl-phthalazine-ό-carboxylic acid (3-trifluoromethyl-phenyl)-amide A mixture of l-methoxy-4-phenyl-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (80 mg, 0.189 mmol), dioxane (2 mL) and 48 % HBr (4 mL) was stirred at 40 ⁰ C for 48 hours. Concentration followed by chromatography (Hex/EtOAc) afforded l-hydroxy-4-phenyl-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (12 mg) as a white solid, ¹ H (500 MHz, CDCl ₃ , 55 ⁰ C) δ: 7.47 (d, IH), 7.52 (t, IH), 7.56-7.65 (m, 5H), 7.84 (d, IH), 7.90-7.96 (m, 2H), 8.21 (d, IH), 8.29 (s, IH), 8.65 (d, IH), 10.40 (s, IH) ppm. m/z 410.00.

Example 45: Synthesis of l-hydroxy-4-pyridin-2-yl-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide

l-methoxy-4-pyridin-2-yl-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)' amide

A mixture of 4-iodo- l-methoxy-phthalazine-δ-carboxylic acid (3-trifiuoromethyl- phenyl)-amide (0.128 g, 0.27 mmol), K ₂ CO ₃ (0.075 g, 0.54 mmol), water (0.5 mL), toluene (3 mL), methanol (3 mL), 3-pyridineboronic acid (0.04 g, 0.325 mmol),

Pd(PPh ₃ ) ₄ (0.094 g, 0.081 mmol) was heated to 65 ⁰ C for 2 hour. The reaction was cooled, filtered through celite, rinsed with methanol and concentrated. The residue was taken up in EtOAc, washed with sat. aq. NaHCO ₃ and dried (Na ₂ SO ₄ ). Column chromatography (Hex/EtOAc) afforded l-methoxy-4-pyridin-2-yl-phthalazine-6- carboxylic acid (3-trifluoromethyl-phenyl)-amide (57 mg), m/z 425.01

1 -hydroxy^-pyridin^-yl-phthalazine-ό-carboxylic acid (3-trtfluoromethyl-phenyl)-amide

A mixture of l-methoxy-4-pyridin-2-yl-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (57 mg, 0.134 mmol), dioxane (3 mL) and 48 % HBr (4 mL) was stirred at 40 ⁰ C for 1.5 hours. Concentration followed by chromatography (Hex/EtOAc) afforded l-hydroxy-4-pyridin-2-yl-phthalazine-6-carboxylic acid (3- trifluoromethyl-phenyl)-amide (56 mg) as a white solid, ¹ H NMR (400 MHz, 4: 1 CDC^d ₆ -DMSO) δ: 7.27 (d, IH), 7.36-7.44 (m, 2H), 7.90-7.95 (m, 2H), 8.05 (s, IH), 8.21 (s, IH), 8.33 (dd, IH), 8.47 (d, IH), 8.65 (dd, IH), 8.81 (d, IH), 10.50 (s, IH), 12.80 (s, IH) ppm. m/z 410.96. Example 46 and 47: Synthesis of 4-hydroxy-l-methoxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-pyridin-2-yl)-amide and l-hydroxy-4-methoxy-phthalazine- 6-carboxylic acid (4-trifluoromethyl-pyridin-2-yl)-amide

1, ^dichloro-phthalazine-ό-carboxylic acid (4-trifluoromethyl-pyridin-2-yl)-amide

A mixture of l,4-dihydroxy-phthalazine-6-carboxylic acid (1.429 g, 6.931 mmol) in thionyl chloride (13 mL) was refluxed for 3 hours. Phosphorous oxychloride (13 mL) was added and the reaction refluxed for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (7 mL) and added dropwise to a 0 ⁰ C solution of 2-amino-4-(trifluoromethyl) pyridine (1.35 g, 7.00 mmol), DMF (4 mL) and NEt ₃ (2.9 mL, 21.0 mmol). The reaction was stirred at 0 ⁰ C for Ih, diluted with water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed

with water (x3), sat. aq. NH ₄ Cl, brine and dried (Na ₂ SO ₄ ). Column chromatography (Hex/EtOAc) afforded l^-dichloro-phthalazine-ό-carboxylic acid (4-trifiuoromethyl- pyridin-2-yl) amide (0.487 g, 18.1 %). m/z 386.95.

1, 4-dimethoxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-pyridin-2-yl)-amide A mixture of 1 ^-dichloro-phthalazine-ό-carboxylic acid (4-trifluoromethyl- pyridin-2-yl) amide (0.487 g, 1.258 mmol), NaOMe (0.333 g, 6.164 mmol) and DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was poured onto water, neutralized with 2N HCl and extracted into EtOAc (x3). The combined organic layer was washed with water, brine and dried (Na ₂ SO ₄ ). Chromatography (Hex/EtOAc) afforded l,4-dimethoxy-phthalazine-6-carboxylic acid (4-trifiuoromethyl-pyridin-2-yl)- amide (0.24 g), m/z (M+ 1) 379.11.

4-hydroxy-l-methoxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-pyridin-2-yl)- amide and l-hydroxy^-methoxy-phthalazine-ό-carboxylic acid (4-trifluoromethyl- pyridin-2-yl)-amide A mixture of 1 ^-dimethoxy-phthalazine-ό-carboxylic acid (4-trifluoromethyl- pyridin-2-yl)-amide (0.24 g, 0.634 mmol), dioxane (3 mL) and 48 % HBr (0.1 mL) was stirred at room temperature for 18 hours. The reaction was poured onto water, neutralized with 2N NaOH and extracted with EtOAc. The combined organic layers were washed with water, brine and dried (Na ₂ SO ₄ ). Chromatography (Hex/EtOAc) afforded 4-hydroxy- 1 -methoxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-pyridm- 2-yl)-amide (5 mg), m/z (M+l) 379.11; and l-hydroxy-4-methoxy-phthalazine-6- carboxylic acid (4-trifluoromethyl-pyridin-2-yl)-amide (16 mg), ¹ H NMR (600 MHz, CDCl ₃ ) δ: 3.94 (s, 3H), 7.26 (d, IH), 8.29 (dd, IH), 8.41 (d, IH), 8.46 (d, IH), 8.50 (s, IH), 8.62 (s, IH), 9.75 (s, IH), 10.53 (s, IH) ppm. m/z 364.95. Example 48 and 49: Synthesis of 6-{[(2,4-Dichlorophenyl)methyl]amino}-4-chIoro- IH-phthalazin-l-one and T-IKZ^-dichloropheny^methyllaminoJ^-chloro-lH- phthalazin-1-one

6-Bromo-2,3-dihydro-phthalazine-l,4-dione

A mixture of 5-Bromo-isobenzofuran-l,3-dione (6.Og, 26.4mmol) and hydrazine hydrate (1.5ImL, 32.4mmol) in isopropanol (12OmL) was heated at reflux for 4h. The mixture was allowed to cool and the precipitate was filtered and washed with water (50 mL). The filter cake was dried to afford the title compound (4.6g, 72.3%) as a white solid. m/z (M+l) = 241.05 Bromo-4-chloro-2H-phthalazin-l -one and 7-Bromo-4-chloro-2H-phthalazin-l-one

A mixture of 6-Bromo-2,3-dihydro-phthalazine-l,4-dione (4.6g, 19.1 mmol) in SOCl ₂ (50 mL) and POCl ₃ (50 mL) was heated at reflux for 4h. The mixture was allowed to cool and concentrated. The residue was taken up in EtOAc (100 mL) and neutralize with sodium bicarbonate. The layers were separated and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in dioxane (20OmL) and 2N NaOH (96mL, 191 mmol). The mixture was heated at 40 ⁰ C for 2.5h then allowed to cool and concentrated. The residue was triturated with EtOAc (300 mL) and water (200 mL) and the solids were filtered. The organic phase was dried over anhydrous sodium sulfate and concentrated to yield the title compounds (2.3g, 46%); m/z (M+l) = 259.32.

6-{[(2,4-Dichlorophenyl)methyl]amino}-4-chloro-2H-phthalazin -l-one and 7 -{[(2,4- dichlorophenyl)methyl]amino}-4-chloro-2H-phthalazin-l-one A mixture ό-Bromo^-chloro^H-phthalazin- 1 -one and 7-Bromo-4-chloro-2H- phthalazin-1-one (150mg, 0.58 mmol), (2,4-dichlorophenyl)methylamine (0.10OmL, 0.75 mmol), Pd ₂ (dba) ₃ (53mg, 0.058 mmol), rac-BINAP (108mg, 0.17 mmol) and NaO^-Bu (164mg, 1.74 mmol) in DMA (12mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated.

Chromatography on silica (EtOAc/hexanes) yielded the title compounds. 6- {[(2,4- Dichlorophenyl)methyl]amino}-4-chloro-2H-phthalazin-l-one: 33 mg (18.0%): m/z (M+η)=354. ¹ H-NMR (DMSO-^ ₅ ) δ: 12.4 (s,lH), 7.96 (d,lH), 7.68 (m,2H), 7.42 (d, 2H),7.15 (dd,lH), 6.81 (s,lH), 4.51 (d,2H). 7-{[(2,4-Dichlorophenyl)methyl]amino}-4- chloro-2H-phthalazin-l-one: 16 mg (8.7%): m/z (M+η)=354. ¹ H-NMR (DMSO-J ₆ ) δ:

12.45 (s,lH), 7.72 (d,lH), 7.66 (m,2H), 7.41 (dd,lH), 7.36 (m,lH). 7.27 (dd,lH), 7.13

(s, IH), 4.49 (d,2H).

Example 50 and 51: Synthesis of 6-{[(4-Chlorophenyl)methyl]amino}-4-chloro-2H ^r - phthalazin-1-one and 7- { [(4-Chlorophenyl)methyl] amino}-4-chloro-2H-phthalazin-

1-one

A mixture 6-bromo-4-chloro-2H-phthalazin- 1 -one and 7-Bromo-4-chloro-2H- phthalazin-1-one (150mg, 0.58 mmol), (4-chlorophenyl)methylamine (0.092mL, 0.75 mmol), Pd ₂ (dba) ₃ (53mg, 0.058 mmol), rac-BINAP (108mg, 0.17 mmol) and NaOf-Bu (164mg, 1.74 mmol) in DMA (12mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compounds. 6-{[(4- Chlorophenyl)methyl]amino}-4-chloro-2H-phthalazin-l-one: 38 mg (20.5%): m/z (M+η)=320. ¹ H-NMR (DMSO-Js) δ: 12.36 (s,lH), 7.94 (d,lH), 7.68 (m,lH), 7.41 (m, 4H), 7.15 (dd,lH), 6.81 (s,lH),4.44 (d,2H); and 7-{[(4-Chlorophenyl)methyl]amino}-4- chloro-2H-phthalazin-l-one: 21 mg (11.3%): m/z (M+η)=320. ¹ H-NMR (DMSO-J ₆ ) δ: 12.4 (s,lH), 7.68 (m,2H), 7.39 (m,4H), 7.26 (dd,lH), 7.25 (s,lH), 4.45 (d,2H). Example 52 and 53: Synthesis of 6-{ [(3-Methoxyphenyl) methyl] amino}-4-chloro-2H- phthalazin-1-one and 7-{[(3-Methoxyphenyl)methyl]amino}-4-chloro-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one and 7-Bromo-4-chloro-2H- phthalazin-1-one (150mg, 0.58 mmol), (3-methoxyphenyl)methylamine (0.097mL, 0.75 mmol), Pd ₂ (dba) ₃ (53mg, 0.058 mmol), rac-BINAP (108mg, 0.17 mmol) and NaOf-Bu

(164mg, 1.74 mmol) in DMA (12mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compounds. 6-{[(3- Methoxyphenyl)methyl]amino}-4-chloro-2H-phthalazin-l-one: 46 mg (25.1%): m/z (M+η)=316. ¹ H-NMR (DMSO-J ₆ ) δ: 12.34 (s,lH), 7.93 (d, IH), 7.65 (m,lH), 7.26 (m,lH), 7.16 (dd,lH), 6.96 (m,2H), 6.83 (m,2H), 4.40 (d,2H), 3.73 (s,3H); and 7-{[(3- Methoxyphenyl)methyl]amino}-4-chloro-2H-phthalazin-l-one: 21 mg (11.5%): m/z (M+η)=316. ¹ H-NMR (DMSO-J ₆ ) δ:12.40 (s,lH), 7.69 (d,lH), 7.64 (m,lH), 7.26 (m,2H), 7.18 (s,lH), 6.94 (m,2H), 6.82 (dd,lH), 4.42 (d,2H), 3.72 (s,3H).

Example 54 and 55: Synthesis of 6-{[(3,4-Difluorophenyl)methyl]amino}-4-chIoro- 2H-phthalazin-l-one and 7-{[(3,4-Difluorophenyl)methyl]amino}-4-chloro-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one and 7-Bromo-4-chloro-2H- phthalazin-1-one (150mg, 0.58 mmol), (2,4-dichlorophenyl)methylamine (0.10OmL, 0.75 mmol), Pd ₂ (dba) ₃ (53mg, 0.058 mmol), rac-BINAP (108mg, 0.17 mmol) and NaO^-Bu (164mg, 1.74 mmol) in DMA (12mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated.

Chromatography on silica (EtOAc/hexanes) yielded the title compounds. 6- {[(3 ,4- Difluorophenyl)methyl]amino}-4-chloro-2H-phthalazin-l-one: 37 mg (19.8%): m/z (M+η)=322. ¹ H-NMR (DMSO-J ₆ ) δ: 12.38 (s,lH), 7.95 (d,lH),7.66 (m,lH), 7.42 (m, 2H), 7.24 (m,lH), 7.16 (dd,lH) 6.82 (s,lH), 4.44 (d,2H); and 7- {[(3 ,4-Di fluorophenyl) methyl]amino} -4-chloro-2H-phthalazin- 1 -one: 27 mg (14.5%): m/z (M+η)=322. ¹ H- NMR (DMSO-J ₆ ) δ: 12.41 (s,lH), 7.70 (d,lH), 7.65 (m,lH), 7.41 (m,2H), 7.27 (dd,lH), 7.21 (m,lH), 7.16 (s,lH), 4.45 (d,2H).

Example 56 and 57: Synthesis of 6-{[(3-Methylphenyl)methyl]amino}-4-chloro-2H- phthalazin-1-one and 7-{[(3-Methylphenyl)methyl]amino}-4-chloro-2H-phthalazin-

1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one and 7-Bromo-4-chloro-2H- phthalazin-1-one (150mg, 0.58 mmol), (3-methylphenyl)methylamine (0.094mL, 0.75 mmol), Pd ₂ (dba) ₃ (53mg, 0.058 mmol), rac-BINAP (108mg, 0.17 mmol) and NaO^-Bu (164mg, 1.74 mmol) in DMA (12mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compounds. 6- {[(3- Methylphenyl)methyl]amino}-4-chloro-2H-phthalazin-l-one: 23 mg (13.2%): m/z (M+η)=300. ¹ H-NMR (DMSO-J ₆ ) δ: 12.34 (s,lH), 7.92 (d,lH), 7.64 (m,lH), 7.20 (m,5H), 6.84 (s,lH), 4.40 (d,2H), 2.90 (s, 3H); and 7-{[(3-Methylphenyl)methyl]amino}- 4-chloro-2H-phthalazin-l-one: 35 mg (20.1%): m/z (M+η)=300. ¹ H-NMR δ: 12.40 (s,lH), 7.68 (d,lH), 7.62 (m,lH), 7.26 (dd,lH), 7.20 (m,4H), 7.06 (m,lH), 4.40 (d,2H), 2.28 (s,3H).

Example 58 and 59: Synthesis of 6-{[(2-Methoxyphenyl)methyl]amino}-4-chIoro-2H- phthalazin-1-one and 7-{ [(2-Methoxyphenyl)methyl] amino}-4-chloro-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one and 7-Bromo-4-chloro-2H- phthalazin-1-one (150mg, 0.58 mmol), (2-methoxyphenyl)methylamine (0.097mL, 0.75 mmol), Pd ₂ (dba) ₃ (53mg, 0.058 mmol), rac-BINAP (108mg, 0.17 mmol) and NaO^-Bu (164mg, 1.74 mmol) in DMA (12mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The

organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compounds. 6-{[(2- Methoxyphenyl)methyl]amino}-4-chloro-2H-phthalazin-l-one: 26 mg (14.2%): m/z (M+η)=316. ¹ H-NMR (DMSO-J ₆ ) δ: 12.24 (s,lH), 7.92 (dd,lH), 7.52 (m,lH), 7.26 (m,2H), 7.14 (dd,lH), 7.04 (d,lH), 6.91 (m,lH), 6.83 (s,lH), 4.37 (d,2H), 3.86 (s,3H); and 7-{[(2-Methoxyphenyl)methyl]amino}-4-chloro-2H-phthalazin-l- one: 35 mg (19.1%): m/z (M+η)=316. ¹ H-NMR (DMSO-J ₁₅ ) δ: 12.40 (s,lH), 7.68 (d,lH), 7.50 (m,lH), 7.26 (m,2H), 7.20 (dd,lH), 7.14 (s,lH), 7.04 (d,lH), 6.89 (m,lH), 4.39 (d,2H), 3.86 (s,3H). Example 60: Synthesis of 6-(4-Methoxy-benzylamino)-2H-phthalazin-l-one

A mixture of 6-bromo-2H-phthalazin- 1 -one (50mg, 0.22 mmol), 4- methoxybenzylamine (0.03OmL, 0.24 mmol), Pd ₂ (dba) ₃ (20mg, 0.022 mmol), rac-BINAP (41mg, 0.066 mmol) and NaOt-Bu (52mg, 0.55 mmol) in toluene (1OmL) was heated at reflux for 3h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with NaHCO ₃ (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound (22mg, 35%). ¹ H-NMR (DMSO-J ₆ ) δ: 12.1 (s, IH), 8.05 (s, IH), 7.88 (d, IH), 7.30 (m, 3H), 7.10 (dd, IH), 6.90 (d, 2H), 6.75 (s, IH), 4.20 (d, 2H), 3.85 (s, 3H); m/z (M+l) = 282.22. Example 61 and 62: Synthesis of 6-Benzylamino-4-chIoro-2H-phthalazin-l-one and

7-Benzylamino-4-chloro-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one and 7-bromo-4-chloro-2H- phthalazin-1-one (lOOmg, 0.39 mmol), benzylamine (O.O55mL, 0.50 mmol), Pd ₂ (dba) ₃ (36mg, 0.039 mmol), rac-BINAP (73mg, 0.12 mmol) and NaOt-Bu (1 lOmg, 1.17 mmol)

in toluene (1OmL) was heated at reflux for 3h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with NaHCO ₃ (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compounds. 6-Benzylamino-4-chloro-2H-phthalazin- 1-one. ¹ H-NMR (DMSO-J ₆ ) δ: 12.32 (s, IH), 7.90 (d, IH), 7.65 (t, IH), 7.35 (m, 4H), 7.24 (m, IH), 7.14 (dd, IH), 6.81 (s, IH), 4.41 (d, 2H); 7-Benzylamino-4-chloro-2H- phthalazin-1-one. ¹ H-NMR (DMSO-d ₆ ) δ: 12.38 (s, IH), 7.65 (m, 2H), 7.32 (m, 4H), 7.23 (m, 2H), 7.25 (m, IH), 3.91 (d, 2H).

Example 63 and 64: Synthesis of 4-Chloro-6-(3-trifluoromethyl-phenylamino)-2H- phthalazin-1-one and 4-ChIoro-7-(3-trifluoromethyl-phenylamino)-2H-phthalazin-l - one

A mixture 6-bromo-4-chloro-2H-phthalazin- 1 -one and 7-bromo-4-chloro-2H- phthalazin-1-one (200mg, 0.77 mmol), 3-trifluoromethylaniline (0.14mL, 1.16 mmol), Pd ₂ (dba) ₃ (7 lmg, 0.077 mmol), rac-BINAP (144mg, 0.23 mmol) and NaOt-Bu (217mg, 2.31 mmol) in DMF (1OmL) was heated at 8O ⁰ C for 2h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with NaHCO ₃ (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compounds. 4-Chloro-6-(3-trifluoromethyl- phenylamino)-2H-phthalazin-l-one: ¹ H-NMR (DMSO-J ₆ ) δ: 12.56 (s, IH), 9.49 (s, IH), 8.10 (d, IH), 7.54 (m, 4H), 7.42 (d, IH), 7.36 (m, IH); m/z (M+ 1) = 340.10; and 4- Chloro-7-(3-trifluoromethyl-phenylamino)-2H-phthalazin-l-one : ¹ H-NMR (DMSO-J ₆ ) δ: 12.61 (s, IH), 9.47 (s, IH), 7.86 (d, IH), 7.75 (d, IH), 7.60 (m, 3H), 7.47 (s, IH), 7.36 (d, IH); m/z (M+ 1) 340.10. Example 65 and 66: Synthesis of 4-Chloro-6-phenethylamino-2 _J H-phthalazin-l-one and 4-Chloro-7-phenethylamino-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one and 7-bromo-4-chloro-2H- phthalazin-1-one (200mg, 0.77 mmol), phenethylamine (0.14mL, 1.16 mmol), Pd ₂ (dba) ₃ (71mg, 0.077 mmol), rac-BINAP (144mg, 0.23 mmol) and NaO^-Bu (217mg, 2.31 mmol) in DMF (1OmL) was heated at 80 ⁰ C for 2h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with NaHCO ₃ (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compounds. 4-Chloro-6-phenethylamino-2H- phthalazin-1-one: ¹ H-NMR (DMSO-J ₆ ) δ: 12.33 (s, 1η), 7.91 (d, 1η), 7.25 (s, 4η), 7.15 (m, 3H), 6.78 (s, IH), 3.40 (q, 2H), 2.88 (t, 2H); m/z (M+ 1) = 300.15; and 4-Chloro-7- phenethylamino-2H-phthalazin-l-one: ¹ H-NMR (DMSO-J ₆ ) δ: 12.40 (s, IH), 7.67 (d, IH), 7.20 (m, 8H), 3.41 (q, 2H), 2.87 (t, 2H); m/z (M+ 1) = 300.15. Example 67 and 68: Synthesis of 4-[(4-Chloro-l-oxo-l,2-dihydro-phthaIazin-6- ylamino)-methyl]-iV-(2-pyrrolidin-l-yl-ethyl)-benzamide and 4-[(l-Chloro-4-oxo-

3,4-dihydro-phthalazin-6-ylamino)-methyl]-N-(2-pyrrolidin -l-yl-ethyl)-benzamide

[4-(2-Pyrrolidin-l-yl-ethylcarbamoyl)-ben∑ylJ-carbamic acid tert-butyl ester

A mixture of 4-(tert-Butoxycarbonylamino-methyl)-benzoic acid (500mg, 1.99 mmol), 2-Pyrrolidin-l-yl-ethylamine (0.28mL, 2.19 mmol), EDC (459mg, 2.39 mmol), HOBt (323mg, 2.39mmol) and triethylamine (0.4OmL, 2.99 mmol) in DMF (1OmL) was stirred at ambient temperature for 15h. The mixture was diluted with EtOAc (25 mL) and washed with water (25 mL) and NaHCO ₃ (25mL). The aqueous mixture was extracted with EtOAc (2 x 25mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to yield the title compound (421mg, 61%). m/z (M+l) 348.23.

