[01] This application claims the benefit of Indian Patent Application Nos. 202241003918, filed on January 24, 2022, and 202241025747, filed on May 3, 2022, each of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[02] The present invention provides compounds of formula (I) as poly (ADP-ribose) polymerase 7 (PARP7) inhibitors, methods of preparing them, pharmaceutical compositions containing them, and their use in methods of treatment, prevention and/or amelioration of diseases or disorders involving PARP7.

BACKGROUND OF THE INVENTION

[03] Poly (ADP-ribose) polymerase (PARP) defines a family of enzymes that cleaves NAD+ to nicotinamide and ADP-ribose to form long and branched (ADP-ribose) polymers on glutamic acid residues of a number of target proteins, including PARP itself. The addition of negatively charged polymers profoundly alters the properties and functions of the acceptor proteins. Poly (ADP-ribosyl)ation is involved in the regulation of many cellular processes such as DNA repair, gene transcription, cell cycle progression, cell death, chromatin functions and genomic stability PARsylation, in addition to its well-studied role in DNA repair, and has been shown to modulate diverse processes, including cellular proliferation, DNA methylation, apoptosis, transcriptional regulation, and WNT signaling. The PARP family are categorised based in part on their catalytic activity: the poly PARP’s catalyse the transfer of poly-ADP- ribose units onto their substrates, including PARP1, PARP2, PARP5A, PARP5b, and PARP 13 which is the only PARP family member whose catalytic activity could not be demonstrated ether in vitro or in vivo. The mono PARP’s catalyse the transfer of mono-ADP-ribose units onto their substrates, including the majority of PARP family members. The mono PARP protein family plays important roles in multiple stress responses associated with the development of inflammatory diseases, cancer, and neuro degenerative diseases. PARP7 belongs to the mono PARP family and has been demonstrated to be overactive in tumors and plays a key role in cancer cell survival. Inhibition of PARP7 can effectively inhibit the growth of cancer cells and restore interferon signaling, which effectively prevents cancer cells from evading the immune system. [04] The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix/period-ARNT-single- minded ligand-activated transcription factor essential in mediating the adaptive responses to xenobiotics. It is activated by the environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) but also by numerous other endogenous and dietary compounds (Denison et. al., Toxicol. Sci., 124, 1-22, 2011). The AHR can be activated by a broad number of ligands including endogenous tryptophan metabolites such as kynurenine (Opitz et al., Nature, 478, 197-203, 2011) and certain polycyclic aromatic hydrocarbons such as 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) (Bock, Biochem. Pharmacol., 112, 1-5, 2016). Activation of the AHR induces target gene expression, including genes involved in metabolism such as cytochrome P4501A1 and P4501B1. Activation of AHR also leads to an increase in the AHR target gene, TCDD-inducible poly (ADP-ribose) polymerase (TIPARP, also referred to as PARP7), which functions as a negative regulator of certain AHR transcriptional targets (MacPherson et al., Int. J. Mol. Sci., 15, 7939-7957, 2014). Aryl hydrocarbon receptor repressor and TIPARP (ARTD14) use similar, but distinct, mechanisms to repress aryl hydrocarbon receptor signalling. [05] PARP7 is a gene regulated by AHR and an important member of the PARP family. PARP7 can only transfer a single ADP-ribose (MAR), which belongs to monoPARP. The PARP catalytic domain of PARP7 contains a zinc finger motif that can confer DNA binding and a WWE domain that can mediate protein interaction (Ma et al., Biochem., 289, 499-506, 2001). PARP7 mediated single ADP ribosylation is a reversible post-translational modification involving a variety of important biological processes, such as immune cell function, transcription regulation, protein expression and DNA repair. PARP7 is part of the negative feedback loop that regulates AHR activity, and AHR can regulate immune function, inflammation and stem cell differentiation, and play a role in cancer. PARP7 has been shown to be overactive in certain tumors and plays a key role in cancer cell survival. More importantly, many cancer cells rely on PARP7 to achieve internal cell survival, and studies have shown that PARP7 can enable cancer cells to "hide" out of the immune system. Inhibiting PARP7 can effectively inhibit the growth of cancer cells and restore interferon signal transduction and suppression of the "brake" of innate and adaptive immune mechanisms. In several cancer models, PARP7 inhibitors have shown long-lasting tumor growth inhibitory effects, effective anti-proliferative activity, and restoration of interferon signalling. [06] RBN-2397, being developed by Ribon Therapeutics, is the first PARP7 inhibitor that is in early phase of clinical trials demonstrated anti-tumor growth effect and induced tumor- specific adaptive immune memory in preclinical models (M.Gozgit et al., Cancer Cell, 39(9), 1214-1226, 2021). This indicates that PARP7 inhibitors may be excellent tumor treatment drugs. [07] However, there are still no PARP7 inhibitors widely used in clinical practice, and the function of PARP7 still needs to be elucidated. Whether it is to deepen the research on the mechanism and effects of PARP7 and/or to benefit cancer patients, there is a need for new PARP7 inhibitors. SUMMARY OF THE INVENTION [08] The present invention relates to compounds of formula (I), methods for their preparation, pharmaceutical compositions containing them, and methods of treatment using them. In particular, the compounds of formula (I), and pharmaceutically acceptable salts thereof, are useful in the treatment, prevention and/or amelioration of diseases or disorders involving PARP7. [09] In one aspect, the present invention relates to a compound of formula (I): or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salt thereof; wherein each ------ (dotted line) independently represents an optional bond; W ¹ , W ² , W ³ , and W ⁴ are independently selected from N, NR ¹ , CR ¹ , and CR ¹ R ^1a ; each occurrence of R ¹ and R ^1a is independently selected from hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted amino; L ¹ is selected from -(CR ^a R ^b )n-, -(CR ^a R ^b )n-O-, -C(R ^a )=C(R ^b )-, -O-, -NR ^a , -(CR ^a R ^b )n- NR ^a -, -S-, -S(O)-, and -S(O) ₂ ; L ² is absent or selected from -(CR ^a R ^b )n-, -(CR ^a R ^b )n-O-, -C(R ^a )=C(R ^b )-, -O-, -NR ^a , - (CR ^a R ^b ) _n -NR ^a -, -S-, -S(O)-, and -S(O) ₂ ; each occurrence of R ^a and R ^b is independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ^a and R ^b together with the carbon atom to which they are attached form a carbonyl group (-C(=O)-), spiro group, substituted or unsubstituted carbocyclic ring or substituted or unsubstituted heterocyclyl ring; R ² and R ³ are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ² and R ³ together with the carbon atom to which they are attached form a carbonyl group (-C(=O)-), spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; R ^2a and R ^3a are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl and substituted or unsubstituted alkyl; or both R ^2a and R ^3a can be taken together with the carbon atom to which they are attached to form a carbonyl group (-C(=O)-), spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring Z is CH or N;

with the provisos that (a) when Ring is (i), each occurrence of R ⁴ and R ^4a is independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, and substituted or unsubstituted carbocyclyl; or both R ⁴ and R ^4a together with the carbon atom to which they are attached can form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; (b) when Ring is (ii), each occurrence of R ⁴ and R ^4a is independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, and substituted or unsubstituted carbocyclyl; (c) when Ring is (iii), each occurrence of R ⁴ and R ^4a is independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, and substituted or unsubstituted carbocyclyl; or both R ⁴ and R ^4a together with the carbon atom to which they are attached can form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; and (d) when Ring is (iv), each occurrence of R ⁴ and R ^4a is independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, and substituted or unsubstituted carbocyclyl ring; X is absent or selected from -C(O)-, -NH-, -S-, -S(O)-, and S(O)2; Y is selected from substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl; ‘m’ is 0, 1 or 2; and each occurrence of ‘n’ is independently 1, 2 or 3. In one embodiment, each ------ (dotted line) represents a bond. In one embodiment, each ------ (dotted line) does not represent a bond. [10] In one aspect of the present invention, the compound of formula (I) is a compound of formula (IA): or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salt thereof; wherein each ------ (dotted line) independently represents an optional bond; W ¹ , W ² , W ³ , and W ⁴ are independently selected from N, NR ¹ , CR ¹ , and CR ¹ R ^1a ; each occurrence of R ¹ and R ^1a is independently selected from hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted amino; L ¹ is selected from –(CR ^a R ^b )n-, -(CR ^a R ^b )n-O-, -C(R ^a )=C(R ^b )-, -O-, -(CR ^a R ^b )n-NR ^a -, - NR ^a , -S-, -S(O)-, and -S(O) ₂ ; L ² is absent or selected from –(CR ^a R ^b )n-, -(CR ^a R ^b )n-O-, -C(R ^a )=C(R ^b )-, -O-, -NR ^a , - (CR ^a R ^b ) _n -NR ^a -, -S-, -S(O)-, and -S(O) ₂ ; each occurrence of R ^a and R ^b is independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ^a and R ^b together with the carbon atom to which they are attached form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; R ² and R ³ are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ² and R ³ together with the carbon atom to which they are attached form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; R ^2a and R ^3a are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl and substituted or unsubstituted alkyl; or both R ^2a and R ^3a can be taken together with the carbon atom to which they are attached to form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclyl ring; each occurrence of R ⁴ and R ^4a is independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, and substituted or unsubstituted carbocyclyl; or both R ⁴ and R ^4a together with the carbon atom to which they are attached form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; X is absent or selected from -C(O)-, -NH-, -S-, -S(O)-, and S(O) ₂ ; Y is selected from substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl; ‘m’ is 0, 1 or 2; and each occurrence of ‘n’ is independently 1, 2 or 3. In one embodiment, each ------ (dotted line) represents a bond. In one embodiment, each ------ (dotted line) does not represent a bond. [11] In one embodiment, the ring in formula (I) or (IA) is , , , , , , , or . [12] In one embodiment of the present invention, the compound of formula (I) or (IA) is a compound of formula (IA-a): or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salt thereof; wherein each ------ (dotted line) independently represents an optional bond; W ¹ , W ² , W ³ , and W ⁴ are independently selected from N, NR ¹ , CR ¹ , and CR ¹ R ^1a ; each occurrence of R ¹ and R ^1a is independently selected from hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted amino; L ¹ is selected from –(CR ^a R ^b )n-, -(CR ^a R ^b )n-O-, -C(R ^a )=C(R ^b )-, -O-, -(CR ^a R ^b )n-NR ^a -, - NR ^a , -S-, -S(O)-, and -S(O) ₂ ; L ² is absent or selected from –(CR ^a R ^b ) _n -, -(CR ^a R ^b ) _n -O-, -C(R ^a )=C(R ^b )-, -O-, -NR ^a , - (CR ^a R ^b )n-NR ^a -, -S-, -S(O)-, and -S(O)2; each occurrence of R ^a and R ^b is independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ^a and R ^b together with the carbon atom to which they are attached can form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclyl ring; R ² and R ³ are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ² and R ³ together with the carbon atom to which they are attached can form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclyl ring; R ^2a and R ^3a are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl and substituted or unsubstituted alkyl; or both R ^2a and R ^3a can be taken together with the carbon atom to which they are attached to form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclyl ring; X is absent or selected from -C(O)-, -NH-, -S-, -S(O)-, and S(O)2; Y is selected from substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl; ‘m’ is 0, 1 or 2; and each occurrence of ‘n’ is independently 1, 2 or 3. [13] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein each ----- (dotted line) is a bond. [14] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein each ----- (dotted line) is not a bond. [15] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein W ¹ , W ² , W ³ and W ⁴ are independently CR ¹ or N. [16] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein W ¹ , W ² , and W ³ are independently CR ¹ . [17] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein W ⁴ is CR ¹ or N, and R ¹ is hydrogen or halogen (e.g., fluoro). [18] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein W ⁴ is N. [19] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L ¹ is - (CR ^a R ^b ) _n - wherein R ^a and R ^b are hydrogen, and n is 1. [20] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L ¹ is - (CR ^a R ^b )n- wherein one of R ^a and R ^b is substituted or unsubstituted alkyl (e.g., methyl) and n is 1. [21] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L ¹ is - (CR ^a R ^b ) _n -O- wherein R ^a and R ^b are hydrogen and n is 1. [22] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L ¹ is -O-. [23] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L ¹ is - (CR ^a R ^b ) _n -NR ^a -, R ^a and R ^b are each independently hydrogen or alkyl and n is 1. [24] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L ¹ is –CH ₂ - NH-. [25] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L ¹ is –CH ₂ - N(CH3)-. [26] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein R ² and R ³ are hydrogen. [27] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L ² is absent. [28] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L ² is -O-. [29] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L ² is - (CR ^a R ^b ) _n -, R ^a and R ^b are hydrogen and n is 1. [30] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L ² is - (CR ^a R ^b ) _n -, R ^a is hydrogen, R ^b is hydroxy and n is 1. [31] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein R ^2a and R ^3a are hydrogen. [32] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein R ^2a and R ^3a , together with the carbon atom to which they are attached, form a -C(O)- group (also known as –C(=O)-). [33] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein X is absent. [34] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein X is -C(O)- or -S(O) ₂ -. [35] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein Y is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkyl. [36] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein Y is cyclopropyl or methyl. [37] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein Y is substituted or unsubstituted heterocyclyl. [38] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein Y is substituted or unsubstituted heteroaryl. [39] One embodiment is a compound of formula (I), (IA), or (IA-a), wherein Y is , , , , , , , , , , , , , , , , , , , , . , , , or . [40] In one embodiment of the present invention, the compound of formula (I) or (IA) is a compound of formula (IA-b): or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salt thereof; wherein each ------ (dotted line) independently represents an optional bond, W ¹ , W ² , W ³ , and W ⁴ are independently selected from N, NR ¹ , CR ¹ , and CR ¹ R ^1a ; each occurrence of R ¹ and R ^1a is independently selected from hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted amino; L ¹ is selected from –(CR ^a R ^b )n-, -(CR ^a R ^b )n-O-, -C(R ^a )=C(R ^b )-, -O-, -(CR ^a R ^b )n-NR ^a -, - NR ^a , -S-, -S(O)-, and -S(O) ₂ ; L ² is absent or selected from –(CR ^a R ^b )n-, -(CR ^a R ^b )n-O-, -C(R ^a )=C(R ^b )-, -O-, -NR ^a , - (CR ^a R ^b ) _n -NR ^a -, -S-, -S(O)-, and -S(O) ₂ ; each occurrence of R ^a and R ^b is independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ^a and R ^b together with the carbon atom to which they are attached form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; R ² and R ³ are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ² and R ³ together with the carbon atom to which they are attached form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; R ^2a and R ^3a are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl and substituted or unsubstituted alkyl; or both R ^2a and R ^3a can be taken together with the carbon atom to which they are attached to form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclyl ring; X is absent or selected from -C(O)-, -NH-, -S-, -S(O)-, and S(O)2; Y is selected from substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl; ‘m’ is 0, 1 or 2; and each occurrence of ‘n’ is independently 1, 2 or 3. [41] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein each ----- (dotted line) is a bond. [42] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein each ----- (dotted line) is not a bond. [43] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein W ¹ , W ² , W ³ , and W ⁴ are CR ¹ or N. [44] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein W ¹ , W ² , W ³ , are CR ¹ . [45] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein W ⁴ is CR ¹ or N and R ¹ is hydrogen or halogen (e.g., fluoro). [46] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein W ⁴ is N. [47] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein L ¹ is - (CR ^a R ^b )n- wherein R ^a and R ^b are hydrogen and n is 1. [48] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein L ¹ is - (CR ^a R ^b ) _n -NR ^a - wherein R ^a and R ^b are each, independently, hydrogen or substituted or unsubstituted alkyl and n is 1. [49] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein L ¹ is -CH ₂ - or –CH2-NH-, [50] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein R ² and R ³ are hydrogen. [51] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein L ² is - (CR ^a R ^b ) _n - wherein R ^a and R ^b are hydrogen and n is 1. [52] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein R ^2a and R ^3a , together with the carbon atom to which they are attached, form a -C(O)- group. [53] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein X is absent. [54] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein Y is substituted or unsubstituted heterocyclyl. [55] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein Y is substituted or unsubstituted heteroaryl. [56] One embodiment is a compound of formula (I), (IA), or (IA-b), wherein Y is , , , , , , , , , , , , , , , , or . [57] In another aspect of the present invention, the compound of formula (I) is a compound of formula (IB): or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salt thereof; wherein each ------ (dotted line) independently represents an optional bond; W ¹ , W ² , W ³ , and W ⁴ are independently selected from N, NR ¹ , CR ¹ , and CR ¹ R ^1a ; each occurrence of R ¹ and R ^1a is independently selected from hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted amino; L ¹ is selected from –(CR ^a R ^b ) _n -, -(CR ^a R ^b ) _n -O-, -C(R ^a )=C(R ^b )-, -O-, -(CR ^a R ^b ) _n -NR ^a -, - NR ^a , -S-, -S(O)-, and -S(O)2; L ² is absent or selected from –(CR ^a R ^b )n-, -(CR ^a R ^b )n-O-, -C(R ^a )=C(R ^b )-, -O-, -NR ^a , - (CR ^a R ^b ) _n -NR ^a -, -S-, -S(O)-, and -S(O) ₂ ; each occurrence of R ^a and R ^b are each independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ^a and R ^b together with the carbon atom to which they are attached form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; R ² and R ³ are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ² and R ³ together with the carbon atom to which they are attached form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; R ^2a and R ^3a are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl and substituted or unsubstituted alkyl; or both R ^2a and R ^3a can be taken together with the carbon atom to which they are attached to form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclyl ring; each occurrence of R ⁴ and R ^4a is independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, and substituted or unsubstituted carbocyclyl; X is absent or selected from -C(O)-, -NH-, -S-, -S(O)-, and S(O)2; Y is selected from substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl; ‘m’ is 0, 1 or 2; and each occurrence of ‘n’ is independently 1, 2 or 3. [58] One embodiment is a compound of formula (I) or (IB), wherein each ----- (dotted line) is a bond. [59] One embodiment is a compound of formula (I) or (IB), wherein each ----- (dotted line) is not a bond. [60] One embodiment is a compound of formula (I) or (IB), wherein W ¹ , W ² , W ³ , and W ⁴ are CR ¹ ; and R ¹ is hydrogen. [61] One embodiment is a compound of formula (I) or (IB), wherein L ¹ is -(CR ^a R ^b )n- wherein R ^a and R ^b are hydrogen and n is 1. [62] One embodiment is a compound of formula (I) or (IB), wherein R ² and R ³ are hydrogen. [63] One embodiment is a compound of formula (I) or (IB), wherein L ² is -(CR ^a R ^b )n- wherein R ^a and R ^b are hydrogen and n is 1. [64] One embodiment is a compound of formula (I) or (IB), wherein R ^2a and R ^3a , together with the carbon atom to which they are attached, form a -C(O)- group. [65] One embodiment is a compound of formula (I) or (IB), wherein X is absent. [66] One embodiment is a compound of formula (I) or (IB), wherein X is -NH-. [67] One embodiment is a compound of formula (I) or (IB), wherein Y is substituted or unsubstituted heterocyclyl. [68] One embodiment is a compound of formula (I) or (IB), wherein Y is substituted or unsubstituted heteroaryl. [69] One embodiment is a compound of formula (I) or (IB), wherein Y is , , or . [70] In another aspect of the present invention, the compound of formula (I) is a compound of formula (IC): or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salt thereof; wherein each ------ (dotted line) independently represents an optional bond; W ¹ , W ² , W ³ , and W ⁴ are independently selected from N, NR ¹ , CR ¹ , or CR ¹ R ^1a ; each occurrence of R ¹ and R ^1a is independently selected from hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted amino; L ¹ is selected from –(CR ^a R ^b ) _n -, -(CR ^a R ^b ) _n -O-, -C(R ^a )=C(R ^b )-, -O-, -(CR ^a R ^b ) _n -NR ^a -, - NR ^a , -S-, -S(O)-, and -S(O)2; L ² is absent or selected from –(CR ^a R ^b ) _n -, -(CR ^a R ^b ) _n -O-, -C(R ^a )=C(R ^b )-, -O-, -NR ^a , - (CR ^a R ^b )n-NR ^a -, -S-, -S(O)-, and -S(O)2; each occurrence of R ^a and R ^b is independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ^a and R ^b together with the carbon atom to which they are attached form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; R ² and R ³ are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ² and R ³ together with the carbon atom to which they are attached form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; R ^2a and R ^3a are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl and substituted or unsubstituted alkyl; or both R ^2a and R ^3a , together with the carbon atom to which they are attached, form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclyl ring; each occurrence of R ⁴ and R ^4a is independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, and substituted or unsubstituted carbocyclyl; or both R ⁴ and R ^4a together with the carbon atom to which they are attached form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; X is absent or selected from -C(O)-, -S-, -S(O)-, and S(O) ₂ ; Y is selected from substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl; ‘m’ is 0, 1 or 2; and each occurrence of ‘n’ is independently 1, 2 or 3. [71] One embodiment is a compound of formula (I) or (IC), wherein each ----- (dotted line) is a bond. [72] One embodiment is a compound of formula (I) or (IC), wherein each ----- (dotted line) is not a bond. [73] One embodiment is a compound of formula (I) or (IC), wherein W ¹ , W ² , W ³ , and W ⁴ are CR ¹ ; and R ¹ is hydrogen. [74] One embodiment is a compound of formula (I) or (IC), wherein L ¹ is -(CR ^a R ^b )n-; wherein R ^a and R ^b are hydrogen; and n is an integer “1”. [75] One embodiment is a compound of formula (I) or (IC), wherein R ² and R ³ are hydrogen. [76] One embodiment is a compound of formula (I) or (IC), wherein L ² is -(CR ^a R ^b )n-; wherein R ^a and R ^b are hydrogen; and n is an integer “1”. [77] One embodiment is a compound of formula (I) or (IC), wherein R ^2a and R ^3a are taken together with the carbon atom to which they are attached to form a -C(O)- group. [78] One embodiment is a compound of formula (I) or (IC), wherein X is absent. [79] One embodiment is a compound of formula (I) or (IC), wherein Y is optionally substituted heterocyclyl. [80] One embodiment is a compound of formula (I) or (IC), wherein Y is optionally substituted heteroaryl. [81] One embodiment is a compound of formula (I) or (IC), wherein Y is . [82] In another aspect of the present invention, the compound of formula (I) is a compound of formula (ID):