[3-(2-Pyrrolidin-l -yl-ethylcarbamoyl) -benzyl] -carbamic acid tert-butyl ester

A mixture of 3-(tert-Butoxycarbonylamino-methyl)-benzoic acid (500mg, 1.99 mmol), 2-Pyrrolidin-l-yl-ethylamine (0.28mL, 2.19 mmol), EDC (459mg, 2.39 mmol), HOBt (323mg, 2.39mmol) and triethylamine (0.4OmL, 2.99 mmol) in DMF (1OmL) was stirred at ambient temperature for 15h. The mixture was diluted with EtOAc (25 mL) and washed with water (25 mL) and NaHCO ₃ (25mL). The aqueous mixture was extracted with EtOAc (2 x 25mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to yield the title compound (403mg, 58%). m/z (M+l) 348.21. 4-Aminomethyl-N-(2-pyrrolidin-l-yl-ethyl)-benzamide dihydrochloride

To a solution of [4-(2-Pyrrolidin-l-yl-ethylcarbamoyl)-benzyl] -carbamic acid tert-butyl ester (400mg, 1.15mmol) in MeOH (3OmL) was added 6M HCl in IPA (25mL). The mixture was stirred at ambient temperature for 5h. After this time a precipitate had formed and was filtered and dried to yield the title compound, m/z (M+l) 248.34. 4-[(4-Chloro-l -oxo-1 ,2-dihydro-phthalazin-6-ylamino)-methyl] -N-(2-pyrrolidin-l-yl- ethyl)-benzamide and 4-[(l-Chloro-4-oxo-3, 4-dihydro-phthalazin-6-ylamino)-methyl]-N- (2-pyrrolidin-l-yl-ethyl)-benzamide

A mixture 6-Bromo-4-chloro-2H-phthalazin-l-one and 7-Bromo-4-chloro-2H- phthalazin-1-one (200mg, 0.77 mmol), 4-Aminomethyl-N-(2-pyrrolidin-l-yl-ethyl)- benzamide dihydrochloride (319mg, 1.00 mmol), Pd ₂ (dba) ₃ (71mg, 0.077 mmol), rac- BIνAP (144mg, 0.23 mmol) and NaOt-Bu (217mg, 2.31 mmol) in DMF (1OmL) was heated at 80 ⁰ C for 2h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with NaHCO ₃ (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (MeOH/EtOAc) yielded the title compounds as a mixture of two regioisomers. ¹ H-NMR (DMSO-J^) δ: 12.40 (bs, 2H), 3.38 (m, 2H), 7.92 (d, IH), 7.80 (m, 4H), 7.68 (m, 3H), 7.41 (m, 4H), 7.25 (dd, IH), 7.15 (m, 2H), 6.80 (s, IH), 4.50 (t, 4H), 3.35 (q, 4H), 2.55 (t, 4H), 2.45 (m, 8H), 1.65 (m, 8H); m/z (M+l) 426.03. Example 69 and 70: Synthesis of 3-[(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6- ylamino)-methyl]-iV-(2-pyrrolidin-l-yl-ethyl)-benzamide and 3-[(l-Chloro-4-oxo- 3,4-dihydro-phthalazin-6-ylamino)-methyl]-N-(2-pyrrolidin-l- yl-ethyl)-benzamide

3-Aminomethyl-N-(2-pyrrolidin-l-yl-ethyl)-benzamide dihydrochloride

To a solution of [4-(2-Pyrrolidin-l-yl-ethylcarbamoyl)-benzyl]-carbamic acid tert-buty\ ester (400mg, 1.15mmol) in MeOH (3OmL) was added 6M HCl in IPA (25mL). The mixture was stirred at ambient temperature for 5h. After this time the mixture was concentrated and dried to yield the title compound, m/z (M+l) 248.34. 3-[(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-ylamino)-methyl] -N-(2-pyrrolidin-l-yl- ethyl) -benzamide and 3-[(l-Chloro-4-oxo-3, 4-dihydro-phthalazin-6-ylamino)-methyl]-N- (2-pyrrolidin-l-yl-ethyl)-benzamide A mixture 6-Bromo-4-chloro-2H-phthalazin- 1 -one and 7-Bromo-4-chloro-2H- phthalazin-1-one (200mg, 0.77 mmol), 3-Aminomethyl-N-(2-pyrrolidin-l-yl-ethyl)- benzamide dihydrochloride (319mg, 1.00 mmol), Pd ₂ (dba) ₃ (71mg, 0.077 mmol), rac- BIνAP (144mg, 0.23 mmol) and NaOr-Bu (217mg, 2.31 mmol) in DMF (1OmL) was heated at 80 ⁰ C for 2h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with NaHCO ₃ (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (MeOH/EtOAc) yielded the title compound as a mixture of two regioisomers. ¹ H-NMR (DMSO-^) δ: 12.40 (bs, 2H), 8.41 (t, 2H), 7.91 (d, IH), 7.85 (m, 2H), 7.70 (m, 4H), 7.50 (m, 3H), 7.42 (m, IH), 7.37 (m, IH), 7.26 (m, IH), 7.15 (m, 2H), 6.85 (s, IH), 4.50 (t, 4H), 3.35 (m, 4H), 2.55 (t, 4H), 2.45 (m, 8H), 1.65 (m, 8H); m/z (M+l) = 426.10.

Example 71 and 72: Synthesis of N-(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-yl)-3- trifluoromethyl-benzamide and N^l-Chloro^-oxo-S^-dihydro-phthalazin-ό-ylJ-S- trifiuoromethyl-benzamide

A mixture 6-Bromo-4-chloro-2H-phthalazin-l-one and 7-Bromo-4-chloro-2H- phthalazin-1-one (150mg, 0.58 mmol), 3-Trifluoromethyl-benzamide (120mg, 0.64 mmol), Pd ₂ (dba) ₃ (53mg, 0.054 mmol), xantphos (lOlmg, 0.174 mmol) and cesium carbonate (472mg, 1.45 mmol) in dioxane (1OmL) was heated at reflux for 3h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with NaHCO ₃ (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/Hexanes) yielded the title compounds. N-(4-Chloro-l- oxo-l,2-dihydro-phthalazin-6-yl)-3-trifluoromethyl-benzamide : ¹ H-NMR (DMSO-J ₆ ) δ: 12.80 (s, IH), 11.05 (s, IH), 8.59 (s, IH), 8.34 (m, 4H), 8.02 (d, IH), 7.82 (t, IH); m/z (M+l) = 368.06; and N-(I -Chloro^-oxo-S^-dihydro-phthalazin-ό-y^-S-trifluoromethyl- benzamide: ¹ H-NMR (DMSO-^ ₅ ) δ: 12.80 (s, IH), 11.05 (s, IH), 8.80 (d, IH), 8.42 (dd, IH), 8.36 (s, IH), 8.32 (d, IH), 8.03 (d, IH), 8.01 (d, IH), 7.82 (t, IH); m/z (M+l) = 367.99.

Example 73 and 74: Synthesis of 4-Chloro-6-[3-(2-morpholin-4-yl-ethoxy)- benzylamino]-phthalazin-l-ol and 4-Chloro-7-[3-(2-morphoIin-4-yl-ethoxy)- benzylamino]-phthalazin-l-ol

A mixture 6-Bromo-4-chloro-2H-phthalazin-l-one and 7-Bromo-4-chloro-2H- phthalazin-1-one (200mg, 0.77 mmol), 3-(2-Moφholin-4-yl-ethoxy)-benzylamine (0.25mL, 1.00 mmol), Pd ₂ (dba) ₃ (71mg, 0.077 mmol), rac-BINAP (144mg, 0.23 mmol) and NaOr-Bu (217mg, 2.31 mmol) in DMF (1OmL) was heated at 80 ⁰ C for 2h. The

mixture was allowed to cool, diluted with EtOAc (25 niL) and washed with NaHCO ₃ (25 niL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/MeOH) yielded the title compounds. ¹ H-NMR (DMSO-J ₁₅ ) δ: 12.41 (s, IH), 12.35 (s, IH), 7.91 (d, IH), 7.70 (d, IH), 7.65 (m, 2H), 7.25 (m, 4H), 7.16 (m, 2H), 6.94 (m, 4H), 6.82 (m, 4H), 4.40 (t, 4H), 4.15 (m, 4H), 3.57 (m, 8H), 2.63 (m, 4H), 2.42 (m, 8H); m/z (M+l) = 414.98.

Example 75: Synthesis of 4-Methyl-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide

2- A cetyl-terephthalic acid dimethyl ester

A mixture of zinc powder (1.5 eq, 10.98 mmol, 718 mg), cobalt (11) bromide (.1 eq, .732 mmol, 160 mg), allyl bromide (0.1 eq, .732 mmol, 62 μl), and trifluoroacetic acid (1 drop to activate the zinc) are stirred under argon in 7 ml of acetonitrile for 10 minutes at room temperature. 2-Bromo dimethyl ester (2 g, 7.32 mmol) and acetic anhydride (1.1 eq, 8.1 mmol, .766 ml) are then added simultaneously, and the reaction is carried out for 5 hours, until complete conversion of the starting aryl bromide. The reaction is quenched with aqueous sodium bicarbonate and water and extracted with ether. The combined organic layer was separated, dried with anhydrous sodium sulfate, filtered and evaporated under vacuum to give crude product, which was purified via column chromatography (5-10% EtOAc-Hex) to give 95 mg (55%) of the ketone, m/z [M+l] ⁺ = 237. 4-Methyl-l -oxo-1 ,2-dihydro-phthalazine-6-carboxylic acid

A solution of 2-Acetyl-terephthalic acid dimethyl ester (0.68 g, 2.88 mmol) in THF (6 ml), methanol (1.5 ml), and 1.5 ml of 2N (NaOH) was stirred overnight. Solvent was evaporated to dryness 3X (methanol). Isopropyl alcohol (5 ml) was then added to the crude salt followed by the addition of hydrazine hydrate (5 ml). The mixture was

heated to reflux for 3 hours before evaporated to dryness (3X) via methanol to give the crude compound, m/z [M+ 1] ⁺ = 205.

The crude mixture was converted to the corresponding acid chloride by refluxing in thionyl chloride (neat) for 2 hours before evaporated under vacuum to give the crude acid-chloride, which was divided into 4 equal batches then used directly for the next step.

4-Methyl-l -oxo-1 ^-dihydro-phthalazine-ό-carboxylic acid (3-trtfluoromethyl-phenyl)- atnide

A solution of the acid chloride (~ 100 mg, 2.25 mmol), prepared from above, in

DMF (2.5 ml) was added the trifluoromethyl-aniline (2.5 eq, 5.62 mmol) and triethylamine (2.5 eq, 5.62 mmol). The reaction mixture was stirred at room temperature for 5 hrs before quenched with aqueous sodium bicarbonate and water and extracted with

EtOAc. The combined organic layer was separated, dried with anhydrous sodium sulfate, filtered and evaporated under vacuum to give crude product, which was purified via column chromatography (60-80% EtO Ac-Hex) to give 41 mg of the product. ¹ H NMR (DMSO) δ 12.61 (IH), 10.52 (IH), 8.48 (IH), 8.40 (IH), 8.35 (IH), 8.26 (IH), 8.09 (IH),

7.65 (1), 7.52 (IH), 2.62 (3H); m/z [M+l] ⁺ = 348.

Example 76: Synthesis of 4-Methyl-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid

3-trifluoromethyl-benzylamide

An equal batch of the acid chloride (see Example 74) was used for coupling with the trifiuoromethyl-benzylamine. A similar procedure and work up to the previous reaction afforded the title compound. ¹ H NMR (DMSO) δ: 12.52 (IH), 9.58 (IH), 8.48 (IH), 8.38 (IH), 8.34 (IH), 8.28 (IH), 8.16 (IH), 7.78 (1), 7.66 (IH), 4.68 (2), 2.58 (3H); m/z [M+l] ⁺ = 362. Example 77: Synthesis of 4-Methyl-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid 3-methoxy-benzylamide

An equal batch of the acid chloride (see Example 74) was used for coupling with the methyl-oxy-benzylamine. A similar procedure and worked up to the previous reaction afforded the title compound. ¹ H NMR (DMSO) δ: 12.51 (IH), 9.48 (IH), 8.38 (IH), 8.33 (IH), 8.29 (IH), 7.28 (IH), 7.23 (IH), 6.94 (1), 6.82 (IH), 4.54 (2H), 3.75 (3H), 2.55 (3H); m/z [M+lf = 324. Example 78: ^Chloro-β-tS-piperidin-l-ylmethyl-benzylaminoJ-lH-phthalazi n-l- one

6-Bromo-4-chloro-2H-phthalazin-l-one

A mixture of 6-bromo-2,3-dihydro-phthalazine-l,4-dione (42.8 g, 178 mmol) in POCl ₃ (300 mL) was heated at reflux for 3h. The mixture was allowed to cool and concentrated. The residue was taken up in EtOAc (400 mL) and water (200 mL), and neutralized with sodium bicarbonate. The layers were separated, aqueous layer was extracted with EtOAc (3x200 mL), and combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in dioxane (300 mL) and 2N NaOH (25OmL). The mixture was heated at 50 ⁰ C for 30min, poured into water (3L), and stirred for 15 min. Solid was filtered and dried in vacuum at room temperature to give title compound as a greenish solid (12.0 g, 24.3%). M/z (M+l) = 259.32.

4-Chloro-6-(3-piperidin-l-ylmethyl-benzylamino)-2H-phthal azin-l- one

A mixture 6-bromo-4-chloro-2H-phthalazin- 1 -one (70 mg, 0.27 mmol), 3- piperidin-1-ylmethyl-benzylamine (72 mg, 0.35 mmol), Pd ₂ (dba) ₃ (25 mg, 0.027 mmol), rac-BINAP (51 mg, 0.081 mmol) and NaOt-Bu (76 mg, 0.81 mmol) in DMA (6 mL) was

heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 niL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(3-piperidin- 1 -ylmethyl-benzylamino)-2H-phthalazin- 1 -one: 16 mg (15.5%): m/z (M+η)=383. ¹ H-NMR (DMSO-J ₆ ) δ: 12.30 (s,lH), 7.95 (d,lH),7.63 (m,lH), 7.25 (m,3H), 7.15 (m,2H), 6.75 (s,lH), 4.41 (d,2H), 3.37 (s,2H), 2.24 (m,4H), 1.38 (m,4H), 1.32 (m,2H).

Example 79: 4-Chloro-6-[2-(2-morpholin-4-yl-ethoxy)-benzylamino]-2H-phth alazin- 1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (70 mg, 0.27 mmol), 2-(2- morpholin-4-yl-ethoxy)-benzylamine (83 mg, 0.35 mmol), Pd ₂ (dba) ₃ (25 mg, 0.027 mmol), rac-BINAP (51 mg, 0.081 mmol) and NaOt-Bu (76 mg, 0.81 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-[2-(2-morpholin-4-yl-ethoxy)-benzylamino]-2H-phth alazin- 1-one: 28 mg (25.0%): m/z (M+η)=415. ¹ H-NMR (OMSO-d ₆ ) δ: 12.33 (s,lH), 7.91 (d,lH), 7.45 (m,lH), 7.24 (m,2H), 7.13 (m,lH), 7.04 (m,lH), 6.90 (m,lH), 6.79 (s,lH), 4.36 (d,2H), 4.15 (t,2H), 3.51 (t,4H), 2.72 (t,2H), 2.45 (m,4H).

Example 80: 6-(Benzyl-methyl-amino)-4-chloro-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (70 mg, 0.27 mmol), benzyl- methyl-amine (43 mg, 0.35 mmol), Pd ₂ (dba) ₃ (25 mg, 0.027 mmol), rac-BINAP (51 mg,

0.081 mmol) and NaOZ-Bu (76 mg, 0.81 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 6- (Benzyl-methyl-amino)-4-chloro-2H-phthalazin-l-one: 10 mg (12.4%): m/z (M+η)=300. ¹ H-NMR (DMSO-J ₆ ) δ: 12.25 (s,lH), 7.95 (d,lH), 7.35 (m,3H), 7.23 (m, 3H), 6.87 (d,lH), 4.79 (s,2H), 3.28 (s, 3H).

Example 81 : 4-Chloro-6-(2,5-dichloro-benzylamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2,5- dichloro-benzylamine (0.085 mL, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac- BINAP (108 mg, 0.17 mmol) and NaOf-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2,5-dichloro-benzylamino)-2H-phthalazin-l-one: 6 mg (2.9%): m/z (M+η)=354. ¹ H-NMR (DMSO-^) δ: 12.39 (s,lH), 7.96 (d,lH), 7.66 (m,lH), 7.53 (d, IH), 7.47 (m,lH), 7.40 (dd,lH), 7.16 (dd,lH), 6.82 (s,lH), 4.50 (d,2H). Example 82: 4-Chloro-6-(2-methyl-benzylamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin- 1 -one (150 mg, 0.58 mmol), 2- methyl-benzylamine (0.080 mL, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac- BINAP (108 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was

heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-methyl-benzylamino)-2H-phthalazin-l-one: 36 mg (20.7%): m/z (M+η)=300. ¹ H-NMR (DMSO-J ₆ ) δ: 12.34 (s,lH), 7.93 (d,lH),7.50 (m,lH), 7.26 (m, IH), 7.16 (m,4H) 6.84 (s,lH), 4.37 (d,2H), 2.48 (s, 3H). Example 83 : 4-Chloro-6-(2-chloro-6-fluoro-benzylamino)-2H-phthalazin-l -one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2- chloro-6-fluoro-benzylamine (102 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac- BINAP (108 mg, 0.17 mmol) and NaOr-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-chloro-6-fluoro-benzylamino)-2H-phthalazin-l-o ne: 31 mg (15.8%): m/z (M+η)=338. ¹ H-NMR (DMSO-J ₆ ) δ: 12.38 (s,lH), 7.94 (d,lH), 7.42 (m,3H), 7.30 (m, IH), 7.21 (dd,lH) 6.93 (s,lH), 4.49 (d,2H). Example 84: 4-Chloro-6-(2-pyrazol-l-yl-benzylamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2- pyrazol-1-yl-benzylamine (111 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac- BINAP (108 mg, 0.17 mmol) and NaOz-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate

and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-pyrazol-l-yl-benzylamino)-2H-phthalazin-l-one: 46 mg (22.5%): m/z (M+η)=352. ¹ H-NMR (DMSO-J ₆ ) δ: 12.34 (s,lH), 8.13 (d,lH), 7.90 (d,lH), 7.78 (d, IH), 7.59 (m,lH), 7.50 (m,lH), 7.43 (m,3H), 7.05 (d,lH), 6.68 (s,lH), 6.54 (t,lH), 4.38 (d,2H).

Example 85: 4-Chloro-6-(3-pyrazol-l-yl-benzylamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 3- pyrazol-1-yl-benzylamine (111 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac- BINAP (108 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(3-pyrazol-l-yl-benzylamino)-2H-phthalazin-l-one: 60 mg (30.4%): m/z (M+η)=352. ¹ H-NMR (DMSO-J ₆ ) δ: 12.34 (s,lH), 8.46 (d,lH), 7.93 (m,2H), 7.72 (m,3H), 7.45 (m,lH), 7.32 (d,lH), 7.19 (dd,lH) 6.86 (s,lH), 6.52 (t,lH), 4.50 (d,2H). Example 86: 4-Chloro-6-(2-pyridin-3-yl-benzylamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2- pyridin-3-yl-benzylamine dihydrochloride (165 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOt-Bu (251 mg, 2.61 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous

sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-pyridin-3-yl-benzylamino)-2H-phthalazin-l-one: 51 mg (24.2%): m/z (M+η)=363. ¹ H-NMR (DMSO-d ₆ ) δ: 12.32 (s,lH), 8.65 (d,lH), 8.58 (dd,lH), 7.88 (m,2H), 7.61 (m,lH), 7.46 (m,4H), 7.34 (m,lH), 7.06 (dd,lH), 6.55 (s,lH), 4.30 (d,2H). Example 87: 4-Chloro-6-(2-piperidin-l-yl-benzylamino)-2H-phthalazin-l-on e

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2- piperidin-1-yl-benzylamine (122 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac- BINAP (108 mg, 0.17 mmol) and NaOf-Bu (251 mg, 2.61 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-piperidin-l-yl-benzylamino)-2H-phthalazin-l-on e: 62 mg (29.0%): m/z (M+η)=369. ¹ H-NMR (DMSCW ₆ ) δ: 12.35 (s,lH), 7.90 (d,lH),7.77

(m,lH), 7.32 (dd, IH), 7.15 (m,3H), 6.96 (m,lH) 6.62 (s,lH), 4.41 (d,2H), 1.71 (m,4H),

1.55 (m,2H).

Example 88: 4-Chloro-6-(2-thiophen-2-yl-benzylamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2- thiophen-2-yl-benzylamine hydrochloride (145 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOf-Bu (200 mg, 2.1 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc

(25 mL) and washed with water (25 niL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-thiophen-2-yl-benzylamino)-2H-phthalazin-l-one : 65 mg (30.5%): m/z (M+η)=368. ¹ H-NMR (DMSO-J ₆ ) δ: 12.34 (s,lH), 7.91 (d,lH), 7.64 (m,2H), 7.47 (m, 2H), 7.37 (m,2H), 7.25 (dd,lH), 7.16 (m,lH), 7.11 (m,lH), 6.64 (s,lH), 4.43 (d,2H).

Example 89: 4-Chloro-6-(3-thiophen-2-yl-benzylamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 3- thiophen-2-yl-benzylamine (121 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac- BINAP (108 mg, 0.17 mmol) and NaOf-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(3-thiophen-2-yl-benzylamino)-2H-phthalazin-l-one : 69 mg (32.3%): m/z (M+η)=368. ¹ H-NMR (DMSO-J ₆ ) δ: 12.34 (s,lH), 7.93 (d,lH), 7.70 (m,2H), 7.54 (m, 2H), 7.48 (dd,lH), 7.39 (m,lH), 7.32 (m,lH), 7.18 (dd,lH), 7.13 (m,lH), 6.86 (s,lH), 4.47 (d,2H). Example 90: 4-Chloro-6-(2-furan-2-yl-benzylamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2-furan- 2-yl-benzylamine (111 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOf-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed

with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4- Chloro-6-(2-furan-2-yl-benzylamino)-2H-phthalazin-l-one: 54 mg (26.5%): m/z (M+η)=351. ¹ H-NMR (DMSO-d ₆ ) δ: 12.34 (s,lH), 7.93 (d,lH), 7.82 (m,lH), 7.70 (dd, IH), 7.64 (m,lH), 7.44 (m,lH), 7.35 (m,2H), 7.12 (dd,lH), 6.76 (m,2H), 6.63 (m,lH), 4.56 (d,2H).

Example 91 : 4-Chloro-6-[3-(4-methyl-piperazin-l-yl)-benzylamino]-2H-phth alazin- 1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 3-(4- methyl-piperazin-l-yl)-benzylamine (111 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOr-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-[3-(4-methyl-piperazin- 1 -yl)-benzylamino]-2H-phthalazin- 1-one: 50 mg (22.5%): m/z (M+η)=384. ¹ H-NMR (DMSO-J ₆ ) δ: 12.33 (s,lH), 7.91 (d,lH), 7.59 (m,lH), 7.16 (m,2H), 6.98 (s,lH), 6.80 (m,3H), 4.34 (d,2H), 3.11 (m,4H), 2.42 (m,4H), 2.20 (s,3H). Example 92: 4-Chloro-6-(2-morpholin-4-ylmethyI-benzyIamino)-2H-phthalazi n-l- one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2- moφholin-4-ylmethyl-benzylamine (132 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058

mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-morpholin-4-ylmethyl-benzylamino)-2H-phthalazi n- 1 - one: 52 mg (23.3%): m/z (M+η)=385. ¹ H-NMR (DMSO-J ₆ ) δ: 12.27 (s,lH), 7.85 (d,lH), 7.51 (m,lH), 7.22 (m,2H), 7.16 (m,2H), 7.11 (dd,lH), 6.73 (s,lH), 4.55 (d,2H), 3.50 (m,6H), 2.23 (m, 4H). Example 93: 4-ChIoro-6-(3-thiophen-3-yl-benzylamino)-2H-phthaIazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 3- thiophen-3-yl-benzylamine (122 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac- BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(3-thiophen-3-yl-benzylamino)-2H-phthalazin-l-one : 38 mg (17.8%): m/z (M+η)-368. ¹ H-NMR (DMSO-J ₆ ) δ: 12.34 (s,lH), 7.93 (d,lH), 7.84 (m,lH), 7.75 (m,lH), 7.64 (m,3H), 7.52 (dd,lH), 7.39 (m,lH), 7.31 (m,lH), 7.19 (dd,lH), 6.87 (s,lH), 4.47 (d,2H).