or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salt thereof; wherein each ------ (dotted line) independently represents an optional bond; W ¹ , W ² , W ³ , and W ⁴ are independently selected from N, NR ¹ , CR ¹ , or CR ¹ R ^1a ; each occurrence of R ¹ and R ^1a is independently selected from hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted amino; L ¹ is selected from –(CR ^a R ^b )n-, -(CR ^a R ^b )n-O-, -C(R ^a )=C(R ^b )-, -O-, -(CR ^a R ^b )n-NR ^a -, - NR ^a , -S-, -S(O)-, and -S(O) ₂ ; L ² is absent or selected from –(CR ^a R ^b )n-, -(CR ^a R ^b )n-O-, -C(R ^a )=C(R ^b )-, -O-, -NR ^a , - (CR ^a R ^b ) _n -NR ^a -, -S-, -S(O)-, and -S(O) ₂ ; each occurrence of R ^a and R ^b is independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ^a and R ^b together with the carbon atom to which they are attached form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclyl ring; R ² and R ³ are independently selected from hydrogen, halogen, haloalkyl, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted alkyl; or both R ² and R ³ together with the carbon atom to which they are attached form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; each occurrence of R ⁴ and R ^4a is independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, and substituted or unsubstituted carbocyclyl; X is absent or selected from -C(O)-, -S-, -S(O)-, and S(O) ₂ ; Y is selected from substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl; ‘m’ is 0, 1 or 2; and each occurrence of ‘n’ is independently 1, 2 or 3. [83] One embodiment is a compound of formula (I) or (ID), wherein each ----- (dotted line) is a bond. [84] One embodiment is a compound of formula (I) or (ID), wherein each ----- (dotted line) is not a bond. [85] One embodiment is a compound of formula (I) or (ID), wherein W ¹ , W ² , W ³ , and W ⁴ are CR ¹ and R ¹ is hydrogen. [86] One embodiment is a compound of formula (I) or (ID), wherein L ¹ is -(CR ^a R ^b ) _n - wherein R ^a and R ^b are hydrogen and n is 1. [87] One embodiment is a compound of formula (I) or (ID), wherein R ² and R ³ are hydrogen. [88] One embodiment is a compound of formula (I) or (ID), wherein L ² is -(CR ^a R ^b ) _n - wherein R ^a and R ^b are hydrogen and n is 1. [89] One embodiment is a compound of formula (I) or (ID), wherein R ^2a and R ^3a together with the carbon atom to which they are attached form a -C(O)- group. [90] One embodiment is a compound of formula (I) or (ID), wherein X is absent. [91] One embodiment is a compound of formula (I) or (ID), wherein Y is substituted or unsubstituted heterocyclyl. [92] One embodiment is a compound of formula (I) or (ID), wherein Y is substituted or unsubstituted heteroaryl. [93] One embodiment is a compound of formula (I) or (ID), wherein Y is . [94] Representative compounds of the present invention include those recited below. The present invention should not be construed to be limited to the compounds recited below: 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1 -yl)butyl)phthalazin- 1(2H)-one, 4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-4-oxobutyl)pht halazin-1(2H)-one, 4-(4-(4-(methylsulfonyl)piperazin-1-yl)-4-oxobutyl)phthalazi n-1(2H)-one, 4-(4-oxo-4-(4-(pyrimidin-2-yl)piperazin-1-yl)butyl)phthalazi n-1(2H)-one, 4-(4-oxo-4-(4-(pyrazin-2-yl)piperazin-1-yl)butyl)phthalazin- 1(2H)-one, 7-fluoro-4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)pi perazin-1- yl)butyl)phthalazin-1(2H)-one, 4-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-4-oxobutyl)p hthalazin-1(2H)-one, 2-(4-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl)piperazin -1-yl)pyrimidine-5- carbonitrile, 4-(4-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-4-oxobutyl)p hthalazin-1(2H)-one, 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-y l)butyl)phthalazin-1(2H)- one. 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazin-1-y l)butyl)phthalazin-1(2H)- one, 4-(4-(4-(5-(difluoromethyl)pyrimidin-2-yl)piperazin-1-yl)-4- oxobutyl)phthalazin- 1(2H)-one, 4-(4-oxo-4-(4-(pyridazin-3-yl)piperazin-1-yl)butyl)phthalazi n-1(2H)-one, 4-(4-(4-(5-isopropylpyrimidin-2-yl)piperazin-1-yl)-4-oxobuty l)phthalazin-1(2H)-one, 4-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1 -yl)pentyl)phthalazin- 1(2H)-one, 4-(3-hydroxy-4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)p iperazin-1- yl)butyl)phthalazin-1(2H)-one, 4-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1 -yl)pentan-2- yl)phthalazin-1(2H)-one, 4-(4-(4-(5-(difluoromethoxy)pyridin-2-yl)piperazin-1-yl)-4-o xobutyl)phthalazin-1(2H)- one, 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperidin-1-y l)butyl)phthalazin-1(2H)- one, 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-1 -yl)butyl)phthalazin- 1(2H)-one, 4-(4-oxo-4-(4-(6-(trifluoromethyl)pyridazin-3-yl)piperazin-1 -yl)butyl)phthalazin- 1(2H)-one, 4-(4-(4-(5-(difluoromethoxy)pyrimidin-2-yl)piperazin-1-yl)-4 -oxobutyl)phthalazin- 1(2H)-one, 4-(4-(4-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazin-1-yl)-4- oxobutyl)phthalazin- 1(2H)-one, 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)-1,4-diazep an-1-yl)butyl)phthalazin- 1(2H)-one, 6-fluoro-4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)pi perazin-1- yl)butyl)phthalazin-1(2H)-one, 4-(4-oxo-4-(4-(5-(trifluoromethoxy)pyridin-2-yl)piperazin-1- yl)butyl)phthalazin-1(2H)- one, 4-(4-oxo-3,4-dihydrophthalazin-1-yl)butyl 4-(5-(trifluoromethyl)pyrimidin-2- yl)piperazine-1-carboxylate, 4-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperazin-1-yl)-4-o xobutyl)phthalazin-1(2H)- one, 4-(4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)bu tyl)phthalazin-1(2H)-one, 4-(4-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-4-oxobutyl)pht halazin-1(2H)-one, 6-(4-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl)piperazin -1-yl)nicotinonitrile, 4-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1 -yl)propoxy)phthalazin- 1(2H)-one, 4-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)-4-oxo butyl)phthalazin-1(2H)- one, 4-(4-(4-(5-chloropyrimidin-2-yl)-2-oxopiperazin-1-yl)butyl)p hthalazin-1(2H)-one, 4-(3-(4-(5-chloropyrimidin-2-yl)-2-oxopiperazin-1-yl)propyl) phthalazin-1(2H)-one, 4-(4-(4-(5-chloro-4-methylpyrimidin-2-yl)piperazin-1-yl)-4-o xobutyl)phthalazin-1(2H)- one. 4-(4-(4-(5-chloro-4-methylpyridin-2-yl)piperazin-1-yl)-4-oxo butyl)phthalazin-1(2H)- one, 4-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropyl) phthalazin-1(2H)-one, 4-(5-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-5-oxopentyl) phthalazin-1(2H)-one, 4-((3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropox y)methyl)phthalazin- 1(2H)-one, 4-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin- 1- yl)propoxy)methyl)phthalazin-1(2H)-one, 4-((2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin- 1- yl)ethoxy)methyl)phthalazin-1(2H)-one, 4-(4-(4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazin- 1-yl)-4- oxobutyl)phthalazin-1(2H)-one, 4-(5-(4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazin- 1-yl)-5- oxopentyl)phthalazin-1(2H)-one, 4-(4-(4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazin- 1-yl)-4- oxobutyl)phthalazin-1(2H)-one, 4-(5-(4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazin- 1-yl)-5- oxopentyl)phthalazin-1(2H)-one, 4-(((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin -1- yl)propyl)amino)methyl)phthalazin-1(2H)-one, 8-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1 -yl)butyl)pyrido[2,3- d]pyridazin-5(6H)-one, 8-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1 -yl)pentyl)pyrido[2,3- d]pyridazin-5(6H)-one, 4-((methyl(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)pip erazin-1- yl)propyl)amino)methyl)phthalazin-1(2H)-one, 4-(4-oxo-4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazab icyclo[3.2.1]octan-8- yl)butyl)phthalazin-1(2H)-one, 4-(4-oxo-4-(6-(5-(trifluoromethyl)pyrimidin-2-yl)-2,6-diazas piro[3.3]heptan-2- yl)butyl)phthalazin-1(2H)-one, 4-(4-oxo-4-(8-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazab icyclo[3.2.1]octan-3- yl)butyl)phthalazin-1(2H)-one, (±)-4-(4-oxo-4-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-2,5-d iazabicyclo[2.2.2]octan-2- yl)butyl)phthalazin-1(2H)-one,) (±)-4-(4-oxo-4-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-2,5-d iazabicyclo[2.2.1]heptan-2- yl)butyl)phthalazin-1(2H)-one, 4-(4-(3-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octa n-8-yl)-4- oxobutyl)phthalazin-1(2H)-one, 4-(4-oxo-4-(3-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabic yclo[3.2.1]octan-8- yl)butyl)phthalazin-1(2H)-one, 2-(8-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl)-3,8-diaz abicyclo[3.2.1]octan-3- yl)pyrimidine-5-carbonitrile, 6-(8-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl)-3,8-diaz abicyclo[3.2.1]octan-3- yl)nicotinonitrile, 4-(4-(3-(5-chloropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan- 8-yl)-4- oxobutyl)phthalazin-1(2H)-one, 4-(4-oxo-4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-diazab icyclo[3.1.1]heptan-6- yl)butyl)phthalazin-1(2H)-one, 4-(4-oxo-4-(6-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-diazab icyclo[3.1.1]heptan-3- yl)butyl)phthalazin-1(2H)-one, 4-(4-(3-(5-(difluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[ 3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one, 4-(4-(3-(5-(difluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3. 2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one, N-methyl-2-(8-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl) -3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidine-5-carboxamide, 4-(4-(3-(5-(methylsulfinyl)pyrimidin-2-yl)-3,8-diazabicyclo[ 3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one, 2-(8-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl)-3,8-diaz abicyclo[3.2.1]octan-3- yl)-5-(trifluoromethyl)pyridine 1-oxide, 4-(4-(3-(5-(methylsulfonyl)pyrimidin-2-yl)-3,8-diazabicyclo[ 3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one, 4-(4-(3-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,8-diazabicyclo[3 .2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one, 4-(4-(3-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octa n-8-yl)-4-oxobutyl)-8- fluorophthalazin-1(2H)-one, 4-(4-(3-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octa n-8-yl)-4- oxobutyl)phthalazin-1(2H)-one, 4-(4-(3-(9H-purin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4 -oxobutyl)phthalazin- 1(2H)-one, 4-(4-(3-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,8-diazabicyclo[ 3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one, 4-(4-(8-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octa n-3-yl)-4- oxobutyl)phthalazin-1(2H)-one, 4-(4-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3,8-diaza bicyclo[3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one, 4-(5-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3,8-diaza bicyclo[3.2.1]octan-8-yl)-5- oxopentyl)phthalazin-1(2H)-one, 4-((3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabi cyclo[3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one, 8-(3-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8 -yl)-5- oxopentyl)pyrido[2,3-d]pyridazin-5(6H)-one, 4-(3-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8 -yl)-5- oxopentyl)phthalazin-1(2H)-one, 4-(5-oxo-3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicy clo[3.2.1]octan-8- yl)pentyl)phthalazin-1(2H)-one, 8-(5-oxo-5-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazab icyclo[3.2.1]octan-8- yl)pentyl)pyrido[2,3-d]pyridazin-5(6H)-one, 4-(((3-oxo-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diaz abicyclo[3.2.1]octan-8- yl)propyl)amino)methyl)phthalazin-1(2H)-one, 4-(((3-oxo-3-(3-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazab icyclo[3.2.1]octan-8- yl)propyl)amino)methyl)phthalazin-1(2H)-one, or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof or pharmaceutically acceptable salt thereof, [95] Representative structures are shown in Table 1 below. The present invention includes the compounds in Table 1 and tautomers thereof, prodrugs thereof, N-oxides thereof, stereoisomers thereof, pharmaceutically acceptable esters thereof and pharmaceutically acceptable salts thereof. Table 1 Ex. Structure Ex. Structure Ex. Structure No. No. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 ^{22 23} 24 25 26 ²⁷ 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 ^{43 44 45} 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 ^{76 77} 78 79 80 81 82 83 [96] Additional representative compounds are shown in Table 2. The present invention includes the compounds in Table 2 and tautomers thereof, prodrugs thereof, N-oxides thereof, stereoisomers thereof, pharmaceutically acceptable esters thereof and pharmaceutically acceptable salts thereof. Table 2 Ex. Structure Ex. Structure Ex. Structure No. No. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 [97] Yet another aspect of the present invention is a method for inhibiting PARP (such as PARP7) in a patient (e.g., a patient in need thereof) comprising administering to the patient an effective amount of at least one compound of the present invention (for example, a compound of formula (I), as defined above). [98] Yet another embodiment of the present invention is a method for treating an inflammatory, autoimmune, or proliferative disease (e.g., via inhibition of PARP (such as PARP7)) by administering to a patient in need of such treatment an effective amount of at least one compound of the present invention. In one embodiment, the compound of the present invention inhibits PARP (i.e., an effective amount of the compound is administered to inhibit PARP). In one embodiment, the compound of the present invention inhibits PARP7 (i.e., an effective amount of the compound is administered to inhibit PARP7). [99] Yet another embodiment of the present invention is a method for treating an inflammatory, autoimmune, or proliferative disease (e.g., via inhibition of PARP (such as PARP7)) by administering to a patient in need of such treatment an effective amount of at least one compound of the present invention, in combination (simultaneously or sequentially) with at least one other anti-inflammatory, immunomodulator or anti-cancer agent. In one embodiment, the compound of the present invention inhibits PARP (such as PARP7). [100] More particularly, the compounds of formula (I), and pharmaceutically acceptable esters or salts thereof, can be administered for the treatment, prevention and/or amelioration of diseases or disorders associated with PARP (such as PARP7), in particular the amelioration of diseases or disorders mediated by PARP7, including, but not limited to, inflammatory diseases or disorders, autoimmune diseases or disorders, and cancer and other proliferative diseases or disorders. [101] The compounds of the present invention are useful in the treatment of a variety of cancers, including, but not limited to: • solid tumours of breast, non-small cell lung, pancreatic, endometrial, colon, oesophageal, prostate, ovary, urothelial cancer, head and neck cancer. • carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; • hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin’s lymphoma, hairy cell lymphoma and Burkett's lymphoma; • hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; • tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; • brain cancers such as glioblastoma, astrocytoma, and neuroglioma; • tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and • other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma. [102] The compounds of the present invention (e.g., as modulators of apoptosis) are useful in the treatment of cancer (including, but not limited to, those types mentioned herein), viral infections (including but not limited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including, but not limited to, systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anaemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, haematological diseases (including, but not limited to, chronic anaemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including, but not limited to, osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain. [103] The compounds of the present invention are useful in the treatment of cancer metabolic pathway diseases or disorders, non-alcoholic fatty liver disease, diabetes, abnormal lipid metabolism, hypothyroidism, metabolic syndrome, Cushing’s syndrome, and polycystic ovary syndrome (PCOS). [104] The compounds of present invention can modulate the level of cellular RNA and DNA synthesis. The compounds of present invention are therefore useful in the treatment of viral infections (including, but not limited to, HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus). [105] The compounds of the present invention are useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse. The compounds described herein are also useful in inhibiting tumor angiogenesis and metastasis. One embodiment of the invention is a method of inhibiting tumor angiogenesis or metastasis in a patient in need thereof by administering to the patient an effective amount of one or more compounds of the present invention. [106] Another embodiment of the present invention is a method of treating an immune system-related disease (e.g., an autoimmune disease), a disease or disorder involving inflammation (e.g., asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis and disorders of the immune system), cancer or other proliferative disease, a hepatic disease or disorder, a renal disease or disorder, or a metabolic pathway disease or disorder comprising administering to a patient in need thereof an effective amount of one or more compounds of the present invention. [107] Examples of immune disorders include, but are not limited to, psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic disease (e.g., allergic rhinitis), vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune haemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis. [108] In one embodiment, the compounds described herein are used as immunosuppressants to prevent transplant graft rejections, allogeneic or xenogeneic transplantation rejection (organ, bone marrow, stem cells, other cells and tissues), and graft - versus - host disease. In one particular embodiment, transplant graft rejections result from tissue or organ transplants. In further embodiments, graft-versus-host disease results from bone marrow or stem cell transplantation. One embodiment is a method of preventing or decreasing the risk of transplant graft rejection, allogeneic or xenogeneic transplantation rejection (organ, bone marrow, stem cells, other cells and tissues), or graft - versus - host disease by administering to a patient in need of such treatment an effective amount of one or more compounds of the present invention. [109] The compounds of the present invention are also useful in combination (administered together or sequentially) with known anti-cancer treatments, such as, but not limited to, radiation therapy or with cytostatic, cytotoxic or anticancer agents, such as, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones (for example ixabepilone), either naturally occurring or synthetic; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methotrexate, other tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; PI3K inhibitors; EGF inhibitors; VEGF inhibitors; CDK inhibitors; HDAC inhibitors, SRC inhibitors; c-Kit inhibitors; Her1/2 inhibitors and monoclonal antibodies directed against growth factor receptors such as erbitux (EGF) and Herceptin (Her2), and other protein kinase modulators. [110] The compounds of the present invention are also useful in combination (administered together or sequentially) with one or more steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs) or immune selective anti-inflammatory derivatives (ImSAIDs). [111] The present invention further provides a pharmaceutical composition comprising one or more compounds of the present invention (such as a compound having formula (I), or a pharmaceutically acceptable salt thereof) together with a pharmaceutically acceptable carrier. The pharmaceutical composition may further comprise one or more of the additional active ingredients identified above, such as other anti-cancer agents. [112] In one embodiment, the pharmaceutical composition includes a therapeutically effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof. [113] Yet another embodiment is a method of treating cancer in a patient in need thereof by administering a therapeutically effective amount of a compound of the present invention. For example, the compounds of the present invention are effective for treating hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin’s lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, acute myelogenous leukemias, chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia. The compounds of the present invention are also effective for treating carcinoma of the bladder, carcinoma of the breast, carcinoma of the colon, carcinoma of the kidney, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell carcinoma, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma. [114] Yet another embodiment is a method of treating leukemia in a patient in need thereof comprising administering a therapeutically effective amount of a compound of the present invention. In yet another embodiment, the compounds of the present invention are effective for treating carcinoma of the breast, ovarian cancer, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer or stomach cancer. DETAILED DESCRIPTION OF THE INVENTION [115] As used herein the following definitions shall apply unless otherwise indicated. Further, many of the groups defined herein can be optionally substituted. The listing of substituents in the definition is exemplary and is not to be construed to limit the substituents defined elsewhere in the specification. [116] The term “alkyl”, unless otherwise specified, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl, and 1,1-dimethylethyl (t-butyl). The term “C1-6 alkyl” refers to an alkyl group as defined above having 1 to 6 carbon atoms. The term “C _2-4 alkyl” refers to an alkyl group as defined above having 2 to 4 carbon atoms. The term “C1-3 alkyl” refers to an alkyl group as defined above having 1 to 3 carbon atoms. In appropriate circumstances, the term “alkyl” refers to a hydrocarbon chain radical as mentioned above which is bivalent. [117] The term “cycloalkyl”, unless otherwise specified, denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. [118] Examples of multicyclic cycloalkyl groups include, for example, perhydronaphthyl, adamantyl and norbornyl groups, bridged cyclic groups, and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl. The term “C _3-6 cycloalkyl” refers to a cycloalkyl group as defined above having 3 to 6 carbon atoms. [119] The term “aryl”, unless otherwise specified, refers to an aromatic radical having 6 to 20 carbon atoms, such as, for example, phenyl, naphthyl, tetrahydronaphthyl, and indanyl. [120] The term “heterocyclic ring”, unless otherwise specified, refers to a non-aromatic 3-to- 15-member ring radical which consists of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen and sulphur. For purposes of this invention, the heterocyclic ring radical may be a mono-, bi-, tri- or tetracyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom. [121] The term “heterocyclyl”, unless otherwise specified, refers to a heterocylic ring radical as defined above. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom. [122] The term “heteroaryl”, unless otherwise specified, refers to an optionally substituted 5- to14-membered aromatic ring having one or more heteroatoms selected from N, O, and S as ring atoms. The heteroaryl may be a mono-, bi- or tricyclic ring system. Examples of such “heterocyclic ring” or “heteroaryl” radicals include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom. The term “substituted heteroaryl” also includes ring systems substituted with one or more oxide (=O) substituents, such as pyridinyl N-oxides. [123] The term “substituted” unless otherwise specified, refers to substitution with any one or any combination of the following substituents which may be the same or different and are independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclically ring, substituted or unsubstituted guanidine, –COOR ^t , -C(O)R ^v , -C(S)R ^v , - C(O)NR ^t R ^u , -C(O)ONR ^t R ^u , -NR ^t R ^u ,-NR ^t CONR ^u R ^v , -N(R ^t )SOR ^u , -N(R ^t )SO2R ^u , -(=N- N(R ^t )R ^u ), - NR ^t C(O)OR ^u , -NR ^t R ^u , -NR ^t C(O)R ^u -, -NR ^t C(S)R ^u -NR ^t C(S)NR ^t R ^u , -SONR ^t R ^u , - SO ₂ NR ^t R ^u , -OR ^t , -OR ^t C(O)NR ^u R ^v , -OR ^t C(O)OR ^u , -OC(O)R ^t , -OC(O)NR ^t R ^u , - R ^t NR ^u C(O)R ^v , -R ^t OR ^u , -R ^t C(O)OR ^u , -R ^t C(O)NR ^u R ^v , -R ^t C(O)R ^u , -R ^t OC(O)R ^u , -SR ^t , -SOR ^t , -SO2R ^t , and - ONO ₂ , wherein R ^t , R ^u and R ^v in each of the above groups can independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted heterocyclic ring, or substituted heterocyclically ring, or any two of R ^t , R ^u and R ^v may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR ^t1 (e.g., R ^t1 can be hydrogen or C1-6 alkyl) or S. Substitution or the combinations of substituents envisioned by this invention are preferably those that result in the formation of a stable or chemically feasible compound. The term stable as used herein refers to the compounds or the structure that are not substantially altered when subjected to conditions to allow for their production, detection and preferably their recovery, purification and incorporation into a pharmaceutical composition. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl". [124] The term “carbonyl” refers to -C(=O)-. [125] The term "halo", "halide", or, alternatively, "halogen" means fluoro, chloro, bromo or iodo. The terms "haloalkyl," "haloalkenyl," "halo alkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures, respectively, that are substituted with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine. [126] The term "protecting group" or "PG" refers to a substituent that is employed to block or protect a particular functionality. Other functional groups on the compound may remain reactive. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups include, but are not limited to, acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Suitable carboxy-protecting groups include, but are not limited to, -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, and nitroethyl. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991. [127] The following abbreviations have the meanings provided: “rt” refers to room temperature, “NBS” refers to N-bromo succinimide, “AIBN” refers to azobisisobutyronitrile, “DCM” refers to dichloromethane, “TEA” refers to triethylamine, “EtOH” refers to ethanol, “MeOH” refers to methanol, “THF” refers to tetrahydrofuran, “DMF” refers to dimethylformamide, “DIPEA” refers to N,N-diisopropylethylamine, and “BOC” refers to tert- butoxycarbonyl (Boc) [128] Certain of the compounds described herein contain one or more asymmetric centres and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Non-limiting examples of intermediate mixtures include a mixture of isomers in a ratio of 10:90, 13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. [129] The terms “tautomer” and "tautomers" refer to compounds, which are characterized by relatively easy interconversion of isomeric forms in equilibrium. These isomers are intended to be covered by this invention. “Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. [130] A "leaving group or atom" is any group or atom that, under the reaction conditions, cleaves from the starting material, thus promoting reaction at a specified site. Suitable examples of leaving groups, unless otherwise specified, are halogen atoms and mesyloxy, p- nitrobenzensulphonyloxy and tosyloxy groups. [131] The term "prodrug" refers to a compound, which is an inactive precursor of a compound, converted into its active form in the body by normal metabolic processes. Prodrug design is discussed generally in Hardma, et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion is provided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol.14, ASCD Symposium Series, and in Roche (ed.), Bio reversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). To illustrate, prodrugs can be converted into a pharmacologically active form through hydrolysis of, for example, an ester or amide linkage, thereby introducing or exposing a functional group on the resultant product. The prodrugs can be designed to react with an endogenous compound to form a water-soluble conjugate that further enhances the pharmacological properties of the compound, for example, increased circulatory half-life. Alternatively, prodrugs can be designed to undergo covalent modification on a functional group with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugate can be inactivated and excreted in the urine or rendered more potent than the parent compound. High molecular weight conjugates also can be excreted into the bile, subjected to enzymatic cleavage, and released back into circulation, thereby effectively increasing the biological half-life of the originally administered compound. [132] The term "ester" refers to a compound, which is formed by reaction between an acid and an alcohol with elimination of water. An ester can be represented by the general formula RCOOR' wherein, e.g., R’ is alkyl. [133] These prodrugs and esters are intended to be covered within the scope of this invention. [134] Additionally, the instant invention also includes the compounds which differ only in the presence of one or more isotopically enriched atoms for example replacement of hydrogen with deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon. [135] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabelled with radioactive isotopes, such as for example tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [136] Pharmaceutically acceptable salts forming part of this invention include, but are not limited to, salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine; chiral bases such as alkylphenylamine, glycinol, and phenyl glycinol; salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, omithine, lysine, arginine, and serine; quaternary ammonium salts of the compounds of invention with alkyl halides, alkyl sulphates such as MeI and (Me) ₂ SO ₄ ; non-natural amino acids such as D-isomers or substituted amino acids; guanidine; and substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides (e.g., hydrochlorides), acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates. [137] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub combinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% (such as between 1% and 5%) of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes those embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, that "consist of” or "consist essentially of” the described features. [138] The term "cell proliferation" refers to a phenomenon by which the cell number has changed because of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal. [139] The terms "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompasses administration of two or more active agents to an animal so that both active agents and/or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or simultaneous administration in a composition in which both agents are present. [140] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to show the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration. The specific dose will vary depending on the compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. In one embodiment, the amount of compound administered ranges from about 0.1 mg to about 5 g, from about 1 mg to about 2.0 g, from about 100 mg to about 1.5 g, from about 200 mg to about 1.5 g, from about 400 mg to about 1.5 g, or from about 400 mg to about 1 g. [141] As used herein, "treatment," "treating," or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. [142] A "therapeutic effect," as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. [143] The term "subject" or “patient” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications (e.g., dogs, cats, cows, sheep, pigs, horses, goats, chickens, turkeys, ducks, and geese). [144] In some embodiments, the patient is a mammal, and in some embodiments, the patient is human. [145] "Radiation therapy" means exposing a patient, using routine methods and compositions known to the practitioner, to radiation emitters such as alpha-particle emitting radionuclides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters (i.e. beta emitters), conversion electron emitters (e.g. strontium-89 and samarium-153- EDTMP), or high-energy radiation, including without limitation x-rays, gamma rays, and neutrons. [146] The term "pharmaceutically acceptable excipient" includes, but is not limited to, all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavoring, carriers, buffers, stabilizers, solubilizers, and combinations thereof. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions. [147] The methods of the invention may be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, as within an animal or human or in a subject's body. In this context, the methods of the invention may be used therapeutically or prophylactically in an individual. “Ex vivo" means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including, but not limited to, fluid or tissue samples obtained from individuals. Such samples may be obtained by methods known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the invention may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the invention may be used ex vivo or in vitro to determine the optimal schedule and/or dosing of administration of a PARP inhibitor, more specifically a PARP7 inhibitor, for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental or diagnostic purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the invention may be suited are described below or will become apparent to those skilled in the art. Pharmaceutical Compositions [148] The present invention also provides a pharmaceutical composition comprising one or more compounds of the present invention. The pharmaceutical composition may include one or more additional active ingredients as described herein. The pharmaceutical composition may be administered for any of the disorders described herein. [149] The pharmaceutical compositions described herein are typically formulated to provide a therapeutically effective amount of a compound of the present invention as the active ingredient. Where desired, the pharmaceutical compositions contain a compound of the present invention as the active ingredient and one or more pharmaceutically acceptable carriers or excipients, such as inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. [150] The pharmaceutical compositions described herein can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the subject compounds and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time. [151] Methods described herein include administration of a compound of the present invention by itself, or in combination as described herein, and in each case optionally including one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants, flavorings, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof. [152] Preparations of various pharmaceutical compositions are known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which are incorporated by reference herein in their entirety. [153] The compounds and pharmaceutical compositions of the present invention can be administered by any route that enables delivery of the compounds to the site of action, such as oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal and infusion), topical administration (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. The compounds and pharmaceutical compositions can also be administered intraadiposally or intrathecally. [154] The pharmaceutical compositions can be administered in solid, semi-solid, liquid or gaseous form, or may be in dried powder form, such as lyophilized form. The pharmaceutical compositions can be packaged in forms convenient for delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatins, papers, tablets, capsules, suppositories, pellets, pills, troches, and lozenges. The type of packaging will generally depend on the desired route of administration. Implantable sustained release formulations are also contemplated, as are transdermal formulations. Method of Treatment [155] The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including, but not limited to, diseases associated with overexpression of PARP and/or due to an excess of PARP. [156] One embodiment is a method of inhibiting PARP (e.g., PARP7) in a subject (e.g., a human subject) in need thereof comprising administering an effective amount of a compound described herein. [157] The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including, but not limited to, diseases associated with overexpression of PARP7 and/or due to an excess of PARP7. [158] The treatment methods provided herein comprise administering to the subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides a method of treating an inflammation disorder, including autoimmune diseases in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention. [159] It will be appreciated that the treatment methods described herein are useful in the fields of human medicine and veterinary medicine. Thus, the individual to be treated may be a mammal, preferably human, or another animal. For veterinary purposes, individuals include but are not limited to farm animals including cows, sheep, pigs, horses, and goats; companion animals such as dogs and cats; exotic and/or zoo animals; laboratory animals including mice, rats, rabbits, guinea pigs, and hamsters; and poultry such as chickens, turkeys, ducks, and geese. [160] The present invention also relates to a method of treating a hyperproliferative disorder in a subject (e.g., a mammal) that comprises administering to the subject a therapeutically effective amount of a compound of the present invention. In some embodiments, the method relates to the treatment of cancer, such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS- related (e.g. lymphoma and Kaposi's sarcoma) or viral-induced cancer. In some embodiments, the method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)). [161] The present invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a subject (e.g., a mammal) that comprises administering to the subject a therapeutically effective amount of a compound of the present invention. In some embodiments, the method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer. [162] Patients that can be treated with compounds of the present invention according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis; restenosis; atherosclerosis; BPH; breast cancer such as a ductal carcinoma in duct tissue in a mammary gland, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as adenocarcinoma in the cervix epithelial including squamous cell carcinoma and adenocarcinomas; prostate cancer, such as a prostate cancer selected from the following: an adenocarcinoma or an adenocarinoma that has migrated to the bone; pancreatic cancer such as epitheliod carcinoma in the pancreatic duct tissue and an adenocarcinoma in a pancreatic duct; bladder cancer such as a transitional cell carcinoma in urinary bladder, urothelial carcinomas (transitional cell carcinomas), tumors in the urothelial cells that line the bladder, squamous cell carcinomas, adenocarcinomas, and small cell cancers; leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS); bone cancer; lung cancer such as non-small cell lung cancer (NSCLC), which is divided into squamous cell carcinomas, adenocarcinomas, large cell undifferentiated carcinomas, and small cell lung cancer; skin cancer such as basal cell carcinoma, melanoma, squamous cell carcinoma and actinic keratosis, which is a skin condition that sometimes develops into squamous cell carcinoma; eye retinoblastoma; cutaneous or intraocular (eye) melanoma; primary liver cancer (cancer that begins in the liver); kidney cancer; thyroid cancer such as papillary, follicular, medullary and anaplastic; AIDS-related lymphoma