Example 94: 4-Chloro-6-[2-(4-methyl-piperazin-l-yl)-benzylamino]-2H-phth alazin- 1-one

A mixture 6-bromo-4-chloro-2H-ρhthalazin-l-one (150 mg, 0.58 mmol), 2-(4- methyl-piperazin-l-yl)-benzylamine (132 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-[2-(4-methyl-piperazin- 1 -yl)-benzylamino]-2H-phthalazin- 1-one: 46 mg (20.7%): m/z (M+η)=384. ¹ H-NMR (DMSO-J ₆ ) δ: 12.31 (s,lH), 7.89 (d,lH), 7.77 (m,lH), 7.33 (dd,lH), 7.20 (m,lH), 7.13 (m,2H), 7.00 (m,lH), 6.63 (s,lH), 4.42 (d,2H), 2.98 (m,4H), 2.52 (m,4H), 2.23 (s,3H).

Example 95: 4-Chloro-6-(2-phenoxy-benzyIamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2- phenoxy-benzylamine hydrochloride (151 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (200 mg, 2.1 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-phenoxy-benzylamino)-2H-phthalazin-l-one: 81 mg (37.0%): m/z (M+η)=378. ¹ H-NMR (DMSO-J ₅ ) δ: 12.77 (s,lH), 8.34 (d,lH), 8.03

(m,lH), 7.82 (m,3H), 7.71 (m,lH), 7.56 (m,3H), 7.42 (m,2H), 7.33 (dd,lH), 7.20 (s,lH), 4.84 (d,2H).

Example 96: 4-ChIoro-6-[(2,3-dihydro-benzo[l,4]dioxin-5-ylmethyl)-amino] -2//- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), (2,3- dihydro-benzo[l,4]dioxin-5-yl)-methylamine hydrochloride (129 mg, 0.64 mmol), Pd- ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (200 mg, 2.1 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-[(2,3-dihydro-benzo[l,4] dioxin-5-ylmethyl)-amino]-2H-phthalazin-l-one: 41 mg (20.6%): m/z (M+η)=344. ¹ H- NMR (DMSO-40 δ: 12.33 (s,lH), 7.92 (d,lH), 7.53 (m,lH), 7.13 (dd,lH), 6.82 (m,4H), 4.33 (m,4H), 4.26 (m,2H).

Example 97: 4-Chloro-6-[(2,3-dihydro-benzofuran-5-yImethyl)-amino]-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), (2,3- dihydro-benzofuran-5-yl)-methylamine hydrochloride (119 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (200 mg, 2.1 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-[(2,3-dihydro-benzofuran-5- ylmethyl)-amino]-2H-phthalazin-l-one: 25 mg (13.2%): m/z (M+η)=328. ¹ H-NMR (DMSO-d ₆ ) δ: 12.28 (s,lH), 7.86 (d,lH), 7.51 (m,lH), 7.19 (s,lH), 7.10 (dd,lH), 7.05 (d,lH), 6.78 (s,lH), 6.67 (d,lH), 4.44 (t,2H), 4.26 (d,2H), 3.09 (t,2H).

Example 98: 4-Chloro-6-(2-piperazin-l-yl-benzylamino)-2H-phthalazin-l-on e

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 4-(2- aminomethyl-phenyl)-piperazine-l-carboxylic acid tert-buty\ ester (187 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOf-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded 4- {2-[(4-chloro- 1 -oxo- 1 ,2-dihydro-phthalazin-6-ylamino)- methyl]-phenyl}-piperazine-l-carboxylic acid tert-butyl ester. Deprotection with TFA in DCM yielded the title compound. 4-Chloro-6-(2-piperazin-l-yl-benzylamino)-2H- phthalazin-1-one: 46 mg (16.9%): m/z (M+η)=370.00. ¹ H-NMR (OMSO-d ₆ ) δ: 12.31 (s,lH), 7.89 (d,lH), 7.77 (m,lH), 7.33 (d,lH), 7.21 (m,lH), 7.14 (dd,lH), 7.10 (m,lH), 7.00 (m,lH), 6.64 (s,lH), 4.43 (d,2H), 2.90 (m,5H), 2.82 (m,4H).

Example 99: 4-Chloro-6-(2-fluoro-5-trifluoromethyl-benzylamino)-2H-phtha Iazin-l- one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2- fluoro-5-trifluoromethyl-benzylamine (124 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOf-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous

sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-fluoro-5-trifluoromethyl-benzylamino)-2H-phtha lazin- 1 - one: 27 mg (12.5%): m/z (M+η)=372. ¹ H-NMR (DMSO-d ₆ ) δ: 12.38 (s,lH), 7.95 (d,lH), 7.85 (m,lH), 7.75 (m,lH), 7.65 (m,lH), 7.49 (m,lH), 7.19 (dd,lH), 6.87 (s,lH), 4.56 (d,2H).

Example 100: 4-Chloro-6-(5-chloro-2-methyl-benzylamino)-2H-phthalazin-l-o ne

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 5- chloro-2-methyl-benzylamine (100 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac- BINAP (132 mg, 0.17 mmol) and NaOBu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(5-chloro-2-methyl-benzylamino)-2H-phthalazin-l-o ne: 20 mg (10.3%): m/z (M+η)=334. ¹ H-NMR (DMSO-J ₆ ) δ: 12.63 (s,lH), 8.21 (d,lH), 7.78 (m,lH), 7.56 (m, IH), 7.50 (m,2H), 7.42 (dd,lH), 7.10 (s,lH), 4.66 (d,2H), 2.60 (s,3H). Example 101 : 4-Chloro-6-(2-chloro-5-trifluoromethyl-benzylamino)-2H-phtha lazin- 1-one

A mixture 6-bromo-4-chloro-2H-phthalazin- 1 -one (150 mg, 0.58 mmol), 2- chloro-5-trifluorornethyl-benzylamine (135 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOZ-Bu (140 mg, 1.45 mmol) in DMA (6

mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-chloro-5-trifluoromethyl-benzylamino)-2H-phtha lazin- 1 - one: 18 mg (8.0%): m/z (M+η)=388. ¹ H-NMR (DMSO-J ₆ ) δ: 12.39 (s,lH), 7.96 (d,lH), 7.80 (m,lH), 7.75 (m,lH), 7.70 (m,2H), 7.18 (dd,lH), 6.84 (s,lH), 4.59 (d,2H). Example 102 : 4-Chloro-6-(2-chloro-3-trifluoromethyl-benzylamino)-2H-phtha lazin- 1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2- chloro-3-trifluoromethyl-benzylamine (124 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOr-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-chloro-3-trifluoromethyl-benzylamino)-2H-phtha lazin- 1 - one: 38 mg (17.6%): m/z (M+η)=372. ¹ H-NMR (DMSO-^) δ: 12.38 (s,lH), 7.95 (d,lH), 7.71 (m, 3H), 7.39 (m,lH), 7.19 (dd,lH), 6.85 (s,lH), 4.57 (d,2H).

Example 103: 4-Chloro-6-(2-chIoro-6-phenoxy-benzylamino)-2H-phthalazin-l- one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2- chloro-6-phenoxy-benzylamine (150 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol),

rac-BINAP (132 mg, 0.17 mmol) and NaOZ-Bu (140 mg, 1.45 mmol) in DMA (6 ml) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 niL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-chloro-6-phenoxy-benzylamino)-2H-phthalazin-l- one: 39 mg (16.3%): m/z (M+η)=412. ¹ H-NMR (DMSO-J ₆ ) δ: 12.34 (s,lH), 7.90 (d,lH), 7.35 (m,5H), 7.21 (dd,lH), 7.15 (m,lH), 7.02 (m,2H), 6.95 (d,lH), 6.84 (dd,lH), 4.50 (d,2H). Example 104: 4-Chloro-6-(2,5-dimethyl-benzylamino)-2H-phthalazin-l-one

A mixture ό-bromo^-chloro^H-phthalazin- 1 -one (150 mg, 0.58 mmol), 2,5- dimethyl-benzylamine (87 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaO^-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4- Chloro-6-(2,5-dimethyl-benzylamino)-2H-phthalazin-l-one: 31 mg (17.0%): m/z (M+η)=314. ¹ H-NMR (DMSO-d ₆ ) δ: 12.34 (s,lH), 7.92 (d,lH), 7.45 (m,lH), 7.16 (dd,lH), 7.10 (m,2H), 6.99 (m,lH), 6.85 (s,lH), 4.32 (d,2H), 2.29 (s,3H), 2.22 (s,3H). Example 105 : 4-Chloro-6-(3-morpholin-4-yl-benzylamino)-2H-phthalazin-l -one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 3- morpholin-4-yl-benzylamine (123 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac- BINAP (132 mg, 0.17 mmol) and NaOZ-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and

washed with water (25 niL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(3-morpholin-4-yl-benzylamino)-2H-phthalazin-l-on e: 52 mg (24.2%): m/z (M+η)=371. ¹ H-NMR (DMSO-^) δ: 12.33 (s,lH), 7.91 (d,lH), 7.60 (m,lH), 7.16 (m, 2H), 6.98 (m,lH), 6.82 (m,3H), 4.35 (d,2H), 3.72 (m,4H), 3.08 (m,4H). Example 106: 4-Chloro-6-(2,3-dimethyl-benzylamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 2,3- dimethyl-benzylamine (87 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP ( 132 mg, 0.17 mmol) and NaOf-Bu ( 140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4- Chloro-6-(2,3-dimethyl-benzylamino)-2H-phthalazin-l-one: 43 mg (23.6%): m/z (M+η)=314. ¹ H-NMR (DMSO-^) δ: 12.34 (s,lH), 7.92 (d,lH), 7.44 (m,lH), 7.10 (m,4H), 6.85 (s,lH), 4.36 (d,2H), 2.62 (s,3H), 2.22 (s,3H).

Example 107: 4-Chloro-6-[(3,4-dihydro-2H-benzo[6] [l,4]dioxepin-6-yImethyl)- amino]-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), (3,4- dihydro-2H-benzo[6][l,4]dioxepin-6-yl)-methylamine hydrochloride (140 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOf-Bu (200 mg, 2.1 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The

organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. (4-Chloro-6- [(3 ,4-dihydro-2H-benzo[6][ 1 ,4]dioxepin-6-ylmethyl)-amino]-2H-phthalazin- 1 -one: 52 mg (25.1%): m/z (M+η)=358. ¹ H-NMR (DMSCW ₆ ) δ: 12.33 (s,lH), 7.92 (d,lH), 7.51 (m,lH), 7.15 (dd,lH), 6.97 (m,lH), 6.89 (m,2H), 6.83 (s,lH), 4.38 (d,2H), 4.17 (t,2H), 4.11 (t,2H), 2.12 (m,2H).

Example 108: 4-Chloro-6-(3-furan-2-yl-benzylamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), 3-furan- 2-yl-benzylamine (112 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaO^-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4- Chloro-6-(3-furan-2-yl-benzylamino)-2H-phthalazin-l-one: 59 mg (26.0%): m/z

(M+η)=352. ¹ H-NMR (DMSO-d ₆ ) δ: 12.34 (s,lH), 7.93 (d,lH), 7.72 (m,3H), 7.59 (d, IH), 7.40 (m,lH), 7.30 (m,lH), 7.18 (dd,lH), 6.92 (d,lH), 6.86 (s,lH), 6.58 (m,lH), 4.47 (d,2H).

Example 109: 4-ChIoro-6-[(6-nuoro-4H-benzo[l,3]dioxin-8-ylmethyl)-amino]- 2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), (6- fluoro-4H-benzo[l,3]dioxin-8-yl)-methylamine hydrochloride (141 mg, 0.64 mmol), Pd-

₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (200 mg, 2.1 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-[(6-fluoro-4H- benzo[l,3]dioxin-8-ylmethyl)-amino]-2H-phthalazin-l-one: 14 mg (6.7%): m/z (M+η)=362. ¹ H-NMR (DMSO-d ₆ ) δ: 12.35 (s,lH), 7.93 (d,lH), 7.55 (m,lH), 7.14 (dd,lH), 6.97 (dd,lH), 6.88 (dd,lH), 6.84 (s,lH), 5.34 (s,2H), 4.89 (s,2H), 4.35 (dd,2H). Example 110: 4-Chloro-6-[(5-methyl-2-phenyl-furan-3-ylmethyl)-amino]-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150 mg, 0.58 mmol), (5- methyl-2-phenyl-furan-3-yl)-methylamine (120 mg, 0.64 mmol), Pd ₂ (dba) ₃ (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-[(5-methyl-2-phenyl-furan-3-ylmethyl)-amino]-2H- phthalazin-1-one: 30 mg (14.1%): m/z (M+η)=366. ¹ H-NMR (DMSO-d ₆ ) δ: 12.34 (s,lH), 7.91 (d,lH), 7.58 (m,2H), 7.52 (m,lH), 7.45 (m,2H), 7.32 (m,lH), 7.14 (dd,lH), 6.74 (s,lH), 6.22 (s,lH), 4.38 (d,2H), 2.30 (s,3H).

Examples 111 and 112: Synthesis of l-Chloro-4-oxo-3,4-dihydro-phthalazine-6- carboxylic acid (3-difluoromethoxy-phenyl)-amide and 4-Chloro-l-oxo-l,2-dihydro- phthaIazine-6-carboxylic acid (3-difIuoromethoxy-phenyl)-amide

1, 4-Dichloro-phthalazine-6-carboxylic acid (3-difluoromethoxy-phenyl)-amide

A mixture of l^-dihydroxy-phthalazine-ό-carboxylic acid (0.6g, 2.91 mmol) in thionyl chloride (6 mL) was refluxed for 3 hours. Phosphorous oxychloride (6 mL) was added and the reaction refluxed for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (5 mL) and added drop wise to a 0 ⁰ C solution of 3-difiuoromethoxy-benzylamine (509 mg, 3.2 mmol), DMF (4 mL) and NEt ₃ (1.22 mL, 8.73 mmol). The reaction was stirred at 0 ⁰ C for Ih, diluted with water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with water (x3), sat. aq. NH ₄ Cl, brine and dried (Na ₂ SO ₄ ). Column chromatography (Hex/EtOAc) afforded l,4-dichloro-phthalazine-6-carboxylic acid (3-difluoromethoxy- phenyl)-amide (0.26 g). m/z (M+H)=384. l-Chloro-4-oxo-3, 4-dihydro-phthalazine-6-carboxylic acid (3-dtfluoromethoxy-phenyl)- amide and 4-Chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3- difluoromethoxy-phenyl)-amide A mixture of 1 ^-dichloro-phthalazine-ό-carboxylic acid (3-difluoromethoxy- phenyl)-amide (0.26 g, 0.68 mmol), 2N NaOH (3.4 mL, 6.8 mmol) and dioxane (4 mL) was heated to 50 ⁰ C for 2 hours. The reaction was diluted with water, acidified with cone. HCl to ~pH 4 and extracted with EtOAc (x3). The combined organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. Chromatography (Hex/EtOAc) afforded l-chloro^-oxo-S^-dihydro-phthalazine-ό-carboxylic acid (3-difluoromethoxy- phenyl)-amide (60 mg), ¹ H-NMR (DMSO-(Z ₆ ) δ: 13.02 (s,lH), 10.88 (s,lH), 8.88 (d,lH), 8.52 (dd,lH), 8.14 (d,lH), 7.75 (m,lH), 7.69 (m,lH), 7.43 (m,lH), 7.23 (t,lH), 6.96 (dd,lH). m/z (M+H)=366; and 4-chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic

acid (3-difluoromethoxy-phenyl)-amide (39 mg), ¹ H-NMR (DMSO-J ₆ ) δ: 12.85 (s,lH), 10.87 (s, IH), 8.47 (m,lH), 8.42 (m,2H), 7.73 (m,lH), 7.65 (m,lH), 7.44 (m,lH), 7.23 (t,lH), 6.96 (dd, IH). m/z (M+H)=366.

Example 113 and 114: Synthesis of 4-ChIoro-7-(3-fluoro-benzylamino)-2H- phthaIazin-l-one and 4-Chloro-6-(3-fluoro-benzylamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one and 7-bromo-4-chloro-2H- phthalazin-1-one (150mg, 0.58 mmol), 3-fluorobenzylamine (0.08mL, 0.70 mmol), Pd- ₂ (dba) ₃ (43mg, 0.047 mmol), rac-BINAP (118mg, 0.190 mmol) and Naθ'-Bu (139mg, 1.45 mmol) in DMA (8mL) was heated at 8O ⁰ C for 40min. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-7-(3-fluoro-benzylamino)-2H-phthalazin-l-one (32 mg) as a white solid, ¹ H (600 MHz, CDCl ₃ ) δ: 4.44 (s, 2H), 6.92 (m, IH), 7.00 (d, IH), 7.05 (dd, IH), 7.08 (d, IH), 7.26 (m,lH), 7.37 (d, IH), 7.71 (d, IH), 10.40 (s, IH) ppm. m/z (M+ 1) 303.97; 4-chloro-6-(3-fluoro-benzylamino)-2H-phthalazin-l-one (23 mg) as an off white solid, ¹ H (600 MHz, CDCl ₃ ) δ: 4.35 (s,2H), 6.78 (d,lH), 6.86 (m,lH), 6.94 (dd, IH), 6.97 (bd,lH), 7.05(d,lH), 7.21 (m,lH), 8.00 (d,lH), 11.00 (s,lH) ppm. m/z (M+ 1) 303.97.

Example 115 and 116: Synthesis of 4-Chloro-7-(3-trifluoromethoxy-benzyIamino)- 2H-phthalazin-l-one and 4-Chloro-6-(3-trifluoromethoxy-benzylamino)-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one and 7-bromo-4-chloro-2H- phthalazin-1-one (150mg, 0.58 mmol), 3-(trifluoromethoxy)benzylamine (0.08mL, 0.636

mmol), Pd ₂ (dba) ₃ (61mg, 0.0667 mmol), rac-BINAP (120mg, 0.193 mmol) and NaO'-Bu (155mg, 1.613 mmol) in DMA (8mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-7-(3-trifluoromethoxy- benzylamino)-2H-phthalazin-l-one (28 mg) as an off white solid, ¹ H (600 MHz, CDCl ₃ ) δ: 4.50 (s,2H), 7.06 (dd,lH), 7.14 (d,lH), 7.18 (s,lH), 7.28 (d,lH), 7.38 (t,lH), 7.44 (d, IH), 7.78 (d,lH), 9.48 (s,lH), m/z (M+l) 369.93; 4-chloro-6-(3-trifluoromethoxy- benzylamino)-2H-phthalazin-l-one (22 mg) as an off white solid, ¹ H (600 MHz, CDCl ₃ ) δ: 4.41 (s,2H), 6.83 (d,lH), 6.98 (dd,lH), 7.08 (bd,lH), 7.16 (bs,lH), 7.25 (s,lH), 7.32 (t,lH), 8.06 (d, IH), 10.15 (s,lH) ppm. m/z (M+l) 369.93.

Example 117: Synthesis of 4-ChIoro-6-(3-chloro-benzylamino)-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (lOOmg, 0.385 mmol), 3- chlorobenzylamine (0.052mL, 0.424 mmol), Pd ₂ (dba) ₃ (35mg, 0.0385 mmol), rac-BINAP

(75mg, 0.120 mmol) and Naθ'-Bu (11 lmg, 1.155 mmol) in DMA (6mL) was heated at

8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ).

Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3-chloro-benzylamino)- 2H-phthalazin-l-one (15 mg) as a white solid, ¹ H (400 MHz, CDCl ₃ ) δ: 4.23 (s, 2H), 6.69

(d, IH), 6.88 (dd, IH), 7.05 (m, 3H), 7.19 (s, IH), 7.88 (d, IH), 11.45 (s, IH) ppm. m/z

(M+l) 320.00.

Example 118: Synthesis of 4-Chloro-6-(2-trifluoromethyl-benzylamino)-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (lOOmg, 0.385 mmol), 2- (trifluoromethyl)benzylamine (0.3ImL, 0.424 mmol), Pd ₂ (dba) ₃ (35mg, 0.0385 mmol), rac-BINAP (81mg, 0.120 mmol) and NaO'-Bu (92mg, 0.963 mmol) in DMA (6mL) was heated at 8O ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2- trifluoromethyl-benzylamino)-2H-phthalazin-l-one (7 mg) as a white solid, ¹ H (400 MHz, CDCl ₃ ) δ: 4.63 (s, 2H), 6.84 (d, IH), 6.97 (m, IH), 7.35 (m, IH), 7.43 (d, IH), 7.47 (t, 2H), 8.09 (d, IH), 10.15 (s, IH) ppm. m/z (M+l) 353.97.

Example 119: Synthesis of 4-Chloro-6-(3,5-dimethoxy-benzyIamino)-2H-phthalazin- 1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (105mg, 0.405 mmol), 3,5- dimethoxybenzylamine (0.64mL, 0.424 mmol), Pd ₂ (dba) ₃ (25mg, 0.027 mmol), rac- BINAP (78mg, 0.125 mmol) and Naθ'-Bu (92mg, 0.963 mmol) in DMA (6mL) was heated at 8O ⁰ C for 45minutes. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3,5- dimethoxy-benzylamino)-2H-phthalazin-l-one (3 mg) as a brown solid, ¹ H (400 MHz, CDCl ₃ ) δ: 3.65 (d, 6H), 4.28 (s, 2H), 6.25 (m, IH), 6.42 (m, 2H), 6.81 (m, IH), 6.95 (m, 2H), 8.00 (m, IH), ppm. m/z (M+l) 345.92.

Example 120: Synthesis of 4-Chloro-6-(3-hydroxy-benzylamino)-2H-phthalazin-l- one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (lOOmg, 0.385 mmol), 3- (aminomethyl)phenol (59mg, 0.479 mmol), Pd ₂ (dba) ₃ (40mg, 0.044 mmol), rac-BINAP (79mg, 0.127 mmol) andNaO'-Bu (92mg, 0.963 mmol) in DMA (6mL) was heated at 8O ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3-hydroxy- benzylamino)-2H-phthalazin-l-one (8 mg) as a brown solid, ¹ H (400 MHz, CDCl ₃ ) δ: 4.48 (s, 2H), 6.77 (dd, IH), 6.83 (m, 2H), 6.92 (d, IH), 7.02 (m, IH), 7.17 (t, IH), 8.15 (d, IH), 10.34 (s, IH) ppm. m/z (M+l) 301.99.

Example 121: Synthesis of 4-ChIoro-6-(3,5-difluoro-benzylamino)-2H-phthalazin-l- one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (50mg, 0.193 mmol), 3,5- difluorobenzylamine (0.026mL, 0.212 mmol), Pd ₂ (dba) ₃ (6mg, 0.0066 mmol), rac- BINAP (18mg, 0.029 mmol) and Naθ'-Bu (46mg, 0.482 mmol) in DMA (3mL) was heated at 8O ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3,5-difluoro -benzylamino)-2H-phthalazin-l-one (3 mg) as a brown solid, ¹ H (400 MHz, CDCl ₃ ) δ: 4.41 (s, 2H), 6.67 (m, IH), 6.83 (m, 3H), 6.96 (dd, IH), 8.10 (d, IH), 9.58 (s, IH) ppm; m/z (M+l) 321.98.

Example 122: Synthesis of 4-Chloro-6-(2,5-difluoro-benzylamino)-2H-phthalazin-l- one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (48mg, 0.185 mmol), 2,5- difluorobenzylamine (0.026mL, 0.222 mmol), Pd ₂ (dba) ₃ (6mg, 0.0066 mmol), rac- BINAP (21mg, 0.021 mmol) and NaO'Bu (45mg, 0.468 mmol) in DMA (3mL) was heated in a microwave at 9O ⁰ C for 5 minutes. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq.

NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Column chromatography (Hex/EtOAc) afforded 4- chloro-6-(2,5-difluoro-benzylamino)-2H-phthalazin-l-one (3 mg) as an off white solid, ¹ H (400 MHz, CDCl ₃ ) δ: 4.46 (s, 2H), 6.90 (m, 2H), 7.00 (m, 3H), 8.10 (d, IH), 10.09 (s, IH) ppm; m/z (M+l) 321.98. Example 123: Synthesis of 7V-{3-[(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6- ylamino)-methyl]-phenyl}-acetamide

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (lOOmg, 0.385 mmol), N- [3- (aminomethyl)phenyl]acetamide hydrochloride (90mg, 0.448 mmol), Pd ₂ (dba) ₃ (40mg, 0.044 mmol), rac-BINAP (81mg, 0.130 mmol) and NaO'Bu (lOlmg, 1.05 mmol) in

DMA (6mL) was heated at 8O ⁰ C for 3h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded N- {3- [(4-chloro- 1 -oxo- 1 ,2-dihydro-phthalazin-6-ylamino)-methyl]-phenyl} -acetamide (3 mg) as a light brown solid, ¹ H (400 MHz, CDCl ₃ ) δ: 2.09 (s, 3H), 4.38 (s, 2H), 6.85 (d, IH), 7.00 (m, 2H), 7.21 (t, IH), 7.38 (m, IH), 7.53 (m, IH), 7.61 (s, IH), 8.05 (d, IH), 8.75 (bs, IH), 10.90 (bs, IH) ppm; m/z (M+ 1) 342.98.

Example 124: Synthesis of 4-Chloro-6-(3,5-dichloro-benzylamino)-2H-phthalazin-l- one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (97mg, 0.374 mmol), 3,5- dichlorobenzylamine (0.057mL, 0.424 mmol), Pd ₂ (dba) ₃ (29mg, 0.032 mmol), rac- BINAP (70mg, 0.112 mmol) and NaO'Bu (104mg, 1.08 mmol) in DMA (5mL) was heated at 8O ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3,5-dichloro -benzylamino)-2H-phthalazin-l-one (3 mg) as a white solid, ¹ H (400 MHz, CDCl ₃ ) δ: 4.40 (s, 2H), 6.84 (m, IH), 6.99 (m, IH), 7.22 (m, 3H), 8.14 (m, IH), 10.80 (s, IH) ppm; m/z (M+l) 353.83.

Example 125: Synthesis of 6-[(Biphenyl-3-ylmethyl)-amino]-4-chloro-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (95mg, 0.366 mmol), 3- phenylbenzylamine (95mg, 0.518 mmol), Pd ₂ (dba) ₃ (40mg, 0.044 mmol), rac-BINAP

(76mg, 0.122 mmol) and NaO'Bu (lOlmg, 1.05 mmol) in DMA (5mL) was heated at

8O ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ).

Chromatography on silica (EtOAc/hexanes) afforded 6-[(biphenyl-3-ylmethyl)-amino]-4- chloro-2H-phthalazin-l-one (3 mg) as an off white solid, ¹ H (400 MHz, CDCl ₃ ) δ: 4.49

(s, 2H), 7.00 (m, 2H), 7.50 (m, 9H), 8.05 (d, IH), 10.87 (s, IH) ppm; m/z (M+l) 361.95.

Example 126: Synthesis of 4-Chloro-6-(4-phenyl-piperazin-l-yl)-2H-phthalazin-l- one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (lOOmg, 0.385 mmol), 1- phenylpiperazine (0.064mL, 0.424 mmol), Pd ₂ (dba) ₃ (15mg, 0.016 mmol), rac-BINAP (36mg, 0.058 mmol) and NaO'Bu (46mg, 0.479 mmol) in DMA (3mL) was heated in a microwave at 9O ⁰ C for 10 minutes. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(4- phenyl-piperazin-l-yl)-2H-phthalazin-l-one (20 mg) as an orange solid, ¹ H (400 MHz, d ₆ -DMSO) δ: 3.32 (m, 4H), 3.61 (m, 4H), 6.81 (t, IH), 7.00 (d, 2H), 7.15 (d, IH), 7.24 (t, 2H), 7.62 (dd, IH), 8.07 (d, IH), 12.57 (s, IH) ppm; m/z (M+ 1) 341.01. Example 127: Synthesis of 4-Chloro-6-(3-difluoromethoxy-benzylamino)-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150mg, 0.578 mmol), 3- (difluoromethoxy)benzylamine (0.074mL, 0.645 mmol), Pd ₂ (dba) ₃ (48mg, 0.052 mmol), rac-BINAP (108mg, 0.173 mmol) and NaO'Bu (139mg, 1.445 mmol) in DMA (6mL) was heated at 8O ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3- difluoromethoxy-benzylamino)-2H-phthalazin-l-one (17 mg) as an off white solid, ¹ H (400 MHz, CDCl ₃ ) δ: 4.32 (s, 2H), 6.36 (t, IH), 6.77 (d, IH), 6.90 (t, 2H), 6.99 (s, IH), 7.08 (d, IH), 7.21 (t, IH), 8.00 (d, IH), 10.15 (s, IH) ppm; m/z (M+ 1) 351.92.

Example 128: Synthesis of 4-Chloro-6-(2,3-difluoro-benzylamino)-2H-phthalazin-l- one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (156mg, 0.601 mmol), 2,3- difluorobenzylamine (0.074mL, 0.646mmol), Pd ₂ (dba) ₃ (53mg, 0.058 mmol), rac-BINAP (104mg, 0.167 mmol) and NaO'Bu (134mg, 1.39 mmol) in DMA (6mL) was heated at 8O ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2,3-difluoro- benzylamino)-2H-phthalazin- 1 -one (27 mg) as an off white solid, ¹ H (400 MHz, CDCl ₃ ) δ: 4.45 (s, 2H), 6.84 (d, IH), 6.96 (m, 2H), 7.03 (m, 2H), 8.01 (d, IH), 11.00 (s, IH) ppm; m/z (M+l) 321.91.

Example 129: Synthesis of 4-Chloro-6-(2-chloro-benzylamino)-2//-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150mg, 0.578 mmol), 2- chlrorobenzylamine (0.078mL, 0.644mmol), Pd ₂ (dba) ₃ (47mg, 0.051 mmol), rac-BINAP (112mg, 0.180 mmol) and NaO'Bu (139mg, 1.445 mmol) in DMA (6mL) was heated at 8O ⁰ C for 2h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2-chloro-benzylamino)- 2H-phthalazin-l-one (21 mg) as a beige solid, ¹ H (400 MHz, CDCl ₃ ) δ: 4.45 (s, 2H), 6.82 (d, IH), 6.95 (dd, IH), 7.14 (m, 2H), 7.30 (m, 2H), 8.00 (d, IH), 11.20 (s, IH) ppm; m/z (M+l) 319.93.

Example 130: Synthesis of 4-Chloro-6-(3,4-dimethyI-benzylamino)-2H-phthalazin-l- one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150mg, 0.578 mmol), 3,4- dimethylbenzylamine (0.09mL, 0.636 mmol), Pd ₂ (dba) ₃ (58mg, 0.063 mmol), rac-BINAP (104mg, 0.167 mmol) and NaO'Bu (155mg, 1.613 mmol) in DMA (6mL) was heated at 85 ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3,4-dimethyl- benzylamino)-2H-phthalazin- 1 -one (21 mg) as a white solid, ¹ H (400 MHz, d ₆ -DMSO) δ: 2.15 (d, 6H), 4.25 (d, 2H), 6.79 (s, IH), 7.05 (s, 2H), 7.10 (m, 2H), 7.57 (t, IH), 7.87 (d, IH), 12.30 (s, IH) ppm; m/z (M+ 1) 313.99.

Example 131: Synthesis of 4-Chloro-6-(3-dimethylamino-benzylamino)-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150mg, 0.578 mmol), N-[3- (aminomethyl)phenyl]-N,N-dimethylamine (102mg, 0.679 mmol), Pd ₂ (dba) ₃ (53mg, 0.0578 mmol), rac-BINAP (112mg, 0.180 mmol) and NaO'Bu (139mg, 1.445 mmol) in DMA (6mL) was heated at 85 ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4- chloro-6-(3-dimethylamino-benzylamino)-2H-phthalazin-l-one (28 mg) as a beige solid, ¹ H (400 MHz, de-DMSO) δ: 2.87 (s, 6H), 4.33 (d, 2H), 6.61 (dd, IH), 6.66 (d, IH), 6.76 (m, IH), 6.85 (m, IH), 7.14 (m, 2H), 7.61 (t, IH), 7.91 (d, IH), 12.32 (s, IH) ppm. m/z (M+l) 329.00.

Example 132: Synthesis of 4-Chloro-6-(3-isopropoxy-benzylamino)-2H-phthalazin-

1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (156mg, 0.601 mmol), l-(3- isopropoxyphenyl)methanamine (116mg, 0.702 mmol), Pd ₂ (dba) ₃ (53mg, 0.0578 mmol), rac-BINAP (113mg, 0.181 mmol) and NaO'Bu (139mg, 1.445 mmol) in DMA (6mL) was heated at 85 ⁰ C for 2h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3- isopropoxy-benzylamino)-2H-phthalazin-l-one (45 mg) as an off white solid, ¹ H (400 MHz, d ₆ -DMSO) δ: 1.22 (d, 6H), 4.40 (d, 2H), 4.57 (quintet, IH), 6.80 (m, 2H), 6.91 (m, 2H), 7.16 (dd, IH), 7.22 (t, IH), 7.64 (t, IH), 7.92 (d, IH), 12.34 (s, IH) ppm; m/z (M+l) 344.01. Example 133: Synthesis of 4-ChIoro-6-(2-pyrrol-l-yl-benzylamino)-2//-phthalazin- 1-one

A mixture 6-bromo-4-chloro-2H-phthalazin- 1-one (150mg, 0.578 mmol), 2-(l- pyrrolyl)benzylamine (122mg, 0.708 mmol), Pd ₂ (dba) ₃ (56mg, 0.061 mmol), rac-BINAP (108mg, 0.173 mmol) and NaO'Bu (139mg, 1.445 mmol) in DMA (5mL) was heated at 85 ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2-pyrrol-l-yl- benzylamino)-2H-phthalazin- 1-one (33 mg) as an off white solid, ¹ H (400 MHz, d ₆ - DMSO) δ: 4.22 (d, 2H), 6.26 (t, 2H), 6.60 (bs, IH), 7.04 (t, 2H), 7.08 (d, IH), 7.35 (m,lH), 7.40 (m, 2H), 7.49 (m, IH), 7.62 (t, IH), 7.91 (d, IH) ppm; m/z (M+l) 350.97.

Example 134: Synthesis of 6-(4-tert-Butoxy-benzylamino)-4-chloro-2H-phthalazin-l- one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150mg, 0.578 mmol), 4- (trifluoromethoxy)benzylamine (0.098mL, 0.642 mmol), Pd ₂ (dba) ₃ (50mg, 0.055 mmol), rac-BINAP (112mg, 0.180 mmol) and NaO'Bu (151mg, 1.571 mmol) in DMA (5mL) was heated at 85 ⁰ C for 2h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat. aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 6-(4-fert-butoxy- benzylamino)-4-chloro-2H-phthalazin-l-one (37 mg) as a beige solid, ¹ H (400 MHz, d ₆ - DMSO) δ: 4.47 (d, 2H), 6.81 (s, IH), 7.16 (dd, IH), 7.35 (d, 2H), 7.50 (d, 2H), 7.69 (t, IH), 7.93 (d, IH), 12.35 (s, IH) ppm; m/z (M+l) 369.93.

Example 135: Synthesis of 4-Chloro-6-[(pyridin-3-yImethyl)-amino]-2H-phthalazin- 1-one hydroformate

A mixture 6-bromo-4-chloro-2H-phthalazin- 1 -one (150mg, 0.578 mmol), 3- (aminomethyl)pyridine (0.064mL, 0.636 mmol), Pd ₂ (dba) ₃ (53mg, 0.058 mmol), rac- BINAP (115mg, 0.185 mmol) and NaO'Bu (169mg, 1.759 mmol) in DMA (5mL) was heated at 85 ⁰ C for 2h. The mixture was allowed to cool, then filtered. Preparatory ηPLC afforded 4-chloro-6-[(pyridin-3-ylmethyl)-amino]-2H-phthalazin-l-one hydroformate (31 mg) as a yellow solid, ¹ H (400 MHz, d _ό -DMSO) δ: 4.41 (d, 2H), 6.78 (d, IH), 7.12 (dd, IH), 7.31 (dd, IH), 7.60 (t, IH), 7.10 (m, IH), 7.88 (d, IH), 8.09 (s, IH), 8.41 (dd, IH), 8.56 (d, IH), 12.31 (s, IH) ppm; m/z (M+l) 286.99.

Example 136: Synthesis of 4-Chloro-6-(2,3-dimethoxy-benzylamino)-2H-phthalazin-

1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150mg, 0.578 mmol), 2,3- dimethoxybenzylamine (0.094mL, 0.636 mmol), Pd ₂ (dba) ₃ (53mg, 0.058 mmol), rac- BINAP (112mg, 0.180 mmol) and NaO'Bu (139mg, 1.445 mmol) in DMA (5mL) was heated at 85 ⁰ C for 2h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2,3- dimethoxy-benzylamino)-2H-phthalazin-l-one (37 mg) as an off white solid, ¹ H (400 MHz, d ₆ -DMSO) δ: 3.79 (s, 3H), 3.80 (s, 3H), 4.40 (d, 2H), 6.83 (s, IH), 6.88 (dd, IH), 7.00 (m, 2H), 7.14 (dd, IH), 7.53 (t, IH), 7.91 (d, IH), 12.33 (bs, IH) ppm; m/z (M+l) 345.92.

Example 137: Synthesis of 4-Chloro-6-(2,5-dimethoxy-benzylamino)-2H-phthaIazin- 1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (155mg, 0.597 mmol), 2,5- dimethoxybenzylamine (0.096mL, 0.636 mmol), Pd ₂ (dba) ₃ (61mg, 0.067 mmol), rac- BINAP (11 lmg, 0.178 mmol) and NaO'Bu (139mg, 1.445 mmol) in DMA (5mL) was heated at 85 ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2,5- dimethoxy-benzylamino)-2H-phthalazin-l-one (37 mg) as an off white solid, ¹ H (400

MHz, d ₆ -DMSO) δ: 3.45 (s, 3H), 3.61 (s, 3H), 4.17 (d, 2H), 6.63 (m, 3H), 6.76 (d, IH), 6.94 (dd, IH), 7.33 (t, IH), 7.72 (d, IH), 12.14 (s, IH) ppm; m/z (M+l) 345.92. Example 138: Synthesis of 4-Chloro-6-[(pyridin-2-ylmethyl)-amino]-2H-phthalazin- 1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (153mg, 0.590 mmol), 2- (aminomethyl)pyridine (0.066mL, 0.646 mmol), Pd ₂ (dba) ₃ (49mg, 0.0535 mmol), rac- BINAP (113mg, 0.181 mmol) and NaO'Bu (160mg, 1.665 mmol) in DMA (5mL) was heated at 85 ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-[(pyridin-2- ylmethyl)-amino]-2H-phthalazin-l-one (3 mg) as a yellow brown solid, ¹ H (400 MHz, d ₆ -DMSO) δ: 4.53 (d, 2H), 6.84 (s, IH), 7.18 (dd, IH), 7.28 (m, IH), 7.38 (d, IH), 7.75 2H), 7.92 (d, IH), 8.55 (d, IH), 12.35 (s, IH) ppm; m/z (M+l) 286.99. Example 139: Synthesis of 4-Chloro-6-(2-trifluoromethoxy-benzylamino)-2//- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150mg, 0.578 mmol), 2- (trifluoromethoxy)benzylamine (122mg, 0.636 mmol), Pd ₂ (dba) ₃ (49mg, 0.0535 mmol), rac-BINAP (104mg, 0.167 mmol) and NaO'Bu (142mg, 1.478 mmol) in DMA (5mL) was heated at 85 ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2- trifiuoromethoxy-benzylamino)-2H-phthalazin-l-one (41 mg) as a beige solid, ¹ H (400

MHz, d ₆ -DMSO) δ: 4.50 (s, 2H), 6.78 (s, IH), 7.16 (dd, IH), 7.40 (m, 3H), 7.47 (d, IH),

7.68 (t, lH)m 7.95 (d, IH), 12.37 (s, IH) ppm; m/z (M+l) 369.86.

Example 140: Synthesis of 4-Chloro-6-(2-difluoromethoxy-benzylamino)-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150mg, 0.578 mmol), 2- (difluoromethoxy)benzylamine (l lOmg, 0.636 mmol), Pd ₂ (dba) ₃ (47mg, 0.051 mmol), rac-BINAP (108mg, 0.173 mmol) and NaO'Bu (139mg, 1.445 mmol) in DMA (5mL) was heated at 85 ⁰ C for 2h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2- difluoromethoxy-benzylamino)-2H-phthalazin-l-one (14 mg) as a yellow solid, ¹ H (400 MHz, d ₆ -DMSO) δ: 4.43 (d, 2H), 6.81 (s, IH), 7.14 (dd, IH), 7.22 (m, 2H), 7.27 (t, IH), 7.37 (m, 2H), 7.60 (t, IH), 7.93 (d, IH), 12.35 (s, IH) ppm; m/z (M+l) 351.92. Example 141: Synthesis of 4-Chloro-6-(2-imidazol-l-yl-benzylamino)-2 _J fiT- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (148mg, 0.570 mmol), 2- imidazol-1-yl-benzylamine (1 lOmg, 0.635 mmol), Pd ₂ (dba) ₃ (53mg, 0.0578 mmol), rac- BINAP (117mg, 0.188 mmol) and NaO'Bu (227mg, 2.362 mmol) in DMA (5mL) was heated at 85 ⁰ C for 45 minutes. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2-imidazol- l-yl-benzylamino)-2H-phthalazin-l-one (17 mg) as a yellow solid, ¹ H (400 MHz, d ₆ -

DMSO) δ: 4.24 (d, 2H), 6.64 (s, IH), 7.06 (dd, IH), 7.11 (s, IH), 7.41 (m, IH), 7.46 (m, 2H), 7.52 (m, 2H), 7.59 (t, IH), 7.92 (m, 2H), 12.36 (IH) ppm; m/z (M+l) 351.99. Example 142: Synthesis of 4-Chloro-6-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- 2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150mg, 0.578 mmol), 1- (α,α,α-trifluoro-m-tolyl)piperazine (0.12mL, 0.639 mmol), Pd ₂ (dba) ₃ (53mg, 0.0578 mmol), rac-BINAP (123mg, 0.198 mmol) andNaO'Bu (176mg, 1.831 mmol) in DMA (5mL) was heated at 85 ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-[4-(3- trifluoromethyl-phenyl)-piperazin-l-yl]-2H-phthalazin-l-one (15 mg) as a beige solid, ¹ H (400 MHz, d ₆ -DMSO) δ: 3.21 (m, 4H), 3.40 (m, 4H), 6.86 (d, IH), 6.91 (d, IH), 6.98 (s, IH), 7.05 (m, IH), 7.22 (t, IH), 7.38 (dd, IH), 7.85 (d, IH), 12.28 (s, IH) ppm; m/z (M+l) 408.82.

Example 143: Synthesis of 4-Chloro-6-(2-[l,2,4]triazol-l-yl-benzylamino)-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150mg, 0.578 mmol), [3-(lη- l,2,4-triazol-l-yl)phenyl]methylamine (1 lOmg, 0.636 mmol), Pd ₂ (dba) ₃ (53mg, 0.0578 mmol), rac-BINAP (108mg, 0.173 mmol) and NaO'Bu (246mg, 2.560 mmol) in DMA (5mL) was heated at 85 ⁰ C for 45 minutes. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-

chloro-6-(2-[l,2,4]triazol-l-yl-benzylamino)-2H-phthalazin-l -one (24 mg) as a yellow solid, ¹ H (400 MHz, d ₆ -DMSO) δ: 4.54 (d, 2H), 6.86 (s, IH), 7.18 (dd, IH), 7.43 (d, IH),

7.54 (t, IH), 7.76 (m, 2H), 7.91 (s, IH), 7.94 (d, IH), 8.22 (s, IH), 9.28 (s, IH), 12.35 (s,

IH) ppm; m/z (M+l) 352.88.

Example 144: Synthesis of 4-Chloro-6-(3-morpholin-4-ylmethyl-benzylamino)-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150mg, 0.578 mmol), [3- (morpholinomethyl)phenyl]methylamine (131mg, 0.636 mmol), Pd ₂ (dba) ₃ (53mg, 0.0578 mmol), rac-BINAP (108mg, 0.173 mmol) and NaO'Bu (139mg, 1.445 mmol) in DMA (5mL) was heated at 85 ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3- morpholin-4-ylmethyl-benzylamino)-2H-phthalazin-l-one (42 mg) as an off white solid, ¹ H (400 MHz, d ₆ -DMSO) δ: 2.11 (m, 4H), 3.23 (s, 2H), 3.30 (t, 4H), 4.25 (d, 2H), 6.60 (s, IH), 6.98 (m, 2H), 7.10 (m, 3H), 7.50 (t, IH), 7.74 (d, IH), 12.16 (s, IH) ppm; m/z (M+l) 384.94.

Example 145: Synthesis of 4-Chloro-6-(3-pyrrol-l-yl-benzylamino)-2H-phthalazin- 1-one

A mixture ό-bromo^-chloro^H-phthalazin- 1 -one (160mg, 0.617 mmol), 3 -(1H- pyrol-l-yl)benzylamine (lOOmg, 0.581 mmol), Pd ₂ (dba) ₃ (58mg, 0.063 mmol), rac- BINAP (116mg, 0.186 mmol) and NaO'Bu (160mg, 1.665 mmol) in DMA (5mL) was heated at 85 ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried

(Na ₂ SO ₄ ). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3 -pyrrol- 1 - yl-benzylamino)-2H-phthalazin-l-one (47 mg) as an off white solid, ¹ H (400 MHz, d ₆ -

DMSO) δ: 4.49 (d, 2H), 6.26 (t, 2H), 6.87 (s, IH), 7.19 (dd, IH), 7.25 (d, IH), 7.33 (t,

2H), 7.42 (t, IH), 7.47 (m, IH), 7.61 (s, IH), 7.67 (t, IH), 7.94 (d, IH), 12.35 (s, IH) ppm; m/z (M+l) 350.90.

Example 146: Synthesis of 4-Chloro-6-[3-(4-methyl-piperidin-l-ylmethyl)- benzylamino]-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (148mg, 0.570 mmol), {3-[4- methylpiperidino)methyl]phenyl}methanamine (139mg, 0.636 mmol), Pd ₂ (dba) ₃ (60mg, 0.0655 mmol), rac-BINAP (113mg, 0.181 mmol) and NaO'Bu (152mg, 1.580 mmol) in DMA (5mL) was heated at 85 ⁰ C for 45 minutes. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Preparatory HPLC afforded 4-chloro-6-[3-(4- methyl-piperidin- 1 -ylmethyl)-benzylamino]-2H-phthalazin- 1 -one hydro formate (47 mg) as an off white solid, ¹ H (400 MHz, d ₆ -DMSO) δ: 0.82 (d, 3H), 1.00 (m,2H), 1.23 (bs, IH), 1.44 (d, 2H), 1.81 (t, 2H), 2.67 (m, 2H), 3.39 (s, 2H), 4.43 (d, 2H), 6.78 (s, IH), 7.14 (m, 2H), 7.26 (m,3H), 7.68 (t, IH), 7.90 (d, IH), 8.16 (s, IH), 12.33 (s, IH) ppm; m/z (M+l) 397.01. Example 147: Synthesis 4-Chloro-6-(2,3,5,6-tetrahydro-[l,2']bipyrazinyl-4-yl)-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (145mg, 0.559 mmol), l-(2- pyrazinyl)piperazine (104mg, 0.633 mmol), Pd ₂ (dba) ₃ (43mg, 0.047 mmol), rac-BINAP

(116mg, 0.186 mmol) and NaO'Bu (167mg, 1.738 mmol) in DMA (5mL) was heated at 85 ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Preparatory HPLC afforded 4-chloro-6-(2,3,5,6-tetrahydro-[l,2']bipyrazinyl-4-yl)-2H- phthalazin-1-one (32 mg) as a yellow solid, ¹ H (400 MHz, de-DMSO) δ: 3.62 (m, 4H), 3.78 (m, 4H), 7.12 (d, IH), 7.60 (dd, IH), 7.87 (d, IH), 8.07 (d, IH), 8.11 (m, IH), 8.37 (s, IH), 12.51 (s, IH) ppm. m/z (M+l) 342.98.