such as diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma and small non-cleaved cell lymphoma; Kaposi's Sarcoma; viral-induced cancers including hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-I) and adult T-cell leukemia/lymphoma; and human papilloma virus (HPV) and cervical cancer; central nervous system cancers (CNS) such as primary brain tumor, which includes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma, Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheral nervous system (PNS) cancers such as acoustic neuromas and malignant peripheral nerve sheath tumor (MPNST) including neurofibromas and schwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and malignant mixed Mϋllerian tumor; oral cavity and oropharyngeal cancer such as, hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, and oropharyngeal cancer; stomach cancer such as lymphomas, gastric stromal tumors, and carcinoid tumors; testicular cancer such as germ cell tumors (GCTs), which include seminomas and nonseminomas, and gonadal stromal tumors, which include Leydig cell tumors and Sertoli cell tumors; thymus cancer such as thymomas, thymic carcinomas, Hodgkin disease, non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; and colon cancer. [163] In another aspect of the present invention, methods are provided for treating an ophthalmic disease comprising administering one or more compounds or pharmaceutical compositions described herein to the eye (or eyes) of a subject in need thereof. [164] The present invention further provides methods of inhibiting PARP7 by contacting a PARP7 enzyme with an amount of a compound of the invention sufficient to inhibit the activity of the PARP7 enzyme. In some embodiments, the present invention provides methods of inhibiting PARP7 enzyme activity by contacting a PARP7 enzyme with an amount of a compound of the invention sufficient to inhibit the activity of the PARP7 enzyme. In some embodiments, the present invention provides methods of inhibiting PARP7 enzyme activity. Such inhibition can take place in solution, in a cell expressing one or more PARP7 enzyme, in a tissue comprising a cell expressing PARP7, or in an organism expressing PARP7. In some embodiments, the present invention provides methods of inhibiting PARP7 activity in an animal (including a mammal such as a human) by contacting the animal with an amount of a compound of the present invention sufficient to inhibit the activity of the PARP7 enzyme in the animal. Synthesis of Compounds of Formula (I) [165] The following general methodology described below provides an exemplary manner and process of making the compounds of the present invention and are illustrative rather than limiting. Further modification of this methodology and additionally new methods may also be devised to achieve and serve the purposes of the present invention. Accordingly, there may be other embodiments which fall within the spirit and scope of the invention as defined by the specification hereto. Scheme-1 A compound of formula (I) can be synthesized by an amide coupling reaction of a compound of formula (1) where both R ^2a and R ^3a together with the carbon atom to which they are attached form a carbonyl group, with a compound of formula (2), using a coupling agent such as, e.g., HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyr idinium 3-oxide hexafluorophosphate), HBTU (3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate), T ₃ P (propylphosphonic anhydride) (PPAA), or EDC-HCl (1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride). This scheme is illustrated below as Illustrations 1-5. Illustration 1:

Illustration 2:

Illustration 3:

Illustration 5: Scheme-2 A compound of formula (I) can be synthesized as shown in Scheme-2 by Wittig reaction of a compound of formula (3) with a compound of formula (4) to form a compound of formula (5), which is then reacted with hydrazine. This scheme is illustrated below as Illustration 6. Illustration 6:

Scheme-3 A compound of formula (I) can be synthesized by N-arylation, N-alkylation, N- acylation/sulfonylation or Buchwald coupling reaction of a compound of formula (6) with a compound of formula (7), where Lg is halogen or other leaving group, or a boronate functional group, in a suitable solvent, such as DMF, THF, DMSO, n-BuOH, i-prOH, toluene or N- methylpyrrolidone, in the presence of a suitable base, such as potassium carbonate, cesium carbonate, sodium tert-butoxide or DIPEA and a suitable palladium catalyst, such as Pd(Ph ₃ P) ₄ or Pd2dba3. This scheme is illustrated below as Illustration 7. Illustration 7:

[166] General Procedure-1 for Wittig Reaction: Aldehyde (1 eq.) and Wittig Salt (1 eq.) are dissolved in dichloromethane (10 vols.). Triethylamine (2 eq.) is added to this mixture. The reaction mixture is then stirred for 1 hour at room temperature. After completion of the reaction, the reaction mixture is diluted with dichloromethane, washed with water and the organic layer is separated. The organic layer is dried over anhydrous Na2SO4 and distilled to obtain a crude product. The crude product is then purified by combi-flash or column chromatography using a suitable mixture of ethyl acetate and petroleum ether. [167] General Procedure-2 for Phthalazinone Formation: Olefin (1 eq.) and hydrazine hydrate (1.5 eq.) are dissolved in ethanol (15 vols.). The reaction mixture is then stirred at room temperature for 6-24 hours. After completion of the reaction, the reaction mixture is diluted with water and extracted with a MeOH and DCM (1:9) mixture. The organic layer is dried over anhydrous Na ₂ SO ₄ and distilled to obtain a crude product. The crude product is purified by combi-flash or column chromatography using a suitable mixture of MeOH and DCM. [168] General Procedure-3 for Ester Hydrolysis. To ester (1 eq.) in THF (25 vols.) cooled to 0°C, NaOH (6.65 eq., 2M solution in water) is added, and the reaction mixture is stirred at 0°C for 1 hour. The pH of the reaction mixture is then adjusted to pH 4-5 using 2N HCl. The precipitate thus formed is filtered, washed with water and dried in vacuo. [169] General Procedure-4 for N-Arylation: To amine (1 eq.) and chloro compound (1 eq.) in a suitable solvent (such as DMF, THF or N-methylpyrrolidone), a suitable base (such as potassium carbonate or cesium carbonate) (2 - 3 eq.) is added and stirred at 80°C for 1-12 hours. The reaction mixture is then cooled to room temperature, diluted with water, and the solid precipitate is filtered and dried in vacuo. Alternatively, the reaction mixture is extracted with a suitable solvent(s) (such as ethyl acetate, dichloromethane or a mixture of methanol and dichloromethane). The organic layer is washed with water, dried using anhydrous Na2SO4 and distilled in vacuo using a rotavapor to obtain a crude product. The crude product is purified by combi-flash using a suitable mixture of ethyl acetate and petroleum ether or a mixture of methanol and dichloromethane. N-Arylation reactions are also performed by Buckwald reaction in suitable solvents like DMF, DMSO, Toluene or N-methylpyrrolidone, suitable bases like potassium carbonate, caesium carbonate, sodium tert-butoxide or DIPEA and suitable palladium catalysts like Pd(Ph3P)4 or Pd2dba3. [170] General Procedure-5 for Boc-Cleavage: To a Boc-protected compound (1 eq.), 2M HCl in dioxan or trifluoroacetic acid in dichloromethane is added and stirred at room temperature for 1-24 hours. The reaction mixture is concentrated under reduced pressure, or the precipitated solid is filtered and dried in vacuo. [171] General Procedure-6 for Amide coupling or Amide formation: To amine (1-1.1 eq.), acid (1 eq.) and a suitable coupling agent (such as HATU, HBTU, EDC-HCl or T3P) (3 to 5 eq.) in a suitable solvent (such as DMF, THF, ethyl acetate or dichloromethane), a suitable base (such as N,N-diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine or pyridine) (3-4 eq.) is added and the resulting mixture is stirred at room temperature for 1-24 hours. The reaction mixture is then diluted with water and extracted using a suitable solvent (such as ethyl acetate, dichloromethane or a mixture of methanol and dichloromethane). The organic layer is washed with saturated sodium bicarbonate solution, water, brine solution, then dried using anhydrous Na2SO4 and distilled in vacuo using a rotavapor to obtain a crude product. The crude product is purified by combi-flash using a suitable mixture of ethyl acetate and petroleum ether or a mixture of methanol and dichloromethane. [172] Many of the intermediates below are commercially available or prepared by methods known in the literature. Novel intermediates described below are part of the present invention. Intermediate 1: 3-Bromoisobenzofuran-1(3H)-one [173] Phthalide (100 g, 0.745 mol) suspended in Carbon tetrachloride (500 ml) and added N- Bromosuccinimide (146 g, 0.82 mol) to this mixture. Reaction mixture heated to 85°C and Azobisisobutyronitrile (AIBN) (6.12 g, 37.2 mmol) was added to the reaction mixture lot-wise (10 lots). After 4 h reaction mixture cooled to room temperature. Reaction mixture quenched with water and separated organic layer. Aqueous layer extracted with DCM and combined organic layers dried on anhydrous Na2SO4. Organic layer evaporated on rotavapor to obtain crude solid. Crude solid was suspended in Petroleum ether (300 ml) and stirred for 15 mins to obtain a solid. Filtered the solid and washed the solid with Petroleum ether (100 ml). Solid dried under vacuum for 1 hr to obtain the titled compound as a brown solid (145 g). Yield: 91.39%. ¹ H-NMR (δ ppm, CDCl3, 400 MHz): 7.94 (d, J 8, 1H), 7.79 (t, J 7.6, 1H), 7.64 (d, J 7.6, 2H), 7.40 (s, 1H). Intermediate 2: (3-Oxo-1,3-dihydroisobenzofuran-1-yl)triphenylphosphonium bromide [174] Intermediate 1 (50 g, 0.234 mols) suspended in acetonitrile (180 ml) and added triphenylphosphine (61.54 g, 0.234 mols). This mixture was heated to 90°C and stirred for 2.5 h. Reaction mixture cooled to room to temperature to obtain a solid. Solid was filtered and washed with diethyl ether (125 ml). Solid dried under vacuum for 30 mins to obtain the titled compound as a white solid (94 g). Yield: 84%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.61 (s, 1H), 8.00-7.93 (m, 3 H), 7.86-7.70 (m, 15 H), 6.95 (d, J 7.6, 1H). Intermediate 3: (2-Bromo-4-fluorophenyl)methanol [175] 2-Bromo-4-fluorobenzaldehyde (12 g, 59.11 mmol) was suspended in MeOH (120 ml) and cooled to 0°C. Sodium borohydride (4.47 g, 118.2 mmol) was added lot-wise to the above mixture and stirred for 1 h at 0°C. After 1 h reaction mixture quenched with aqueous saturated ammonium chloride solution (150 ml). Distilled out the reaction mixture to remove MeOH and aqueous layer extracted with ethyl acetate (2*200 ml). Combined ethyl acetate layers were dried on anhydrous Na2SO4 and evaporated to obtain the titled compound as an Off-White solid (11.6 g). Yield: 95.71%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 7.46 (dd, J 8.4, 6.1, 1H), 7.31 (dd, J 8.2,2.5, 1H), 7.05 (dd, J 8.3, 5.9, 1H), 4.72 (d, J 5.1, 2H), 1.96 (t, J 5.7, 1H). Intermediate 4: 6-Fluoroisobenzofuran-1(3H)-one [176] Intermediate 3 (11.5 g, 56.1 mmol) was dissolved in DMF (50 ml) under nitrogen atmosphere. To this copper cyanide (10.04 g, 112.2 mmol) was added and heated the reaction mixture to 180°C for 2.5 h. After 2.5 h, reaction mixture cooled to 100°C and water was added to the reaction mixture. Continued the reaction at 100°C for 18 h. After 18 h, reaction mixture cooled to room temperature and diluted with ethyl acetate (250 ml). Reaction mixture filtered on a plug of celite and celite bed washed with ethyl acetate (100 ml). Combined ethyl acetate filtrates were washed with water (200 ml), brine solution (200 ml) and saturated aqueous lithium chloride solution (200 ml). Organic layer dried on anhydrous Na2SO4 and evaporated to obtain a crude. Crude was purified by combi-flash using ethyl acetate and petroleum ether (16:84) as eluent. Combined pure fractions from column were evaporated to obtain the titled compound as a brown solid (3 g). Yield: 36%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 7.59 (dd, J 7.2, 2, 1H), 7.48 (dd, J 8.3, 4.3, 1H), 7.41 (td, J 8.5, 2.2, 1H), 5.31 (s, 2H). Intermediate 5: 3-Bromo-6-fluoroisobenzofuran-1(3H)-one [177] Intermediate 4 (1.5 g, 9.86 mmol) suspended in Carbon tetrachloride (20 ml) and added N-Bromosuccinimide (1.93 g, 10.84 mmol). Reaction mixture heated to 85°C and azobisisobutyronitrile (AIBN) (80 mg, 0.49 mmol) was added to the reaction mixture lot-wise (2 lots). After 4 h reaction mixture cooled to room temperature. Reaction mixture quenched with water and separated organic layer. Aqueous layer extracted with DCM and combined organic layers dried on anhydrous Na ₂ SO ₄ . Organic layer evaporated to obtain the titled compound as a brown gel (2.27 g). Yield: 100%. ¹ H-NMR (δ ppm, CDCl3, 400 MHz): 7.62 (dd, J 8.4, 4.2, 1H), 7.57 (dd, J 6.8, 2.2, 1H), 7.50 (td, J 8.5, 2.3, 1H), 7.38 (s, 1H). Intermediate 6 (5-Fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl)triphenylphosp honium bromide [178] Intermediate 5 (5 g, 21.6 mmol) suspended in acetonitrile (20 ml) and added triphenylphosphine (5.67 g, 21.6 mmol). This