Example 148: Synthesis of of 4-Chloro-6-[4-(2-morpholin-4-yl-ethyl)-piperazin-l- yl]-2H-phthalazin-l-one hydroformate

A mixture ό-bromo^-chloro^H-phthalazin- 1 -one (150mg, 0.578 mmol), l-[2- (morpholin-4-yl)ethyl]piperazine (127mg, 0.636 mmol), Pd ₂ (dba) ₃ (53mg, 0.0578 mmol), rac-BINAP (108mg, 0.173 mmol) andNaO'Bu (139mg, 1.445 mmol) in DMA (5mL) was heated at 85 ⁰ C for 2h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Preparatory HPLC afforded 4-chloro-6-[4-(2-morpholin-4-yl-ethyl)-piperazin- l-yl]-2H-phthalazin-l-one hydroformate (43 mg) as an orange solid, ¹ H (400 MHz, d ₆ - DMSO) δ: 2.39 (m, 4H), 2.45 (m, 4H), 2.56 (m, 4H), 3.41 (m, 4H), 3.55 (t, 4H), 7.08 (d, IH), 7.54 (dd, IH), 8.03 (d, IH), 8.15 (s, IH), 12.49 (s, IH) ppm; m/z (M+l) 378.05. Example 149: Synthesis of 4-Chloro-6-[4-(3-dimethylamino-propyl)-piperazin-l-yl]- 2H-phthalazin-l-one hydroformate

.HCO ₂ H

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (150mg, 0.578 mmol), l-[3- (dimethylamino)propyl]piperazine (112mg, 0.654 mmol), Pd ₂ (dba) ₃ (53mg, 0.0578 mmol), rac-BINAP (108mg, 0.173 mmol) and NaO'Bu (139mg, 1.445 mmol) in DMA (5mL) was heated at 85 ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Preparatory HPLC afforded 4-chloro-6-[4-(3-dimethylamino-propyl)- piperazin-l-yl]-2H-phthalazin-l-one hydroformate (38 mg) as a pale brown solid, ¹ H (400 MHz, d ₆ -DMSO) δ: 1.66 (m, 2H), 2.30 (s, 6H), 2.34 (t, 2H), 2.53 (m, 6H), 3.43 (m, 4H),7.09 (d, IH), 7.55 (dd, IH), 8.03 (d, IH), 8.15 (s, IH), 12.50 (s, IH) ppm; m/z (M+l) 350.08.

Example 150: Synthesis of 4-Chloro-6-[3-(3-dimethylamino-propylamino)- benzylamino]-2//-phthalazin-l-one hydroformate

.HCO ₂ H

(3-Iodo-benzyl)-carbamic acid tert-butyl ester A mixture of 3-iodobenzylamine hydrochloride (3g, 11.131 mmol), CH ₂ Cl ₂

(6OmL) and triethylamine (3.ImL, 22.263 mmol) was stirred at room temperature. Boc- anhydride (2.6Og, 11.913 mmol) was added and the reaction stirred at room temperature for Ih. The reaction was poured onto water, extracted with CH ₂ Cl ₂ and dried (Na ₂ SO ₄ ). Preparatory HPLC afforded (3-iodo-benzyl)-carbamic acid tert-butyl ester (3.494g) as a white solid, m/z (M+l) 333.84.

[3-(3-dimethylamino-propylamino)-benzyl]-carbamic acid tert-butyl ester

A mixture of (3-iodo-benzyl)-carbamic acid tert-butyl ester (150mg, 0.450mmol), 3 -(dimethylamino)-l -propylamine (0.084mL, 0.675mmol), K ₂ CO ₃ (129mg, 0.933 mmol), CuI (1 lmg, 0.058 mmol), L-proline (13mg, 0.113mmol) and DMSO (3 mL) was heated at 8O ⁰ C for 1.5h. The reaction was cooled, poured onto water and the aqueous layer extracted with EtOAc (x3). The organic layers were combined and washed with water,

brine and dried (Na ₂ SO ₄ ). Chromatography (MeOH/EtOAc) afforded [3-(3-dimethyl amino-propylamino)-benzyl]-carbamic acid tert-buty\ ester (65mg) as a yellow solid, m/z (M+l) 308.13.

N-(3-Aminomethyl-phenyl)-N' ,N'-dimethyl-propane-l ,3-diamine hydrochloride A mixture of [3 -(3 -dimethyl amino-propylamino)-benzyl]-carbamic acid tert- butyl ester (65mg, 0.21 lmmol), methanol (2 mL) and 4.89N isopropanolic hydrochloric acid (1.3mL, 6.357mmol) was stirred at room temperature overnight. The reaction was concentrated and dried to yield N-(3-aminomethyl-phenyl)- _J /V,N'-dimethyl -propane- 1 ,3- diamine hydrochloride (65mg) as a yellow solid, m/z (M+l) 208.02. 4-Chloro-6-[3-(3-dimethylamino-propylamino)-benzylamino]-2H- phthalazin-l-one

A mixture of N-(3-aminomethyl-phenyl)-N ¹ ,N ^l -dimethyl-propane- 1 ,3-diamine hydrochloride (65mg, 0.267mmol), 6-bromo-4-chloro-2H-phthalazin-l-one (66mg, 0.254), Pd ₂ (dba) ₃ (31mg, 0.0339mmol), rac-BIνAP (57mg, 0.0915mmol), NaOtBu (88mg, 0.916mmol) and DMA (5mL) was heated to 85 ⁰ C until the reaction was completed by ηPLC. The reaction was filtered through celite and purified by preparatory ηPLC to yield 4-chloro-6-[3-(3-dimethylamino-propylamino)-benzylamino]-2H- phthalazin-1-one hydro formate (17mg) as an orange solid. ¹ H (400 MHz, d ₆ -DMSO) δ: 1.62 (quintet, 2H), 2.11 (s, 6H), 2.26 (t, 2H), 2.98 (t, 2H), 4.29 (d, 2H), 6.42 (d, IH), 6.53 (m, 2H), 6.81 (s, IH), 7.10 (t, IH), 7.12 (dd, IH), 7.60 (t, IH), 7.91 (d, IH), 8.20 (s, 2H), 12.32 (s, IH) ppm; m/z (M+l) 385.96.

Example 151: Synthesis of 4-Chloro-6-[3-(2-morpholin-4-yl-ethylamino)- benzylamino]-2H-phthalazin-l -one hydroformate

.HCO ₂ H

[3-(2-Morpholin-4-yl-ethylamino)-benzyl]-carbamic acid isopropyl ester A mixture of (3-iodo-benzyl)-carbamic acid tert-butyl ester (272mg, 0.816mmol),

4-(2-aminoethyl)morpholine (O.lβmL, 1.225 mmol), K ₂ CO ₃ (232mg, 1.679 mmol), CuI

(19mg, 0.10 mmol), L-proline (19mg, 0.163mmol) and DMSO (5 mL) was heated at 85°C for Ih. The reaction was cooled, poured onto water and the aqueous layer extracted with EtOAc (x3). The organic layers were combined and washed with water, brine and dried (Na ₂ SO ₄ ). Chromatography (MeOH/EtOAc) afforded [3-(2-morpholin-4-yl- ethylamino)-benzyl]-carbamic acid isopropyl ester (200mg) as an orange viscous oil. m/z (M+l) 336.16. (3-Aminomethyl-phenyl)-(2-morpholin-4-yl-ethyl)-amine hydrochloride

A mixture of [3-(2-morpholin-4-yl-ethylamino)-benzyl]-carbamic acid isopropyl ester (200mg, 0.596mmol), methanol (4 mL) and 4.89N isopropanolic hydrochloric acid (2.4mL) was stirred at room temperature overnight. The reaction was concentrated and dried to yield (3-aminomethyl-phenyl)-(2-morpholin-4-yl-ethyl)-amine hydrochloride (212mg) as an orange solid, m/z (M+l) 236.04.

4-Chloro-6-[3-(2-morpholin-4-yl-ethylamino)-benzylamino]-2H- phthalazin-l-one hydroformate A mixture of (3-aminomethyl-phenyl)-(2-morpholin-4-yl-ethyl)-arnine hydrochloride (212mg, 0.781mmol), 6-bromo-4-chloro-2H-phthalazin-l-one (184mg, 0.710), Pd ₂ (dba) ₃ (65mg, 0.071mmol), rac-BINAP (142mg, 0.228mmol), NaOtBu (266mg, 2.768mmol) and DMA (5mL) was heated to 85°C until the reaction was completed by ηPLC. The reaction was filtered through celite and purified by preparatory ηPLC to yield 4-chloro-6-[3-(2-moφholin-4-yl-ethylamino)-benzylamino]-2H- phthalazin-1-one hydroformate (62mg) as a light brown solid. ¹ H (400 MHz, dβ-DMSO) δ: 2.29 (m, 4H), 2.36 (t, 2H), 3.02 (m, 2H), 3.48 (m, 4H), 4.24 (d, 2H), 5.38 (bs, IH), 6.40 (dd, IH), 6.47 (d, IH), 6.51 (s, IH), 6.77 (s, IH), 6.97 (t, IH), 7.07 (dd, IH), 7.54 (t, IH), 7.85 (d, IH), 8.10 (s, IH), 12.26 (s, IH) ppm; m/z (M+l) 413.93. Example 152: Synthesis of 4-Chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3-piperidin-l-yImethyl-phenyl)-amide hydroformate

.HCO ₂ H

1 ^-Dichloro-phthalazine-ό-carboxylic acid (3-piperidin-l -ylmethyl-phenyl) -amide hydroformate

A mixture of l^-dihydroxy-phthalazine-ό-carboxylic acid (0.28g, 1.358 mmol) in thionyl chloride (4 mL) was refluxed for 3 hours. Phosphorous oxychloride (4 mL) was added and the reaction refluxed for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (5 mL) and added dropwise to a 0 ⁰ C solution of 3-(piperidin-l-yl-methyl)aniline (0.485 g, 2.55 mmol), DMF (3 mL) and NEt ₃ (0.71 mL, 5.09 mmol). The reaction was stirred at 0 ⁰ C for Ih, diluted with water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with water (x3), sat. aq. NH ₄ Cl, brine and dried (Na ₂ SO ₄ ). Column chromatography (Hex/EtOAc) afforded l,4-dichloro-phthalazine-6-carboxylic acid (3-piperidin-l- ylmethyl-phenyl)-amide (257 mg). m/z (M+ 1) 414.96.

A mixture of l,4-dichloro-phthalazine-6-carboxylic acid (3-piperidin-l-ylmethyl- phenyl)-amide (257 mg, 0.619 mmol), 2NNaOH (3.1 mL, 6.19 mmol) and dioxane (5 mL) was heated to 50 ⁰ C for Ih. The reaction was diluted with water, acidified with cone. HCl to ~pH 6. The reaction mixture was concentrated to low volumn and filtered through celite. Preparatory HPLC afforded the desired regioisomer 4-chloro-l-oxo-l,2- dihydro-phthalazine-6-carboxylic acid (3 -piperidin- 1 -ylmethyl-phenyl)-amide hydroformate (16 mg) as a pale yellow solid, ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 1.54 (m, 2H), 1.44 (m, 4H), 2.28 (m, 4H), 3.37 (s, 2H), 7.00 (m, IH), 7.25 (m, IH), 7.67 (m, 2H), 8.06 (d, IH), 8.10 (s, IH), 8.47 (dd, IH), 8.82 (d, IH), 10.63 (IH), 12.95 (s, IH) ppm; m/z (M+ 1) 396.95. Example 153: Synthesis of 4-Chloro-6-[3-(4-methyl-[l,4]diazepan-l-yl)- benzylamino]-2/y-phthaIazin-l-one hydroformate

.HCO ₂ H

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (lOOmg, 0.385 mmol), 3-(4- methyl-[l,4]diazepan-l-yl)-benzylamine (112mg, 0.654 mmol), Pd ₂ (dba) ₃ (53mg, 0.0578 mmol), rac-BINAP (108mg, 0.173 mmol) and NaO'Bu (139mg, 1.445 mmol) in DMA (5mL) was heated at 85 ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Preparatory HPLC afforded 4-chloro-6-[3-(4-methyl-[l,4]diazepan-l- yl)-benzylamino]-2H-phthalazin-l-one hydroformate (29 mg) as a pale brown solid. ¹ H (400 MHz, d ₆ -DMSO) δ: 1.83 (m, 2H), 2.21 (s, 3H). 2.39 (m, 2H), 2.54 (m, 2H), 3.38 (m, 2H), 3.46 (m, 2H), 4.32 (d, 2H), 6.56 (m, 2H), 6.71 (s, IH), 6.83 (s, IH), 7.09 (t, IH), 7.16 (dd, IH), 7.61 (m, IH), 7.90 (d, IH), 8.19 (s, IH), 12.33 (s, IH) ppm; m/z (M+l) 398.04.

Example 154 and 155: Synthesis of l-Chloro-4-oxo-3,4-dihydro-phthalazine-6- carboxylic acid (2-morpholin-4-yl-5-trifluoromethyl-phenyl)-amide and 4-Chloro-l- oxo-1 ,2-dihydro-phthalazine-6-carboxylic acid (2-morpholin-4-yl-5-trifluoromethyl- phenyl)-amide

1, ^Dichloro-phthalazine-ό-carboxylic acid (2-morpholin-4-yl-5-trifluoromethyl-phenyl)- amide

A mixture of M-dihydroxy-phthalazine-ό-carboxylic acid (617g, 2.99 mmol) in thionyl chloride (6 mL) was refluxed for 3 hours. Phosphorous oxychloride (6 mL) was added and the reaction refluxed for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (5 mL) and added dropwise to a 0 ⁰ C solution of 2-moφholino-5-(trifluoromethyl)aniline (780 mg, 3.168 mmol), DMF (4 mL) and NEt ₃ (1.25 mL, 8.97 mmol). The reaction was stirred at 0 ⁰ C for Ih, diluted with water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with water (x3), sat.aq. NH ₄ Cl, brine and dried (Na ₂ SO ₄ ). Column

chromatography (Hex/EtOAc) afforded l^-dichloro-phthalazine-ό-carboxylic acid (2- morpholin-4-yl-5-trifluoromethyl-phenyl)-amide (322 mg). m/z (M+ 1) 470.91. l-chloro-4-oxo-3, 4-dihydro-phthalazine-6-carboxylic acid (2-morpholin-4-yl-5- trifluoromethyl'phenyl) -amide and 4-chloro-l -oxo-1 ^-dihydro-phthalazine-ό-carboxylic acid (2-morpholin-4-yl-5-trifluoromethyl-phenyl)-amide

A mixture of 1 ^-dichloro-phthalazine-β-carboxylic acid (2-morpholin-4-yl-5- trifluoromethyl-phenyl)-amide (322 mg, 0.683 mmol), 2N NaOH (3.4 mL, 6.83 mmol) and dioxane (5 mL) was heated to 50 ⁰ C for Ih. The reaction was diluted with water, acidified with cone. HCl to ~pH 6. The reaction mixture was concentrated to low volumn and filtered through celite. Chromatography (Hex/EtOAc) afforded l-chloro-4- oxo-3,4-dihydro-phthalazine-6-carboxylic acid (2-morpholin-4-yl-5-trifluoromethyl- phenyl)-amide (49 mg) as a yellow solid, ¹ H NMR (400 MHz, de-DMSO) δ: 2.99 (m, 4H), 3.80 (m, 4H), 7.41 (d, IH), 7.56 (dd, IH), 8.18 (d, IH), 8.28 (s, IH), 8.51 (dd, IH), 8.80 (d, IH), 10.23 (s, IH), 13.05 (s, IH) ppm; m/z (M+ 1) 452.96; and 4-chloro-l-oxo- l,2-dihydro-phthalazine-6-carboxylic acid (2-morpholin-4-yl-5-trifluorornethyl-phenyl)- amide (40mg) as a pale yellow solid. ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 2.99 (m, 4H), 3.80 (m, 4H), 7.41 (d, IH), 7.58 (dd, IH), 8.29 (s, IH), 8.43 (s, 2H), 8.46 (s, IH), 10.23 (s, IH), 13.02 (s, IH) ppm; m/z (M+ 1) 452.96. Example 156 and 157: Synthesis of l-chloro-4-oxo-3,4-dihydro-phthalazine-6- carboxylic acid (3-furan-2-yl-phenyl)-amide and 4-chloro-l-oxo-l,2-dihydro- phthalazine-6-carboxylic acid (3-furan-2-yl-phenyI)-amide

1, 4-Dichloro-phthalazine-6-carboxylic acid (3-furan-2-yl-phenyl)-amide

A mixture of l,4-dihydroxy-phλalazine-6-carboxylic acid (617g, 2.99 mmol) in thionyl chloride (6 mL) was refluxed for 3 hours. Phosphorous oxychloride (6 mL) was added and the reaction refluxed for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (5 mL) and added

dropwise to a 0 ⁰ C solution of 3-(2-furyl)aniline (490 mg, 3.078 mmol), DMF (4 mL) and NEt ₃ (1.25 mL, 8.97 mmol). The reaction was stirred at 0 ⁰ C for Ih, diluted with water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with water (x3), sat.aq. NH ₄ Cl, brine and dried (Na ₂ SO ₄ ). Column chromatography (Hex/EtOAc) afforded l^-dichloro-phthalazine-ό-carboxylic acid (3-furan-2-yl-phenyl)-amide (400 mg). m/z (M+ 1) 383.92. l-Chloro-4-oxo-3, 4-dihydro-phthalazine-6-carboxylic acid (3-furan-2-yl-phenyl)-amide and 4-Chloro-l -oxo-1 J-dihydro-phthalazine-ό-carboxylic acid (3-furan-2-yl-phenyl)- amide A mixture of 1 ^-dichloro-phthalazine-ό-carboxylic acid (3-furan-2-yl-phenyl)- amide (400 mg, 1.041 mmol), 2N NaOH (5.2 mL, 10.41 mmol) and dioxane (5 mL) was heated to 50 °C for 5h. The reaction was diluted with water, acidified with cone. HCl to ~pH 6. The reaction mixture was concentrated to low volumn and filtered through celite. Chromatography (Hex/EtOAc) afforded l-chloro-4-oxo-3,4-dihydro-phthalazine-6- carboxylic acid (3-furan-2-yl-phenyl)-amide (43 mg) as a pale yellow solid, ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 6.76 (m, IH), 7.08 (d, IH), 7.58 (t, IH), 7.64 (m, IH), 7.90 (m, 2H), 8.30 (d, IH), 8.34 (s, IH), 8.70 (dd, IH), 9.05 (s, IH), 10.98 (s, IH), 13.19 (s, IH) ppm; m/z (M+ 1) 365.90; and 4-chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3-furan-2-yl-phenyl)-amide (40mg) as a pale yellow solid. ¹ H NMR (400 MHz, d ₆ - DMSO) δ: 6.62 (m, IH), 6.92 (d, IH), 7.44 (t, IH), 7.50 (m, IH), 7.74 (m, IH), 7.78 (s, IH), 8.17 (m, IH), 8.45 (m, 2H), 8.52 (s, IH), 10.80 (s, IH), 13.01 (s, IH) ppm; m/z (M+ 1) 365.97.

Example 158: Synthesis of 4-Chloro-6-(3-dimethylaminomethyl-benzyIamino)-2H- phthalazin-1-one hydroformate

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (156mg, 0.601 mmol), 3- dimethylaminomethylbenzylamine (1 lOmg, 0.67 mmol), Pd ₂ (dba) ₃ (49mg, 0.0535 mmol), rac-BINAP (108mg, 0.173 mmol) and NaO'Bu (143mg, 1.488 mmol) in DMA

(5mL) was heated at 85 ⁰ C for Ih. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Preparatory HPLC afforded 4-chloro-6-(3-dimethylaminomethyl- benzylamino)-2H-phthalazin-l-one hydroformate (50 mg) as a pale brown solid. ¹ H (400 MHz, de-DMSO) δ: 2.21 (s, 6H), 3.46 (s, 2H), 4.51 (d, 2H), 6.90 (s, IH), 7.25 (m, 2H), 7.36 (m, 2H), 7.40 (s, IH), 7.77 (t, IH), 8.02 (s, IH), 8.27 (s, IH), 12.42 (s, IH), ppm; m/z (M+l) 343.05.

Example 159: Synthesis of 4-Chloro-6-[3-(2-dimethylamino-ethyIamino)- benzylamino]-2H-phthalazin-l-one hydroformate

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (204mg, 0.785 mmol), iV-(3- Aminomethyl-phenyO-N ¹ ^-dimethyl-ethane- 1,2-diamine hydrochloride (198mg, 0.86 mmol), Pd ₂ (dba) ₃ (72mg, 0.0785 mmol), rac-BIνAP (162mg, 0.260 mmol) and νaO'Bu (266mg, 2.77 mmol) in DMA (6mL) was heated at 85 ⁰ C for 3h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Preparatory HPLC afforded 4- chloro-6-[3 -(2-dimethylamino-ethylamino)-benzylamino]-2H-phthalazin- 1 -one hydroformate (81 mg) as a yellow solid. ¹ H (400 MHz, d ₆ -DMSO) δ: 1.95 (s, 6H), 2.40 (m, IH), 2.46 (m, IH), 2.87 (m, 2H), 4.10 (d, 2H), 5.20 (bs, IH), 6.26 (dd, IH), 6.34 (d, IH), 6.37 (s, IH), 6.62 (s, IH), 6.82 (t, IH), 6.93 (dd, IH), 7.40 (t, IH), 7.70 (d, IH), 7.95 (s, IH), 12.12 (s, IH) ppm; m/z (M+l) 372.04.