mixture was heated to 90°C and stirred for 2.5 h at the same temperature. Reaction mixture cooled to room temperature to obtain a solid. Solid was filtered and washed with diethyl ether (20 ml). Solid dried under vacuum for 1 hr to obtain a crude (8.2 g). Crude compound was mixed with ethanol (25 ml) and refluxed for 1 h at 90°C. After one hour, stirred the heterogeneous mixture at room temperature for 15 h. Filtered the solid and solid washed with ethanol (5 ml). Solid dried under vacuum to obtain the titled compound (6 g) as an off-white solid. Yield: 56%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.57 (s, 1H), 8.02-7.94 (m, 3H), 7.84-7.67 (m, 14H), 7.00-6.94 (m, 1H). Intermediate 7: methyl 4-(3-oxoisobenzofuran-1(3H)-ylidene)butanoate [179] Following the general procedure 1, the titled compound was synthesized from Intermediate 2 (3.27 g, 6.89 mmol), Dichloromethane (30 ml), methyl 4-oxobutanoate (0.80 g, 6.89 mmol) and triethylamine (1.39 g, 13.8 mmol). Purification: Combi-Flash. Eluent: Ethyl acetate and petroleum ether (20:80) as eluent. Appearance: Pale yellow semi solid (1.30 g). Yield: 81%. MS (m/z): 233.07([M+H] ⁺ ). Intermediate 8: methyl 4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoate [180] Following the general procedure 2, the titled compound was synthesized from Intermediate 7 (1.30 g, 5.60 mmol), ethanol (19.5 ml), and hydrazine hydrate (0.42 g, 8.40 mmol). Purification: Combi-Flash. Eluent: Methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid (0.40 g). Yield: 29%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.47 (s, 1H), 8.27 (td, J 8.0, 0.8, 1H), 8.02 (d, J 8.0, 1H), 7.96 (dt, J 7.2,1.6, 1H), 7.87 (dt, J 8.0,1.2, 1H), 3.59 (s, 3H), 2.96 (t, J 7.6, 2H), 2.48 (t, J 7.2, 2H), 1.99 (m, 2H). MS (m/z): 247.24 ([M+H] ⁺ ). Intermediate 9: 4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoic acid [181] Following the general procedure 3, the titled compound was synthesized from Intermediate 8 (0.400 g, 1.62 mmol), THF (10 ml), water (4 ml) and NaOH (0.43 g, 10.8 mmol). Appearance: Off-white solid (0.30 g). Yield: 79%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.47 (s, 1H), 12.08 (s, 1H), 8.27 (dd, J 8.0, 0.8, 1H), 8.03 (d, J 8.0, 1H), 7.96 (dt, J 7.2,1.2, 1H), 7.86 (dt, J 8.0,0.8, 1H), 2.96 (t, J 8.0, 2H), 2.39 (t, J 7.6, 2H), 1.95 (m, 2H). MS (m/z): 233.27 ([M+H] ⁺ ). Intermediate 10: tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylat e [182] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(trifluoromethyl) pyrimidine (3.80 g, 20.8 mmol), tert-butyl piperazine-1-carboxylate (3.88 g, 20.8 mmol), N-Methylpyrrolidone (30 ml), and potassium carbonate (5.75 g, 41.6 mmol). Purification: Not done Appearance: Brown solid (6.40 g). Yield: 92%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.72 (s, 2H), 3.83 (t, J 5.2, 4H), 3.43 (t, J 5.2, 4H), 1.42 (s, 9H). MS (m/z): 233.22 ([M-Boc] ⁺ ). Intermediate 11: 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine dihydrochloride [183] Following the general procedure 5, the titled compound was synthesized from intermediate 10 (6.30 g, 19.0 mmol) and 2M HCl in dioxan (55 ml). Purification: Not done. Appearance: Brown solid (5.0 g). Yield: 86%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.44 (s, 2H), 8.78 (s, 2H), 4.08 (t, J 5.2, 4H), 3.19 (t, J 5.2, 4H). MS (m/z): 233.17 ([M-2HCl+H] ⁺ ). Intermediate 12: tert-butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate [184] Following the general procedure 6, the titled compound was synthesized from tert-butyl piperazine-1-carboxylate (5.0 g, 26.84 mmol), dichloromethane (340 ml), cyclopropane carboxylic acid (2.54 g, 29.53 mmol), triethylamine (8.15 g, 80.53 mmol) and HBTU (10.18 g, 26.84 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2:98) as eluent. Appearance: Off-white solid (4.5 g). Yield: 65%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 3.64 (br s, 2H), 3.43 (br s, 2H), 3.36 (br s, 2H), 3.21 (br s, 2H), 1.98 (m, 1H), 1.41 (s, 9H), 0.75-0.68 (m, 4H). MS (m/z): 155.12 ([M-Boc] ⁺ ). Intermediate 13: cyclopropyl(piperazin-1-yl)methanone trifluoroacetic acid salt [185] Following the general procedure 5, the titled compound was synthesized from intermediate 12 (2.0 g, 7.86 mmol), dichloromethane (5 ml) and TFA (8.96 g, 78.6 mmol). Purification: Not done Appearance: Brown liquid (4.0 g). Yield: >100% (crude). ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.91 (s, 1H), 3.87 (br s, 2H), 3.65 (br s, 2H), 3.17 (br s, 4H), 2.02 (m, 1H), 0.77-0.73 (m, 4H). MS (m/z): 155.08 ([M-TFA+H] ⁺ ). Intermediate 14: tert-butyl 4-(methylsulfonyl)piperazine-1-carboxylate (VVR-002-0529) [186] To a solution of tert-butyl piperazine-1-carboxylate (2.0 g, 10.74 mmol), triethylamine (1.08 g, 10.74 mmol) in dichloromethane (20 ml) cooled to 0°C, methane sulfonyl chloride (1.23 g, 10.74 mmol) was added and stirred for 3h. After 3h, the reaction mixture was diluted with water (20 ml) and extracted with dichloromethane (3 x 30 ml). The organic layer was dried on anhydrous Na2SO4 and evaporated to obtain a crude. Crude was purified by combi-flash using methanol and dichloromethane (2:98) as eluent. Combined pure fractions from column were evaporated to obtain the titled compound as an off-white solid (1.40 g). Yield: 49%. ¹ H- NMR (δ ppm, DMSO-d6, 400 MHz): 3.42 (t, J 4.8, 4H), 3.08 (t, J 4.8, 4H), 2.87 (s, 3H), 1.40 (s, 9H). MS (m/z): 165.10 ([M-Boc+H] ⁺ ). Intermediate 15: 1-(methylsulfonyl)piperazinetrifluoroaceticacid [187] Following the general procedure 5, the titled compound was synthesized from intermediate 14 (1.00 g, 3.78 mmol), dichloromethane (5 ml) and Trifluoroacetic acid (4.31 g, 37.8 mmol). Purification: Not done Appearance: Brown gummy solid (1.40 g). Yield: >100% (crude). ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.03 (s, 1H), 3.35 (m, 4H), 3.23 (m, 4H), 2.99 (s, 3H). MS (m/z): 165.06 ([M-TFA+H] ⁺ ). Intermediate 16: tert-butyl 4-(pyrimidin-2-yl)piperazine-1-carboxylate [188] Following the general procedure 4, the titled compound was synthesized from 2-chloro pyrimidine (1.80 g, 15.7 mmol), tert-butyl piperazine-1-carboxylate (2.93 g, 15.7 mmol), N- Methylpyrrolidone (18 ml), and potassium carbonate (4.34 g, 31.4 mmol). Purification: Not done Appearance: Off-white solid (2.10 g). Yield: 50%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.37 (d, J 4.8, 2H), 6.66 (t, J 4.4, 1H), 3.72 (m, 4H), 3.40 (m, 4H), 1.42 (s, 9H). MS (m/z): 165.04 ([M-Boc+H] ⁺ ). Intermediate 17: 2-(piperazin-1-yl)pyrimidine dihydrochloride [189] Following the general procedure 5, the titled compound was synthesized from intermediate 16 (2.0 g, 7.57 mmol) and 2M HCl in dioxan (18 ml). Purification: Not done Appearance: Off-white (1.8 g). Yield: >100% (crude). ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.43 (s, 2H), 8.44 (d, J 4.8, 2H), 6.76 (t, J 4.4, 1H), 3.98 (t, J 5.2, 4H), 3.16 (m, 4H). MS (m/z): 165.09 ([M-2HCl+H] ⁺ ). Intermediate 18: tert-butyl 4-(pyrazin-2-yl)piperazine-1-carboxylate [190] Following the general procedure 4, the titled compound was synthesized from 2-chloro- pyrazine (2.0 g, 17.5 mmol), tert-butyl piperazine-1-carboxylate (3.25 g, 17.5 mmol), N- Methylpyrrolidone (20 ml), and potassium carbonate (4.83 g, 34.9 mmol). Purification: Combi- Flash. Eluent: ethyl acetate and petroleum ether (15:85) as eluent. Appearance: Brown solid (1.40 g). Yield: 30%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.31 (d, J, 1.2, 1H), 8.09 (dd, J 2.8,1.6, 1H), 7.85 (d, J 2.8, 1H), 3.56 (m, 4H), 3.44 (m, 4H), 1.42 (s, 9H). MS (m/z): 165.06 ([M-Boc+H] ⁺ ). Intermediate 19: 2-(piperazin-1-yl)pyrazine dihydrochloride

[191] Following the general procedure 5, the titled compound was synthesized from intermediate 18 (1.35 g, 5.10 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done Appearance: Yellow solid (1.20 g). Yield: 91%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.36 (s, 2H), 8.41 (d, J, 1.6, 1H), 8.16 (dd, J 2.8,1.6, 1H), 7.94 (d, J 2.4, 1H), 3.83 (t, J 5.2, 4H), 3.20 (m, 4H). MS (m/z): 165.13 ([M-2HCl+H] ⁺ ). Intermediate 20: methyl 4-(5-fluoro-3-oxoisobenzofuran-1(3H)-ylidene)butanoate [192] Following the general procedure 1, the titled compound was synthesized from Intermediate 6 (2.97 g, 6.03 mmol), Dichloromethane (28 ml), methyl 4-oxobutanoate (0.70 g, 6.03 mmol) and triethylamine (1.22 g, 12.1 mmol). Purification: Combi-Flash. Eluent: Ethyl acetate and petroleum ether (20:80) as eluent. Appearance: Pale yellow semi solid (1.20 g). Yield: 80%, MS (m/z): 251.02 ([M+H] ⁺ ). Intermediate 21: methyl 4-(6-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)butanoate [193] Following the general procedure 2, the titled compound was synthesized from Intermediate 20 (1.20 g, 4.79 mmol), ethanol (20 ml), and hydrazine hydrate (0.36 g, 7.19 mmol). Purification: Combi-Flash. Eluent: Methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid (0.35 g). Yield: 27%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.56 (s, 1H), 8.14 (dd, J 8.8, 4.8, 1H), 7.94 (dd, J 8.8,2.8, 1H), 7.85 (dt, J 8.8,2.8, 1H), 3.58 (s, 3H), 2.96 (t, J 7.2, 2H), 2.48 (t, J 7.2, 2H), 1.98 (m, 2H). MS (m/z): 265.07 ([M+H] ⁺ ). I t di t 22 4 (6 fl 4 3,4-dihydrophthalazin-1-yl)butanoic acid [194] Following the general procedure 3, the titled compound was synthesized from Intermediate 21 (0.35 g, 1.32 mmol), THF 8.7 ml), water (3.5 ml) and NaOH (0.43 g, 10.8 mmol). Appearance: Off-white solid (0.20 g). Yield: 60%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.56 (s, 1H), 12.06 (s, 1H), 8.15 (dd, J 8.8, 4.8, 1H), 7.94 (dd, J 8.8,2.8, 1H), 7.84 (dt, J 8.8,2.8, 1H), 2.95 (t, J 7.2, 2H), 2.38 (t, J 7.2, 2H), 1.94 (m, 2H). MS (m/z): 251.08 ([M+H] ⁺ ). Intermediate 23: tert-butyl 4-(5-fluoropyrimidin-2-yl)piperazine-1-carboxylate [195] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-fluoropyrimidine (1.0 g, 7.55 mmol), tert-butyl piperazine-1-carboxylate (1.41 g, 7.55 mmol), N-Methylpyrrolidone (10 ml), and potassium carbonate (2.09 g, 15.1 mmol). Purification: Not done. Appearance: Off-white solid (1.90 g). Yield: 89%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.46 (d, J 0.8, 2H), 3.67 (m, 4H), 3.40 (t, J 5.2, 4H), 1.42 (s, 9H). MS (m/z): 183.14 ([M-Boc+H] ⁺ ). Intermediate 24: 5-fluoro-2-(piperazin-1-yl)pyrimidine dihydrochloride [196] Following the general procedure 5, the titled compound was synthesized from intermediate 23 (1.9 g, 6.73 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done. Appearance: Pale yellow solid (1.7 g). Yield: 99%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.64 (s, 2H), 8.53 (d, J 0.8, 2H), 3.95 (t, J 5.2, 4H), 3.15 (m, 4H). MS (m/z): 183.12 ([M- 2HCl+H] ⁺ ). Intermediate 25: tert-butyl 4-(5-cyanopyrimidin-2-yl)piperazine-1-carboxylate [197] Following the general procedure 4, the titled compound was synthesized from 2- chloropyrimidine-5-carbonitrile (1.0 g, 7.17 mmol), tert-butyl piperazine-1-carboxylate (1.33 g, 7.17 mmol), N-Methylpyrrolidone (10 ml), and potassium carbonate (1.98 g, 14.3 mmol). Purification: Not done. Appearance: Off-white solid (1.85 g). Yield: 86%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.77 (s, 2H), 3.84 (m, 4H), 3.43 (t, J 5.2, 4H), 1.42 (s, 9H). MS (m/z): 190.12 ([M-Boc+H] ⁺ ). Intermediate 26: 2-(piperazin-1-yl)pyrimidine-5-carbonitrile dihydrochloride [198] Following the general procedure 5, the titled compound was synthesized from intermediate 25 (1.80 g, 6.22 mmol) and 2M HCl in dioxan (25 ml). Purification: Not done. Appearance: Off-white solid (1.30 g). Yield: 80%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.42 (s, 2H), 8.84 (s, 2H), 4.08 (t, J 5.2, 4H), 3.18 (m, 4H). MS (m/z): 190.13 ([M-2HCl+H] ⁺ ). Intermediate 27: tert-butyl 4-(5-chloropyrimidin-2-yl)piperazine-1-carboxylate