Example 160 and 161: Synthesis of l-Chloro-4-oxo-3,4-dihydro-phthalazine-6- carboxylic acid wi-tolylamide and 4-Chloro-l-oxo-l,2-dihydro-phthalazine-6- carboxylic acid m-tolylamide

l^-Dichloro-phthalazine-ό-carboxylic acid m-tolylamide

A mixture of l^-dihydroxy-phthalazine-β-carboxylic acid (0.7Og, 3.395 mmol) in thionyl chloride (7 mL) was refluxed for 3 hours. Phosphorous oxychloride (7 mL) was added and the reaction refluxed for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (8 mL) and added dropwise to a 0 ⁰ C solution of m-toluidine (0.44 mL, 4.074 mmol), DMF (3 mL) and NEt ₃ (1.42 mL, 10.186 mmol). The reaction was stirred at 0 ⁰ C for 2h, diluted with water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with water (x3), sat.aq. NH ₄ Cl, brine and dried (Na ₂ SO ₄ ). Column chromatography (Hex/EtOAc) afforded l,4-dichloro-phthalazine-6-carboxylic acid m-tolylamide (100 mg). m/z (M+l)

332.04. l-Chloro^-oxoS^-dihydro-phthalazine-ό-carboxylic acid m-tolylamide and 4-Chloro-

1 -oxo-1, 2-dihydro-phthalazine-6-carboxylic acid m-tolylamide A mixture of 1 ^-dichloro-phthalazine-ό-carboxylic acid m-tolylamide (350 mg,

0.87 mmol), 2N NaOH (4.4 mL, 8.70 mmol) and dioxane (4 mL) was heated to 50 ⁰ C for 3h. The reaction was diluted with water, acidified with cone. HCl to ~pH 6. The reaction mixture was concentrated to low volumn and filtered through celite. Chromatography (Hex/EtOAc) afforded l-chloro-4-oxo-3,4-dihydro-phthalazine-6- carboxylic acid m-tolylamide (8 mg) as a pale yellow solid, ¹ H NMR (400 MHz, d ₆ - DMSO) δ: 2.32 (s, 3H), 7.96 (d, IH), 7.26 (t, IH), 7.60 (d, IH), 7.65 (s, IH), 8.14 (d, IH), 8.52 (dd, IH), 8.87 (s, IH), 10.67 (s, IH), 13.00 (bs, IH) ppm; m/z (M-I) 312.13; and 4-chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid m-tolylamide (23mg) as a pale yellow solid. ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 2.11 (s, 3H), 6.76 (m, IH), 7.05 (m, IH), 7.40 (m, 2H), 8.25 (m, 3H), 10.42 (s, IH), 12.80 (s, IH) ppm; m/z (M-I) 312.13. Example 162 and 163: Synthesis of l-Chloro-4-oxo-3,4-dihydro-phthalazine-6- carboxylic acid (3-trifluoromethoxy-phenyl)-amide and 4-Chloro-l-oxo-l,2-dihydro- phthalazine-6-carboxylic acid (3-trifIuoromethoxy-phenyl)-amide

1, ^Dichloro-phthalazine-ό-carboxylic acid (3-trifluoromethoxy-phenyl)-amide

A mixture of l^-dihydroxy-phthalazine-ό-carboxylic acid (0.7Og, 3.395 mmol) in thionyl chloride (7 mL) was refluxed for 3 hours. Phosphorous oxychloride (7 mL) was added and the reaction refluxed for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (8 mL) and added dropwise to a 0 ⁰ C solution of 3-(trifluoromethoxy)aniline (0.54 mL, 4.074 mmol), DMF (3 mL) and NEt ₃ (1.42 mL, 10.186 mmol). The reaction was stirred at 0 ⁰ C for 2h, diluted with water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with water (x3), sat.aq. NH ₄ Cl, brine and dried (Na ₂ SO ₄ ). Column chromatography (Hex/EtOAc) afforded l,4-dichloro-phthalazine-6-carboxylic acid (3-trifluoromethoxy- phenyl)-amide(350 mg). m/z (M+ 1) 401.90. l-Chloro^-oxoS^-dihydro-phthalazine-ό-carboxylic acid (3-trifluoromethoxy-phenyl)- amide and 4-Chloro-l -oxo-1 ^-dihydro-phthalazine-ό-carboxylic acid (3-trtfluoro methoxy-phenyl)-amide

A mixture of l^-dichloro-phthalazine-β-carboxylic acid (3-trifluoromethoxy- phenyl)-amide (350 mg, 0.87 mmol), 2N NaOH (4.4 mL, 8.70 mmol) and dioxane (4 mL) was heated to 50 ⁰ C for 3h. The reaction was diluted with water, acidified with cone. HCl to ~pH 6. The reaction mixture was concentrated to low volumn and filtered through celite. Chromatography (Hex/EtOAc) afforded l-chloro-4-oxo-3,4-dihydro- phthalazine-6-carboxylic acid (3-trifiuoromethoxy-phenyl)-amide (14 mg) as a white solid, ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 7.14 (m, IH), 7.52 (t, IH), 7.82 (d, IH), 7.95 (s, IH), 8.14 (d, IH), 8.53 (dd, IH), 8.89 (s, IH), 10.88 (s, IH), 13.04 (s, IH) ppm; m/z (M+l) 384.05; and 4-chloro-l -oxo-1, 2-dihydro-phthalazine-6-carboxylic acid (3- trifluoromethoxy-phenyl)-amide (20mg) as a white solid. ¹ H NMR (400 MHz, d ₆ - DMSO) δ: 7.06 (d, IH), 7.44 (t, IH), 7.70 (d, IH), 7.85 (s, IH), 8.34 (m, 2H), 8.39 (s, IH), 10.87 (s, IH), 12.92 (s, IH) ppm; m/z (M+l) 384.05.

Example 164 and 165: Synthesis of l-Chloro-3-methyl-4-oxo-3,4-dihydro- phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide and 4-Chloro-2- methyl-l-oxo-l^-dihydro-phthalazine-δ-carboxylic acid fS-trifluoromethyl-phenyl)- amide

1, 4-Dioxo-l, 2, 3, 4-tetrahydro-phthalazine-6-carboxylic acid

A mixture of 1,2,4-benzyenetricarboxylic acid (7.Og, 36.43 mmol) and isopropyl alcohol (14OmL) was heated to reflux. Methylhydrazine (5 mL) was added to the reaction and heating continued for 2.5h. The reaction was cooled, followed by acidification to pH3 with 2N HCl. The solids were filtered and rinsed with isopropyl alcohol to afforded l,4-dioxo-l,2,3,4-tetrahydro-phthalazine-6-carboxylic acid (4.53g). m/z (M+l) 221.15. l-Chloro-3-methyl-4-oxo-3, 4-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethyl- phenyl) -amide and 4-Chloro-2-methyl-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide

A mixture of l,4-dioxo-l,2,3,4-tetrahydro-phthalazine-6-carboxylic acid (2.5g, 9.14 mmol), in thionyl chloride (25 mL) was refluxed for 3 hours. Phosphorous oxychloride (25 mL) was added and the reaction refluxed for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (15 mL) and added dropwise to a 0 ⁰ C solution of 3-(trifluoromethyl)aniline (1.71 mL, 13.71 mmol), DMF (15 mL) and NEt ₃ (3.82 mL, 27.42 mmol). The reaction was then heated to 85 ⁰ C for Ih. The reaction was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were washed with water (x3), sat.aq. NH ₄ Cl, brine and dried (Na ₂ SO ₄ ). Column chromatography (Hex/EtOAc) afforded l-chloro-S-methyM-oxo-S^-dihydro-phthalazine-β-carboxylic acid (3- trifluoromethyl-phenyl)-amide (17 mg) as a white solid, ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 3.73 (s, 3H), 7.51 (d, IH), 7.64 (t, IH), 8.10 (d, IH), 8.17 (d, IH), 8.27 (s, IH), 8.54

(dd, IH), 8.93 (d, IH), 11.03 (s, IH) ppm; m/z (M+l) 382.09; and 4-chloro-2-methyl-l- oxo- 1 ^-dihydro-phthalazine-ό-carboxylic acid (3-trifluoromethyl-phenyl)-amide (156mg) as a white solid. ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 3.72 (s, 3H), 7.52 (d, IH), 7.65 (t, IH), 8.08 (d, IH), 8.25 (s, IH), 8.46 (s, 2H), 8.53 (m, IH), 11.02 (s, IH) ppm; m/z (M+l) 382.09.

Example 166 and 167: Synthesis of l-chloro-4-oxo-3,4-dihydro-phthalazine-6- carboxylic acid [5-ethoxymethyl-2-methyl-3-(2-pyrrolidin-l-yl-ethylamino)-ph enyl]- amide hydroformate and 4-chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid [5-ethoxy methyl-2-methyl-3-(2-pyrrolidin-l-yl-ethylamino)-phenyl]-ami de hydroformate

(3,5-Dibromo-4-methyl-phenyl)-methanol

A mixture of methyl 3,5-dibromo-4-methylbenzoate (15g, 48.706mmol), NaBH ₄

(5.53g, 146.18mmol) and absolute ethanol (175mL) was heated to reflux for 4h. The mixture was cooled, followed by acidification with 2N HCl. The solids were filtered through celite and rinsed with EtOAc. The filtrate was poured onto water and extracted.

The organic layer was washed with brine and dried (Na ₂ SO ₄ ). Chromatography

(Hexanes/EtOAc) afforded (3,5-dibromo-4-methyl-phenyl)-methanol (9.94g) as a white solid. ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 2.48 (s, 3H), 4.45 (d, 2H), 5.38 (t, IH), 7.57 (s, 2H) ppm. l,3-Dibromo-5-ethoxymethyl-2-methyl-benzene

A mixture of (3,5-dibromo-4-methyl-phenyl)-methanol (4g, 14.288mmol), 60%

NaH (690mg, 28.75mmol) and THF (72mL) was heated to 7O ⁰ C in a sealed tube for 15 minutes. The reaction was cooled, bromoethane (3.2mL, 42.86mmol) was added and the reaction continued heating at 7O ⁰ C for 6h. The reaction was cooled, poured onto water, extracted with EtOAc (x3). The organics were washed with water, brine and dried

(Na ₂ SO ₄ ). Chromatography (Hexanes/EtO Ac) afforded l,3-dibromo-5-ethoxymethyl-2- methyl-benzene (2.187g) as a colourless oil. ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 1.15 (t, 3H), 2.48 (s, 3H), 3.46 (q, 2H), 4.41 (s, 2H), 7.57 (s, 2H) ppm. Benzyl-(3-bromo-5-ethoxymethyl-2-methyl-phenyl)-amine A mixture of l,3-dibromo-5-ethoxymethyl-2-methyl-benzene (1.322g,

4.29mmol), benzylamine (0.49mL, 4.507mmol), Pd2(dba)3 (409mg, 0.447mmol), rac- BINAP (81 lmg, 1.302mmol), NaOtBu (618mg, 6.435mmol) and toluene (3OmL) was heated at 8O ⁰ C for Ih 45 minutes. The reaction was cooled, poured onto water and extracted with EtOAc (x3). The organics were washed with water, brine and dried (Na ₂ SO ₄ ). Chromatography (Hexanes/EtO Ac) afforded benzyl-(3-bromo-5- ethoxymethyl-2-methyl-phenyl)-amine (1.268g) as a yellow liquid. ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 1.24 (t, 3H), 2.32 (s, 3H), 3.50 (q, 2H), 4.04 (bs, IH), 4.41 (s, 4H), 6.61 (s, IH), 7.00 (s, IH), 7.35 (m, 5H) ppm. N-Benzyl-5-ethoxymethyl-2-methyl-N'-(2-pyrrolidin-l-yl-ethyl )-benzene-l,3-diamine A mixture of benzyl-(3-bromo-5-ethoxymethyl-2-methyl-phenyl)-amine (1.253g,

3.749mmol), xantphos (134mg, 0.232mmol), l-(2-aminoethyl)pyrrolidine (0.7ImL, 5.639mmol), Pd ₂ (dba) ₃ (1 lOmg, 0.120mmol), NaO ¹ Bu (658mg, 6.847mmol) and anhydrous dioxane (4OmL) was heated to 95°C for 14h. The reaction was cooled, filtered through celite, rinsed with EtOAc and concentrated. Chromatography (EtOAc/MeOH) afforded N-benzyl-5-ethoxymethyl-2-methyl-N'-(2-pyrrolidin-l-yl-ethyl )-benzene-l ,3- diamine (81Og) as an orange liquid, m/z (M+l) 368.36. 5-Ethoxymethyl-2-methyl-N-(2-pyrrolidin-l-yl-ethyl)-benzene- l,3-diamine hydrochloride

A mixture of N-benzyl-5-ethoxymethyl-2-methyl-N ^l -(2 -pyrrolidin-1-yl-ethyl)- benzene- 1,3 -diamine (810mg, 2.204mmol), 10% wet Pd/C (catalytic), 2 drops of cone. HCl and MeOH (12mL) was evacuated and flushed (x3) with hydrogen. The reaction was stirred under a hydrogen balloon for 4h. The reaction was filtered through celite, rinsed with MeOH and concentrated to yield 5-ethoxymethyl-2-methyl-N-(2-pyrrolidin- l-yl-ethyl)-benzene-l,3-diamine hydrochloride as a dark oil. m/z (M+l) 278.34 (Free Base). Synthesis ofl-Chloro-^oxoS^-dihydro-phthalazine-β-carboxylic acid and 4-Chloro-l- oxo-1, 2-dihydro-phthalazine-6-carboxylic acid

A mixture of l^-dihydroxy-phthalazine-β-carboxylic acid (2g, 9.701mmol) and thionyl chloride (25mL) was heated to reflux for 3h. To the reaction was added POCl ₃ (25mL) and the reaction heated at reflux for 15h. The reaction was cooled, concentrated and stripped three times with toluene. The solids dissolved in dioxane and cooled in an ice/water bath. A solution of 2N NaOH (48.5mL, 97.01mmol) was carefully added to the reaction. Once addition was complete the reaction was heated to 50 ⁰ C for Ih. The reaction mixture was cooled and concentrated to low volume. Water was added to the mixture and acidified to pH3. The solids were filtered and dried in vacuum to yield a mixture of l-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid and 4-chloro-l- oxo-l,2-dihydro-phthalazine-6-carboxylic acid (1.465g) as an orange solid. ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 8.08 (s, d, IH), 8.40 (m, 4H), 8.73 (s, IH), 12.97 (s, IH), 13.01 (s, IH) ppm; m/z (M+ 1) 225.15 and 225.07. l-Chloro-4-oxo-3, 4-dihydro-phthalazine-6-carboxylic acid [5-ethoxymethyl-2-methyl-3- (2-pyrrolidin-l -yl-ethylamino) -phenyl] '-amide formic acid salt and 4-Chloro-l-oxo-l ,2- dihydro-phthalazine-6-carboxylic acid [5-ethoxymethyl-2-methyl-3-(2-pyrrolidin-l -yl- ethylamino) -phenyl] -amide formic acid salt

A mixture of 5-ethoxymethyl-2-methyl-N-(2-pyrrolidin- 1 -yl-ethyl)-benzene- 1,3- diamine hydrochloride (430mg, 1.55mmol), l-chloro-4-oxo-3,4-dihydro-phthalazine-6- carboxylic acid and 4-chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid (331mg, 1.476mmol), ν-(3-dimethylaminopropyl)-ν'-ethylcarbodiirnide hydrochloride (863mg, 4.50mmol), NEt ₃ (0.82mL, 5.904), 1-hydroxybenzotriazole hydrate (259mg, 1.919mmol) and anhydrous DMF was stirred at room temperature for 2.5h. The reaction mixture was filtered through celite, rinsed with CH ₂ Cl ₂ and concentrated. Preparatory HPLC afforded l-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid [5-ethoxymethyl-2-methyl-3- (2-pyrrolidm-l-yl-ethylamino)-phenyl]-amide formic acid salt (72mg) as an orange solid. ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 1.15 (t, 3H), 1.72 (m, 4H), 1.93 (s, 3H), 2.58 (m, 4H), 2.74 (t, 2H), 3.22 (m, 2H), 3.46 (q, 2H), 4.38 (s, 2H), 4.93 (bs, IH), 6.49 (s, IH), 6.56 (s, IH), 8.18 (s, IH), 8.39 (d, IH), 8.46 (d, IH), 8.52 (s, IH), 10.40 (s, IH), 13.00 (s, IH) ppm; m/z (M+l) 484.33; and 4-chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid [5-ethoxymethyl-2-methyl-3-(2-pyrrolidin-l-yl-ethylamino)-ph enyl]-amide formic acid salt (78mg) as an orange solid. ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 1.14 (t, 3H), 1.73 (m,

4H), 1.93 (s, 3H), 2.61 (m, 4H), 2.77 (t, 2H), 3.24 (m, 2H), 3.47 (m, 2H), 4.37 (s, 2H), 4.95 (bs, IH), 6.50 (s, IH), 6.57 (s, IH), 8.12 (d, IH), 8.18 (s, IH), 8.52 (d, IH), 8.88 (s, IH), 10.40 (s, IH), 13.02 (s, IH) ppm; m/z (M+ 1) 484.33.

Example 168: Synthesis of l-Oxo-l^-dihydro-phthalazine-ό-carboxylic acid [5- ethoxymethyl-2-methyI-3-(2-pyrrolidin-l-yl-ethylamino)-pheny l]-amide

A mixture of 4-chloro-l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid [5- ethoxymethyl-2-methyl-3-(2-pyrrolidin-l-yl-ethylamino)-pheny l]-amide formic acid salt (55mg, 0.104mmol), 10% wet Pd/C (catalytic), 1 drop of cone. HCl and MeOH (4mL) was evacuated and flushed (x3) with hydrogen. The reaction was stirred under a hydrogen balloon for 2.5h. The reaction was filtered through celite, rinsed with MeOH and concentrated to yield l-oxo-l,2-dihydro-phthalazine-6-carboxylic acid [5- ethoxymethyl-2-methyl-3-(2-pyrrolidin-l-yl-ethylamino)-pheny l]-amide (43mg) as a tan solid. ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 1.16 (t, 3H), 1.93 (m, 4H), 2.00 (s, 3H), 2.53 (m, 4H), 3.47 (m, 6H), 4.39 (s, 2H), 5.23 (bs, IH), 6.53 (s, IH), 6.62 (s, IH), 8.34 (s, 2H), 8.48 (s, IH), 8.50 (s, IH), 10.25 (s, IH), 12.80 (s, IH) ppm; m/z (M+ 1) 450.38. Example 169 and 170: Synthesis of l-Chloro-4-oxo-3,4-dihydro-phthalazine-6- carboxylic acid 3-trifluoromethyl-benzylamide and 4-Chloro-l-oxo-l,2-dihydro- phthalazine-6-carboxylic acid 3-trifluoromethyl-benzylamide

A mixture of l-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid and A- chloro-l-oxo-l^-dihydro-phthalazine-ό-carboxylic acid (311mg, 1.385 mmol), catalytic DMF and thionyl chloride (7 mL) was refluxed for 3 hours. The solution was cooled,

concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (3 mL) and added dropwise to a 0 ⁰ C solution of 3-(trifluoromethyl)benzylamine (0.22 mL, 1.524 mmol), DMF (5 mL) and 60% NaH (199mg, 8.31 mmol). The reaction was stirred at room temperature overnight, diluted with water and extracted with EtOAc (x3). The combined organic layers were washed with water, brine and dried (Na ₂ SO ₄ ). Column chromatography (Hex/EtOAc) afforded l-chloro-4-oxo-3,4-dihydro-phthalazine-6- carboxylic acid 3-trifluoromethyl-benzylamide (30 mg) as a white solid. ¹ H NMR (400 MHz, d ₆ -DMSO) δ: 4.62 (d, 2H), 7.65 (m, 4H), 8.10 (d, IH), 8.47 (dd, IH), 8.80 (d, IH), 9.65 (t, IH), 12.99 (s, IH) ppm; m/z (M+l) 382.17; and 4-chloro-l-oxo-l,2-dihydro- phthalazine-6-carboxylic acid 3-trifluoromethyl-benzylamide (33 mg) as a white solid. ¹ H NMR (400 MHz, d _ό -DMSO) δ: 4.63 (d, 2H), 7.65 (m, 4H), 8.38 (m, 2H), 8.46 (s, IH), 9.63 (t, IH), 12.98 (s, IH) ppm; m/z (M+l) 382.24. Example 171: Synthesis of iV-(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-yl)-3- methoxy-benzamide

A mixture of 6-bromo-4-chloro-2H-phthalazin-l-one (lOOmg, 0.39 mmol), 3- methoxy-benzamide (64mg, 0.42 mmol), Pd ₂ (dba) ₃ (36mg, 0.039mmol), xantphos (68mg, 0.12mmol) and Cs ₂ CO ₃ (607mg, 0.98mmol) in dioxane (5mL) was purged with nitrogen for 1 Omin. The mixture was place in a microwave reactor for 5min. After this time the mixture was filtered and purified by preparative ηPLC to yield the title compound hydroformate. m/z (M+η)=329.96, ¹ H-NMR (DMSO-d6) δ: 12.75 (s,lH), 10.85 (s, IH), 8.63 (s,lH), 8.25 (m,2H), 7.60 (d,lH), 7.56 (s,lH), 7.45 (t,lH), 7.20 (dd,lH), 3.85 (s,3H). Example 172: 4-Chloro-6-{4-[3-(2-pyrrolidin-l-yl-ethylamino)-phenyl]-pipe razin-l- yl}-2H-phthalazin-l-one ^» HC0 ₂ H

4-[3-(2-Pyrrolidin-l-yl-ethylamino)-phenyl]-piperazine-l- carboxylic acid tert-butyl ester

A mixture of 4-(3-bromo-phenyl)-piperazine-l-carboxylic acid tert-bυXy\ ester (300mg, 0.88mmol), 2-pyrrolidin-l-yl-ethylamine (0.165mL, 1.32 mmol), Pd ₂ (dba) ₃ (40mg, 0.044mmol), xantphos (50mg, 0.088mmol) and NaOt-Bu (124mg, 1.32mmol) in dioxane (15mL) was bubbled with nitrogen in a sealed tube for lOmin. The mixture was heated at 120°C for 2h. After this time the mixture was cooled and filtered through celite and concentrated. Chromatography on silica (ethyl acetate/MeOH) provided the title compound (203mg, 62%). m/z (M+ 1) 375.53 (3-Piperazin-l-yl-phenyl)-(2-pyrrolidin-l-yl-ethyl)-amine*2H Cl

To a solution of 4-[3-(2-pyrrolidin-l-yl-ethylamino)-phenyl]-piperazine-l- carboxylic acid tert-butyl ester (338mg, 0.90mmol) in MeOH (10 mL) was added a solution of HCl in IPA (5 M, 1.8mL). The mixture was stirred for 18h then concentrated to provide the title compound (339mg, 99%). m/z (M+ 1) 275.49 (free base). 4-Chloro-6-{4-[3-(2-pyrrolidin-l-yl-ethylamino)-phenyl]-pipe razin-l-yl}-2H-phthalazin- l-oneηCO ₂ H

A mixture of 6-bromo-4-chloro-2H-phthalazin-l-one and 7-bromo-4-chloro-2H- phthalazin-1-one (lOOmg, 0.39 mmol), (3-piperazin-l-yl-phenyl)-(2-pyrrolidin-l-yl- ethyl)-amine ^» 2ηCl (162mg, 0.42 mmol), Pd ₂ (dba) ₃ (36mg, 0.039mmol), BINAP (73mg, 0.12mmol) and NaOt-Bu (183mg, 1.95mmol) in DMA (1OmL) was purged with nitrogen for lOmin. The mixture was heated at 110 ⁰ C for 2h. The mixture was allowed to cool, filtered through celite and purified by preparative HPLC to provide the title compound hydroformate. m/z (M+H)= 453.10; ¹ H-NMR (DMSO-d6) δ: 12.05 (s, IH), 8.15 (d, 2H), 7.60 (s, IH), 7.35 (m, IH), 7.12 (m, IH), 6.95 (t, 2H), 6.24 (d, IH), 6.19 (s, IH), 6.12 (d, IH), 3.58 (m, 4H), 3.30 (m, 8H), 2.90 (m, 2H), 2.80 (m, 4H), 1.80 (m, 4H).

Example 173: ^Chloro-d-I^IS-ethoxymethyW-methyl-S-Cl-pyrrolidin-l-yl- ethylamino)-phenyl]-piperazin-l-yl}-2H-phthalazin-l-one»HC� � ₂ H

A mixture of 6-bromo-4-chloro-2H-phthalazin-l-one and 7-bromo-4-chloro-2H- phthalazin-1-one (200mg, 0.77 mmol), (5-ethoxymethyl-2-methyl-3-piperazin-l-yl- phenyl)-(2-pyrrolidin-l-yl-ethyl)-amine»2ηCl (351mg, 0.77 mmol), Pd ₂ (dba) ₃ (71mg, 0.077mmol), BINAP (144mg, 0.23mmol) and NaOt-Bu (398mg, 4.24mmol) in DMA (1OmL) was purged with nitrogen for lOmin. The mixture was heated at HO ⁰ C for 2h. The mixture was allowed to cool, filtered through celite and purified by preparative HPLC to provide the title compound as the formic acid salt, m/z (M+H)= 525.11; ¹ H- NMR (DMSO-λf) δ: 9.45 (s, IH), 8.17 (d, IH), 7.30 (dd, IH), 7.15 (d, IH), 6.45 (s, IH), 6.28 (s, IH), 4.40 (s, 2H), 3.63 (t, 3H), 3.50 (m, 5H), 3.25 (t, 2H), 3.01 (m, 4H), 2.19 (s, 3H), 2.05 (m, 4H), 1.17 (m, 7H).

Example 174 and 175: 2-(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-yl)-N-{2-[(2- dimethylamino-ethyl)-methyl-amino]-phenyl}-acetamide and 2-(l-Chloro-4-oxo-3,4- dihydro-phthalazin-6-yI)-7V-{2-[(2-dimethylamino-ethyl)-meth yl-amino]-phenyl}- acetamide

6-Methyl-2, 3-dihydro-phthalazine-l , 4-dione

A mixture of 5-methyl-isobenzofuran-l,3-dione (6.Og, 34.1mmol) and hydrazine hydrate (2.48mL, 51. lmmol) in isopropanol (12OmL) was heated at reflux for 4h. The mixture was allowed to cool and the precipitate was filtered and washed with water (50 mL). The filter cake was dried to afford the title compound (4.32g, 72%) as a white solid, m/z (M+l) = 177.18

4-Chloro-6-methyl-2H-phthalazin-l -one and 4-Chloro-7-methyl-2H-phthalazin-l -one

A mixture 5-methyl-isobenzofuran-l,3-dione (10.8g, 61.4 mmol) in SOCl ₂ (50 mL) and POCl ₃ (50 mL) was heated at reflux for 4h. The mixture was allowed to cool and concentrated. The residue was taken up in EtOAc (100 mL) and neutralized with sodium bicarbonate. The layers were separated and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in dioxane (20OmL) and 2N NaOH (96mL, 191 mmol). The mixture was heated at 50 ⁰ C for 4h then allowed to cool and concentrated. The residue was triturated with EtOAc (300 mL) and water (200 mL) and the solids were filtered. The organic phase was dried over anhydrous sodium sulfate and concentrated to yield the title compounds (6.07g, 51%); m/z (M+l) = 195.59. 4-Chloro-6-methyl-2H-phthalazin-l-one

A mixture 5-methyl-isobenzofuran-l,3-dione (10.8g, 61.4 mmol) in SOCl ₂ (50 mL) and POCl ₃ (50 mL) was heated at reflux for 4h. The mixture was allowed to cool and concentrated. The residue was taken up in EtOAc (100 mL) and neutralize with sodium bicarbonate. The layers were separated and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in dioxane (20OmL) and 2N NaOH (96mL, 191 mmol). The mixture was heated at 50 ⁰ C for 4h then allowed to cool and stirred at ambient temperature for 15h. The precipitate was filtered and dried to yield the title compound (2.98g, 25%); m/z (M+l) = 195.59.

(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-yl)-acetic acid and (l-Chloro-4-oxo-3,4- dihydro-phthalazin-6-yl)-acetic acid

A mixture of 4-chloro-6-methyl-2H-phthalazin-l-one and 4-chloro-7-methyl-2H- phthalazin-1-one (900mg, 4.64mmol) in anhydrous THF (75mL) under nitrogen was cooled in an ice bath. Sodium hydride (60% in mineral oil) (223mg, 5.57mmol) was added and the mixture was warmed to rt and stirred for 15 min. The mixture was then

cooled to -78°C and n-BuLi (1.6M in hexanes, 3.3mL, 5.34 mmol) was added. The dark mixture was stirred for 30min and freshly crushed dry ice was added and the mixture was allowed to warm to room temperature. The mixture was quenched with water and concentrated. Aqueous sodium bicarbonate was added and the mixture was extracted with EtOAc (25mL). The aqueous phase was acidified with 2N HCl and extracted with EtOAc (2 x 5OmL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to yield the title compound (450mg, 41%). m/z (M+l) = 239.63. 2-(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-yl)-N-{2-[(2-dime thylamino-ethyl)-methyl- amino] -phenylj-acetamide and 2-(l-Chloro-4-oxo-3, 4-dihydro-phthalazin-6-yl)-N-{2- [(2-dimethylamino-ethyl)-methyl-amino] -phenylj-acetamide

(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-yl)-acetic acid and (l-chloro-4-oxo- 3,4-dihydro-phthalazin-6-yl)-acetic acid (250mg, 1.05mmol), N-(2-dimethylamino- ethyl)-N-methyl-benzene-l,2-diamine (242mg, 1.26mmol), EDC (706mg, 3.68mmol), HOBt (170mg, 1.26mmol) and triethylamine (0.73mL, 5.25mmol) in DMF was stirred at ambient temperature for 15h. The mixture was diluted with ethyl acetate (25 mL) and washed with aq. sat. sodium bicarbonate. The aqueous layer was extracted with EtOAc (2 x 2OmL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/MeOH) yielded the title compounds as a mixture of regioisomers (265mg, 61%). m/z (M+H)= 414.00; ¹ H-NMR (DMSO-J6) δ: 12.5 (s, IH), 9.95 (m, IH), 8.25 (s, 0.5H), 8.22 (d, 0.5H), 8.00 (m, 3H), 7.23 (m, IH), 7.05 (m, 2H), 4.00 (m, 2H), 2.80 (t, 2H), 2.60 (s, 3H), 2.20 (t, 2H), 2.16 (s, 6H).

Example 176 and 177: 4-Chloro-6-(2-{2-[(2-dimethylamino-ethyl)-methyl-amino]- phenylamino}-ethyl)-2H-phthalazin-l-one and 4-ChIoro-7-(2-{2-[(2-dimethylamino- ethyl)-methyl-amino]-phenylamino}-ethyl)-2H-phthalazin-l-one

A mixture of 2-(4-chloro- 1 -oxo- 1 ,2-dihydro-phthalazin-6-yl)-N- {2- [(2- dimethylamino-ethyl)-niethyl-amino]-phenyl}-acetamide and 2-(l-chloro-4-oxo-3,4- dihydro-phthalazin-6-yl)-N-{2-[(2-dimethylamino-ethyl)-methy l-amino]-phenyl}- acetamide (194mg, 0.47mmol), and borane-THF complex (IM in THF, 0.23mL, 2.34mmol) in THF (1OmL) was heated at reflux for 4h. After this time MeOH (5mL) was added and the mixture was concentrated. The residue was re-dissolved in MeOH (1OmL) and 4ν HC1/IPA was added (2OmL). The mixture was heated at reflux for 5h and concentrated. The residue was diluted with EtOAc and washed with sat. aq. sodium bicarbonate. The aqueous layer was extracted with EtOAc (2 x 2OmL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/MeOH) yielded the title compounds as a mixture of regioisomers (62mg, 33%). m/z (M+H)= 400.02; ¹ H-NMR (DMSO-λS) δ: 12.5 (s, IH), 9.95 (m, IH), 8.25 (s, 0.5H), 8.22 (d, 0.5H), 8.00 (m, 3H), 7.23 (m, IH), 7.05 (m, 2H), 5.45 (m, IH), 3.40 (m, 2H), 3.20 (s, 3H), 3.05 (m, 2H), 2.75 (m, 2H), 2.20 (m, 3H), 2.02 (s, 6H)

Example 178 and 179: 4-Chloro-l-hydroxy-phthalazine-6-carboxyIic acid [4-chloro- 3'-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-amide, and l-Chloro-4-hydroxy- phthalazine-6-carboxylic acid [4-chloro-3'-(2-dimethylamino-ethoxy)-biphenyl-3-yl]- amide

(5-Bromo-2-chloro-phenyl)-carbamic acid tert-butyl ester

A solution of 5-Bromo-2-Chloro benzoic acid (24 g, 0.1 mol), di- phenylphosphoryl azide (28 mL, 1.3 eq), and Et3N (140 mL, 10 eq) in fert-butanol (300 mL) was refluxed for 3 hrs. The resulting solution was concentrated under reduced pressure, diluted with ether (300 mL) and washed with HCl IN (300 mL), saturated solution of NaHCO3 (200 mL), and brine (200 mL). The organic layers was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/n-hexane) yielded, (26 g, 85%).

(4-chloro-3'-hydroxy-biphenyl-3-yl)-carbamic acid tert-butyl ester

A mixture of the above intermediate (8.55 g, 0.028 mol), 3-hydroxy benzyl boronic acic (5 g, 1.3 eq), sodium carbonate (7.1 g, 2.4 eq), and palladium tetrakis (catalytic amount) in DME (70 mL) and water (35 mL) was heated at 100 ⁰ C in a sealed tube for 5 hrs. The reaction mixture was diluted with ether (100 mL), washed with water (100 mLO, brine (100 mL), dried over anhydrous sodium sulfate and concentrated Chromatography on silica (EtOAc/n-hexane) yielded (4-chloro-3'-hydroxy-biphenyl-3- yl)-carbamic acid tert-butyl ester (6 g, 67%). [4-Chloro-3'-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-carbami c acid tert-butyl ester A solution of the above intermediate (1 g, 3.13 mmol), 2-dimethyl ethyl amino ethanol (0.47 mL, 1.5 eq), triphenyl phosphine (1.23 g, 1.5 eq), and diisopropyl azodicarboxylate (0.92 mL, 1.5 eq) in THF (20 mL) was stirred at RT for 24 hrs. The solution was concentrated and purified by chromatography on silica (EtOAc/n-hexane) to yield [4-Chloro-3'-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-carbami c acid tert-butyl ester (0.8 g, 65%).

4-chloro-3'-(2-dimethylamino-ethoxy)-biphenyl-3-ylamine hydrochloride.

The above intermediate (0.8 g, 2.0 mmol) was dissolved in a solution of HCl in i- PrOH (5-6M, 20 mL). The resulting solution was stirred at RT for 6 hrs then concentrated to provide 4-chloro-3'-(2-dimethylamino-ethoxy)-biphenyl-3-ylaniine hydrochloride (0.6 g, 90%) as a white solid.

4-Chloro-l -hydroxy-phthalazine-6-carboxylic acid [4-chloro-3'-(2-dimethylamino- ethoxy)-biphenyl-3-yl] -amid, and l-chloro-4-hydroxy-phthalazine-6-carboxylic acid [4- chloro-3'-(2-dimethylamino-ethoxy)-biphenyl-3-yl] -amide A mixture of 4-chloro-3'-(2-dimethylamino-ethoxy)-biphenyl-3-ylamine hydrochloride (0.6 g, 1.8 mmol), l-chloro^-oxo-S^-dihydro-phthalazine-ό-carboxylic acid and 4- chloro-l-oxo-l^-dihydro-phthalazine-ό-carboxylic acid (336mg, 1.5mmol), N-(3- dimethylaminopropyl)-N'-ethylcarbodiirnide hydrochloride (0.373 g, 1.95mmol), 4- NMM (0.82mL, 7.5 mmol), 1-hydroxybenzotriazole hydrate (263mg, 1.95mmol) and anhydrous DMF (5 mL)was stirred at room temperature for 48 hrs. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated solution of ammonium chloride (50 mL), saturated solution of NaHCO3 (50 mL), dried and concentrated under reduced

pressure. Preparatory HPLC afforded the title compounds as solid: 4-Chloro-l-hydroxy- phthalazme-6-carboxylic acid [4-chloro-3'-(2-dimethylamino-ethoxy)-biphenyl-3-yl]- amid, ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.52 (s, 6H), 2.97 (t, 2H), 4.24 (t, 2H), 6.92 (dd, IH), 7.14 (m, IH), 7.20 (d, IH), 7.32-7.39 (m, 2H), 7.49 (d, IH), 8.30 (dd, IH), 8.52-8.58 (m, 3H), 8.74 (bd, lH)ppm; m/z (M+ 1) 497; and l-chloro-4-hydroxy-phthalazine-6- carboxylic acid [4-chloro-3'-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-amide hydroformate as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.60 (s, 6H), 3.07 (t, 2H), 4.28 (t, 2H), 6.90 (dd, IH), 7.12 (m, IH), 7.19 (d, IH), 7.31-7.37 (m, 2H), 7.47 (d, IH), 8.14 (dd, IH), 8.50 (dd, IH), 8.60 (s, IH), 8.68 (d, IH), 8.84 (d, IH) ppm; m/z (M+ 1) 497. Example 180 and 181: 4-Chloro-l-hydroxy-phthaIazine-6-carboxylic acid (3 ¹ - hydroxy-biphenyl-3-yl)-amide and 1 -Chloro-4-hydroxy-phthalazine-6-carboxylic acid (3 '-hydroxy-biphenyl-3-yl)-amide

3 '-Amino-biphenyl-3-ol A solution of (4-chloro-3'-hydroxy-biphenyl-3-yl)-carbamic acid tert-butyl ester

(1.8 g, 5.64 mmol) was dissolved in a solution of HCl in i-PrOH (5-6M, 20 niL). The resulting solution was stirred at RT for 6 hrs then concentrated to provided 3'-amino-4'- chloro-biphenyl-3-ol hydrochloride.

The above intermediate was dissolved in MeOH (50 mL), palladium on carbon (catalytic amount) was added and the resulting mixture was hydrogenated (1 arm) for 5 hrs. Filtration thorugh celite and concentration gave the desired intermediate 3'-amino- biphenyl-3-ol hydrochloride (1.0 g, 81%)

^Chloro-l-hydroxy-phthalazine-ό-carboxylic acid (3'-hydroxy-biphenyl-3-yl)-amide and l-Chloro^-hydroxy-phthalazine-ό-carboxylic acid (3'-hydroxy-biphenyl-3-yl)-amide

A mixture of 3 '-Amino-biphenyl-3-ol hydrochloride (1.0 g, 4.5 mmol), 1-chloro- 4-0X0-3, 4-dihydro-phthalazine-6-carboxylic acid and 4-chloro-l-oxo-l,2-dihydro- phthalazine-6-carboxylic acid (1.5 g, 6.7 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (1.3 g, 6.7 mmol), 4-NMM (3.0 mL, 28 mmol), 1-

hydroxybenzotriazole hydrate (0.91 g, 6.7 mmol) and anhydrous DMF (20 mL)was stirred at room temperature for 48 hrs. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated solution of ammonium chloride (50 mL), saturated solution OfNaHCO ₃ (50 mL), dried and concentrated under reduced pressure. Preparatory HPLC afforded the title compounds as solid: 4-Chloro-l-hydroxy- phthalazine-6-carboxylic acid (3'-hydroxy-biphenyl-3-yl)-amide ¹ H NMR (400 MHz, d6- DMSO) δ: 6.78 (dd, IH), 7.04 (t, IH), 7.05-7.10 (m, IH), 7.27 (t, IH), 7.35-7.41 (m, IH), 7.46 (t, IH), 7.77-7.82 (m, IH), 8.08 (m, IH), 8.41 (d, IH), 8.47 (dd, IH), 8.51 (d, IH), 9.56 (s, IH), 10.80 (s, IH), 13.02 (s, IH) ppm; m/z (M+l) 392; and l-Chloro-4- hydroxy-phthalazine-6-carboxylic acid (3'-hydroxy-biphenyl-3-yl)-amide as a solid. H NMR (400 MHz, d6-DMSO) δ: 6.78 (dd, IH), 7.04 (t, IH), 7.07 (dd, IH), 7.28 (t, IH), 7.36-7.40 (m, IH), 7.46 (t, IH), 7.82 (dd, IH), 8.10 (t, IH), 8.15 (d, IH), 8.56 (dd, IH), 8.92 (d, IH), 9.56 (s, IH), 10.81 (s, IH), 13.05 (s, IH) ppm; m/z (M+l) 392. Example 182: Synthesis of 4-Chloro-6-(3-pyrrolidin-l-ylmethyl-benzylamino)-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (200mg, 0.770 mmol), [3-(l- pyrrolidinylmethyl)phenyl]methanamine (161mg, 0.848 mmol), Pd ₂ (dba) ₃ (71mg, 0.077 mmol), rac-BINAP (144mg, 0.231 mmol) andNaO'Bu (230mg, 2.393 mmol) in DMA (6mL) was heated at 85 ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography (Hexanes/EtOAc) afforded 4-chloro-6-(3- pyrrolidin-l-ylmethyl-benzylamino)-2H-phthalazin-l-one (15 mg) as a yellow solid. ¹ H (400 MHz, d ₆ -DMSO) δ: 1.62 (m, 4H), 2.38 (m, 4H), 3.55 (m, 2H), 4.44 (d, 2H), 6.80 (s, IH), 7.17 (m, 2H), 7.3 (m, 3H), 7.68 (m, IH), 7.92 (d, IH), 12.34 (s, IH) ppm; m/z (M+l) 369.26.

Example 183: Synthesis of 4-Chloro-6-(3-pyrrolidin-l-yl-benzylamino)-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (200mg, 0.770 mmol), (3- pyrrolidin-l-ylphenyl)methylamine (149mg, 0.848 mmol), Pd ₂ (dba) ₃ (71mg, 0.077 mmol), rac-BINAP (153mg, 0.246 mmol) and NaO'Bu (200mg, 2.081 mmol) in DMA (6mL) was heated at 85 ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography (Hexanes/EtOAc) afforded 4-chloro-6-(3- pyrrolidin-l-yl-benzylamino)-2H-phthalazin-l-one (11 mg) as a white solid. ¹ H (400 MHz, d ₆ -DMSO) δ: 1.94 (m, 4H), 3.20 (m, 4H), 4.32 (d, 2H), 6.41 (d, IH), 6.57 (s, IH), 6.60 (d, IH), 6.85 (s, IH), 7.11 (t, IH), 7.15 (dd, IH), 7.62 (t, IH), 7.01 (d, IH), 12.33 (s, IH) ppm; m/z (M+l) 355.31.

Example 184: Synthesis of 4-Chloro-6-[(6-pyrrolidin-l-yl-pyridin-2-ylmethyl)- amino] -2H-phthalazin- 1 -one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (200mg, 0.770 mmol), (6- pyrrolidin-ylpyrid-2-yl)methylamine (150mg, 0.848 mmol), Pd ₂ (dba) ₃ (71mg, 0.077 mmol), rac-BINAP (153mg, 0.246 mmol) andNaO'Bu (190mg, 1.977 mmol) in DMA (6mL) was heated at 85 ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography (Hexanes/EtOAc) afforded 4-chloro-6-[(6- pyrrolidin-l-yl-pyridin-2-ylmethyl)-amino]-2H-phthalazin-l-o ne (25 mg) as a white solid. ¹ H (400 MHz, d ₆ -DMSO) δ: 2.12 (m, 4H), 3.39 (m, 4H), 4.32 (d, 2H), 6.30 (d, IH), 6.51 (d, IH), 6.91 (s, IH), 7.18 (dd, IH), 7.42 (t, IH), 7.61 (t, IH), 7.93 (d, IH), 12.33 (s, IH) ppm; m/z (M+l) 356.21.

Example 185: Synthesis of 4-Chloro-6-(2-pyrrolidin-l-yl-benzylamino)-2H- phthalazin-1-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (200mg, 0.770 mmol), (2- pyrrolidin-4-ylphenyl)methylamine (156mg, 0.885 mmol), Pd2(dba) ₃ (71mg, 0.077 mmol), rac-BINAP (155mg, 0.249 mmol) and NaO'Bu (198mg, 2.060 mmol) in DMA (6mL) was heated at 85 ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography (Hexanes/EtOAc) afforded 4-chloro-6-(2- pyrrolidin-l-yl-benzylamino)-2H-phthalazin-l-one (35 mg) as a white solid. ¹ H (400 MHz, de-DMSO) δ: 1.90 (m, 4H), 3.16 (m, 4H), 4.38 (d, 2H), 6.73 (bs, IH), 6.87 (d, IH), 7.00 (d, IH), 7.14 (m, 2H), 7.26 (dd, IH), 7.64 (t, IH), 7.90 (d, 1H),12.32 (s, IH) ppm; m/z (M+l) 355.23.

Example 186: Synthesis of 4-Chloro-6-(2-morpholin-4-yl-benzylamino)-4a,8a- dihydro-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (1.227g, 4.728 mmol), (2- morpholino)benzylamine (1.00 g, 5.201 mmol), Pd ₂ (dba) ₃ (450mg, 0.491 mmol), rac- BINAP (883mg, 1.418 mmol) and NaO'Bu (1.17 g, 12.175 mmol) in DMA (2OmL) was heated at 8O ⁰ C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography (Hexanes/EtOAc) afforded 4-chloro-6-(2-morpholin-4-yl- benzylamino)-4a,8a-dihydro-2H-phthalazin-l-one (180 mg) as a white solid. ¹ H (400 MHz, dό-DMSO) δ: 2.90 (m, 4H), 3.79 (m, 4H), 4.46 (d, 2H), 6.66 (bs, IH), 7.04 (t, IH),

7.15 (m, 2H), 7.24 (m, IH), 7.35 (d, IH), 7.77 (t, IH), 7.90 (d, IH), 12.32 (s, IH) ppm; m/z (M+l) 371.23.

Example 187: Synthesis of 4-Chloro-6-{methyl-[3-(6-methyl-pyrazin-2-yloxy)- benzyl]-amino}-4a,8a-dihydro-2H-phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (225mg, 0.867 mmol), N- methyl-3-[(6-methylpyrazin-2-yl)oxy]benzylamine (250 mg, 1.09 mmol), Pd ₂ (dba) ₃ (95mg, 0.104 mmol), xantphos (180mg, 0.312 mmol) and NaO'Bu (300 g, 3.12 mmol) in dioxane (6mL) was heated at 8O ⁰ C for 3.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq.

NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography (Hexanes/EtOAc) afforded 4- chloro-6- {methyl-[3 -(6-methyl-pyrazin-2-yloxy)-benzyl]-amino} -4a,8a-dihydro-2H- phthalazin-1-one (6 mg) as a yellow solid. ¹ H (400 MHz, d ₆ -DMSO) δ: 2.27 (s, 3H), 3.24 (s, 3H), 4.83 (s, 2H), 6.88 (d, IH), 7.03 (s, IH), 7.07 (d, IH), 7.12 (d, IH), 7.32 (dd, IH), 7.40 (t, IH), 8.00 (d, IH), 8.24 (d, 2H), 12.41 (s, IH) ppm; m/z (M+l) 408.27. Example 188: Synthesis of 4-Chloro-6-[methyl-(4-methyl-3,4-dihydro-2H- pyrido[3,2-A][l,4]oxazin-7-ylmethyl)-amino]-4a,8a-dihydro-2H -phthalazin-l-one

A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (275mg, 1.06 mmol), N- methyl-(4-methyl-3,4-dihydro-2η-pyrido[3,2-b][l,4]oxazin-7- yl)methylamine (250 mg, 1.29 mmol), Pd ₂ (dba) ₃ (113mg, 0.123 mmol), xantphos (214mg, 0.370 mmol) and NaO'Bu (380 g, 3.696 mmol) in dioxane (6mL) was heated at 8O ⁰ C for 3.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography

(Hexanes/EtOAc) afforded 4-chloro-6-[methyl-(4-methyl-3,4-dihydro-2H-pyrido[3,2-

6][l,4]oxazin-7-ylmethyl)-amino]-4a,8a-dihydro-2H-phthalazin -l-one (5 mg) as a yellow solid. ¹ H (400 MHz, d ₆ -DMSO) δ: 2.98 (s, 3H), 3.18 (s, 3H), 3.38 (t, 2H), 4.18 (t, 2H),

4.6 (s, 2H), 6.81 (d, IH), 6.90 (d, IH), 7.37 (dd, IH), 7.61 (d, IH), 8.00 (d, IH), 12.40 (s,

IH) ppm; m/z (M+l) 372.21.

Example 189: Synthesis of 4-Chloro-6-[2-((R)-3-methyl-piperazin-l-yl)-benzyl amino]-4a,8a-dihydro-2H-phthalazin-l-one

2-((R)-3-Methyl-piperazin-l-yl)-benzonitrile A mixture 2-bromobenzonitrile (1.0 g, 5.494 mmol), (S)-(+)-2-methylpiperazine

(0.60 g, 5.99 mmol), Pd ₂ (dba) ₃ (0.503 g, 0.549 mmol), rac-BINAP (1.026 g, 1.648 mmol) and NaO'Bu (2.11 g, 21.976 mmol) in DMA (27 mL) was heated at 8O ⁰ C for 2.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). Chromatography (EtOAc/MeOH) afforded 2-((R)-3 -methyl-piperazin- 1 -yl)-benzonitrile (540 mg) as a white solid. ¹ H (400 MHz, d ₆ -DMSO) δ: ppm; m/z (M+l) 202.21.

2-((R)-3-Methyl-piperazin-l-yl)-benzylamine

A mixture of 2-((R)-3 -methyl-piperazin- l-yl)-benzonitrile (542 mg, 2.69 mmol),

Raney Nickel (3 mL of a slurry in water), ammonia (15 mL, 2M solution in EtOH) was evacuated and flushed with H ₂ , then stirred at room temperature for 3h. The reaction mixture was filtered through celite, rinsed with MeOH, concentrated and dried in vacuum to afford 2-((R)-3 -methyl-piperazin- l-yl)-benzylamine (526 mg) as an orange viscous oil. m/z (M+l) 206.29.

4-Chloro-6-[2-((R)-3-methyl-piperazin-l-yl)-benzylamino]- 4a,8a-dihydro-2H- phthalazin-1-one

A mixture 6-brorno-4-chloro-2H-phthalazin-l-one (670 mg, 2.582 mmol), 2-((R)-

3-methyl-piperazin-l-yl)-benzylamine (542 mg, 2.693 mmol), Pd ₂ (dba) ₃ (246 mg, 0.269

mmol), rac-BINAP (505 mg, 0.811 mmol) and NaO'Bu (774 mg, 8.054 mmol) in DMA (13 mL) was heated at 8O ⁰ C for 2h. The mixture was allowed to cool, filtered through celite and rinsed with EtOAc (this layer was discarded), then MeOH. The MeOH filtrate was concentrated followed by column chromatography (EtOAc/MeOH + 0.1% NH ₄ OH) afforded 4-chloro-6-[2-((R)-3-methyl-piperazin-l-yl)-benzylamino]-4a, 8a-dihydro-2H- phthalazin-1-one (121 mg) as a brown solid. ¹ H (400 MHz, d ₆ -DMSO) δ: 1.22 (d, 3H), 2.73 (m, IH), 2.95 (m, IH), 3.1 (m, 5H), 4.47 (d, 2H), 6.67 (s, IH), 7.06 (m, IH), 7.14 (d, 2H), 7.25 (m, IH), 7.35 (d, IH), 7.78 (t, IH), 7.90 (d, IH), 12.33 (s, IH) ppm; m/z (M+l) 384.28. Example 190: 4-Chloro-6-[2-(hexahydro-pyrrolo[3,4-e]pyrrol-2-yl)-benzylam ino]- 2H-phthalazin-l-one

5-(2-Cyano-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxy lic acid tert-butyl ester A mixture of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (464mg, (2.19 mmol), 2-bromobenzonitrile (400mg, 2.19mmol), Pd ₂ (dba) ₃ (1 OOmg, 0.11 mmol), xantphos (190mg, 0.33mmol), sodium t-butoxide (618mg, 6.57mmol) in degassed anhydrous dioxane (1OmL) was heated at 12O ⁰ C in a sealed tube for Ih. The mixture was allowed to cool and filtered through celite. The filtrate was concentrated and purified by chromatography (EtOAc/hexanes) to yield the title compound (505mg, 74%). m/z (M+l) 313.41.

5-(2-Aminomethyl-phenyl)-hexahydro-pyrrolo[3, 4-c]pyrrole-2-carboxylic acid tert-butyl ester

To a solution of 5-(2-cyano-phenyl)-hexahydro-pyrτolo[3,4-c]pyrrole-2- carboxylic acid tert-butyl ester (150mg, 0.48mmol) in NH ₃ /EtOH (2M, 1OmL) was added Raney Nickel (3mL slurry in water). The atmosphere was exchanged with hydrogen via balloon and the mixture was allowed to stir for 2.5h. After this time the mixture was

filtered through celite and concentrated to yield the title compound (140mg). m/z (M+ 1) 318.29.

5-{2-[(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-ylamino)-meth yl]-phenyl}-hexahydro- pyrrolo[3, 4-c] pyrrole-2-carboxylic acid tert-butyl ester A mixture of β-bromo^-chloro^H-phthalazin- 1 -one (136mg, 0.52 mmol), 5-(2- aminomethyl-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbox ylic acid tert-butyl ester (150mg, 0.48 mmol), Pd ₂ (dba) ₃ (22mg, 0.024mmol), BINAP (49mg, 0.078mmol) and NaOt-Bu (147mg, 1.56mmol) in DMA (1OmL) was purged with nitrogen for lOmin. The mixture was heated at 90 ⁰ C for 2h. The mixture was allowed to cool and diluted with ethyl acetate (30 mL) and washed with ammonium chloride (25mL). The organic layer was dried and concentrated. Chromatography on silica yielded the title compound (50mg, 19%) m/z (M+η)= 496.12.

To a solution of 5-{2-[(4-chloro-l-oxo-l,2-dihydro-phthalazin-6-ylamino)- methyl]-phenyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (50mg, O.lOmmol) in MeOH (5mL) was added a solution of HCl in dioxane (5mL, 4M). The mixture was stirred at ambient temperature for 4h. The residue was crystallized from MeOH/Et ₂ O to yield the title compound as the HCl salt (15mg) m/z (M+H)= 396.28 ¹ H- NMR (DMSO-^6) δ: 12.27 (s, IH), 8.85 (m, 2H), 7.85 (d, IH), 7.24 (m, IH), 7.18 (m, IH), 7.08 (m, 2H), 6.90 (m, IH), 6.60 (m, IH), 4.37 (m, 2H), 3.45 (m, 2H), 3.0 (m, 8H). Example 191: 4-Chloro-6-(2-perhydro-l,4-diazepin-l-yl-benzylamino)-2H- phthalazin-1-one

4-(2-Cyano-phenyl)-perhydro-l,4-diazepine-l-carboxylic acid tert-butyl ester

A mixture of Boc-homopiperazine (900mg, (4.63 mmol), 2-bromobenzonitrile (766mg, 4.21 lmmol), Pd ₂ (dba) ₃ (193mg, 0.21 mmol), xantphos (366mg, 0.63mmol), sodium t-butoxide (1.19g, 12.6mmol) in degassed anhydrous dioxane (1OmL) was heated at 120°C in a sealed tube for 2h. The mixture was allowed to cool and filtered through

celite. The filtrate was concentrated and purified by chromatography (EtOAc/hexanes) to yield the title compound (905mg, 71%). m/z (M+ 1) 301.27. 4-(2-Aminomethyl-phenyl)-perhydro-l ,4-diazepine-l -carboxylic acid tert-butyl ester

To a solution of 4-(2-cyano-phenyl)-perhydro-l,4-diazepine-l -carboxylic acid tert-butyl ester (905mg, 3.Ommol) in NH ₃ /EtOH (2M, 15mL) was added Raney Nickel (5mL slurry in water). The atmosphere was exchanged with hydrogen via balloon and the mixture was allowed to stir for 2.5h. After this time the mixture was filtered through celite and concentrated to yield the title compound (900mg). m/z (M+l) 305.31. 4-{2-[(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-ylamino)-meth yl]-phenyl}-perhydro- 1, 4-diazepine-l -carboxylic acid tert-butyl ester

A mixture of 6-bromo-4-chloro-2H-phthalazin-l-one (140mg, 0.54 mmol), 4-(2- Aminomethyl-phenyl)-perhydro-l, 4-diazepine-l -carboxylic acid tert-butyl ester (150mg, 0.49 mmol), Pd ₂ (dba) ₃ (45mg, 0.049mmol), BINAP (92mg, 0.15mmol) and NaOt-Bu (138mg, 1.47mmol) in DMA (1OmL) was purged with nitrogen for lOmin. The mixture was heated at 90 ⁰ C for 5h. The mixture was allowed to cool and diluted with ethyl acetate (30 mL) and washed with ammonium chloride (25mL). The organic layer was dried and concentrated. Chromatography on silica yielded the title compound (25mg, 11%) m/z (M+η)= 484.72.

To a solution of 4-{2-[(4-chloro-l-oxo-l,2-dihydro-phthalazin-6-ylamino)- methyl] -phenyl } -perhydro- 1 ,4-diazepine- 1 -carboxylic acid tert-butyl ester ( 15mg,

0.051mmol) in MeOH (ImL) was added a solution of HCl in dioxane (5mL, 4M). The mixture was stirred at ambient temperature for 4h. The residue was crystallized from MeOH/Et ₂ O to yield the title compound as the HCl salt (lOmg) m/z (M+H)= 384.28 ¹ H- NMR (DMSO-dtf) δ: 12.27 (s, IH), 8.85 (m, 2H), 7.85 (d, IH), 7.62 (m, IH), 7.25 (d, IH), 7.18 (m, 2H), 7.05 (m, 2H), 6.62 (m, IH), 4.41 (d, 2H), 3.20 (m, 5H), 3.05 (m, 3H), 2.00 (m, 2H).

Example 192: 4-Chloro-6-(2-piperazin-l-yl-5-trifluoromethyl-benzylamino)- 2H- phthalazin-1-one

4-(2-Cyano-4-tήfluoromethyl-phenyl)-piperazine-l-carboxy lic acid tert-butyl ester

A mixture of Boc-piperazine (573mg, (3.08 mmol), 2-bromo-5- trifluoromethylbenzonitrile (700mg, 2.80mmol), Pd ₂ (dba) ₃ (256mg, 0.28 mmol), xantphos (486mg, 0.84mmol), sodium t-butoxide (660mg, 7.0mmol) in degassed anhydrous dioxane (1OmL) was heated at 85°C for Ih. The mixture was allowed to cool and filtered through celite. The filtrate was concentrated and purified by chromatography (EtOAc/hexanes) to yield the title compound (150mg, 15%). m/z (M+ 1) 356.37. 4-(2-Aminomethyl-4-trifluoromethyl-phenyl)-piperazine-l-carb oxylic acid tert-butyl ester To a solution 4-(2-cyano-4-trifluoromethyl-phenyl)-piperazine-l-carboxylic acid tert-butyl ester (150mg, 0.42mmol) in NH ₃ /EtOH (2M, 1OmL) was added Raney Nickel (3mL slurry in water). The atmosphere was exchanged with hydrogen via balloon and the mixture was allowed to stir for 30min. After this time the mixture was filtered through celite and concentrated to yield the title compound (148mg). m/z (M+l) 360.23. 4-{2-[(4-Chloro-l -oxo-1, 2-dihydro-phthalazin-6-ylamino)-methyl]-4-trifluoromethyl- phenyl}-piperazine-l-carboxylic acid tert-butyl ester

A mixture of 6-bromo-4-chloro-2H-phthalazin-l-one (183mg, 0.70 mmol), 4-(2- aminomethyl-4-trifluoromethyl-phenyl)-piperazine-l-carboxyli c acid tert-butyl ester (230mg, 0.64 mmol), Pd ₂ (dba) ₃ (59mg, 0.064mmol), BINAP (120mg, 0.19mmol) and NaOt-Bu (180mg, 1.92mmol) in DMA (1OmL) was purged with nitrogen for lOmin. The mixture was heated at 90 ⁰ C for 5h. The mixture was allowed to cool and diluted with ethyl acetate (30 mL) and washed with ammonium chloride (25mL). The organic layer was dried and concentrated. Chromatography on silica yielded the title compound (25mg) m/z (M+η)= 538.90. To a solution 4-{2-[(4-chloro-l-oxo-l,2-dihydro-phthalazin-6-ylamino)-meth yl]-

4-trifluoromethyl-phenyl}-piperazine-l-carboxylic acid tert-butyl ester (25mg,

0.046mmol) in MeOH (ImL) was added a solution of HCl in dioxane (5mL, 4M). The mixture was stirred at ambient temperature for 4h. The residue was crystallized from MeOH/Et ₂ O to yield the title compound as the HCl salt (lOmg) m/z (M+H)= 438.23 ¹ H- NMR (DMSO-Jd) δ: 12.34 (s, IH), 8.79 (m, 2H), 7.98 (d, IH), 7.78 (t, IH), 7.62 (s, IH), 7.52 (m, IH), 7.29 (d, IH), 7.08 (m, IH), 6.58 (m, IH), 4.42 (d, 2H), 3.55 (m, 4H), 3.10 (m, 4H).

Example 193: 4-Chloro-6-(5-methoxy-2-piperazin-l-yl-benzylamino)-2H- phthalazin-1-one

4-(2-Cyano-4-methoxy-phenyl)-piperazine-l-carboxylic acid tert-butyl ester A mixture of Boc-homopiperazine (483mg, 2.59 mmol), 2-bromo-5- methoxybenzonitrile (500mg, 2.36mmol), Pd ₂ (dba) ₃ (108mg, 0.12 mmol), xantphos (205mg, O.35mmol), sodium t-butoxide (666mg, 7.08mmol) in degassed anhydrous dioxane (1OmL) was heated at 90 ⁰ C for 2h. The mixture was allowed to cool and filtered through celite. The filtrate was concentrated and purified by chromatography (EtOAc/hexanes) to yield the title compound (691mg, 92%). m/z (M+l) 318.39. 4-(2-Aminomethyl-4-methoxy-phenyl)-piperazine-l-carboxylic acid tert-butyl ester

To a solution of 4-(2-cyano-4-methoxy-phenyl)-piperazine-l-carboxylic acid tert- butyl ester (680mg, 2.14mmol) in NH ₃ /EtOH (2M, 15mL) was added Raney Nickel (5mL slurry in water). The atmosphere was exchanged with hydrogen via balloon and the mixture was allowed to stir for 2.5h. After this time the mixture was filtered through celite and concentrated to yield the title compound (650mg). m/z (M+l) 321.57. 4-{2-[(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-ylamino)-meth yl]-4-methoxy-phenyl}- piper azine-1-carboxylic acid tert-butyl ester

A mixture of 6-bromo-4-chloro-2H-phthalazin-l-one and 7-bromo-4-chloro-2H- phthalazin-1-one (300mg, 1.16 mmol), 4-(2-aminomethyl-4-methoxy-phenyl)-piperazine- 1-carboxylic acid tert-butyl ester (338mg, 1.05 mmol), Pd ₂ (dba) ₃ (1 lOmg, 0.12mmol), BINAP (217mg, 0.35mmol) and NaOt-Bu (327mg, 3.48mmol) in DMA (1OmL) was purged with nitrogen for lOmin. The mixture was heated at 90 ⁰ C for 1.5h. The mixture was allowed to cool and diluted with ethyl acetate (30 mL) and washed with ammonium chloride (25mL). The organic layer was dried and concentrated. Chromatography on silica yielded the title compound (102mg, 18%) m/z (M+η)= 500.32.

To a solution of 4-{2-[(4-chloro-l-oxo-l,2-dihydro-phthalazin-6-ylamino)- methyl]-4-methoxy-phenyl}-piperazine-l-carboxylic acid tert-butyl ester (lOOmg,

0.20mmol) in MeOH (ImL) was added a solution of HCl in dioxane (5mL, 4M). The mixture was stirred at ambient temperature for 4h. The residue was crystallized from MeOHZEt ₂ O to yield the title compound as the HCl salt (lOmg) m/z (M+H)= 400.20 ¹ H- NMR (OMSO-d<5) δ: 12.28 (s, IH), 8.90 (bs, 2H), 7.86 (d, IH), 7.68 (bs, IH), 7.10 (m, 2H), 6.86 (d, IH), 6.78 (dd, IH), 6.57 (bs, IH), 4.40 (m, 2H), 3.61 (s, 3H), 3.20 (m, 4H), 2.90 (m, 4H).

Example 194: 6-[2-(4-Amino-piperidin-l-yl)-benzylamino]-4-chloro-2H-phtha lazin- 1-one

[l-(2-Cyano-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester

A mixture of piperidin-4-yl-carbamic acid tert-butyl (695 mg, 3.47 mmol), 2- bromo-benzonitrile (631mg, 3.47 mmol), Pd ₂ (dba) ₃ (159 mg, 0.174 mmol,), xanthphos (300 mg, .52 mmol), sodium tert-butoxide (1 g, 10.41 mmol) in anhydrous 1,4-dioxane (6 ml) was heated at 100-110° C in a sealed tube for Ih. After cooled to room temperature, the mixture was filtered through celite then concentrated before purified by

chromatography (hexanes/EtOAc) to provide the titled compound (240 mg, 23%). m/z

(M+l) 302.30.

[l-(2-Aminomethyl-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester]

To a solution of [l-(2-cyano-ρhenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.224 g, 0.741 mmol) in NH ₃ /EtOH (2M, 15.5 ml) was added Raney Nickel (3.5 ml slurry in water). The mixture was stirred under hydrogen (balloon) for 5 h before filtered through celite and concentrated to give the primary amine (183 mg, 81%). m/z (M+l) 306.30.

(l-{2-[(4-Chloro-l-oxo-l,2-dihydro-phthlalzin-6-ylamino)- methyl]-phenyl}-piperidin-4- yl)-carbamic acid tert-butyl ester

A mixture of [l-(2-aminomethyl-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester] (97 mg, 0.318 mmol), 6-bromo-4-chloro-2H-phthalazin-l-one (82.4 mg, 0.318 mmol), Pd ₂ (dba) ₃ (29 mg, 0.032 mmol), BINAP (59 mg, 0.095 mmol), sodium tert- butoxide (182 mg, 1.9 mmol) in DMA (2.5 ml) was purged with nitrogen before heated at 100° C for Ih. The mixture was cooled and diluted with EtOAc and washed with NH ₄ Cl. The organic layer was dried and concentrated before chromatography using hexanes/EtOAc to yield the titled compound (49 mg, 31%). m/z (M+l) 484.15.

Methanol (3 ml) was added to a solution (l-{2-[(4-chloro-l-oxo-l,2-dihydro- phthlalzin-6-ylamino)-methyl]-phenyl}-piperidin-4-yl)-carbam ic acid tert-butyl ester (0.10 mmol) followed by the addition of 4M HCl solution in dioxane (3 ml). The mixture was stirred at room temperature for 2h before evaporated to give the HCl salt. The salt was dissolved in water/EtOAc and neutralized by the addition OfK ₂ CO ₃ to give the final product, 6-[2-(4-Amino-piperidin- 1 -yl)-benzylamino]-4-chloro-2H-phthalazin- 1 -one (31 mg, 82%). m/z (M+l) 384.15. ¹ H NMR (CDCl ₃ ): δ 8.16 (IH), 7.36 (IH), 7.28 (2H), 7.18 (IH), 7.08 (IH), 7.03 (IH), 6.88 (IH), 5.61 (1 H), 4.58 (2 H), 3.10 (2H), 2.91 (IH), 2.81 (2H), 1.92 (3H), 1.51 (3H) ppm.

Example 195: 4-Chloro-6-(5-fluoro-2-piperazin-l-yl-benzylamino)-2H-phthal azin-l- one

4-(2-Cyano-4-fluoro-phenyl)-piperazine-l-carboxylic acid tert-butyl ester

A mixture of piperazine-1-carboxylic acid tert-butyl ester (1.05 g , 5.65 mmol), 2- bromo-5-fluoro-benzonitrile (1.13 g, 5.65 mmol), Pd ₂ (dba) ₃ (259 mg, 0.283 mmol), xanthphos (490 mg, 0.848 mmol), sodium tert-butoxide (1.63 g, 16.95 mmol) in anhydrous 1,4-dioxane (10 ml) was heated at 100-110° C in a sealed tube for Ih. After cooled to room temperature, the mixture was filtered through celite then concentrated before purified by chromatography (hexanes/EtOAc) to provide compound as indicated (1.31 g, 76%). m/z (M+l) 306.21. 4-(2-Aminomethyl-4-fluoro-phenyl)-piperazine-l-carboxylic acid tert-butyl ester To a solution of 4-(2-cyano-4-fluoro-phenyl)-piperazine-l-carboxylic acid tert- butyl ester (0.778 g, 2.55 mmol) in NH ₃ /EtOH (2M, 30 ml) was added Raney Nickel (4 ml slurry in water). The mixture was stirred under hydrogen (balloon) for 3 h before filtered through celite and concentrated to give the primary amine (690 mg, 88%). m/z (M+l) 310.19. 4- {2-[(4-Chloro- 1 -oxo- 1 ,2-dihydro-phthalzin-6-ylamino)-methyl]-4-fluoro-phenyl} - piperazine-1-carboxylic acid tert-butyl ester

A mixture of 4-(2-aminomethyl-4-fluoro-phenyl)-piperazine-l-carboxylic acid tert-butyl ester (78 mg, 0.252 mmol), 6-bromo-4-chloro-2H-phthalazin-l-one (66 mg, 0.252 mmol), Pd ₂ (dba) ₃ (23 mg, .025 mmol), BINAP (47 mg, 0.076 mmol), sodium tert- butoxide (145 mg, 1.51 mmol) in DMA (2 ml) was purged with nitrogen before heated at 100° C for Ih. The mixture was cooled and diluted with EtOAc and washed with NH ₄ Cl. The organic layer was dried and concentrated before chromatography using hexanes/EtOAc to yield the couple product (26 mg, 22%). m/z (M+l) 488.18. Methanol (1.5 ml) was added to a solution 4-{2-[(4-chloro-l-oxo-l,2-dihydro-phthalzin- 6-ylamino)-methyl]-4-fluoro-phenyl} -piperazine- 1 -carboxylic acid tert-butyl ester(0.053 mmol) followed by the addition of 4M HCl solution in dioxane (1.5 ml). The mixture

was stirred at room temperature for 4 h before evaporated to give the HCl salt. The salt was dissolved in water/EtOAc and neutralized by the addition OfK ₂ CO ₃ to give the final product, 4-chloro-6-(5-fiuoro-2-piperazin- 1 -yl-benzylamino)-2H-phthalazin- 1 -one (19 mg, 92%). m/z (M+l) 388.18. ¹ H NMR (DMS0-d ₆ ): δ 12.35 (IH), 7.95 (IH), 7.75 (IH), 7.25 (2H), 7.15 (3H), 6.50 (IH), 4.48 (2H), 3.28 (4 H), 3.05 (4 H) ppm. Enzyme Inhibition Assay (p70S6K(h))

In a final reaction volume of 25 uL, p70S6K(h) (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 iM KKRNRTLTV, 10 mM MgAcetate and [gamma-33 P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 5 uL of a 3% phosphoric acid solution. 10 uL of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. Evaluation of Anti-Proliferative Activity

The assays used to detect the effect of compounds on tumor cell proliferation were based on the ability of viable cells to cause alamarBlue to change from its oxidized (non-fluorescent, blue) to a reduced (fluorescent, red) form. With the results obtained from the alamarBlue reaction, cell proliferation can be quantified and metabolic activity of viable cells can be examined. All of the human tumor cell lines were obtained from American Type Culture Collection (ATCC).

3

Aliquots of 100 μl of cell suspension (3.0 - 5.0 x 10 cells/well) in growth media were placed in 96-well cell culture plates in an atmosphere of 5% CO2 at 37 ⁰ C. After 24-hour incubation, the growth media were replaced with 100 μl of growth media containing increasing concentrations of test compounds, rapamycin, mitomycin, or vehicle, respectively. The cells were grown for an additional 72-hour. The test compound was evaluated at increasing concentrations of 100, 10, 1, 0.1 and 0.01 μM. At the end of incubation, 20 μl of 90% alamarBlue reagent was added to each well for 6- hour incubation before detection of cell viability by fluorescent intensity. Fluorescent intensity was measured using a fluorescence microplate reader with excitation at 530 nm and emission at 590 nm.

Determination of IC50 and LC50 : The measured results were calculated by the following formula:

PG (%) = 100% x (Mean Ftest -Mean Ftime0)/(Mean Fctrl -Mean FtimeO)

If (Mean Ftest -Mean FtimeO) < 0, then PG (%) = 100% x (Mean Ftest -Mean Ftime0)/(Mean FtimeO -Mean Fblank)

Where:

PG: percent growth

Mean FtimeO = The average of measured fluorescent intensities of reduced alamarBlue at the time just before exposure of cells to the test substance. Mean Ftest = The average of measured fluorescent intensities of alamarBlue after 72- hour exposure of cells to the test substance.

Mean Fctrl = The average of measured fluorescent intensities of alamarBlue after 72-hour incubation without the test substance.

Mean Fblank = The average of measured fluorescent intensities of alamarBlue in medium without cells after 72 -hour incubation.

The compounds of the present invention typically show more then 50 % inhibition of P70S6K enzyme at lOμM concentration. For example the compounds of Examples 24,

26, 42, 64, 107 and 126 show more than 50% inhibition at 0.3 μM concentration.

While the invention has been depicted and described by reference to exemplary embodiments of the invention, such a reference does not imply a limitation on the invention, and no such limitation is to be inferred. The invention is capable of considerable modification, alteration, and equivalents in form and function, as will occur to those ordinarily skilled in the pertinent arts having the benefit of this disclosure. The depicted and described embodiments of the invention are exemplary only, and are not exhaustive of the scope of the invention. Consequently, the invention is intended to be limited only by the spirit and scope of the appended claims, giving full cognizance to equivalence in all respects.

All references cited herein are hereby incorporated by reference in their entirety.