[199] Following the general procedure 4, the titled compound was synthesized from 2,5- dichloropyrimidine (1.0 g, 6.71 mmol), tert-butyl piperazine-1-carboxylate (1.25 g, 6.71 mmol), N-Methylpyrrolidone (25 ml), and potassium carbonate (1.86 g, 13.4 mmol). Purification: Not done. Appearance: Off-white solid (1.80 g). Yield: 90%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.43 (s, 2H), 3.71 (m, 4H), 3.40 (t, J 5.2, 4H), 1.42 (s, 9H). MS (m/z): 199.12 ([M-Boc+H] ⁺ ). Intermediate 28: 5-chloro-2-(piperazin-1-yl)pyrimidine dihydrochloride [200] Following the general procedure 5, the titled compound was synthesized from intermediate 27 (0.60 g, 1.81 mmol) and 2M HCl in dioxan (6 ml). Purification: Not done. Appearance: Brown solid (0.50 g). Yield: 91%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.60 (s, 2H), 8.50 (s, 2H), 3.97 (t, J 5.2, 4H), 3.14 (m, 4H). MS (m/z): 199.15 ([M-2HCl+H] ⁺ ). Intermediate 29: tert-butyl 4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate [201] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(trifluoromethyl)pyridine (1.0 g, 5.51 mmol), tert-butyl piperazine-1-carboxylate (1.03 g, 5.51 mmol), N-Methylpyrrolidone (10 ml), and potassium carbonate (1.52 g, 11.0 mmol). Purification: Not done. Appearance: Off-white solid (1.10 g). Yield: 60%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.41 (t, J 0.8, 1H), 7.83 (dd, J 9.2,2.8, 1H), 6.96 (d, J 9.2, 1H), 3.64 (m, 4H), 3.43 (t, J 5.2, 4H), 1.42 (s, 9H). MS (m/z): 232.26 ([M-Boc+H] ⁺ ). Intermediate 30: 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine dihydrochloride [202] Following the general procedure 5, the titled compound was synthesized from intermediate 29 (1.0 g, 3.02 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done. Appearance: Off-white (0.90 g). Yield: 98%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.19 (s, 2H), 8.47 (dd, J 1.6,0.8, 1H), 7.91 (dd, J 9.2,2.4, 1H), 7.06 (d, J 9.2, 1H), 3.88 (t, J 5.2, 4H), 3.19 (m, 4H). MS (m/z): 232.10 ([M-2HCl+H] ⁺ ). Intermediate 31: tert-butyl 4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylate [203] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(trifluoromethyl)pyrazine (0.50 g, 2.7 mmol), tert-butyl piperazine-1-carboxylate (0.51 g, 2.7 mmol), N-Methylpyrrolidone (5 ml), and potassium carbonate (0.76 g, 5.5 mmol). Purification: Not done. Appearance: Brown solid (0.70 g). Yield: 77%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.50 (d, J 0.8, 1H), 8.42 (d, J 1.2, 1H), 3.73 (m, 4H), 3.46 (m, 4H), 1.42 (s, 9H). MS (m/z): 233.26 ([M-Boc+H] ⁺ ). Intermediate 32: 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrazine dihydrochloride [204] Following the general procedure 5, the titled compound was synthesized from intermediate 31 (0.60 g, 1.81 mmol) and 2M HCl in dioxan (6 ml). Purification: Not done. Appearance: Brown (0.50 g). Yield: 91%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.25 (s, 2H), 8.55 (d, J 0.8, 1H), 8.50 (d, J 1.2, 1H), 3.97 (t, J 5.2, 4H), 3.21 (m, 4H). MS (m/z): 233. 18 ([M-2HCl+H] ⁺ ). Intermediate 33: tert-butyl 4-(pyridazin-3-yl)piperazine-1-carboxylate [205] Following the general procedure 4, the titled compound was synthesized from 3- chloropyridazine (0.50 g, 4.4 mmol), tert-butyl piperazine-1-carboxylate (0.81 g, 4.4 mmol), N-Methylpyrrolidone (5 ml), and potassium carbonate (0.76 g, 5.5 mmol). Purification: Combi- Flash. Eluent: ethyl acetate and petroleum ether (74:26) as eluent. Appearance: Brown solid (0.22 g). Yield: 19%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.57 (dd, J 4.4,1.2, 1H), 7.41 (dd, J 9.2,4.4, 1H), 7.26 (dd, J 9.2,1.2, 1H), 3.59 (m, 4H), 3.46 (m, 4H), 1.42 (s, 9H). MS (m/z): 265.12 ([M+H] ⁺ ). Intermediate 34: 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrazine dihydrochloride [206] Following the general procedure 5, the titled compound was synthesized from intermediate 33 (0.20 g, 0.76 mmol) and 2M HCl in dioxan (5 ml). Purification: Not done. Appearance: Brown solid (92 mg). Yield: 51%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.34 (s, 2H), 8.70 (dd, J 4.8,1.2, 1H), 7.61 (dd, J 9.2,4.4, 1H), 7.51 (d, J 9.2, 1H), 3.88 (t, J 5.2, 4H), 3.21 (m, 4H). MS (m/z): 165.12 ([M-2HCl+H] ⁺ ). Intermediate 35: 2-chloro-5-(difluoromethyl)pyrimidine [207] To a solution of 2-chloropyrimidine-5-carbaldehyde (1.0 g, 7.01 mmol) in chloroform (20 mL), (diethylamino)sulfur trifluoride (1.13 g, 7.01 mmol) was added and heated to reflux. After 2h cooled to room temperature, quenched with water (10 ml) and the aqueous layer was extracted with dichloromethane (2 x 50 ml). The organic layer was distilled under vacuum to afford the crude. The crude product was purified by combi-flash using a mixture of ethyl acetate and petroleum ether (10:90) as eluent. Appearance: Brown solid (0.40 g). Yield: 34%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.79 (s, 2H), 6.92 (d, J 55.2, 1H). Intermediate 36: tert-butyl 4-(pyridazin-3-yl)piperazine-1-carboxylate [208] Following the general procedure 4, the titled compound was synthesized from intermediate 35 (0.40 g, 2.43 mmol), tert-butyl piperazine-1-carboxylate (0.45 g, 2.43 mmol), N-Methylpyrrolidone (10 ml), and potassium carbonate (0.67 g, 4.86 mmol). Purification: Not done. Appearance: Off-white solid (0.60 g). Yield: 78%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.57 (t, J 1.2, 2H), 7.11 (t, J 55.2, 1H), 3.80 (m, 4H), 3.42 (t, J 5.2, 4H), 1.42 (s, 9H). MS (m/z): 215.20 ([M-Boc+H] ⁺ ). Intermediate 37: 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrazine dihydrochloride [209] Following the general procedure 5, the titled compound was synthesized from intermediate 36 (0.60 g, 1.91 mmol) and 2M HCl in dioxan (17.2 ml). Purification: Not done Appearance: Off-white solid (500 mg). Yield: 91%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.52 (s, 2H), 8.63 (t, J 1.2, 2H), 7.15 (t, J 55.2, 1H), 4.06 (t, J 5.2, 4H), 3.15 (m, 4H). MS (m/z): 215.15 ([M-2HCl+H] ⁺ ). Intermediate 38: 2-chloro-5-(prop-1-en-2-yl)pyrimidine [210] To 2-chloro-5-iodopyrimidine (5.0 g, 20.80 mmol) in toluene (50 ml), water (25 ml), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (4.19 g, 24.96 mmol), tricyclohexylphosphine (700 mg, 2.49 mmol), potassium phosphate, dibasic (7.24 mmol, 41.5 mmol) were added at room temperature. Pd(OAc) ₂ ( 514 mg, 2.49 mmol) was added and purged under nitrogen for10 min. The reaction mixture was heated to 100°C and stirred for 4h. After 4h, the reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (3:97) as eluent to obtain the title compound as a pale-brown solid (1.2 g). Yield: 37%. MS (m/z): 155.05 ([M+H] ⁺ ). Intermediate 39: 2-chloro-5-isopropylpyrimidine [211] To intermediate 38 (1.0 g, 6.46 mmol) in ethanol (6 ml) and ethyl acetate (6 ml), platinum(IV) oxide (100 mg, 0.44 mmol) was added and stirred under atmospheric pressure of hydrogen for 3h. After 3h, the reaction mixture was filtered, washed with ethyl acetate (20 mL) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (5:97) as eluent to obtain the title compound as a pale-yellow liquid (900 mg). Yield: 88%. MS (m/z): 157.09 ([M+H] ⁺ ). Intermediate 40: tert-butyl 4-(5-isopropylpyrimidin-2-yl)piperazine-1-carboxylate ( [212] Following the general procedure 4, the titled compound was synthesized from intermediate 39 (0.50 g, 3.19 mmol), tert-butyl piperazine-1-carboxylate (0.595 g, 3.19 mmol), N-Methylpyrrolidone (5 ml), and potassium carbonate (0.88 g, 6.39 mmol). Purification: Combi-Flash. Eluent: ethyl acetate and petroleum ether (10:90) as eluent. Appearance: Off- white solid (500 mg). Yield: 51%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.21 (s, 2H), 3.78 (t, J 5.2, 4H), 3.50 (t, J 5.2, 4H), 2.83 (m, 1H), 1.48 (s, 9H), 1.24 (d, J 6.8, 6H). MS (m/z): 306.96 ([M] ⁺ ). Intermediate 41: 5-isopropyl-2-(piperazin-1-yl)pyrimidine dihydrochloride [213] Following the general procedure 5, the titled compound was synthesized from intermediate 40 (0.50 g, 1.63 mmol) and 2M HCl in dioxan (14.7 ml). Purification: Not done. Appearance: Off-white solid (400 mg). Yield: 87%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.54 (s, 2H), 8.39 (s, 2H), 6.12 (s, 1H), 3.97 (t, J 5.2, 4H), 3.18-3.11 (m, 4H), 2.84 (m, 1H), 1.20 (d, J 7.2, 6H). MS (m/z): 207.20 ([M-2HCl+H] ⁺ ). Intermediate 42: 5- ethyl 5-oxopentanoate [214] To ethyl 5-chloro-5-oxopentanoate (5.0 g, 28 mmol) in THF (20 ml) was taken in an autoclave, 2,6-Lutidine (3.0 g, 28 mmol) and 10% Pd/C (500 mg) were added. The reaction mixture was hydrogenated at 4kg/cm ² for 20h. After 20h, the reaction mixture was filtered, washed with ethyl acetate (100 mL) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (15:85) as eluent to obtain the title compound as a colourless liquid (1.83 g). Yield: 45%. ¹ H- NMR (δ ppm, DMSO-d6, 400 MHz): 9.78 (s, 1H), 4.16 (q, J 7.2, 2H), 2.55-2.51 (m, 2H), 2.39- 2.34 (m, 2H), 1.99-1.92 (m, 2H), 1.27 (t, J 7.2, 3H). MS (m/z): 145.07([M+H] ⁺ ). Intermediate 43: ethyl 5-(3-oxoisobenzofuran-1(3H)-ylidene)pentanoate [215] Following the general procedure 1, the titled compound was synthesized from intermediate 2 (6.53 g, 13.7 mmol), Dichloromethane (18 ml), intermediate 42 (1.80 g, 12.5 mmol) and triethylamine (2.53 g, 25.0 mmol). Purification: Combi-Flash. Eluent: Ethyl acetate and petroleum ether (7.5:92.5) as eluent. Appearance: Pale yellow semi solid (3.10 g). Yield: 95%.MS (m/z): 260.99([M] ⁺ ). Intermediate 44: ethyl 5-(4-oxo-3,4-dihydrophthalazin-1-yl)pentanoate [216] Following the general procedure 2, the titled compound was synthesized from intermediate 43 (3.10 g, 11.9 mmol), ethanol (19.5 ml), and hydrazine hydrate (0.89 g, 17.9 mmol). Purification: Combi-Flash. Eluent: ethyl acetate and petroleum ether (40:60) as eluent. Appearance: Off-white solid (0.76 g). Yield: 23%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.45 (s, 1H), 8.27 (dd, J 8.0, 1.2, 1H), 8.00 (d, J 8.0, 1H), 7.95 (dt, J 7.2,1.6, 1H), 7.86 (dt, J 8.0,1.2, 1H), 4.05 (q, J 7.2, 2H), 2.95 (t, J 7.2, 2H), 2.37 (t, J 6.8, 2H), 1.74-1.60 (m, 4H), 1.15 (t, J 7.2, 3H). MS (m/z): 275.30 ([M+H] ⁺ ). Intermediate 45: 5-(4-oxo-3,4-dihydrophthalazin-1-yl)pentanoic acid [217] Following the general procedure 3, the titled compound was synthesized from intermediate 44 (0.380 g, 1.40 mmol), THF (7.6 ml), water (4 ml) and NaOH (0.30 g, 7.6 mmol). Appearance: Off-white solid (0.35 g). Yield: 100%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.45 (s, 1H), 11.99 (s, 1H), 8.27 (dd, J 7.6, 0.8, 1H), 8.05 (d, J 8.0, 1H), 7.95 (dt, J 7.2,1.6, 1H), 7.86 (dt, J 8.0,1.2, 1H), 2.94 (t, J 7.2, 2H), 2.29 (t, J 7.2, 2H), 1.76-1.58 (m, 4H). MS (m/z): 247.30 ([M+H] ⁺ ). Intermediate 46: ethyl 2-hydroxypent-4-enoate [218] To ethyl 2-oxoacetate (2.5 g, 24.49 mmol) in dichloromethane (50 ml) cooled to 0°C, BF3.Et20 (3.47 g, 24.49 mmol) was added followed by allyl trimethylsilane (2.79 g, 24.49 mmol). After stirring at 25°C for 4h, the reaction mixture was quenched with water (50 ml), extracted with dichloromethane (3 x 40 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (10:80) as eluent to obtain the title compound as a colourless liquid (2.0 g). Yield: 56%. MS (m/z): 145.04([M+H] ⁺ ). Intermediate 47: ethyl 2-(benzyloxy)pent-4-enoate [219] To intermediate 46 (2.0 g, 13.87 mmol) in THF (25 ml) cooled to 0°C, NaH (0.37 g, 15.26 mmol) was added followed by tetrabutylammonium iodide (512 mg, 1.38 mmol) and benzyl bromide (2.61 g, 15.26 mmol).2.79 g, 24.49 mmol). After stirring at 25°C for 4h, the reaction mixture was quenched with saturated ammonium chloride solution (20 ml), extracted with diethyl ether (3 x 40 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (1:99) as eluent to obtain the title compound as a colourless liquid (1.30 g). Yield: 40%. ¹ H- NMR (δ ppm, CDCl3, 400 MHz): 7.36-7.27 (m, 5H), 5.88-5.78 (m, 1H), 5.15-5.06 (m, 2H), 4.73 (d, J 12.0, 1H), 4.46 (d, J 11.6, 1H), 4.25-4.17 (m, 2H), 4.00 (t, J 7.2, 1H), 2.55-2.51 (m, 2H), 1.30 (t, J 7.2, 3H). MS (m/z): 234.98([M+H] ⁺ ). Intermediate 48: ethyl 2-(benzyloxy)-4-oxobutanoate [220] To intermediate 47 (1.30 g, 5.54 mmol) in 1,4-Dioxan (26 ml) and water (9 ml) at room temperature, 2,6-lutidine (1.18 g, 11.10 mmol), sodium periodate (4.74 g, 22.19 mmol) were added followed by osmium tetroxide (28.2 mg, 0.11 mmol). After 4h, the reaction mixture was quenched with water (50 ml), extracted with dichloromethane (3 x 50 ml), washed with 2N HCl solution (2 x 20 ml) and distilled under reduced pressure using rotavap to obtain the title compound as a brown liquid (1.10 g). Yield: 84%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 9.74 (s, 1H), 7.36-7.30 (m, 5H), 4.79 (d, J 11.6.0, 1H), 4.54 (d, J 11.2, 1H), 4.46 (dd, J 7.2,4.8, 1H), 4.27-4.20 (m, 2H), 2.89-2.81 (m, 2H), 1.32 (t, J 7.2, 3H). MS (m/z): 259.39 ([M+Na] ⁺ ). Intermediate 49: ethyl 2-(benzyloxy)-4-(3-oxoisobenzofuran-1(3H)-ylidene)butanoate [221] Following the general procedure 1, the titled compound was synthesized from intermediate 2 (2.01 g, 4.23 mmol), Dichloromethane (15 ml), intermediate 48 (1.0 g, 4.23 mmol) and triethylamine (0.85 g, 8.46 mmol). Purification: Combi-Flash. Eluent: Ethyl acetate and petroleum ether (10:90) as eluent. Appearance: Pale brown solid (0.90 g). Yield: 60%. MS (m/z): 353.13([M] ⁺ ). Intermediate 50: ethyl 2-(benzyloxy)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoate [222] Following the general procedure 2, the titled compound was synthesized from intermediate 49 (0.90 g, 2.55 mmol), ethanol (10 ml), and hydrazine hydrate (192 mg, 3.83 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2:98) as eluent. Appearance: Off-white solid (185 mg). Yield: 19%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.47 (s, 1H), 8.27 (d, J 7.2, 1H), 7.94-7.91 (m, 2H), 7.87-7.82 (m, 1H), 7.33-7.25 (m, 5H), 4.64 (d, J 11.6, 1H), 4.45 (d, J 12.0, 1H), 4.17-4.11 (m, 3H), 3.05-3.01 (m, 2H), 2.21-2.04 (m, 2H), 1.22 (t, J 7.2, 3H). MS (m/z): 367.28 ([M+H] ⁺ ). Intermediate 51: 2-(benzyloxy)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoicac id [223] Following the general procedure 3, the titled compound was synthesized from intermediate 50 (0.180 g, 0.55 mmol), THF (6 ml), water (1.8 ml) and NaOH (0.43 g, 10.8 mmol). Appearance: Pale-brown solid (0.15 g). Yield: 86%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.80 (s, 1H), 12.46 (s, 1H), 8.27 (d, J 8.0, 1H), 7.98-7.92 (m, 2H), 7.86-7.82 (m, 1H), 7.33-7.24 (m, 5H), 4.68 (d, J 11.6, 1H), 4.43 (d, J 11.6, 1H), 4.07 (dd, J 8.0, 4.0, 1H), 3.09- 2.97 (m, 2H), 2.22-2.00 (m, 2H). MS (m/z): 339.25 ([M+H] ⁺ ). Intermediate 52: 4-(3-(benzyloxy)-4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2- yl)piperazin-1- yl)butyl)phthalazin-1(2H)-one [224] Following the general procedure 6, the titled compound was synthesized from intermediate 51 (150 mg, 0.43 mmol), DMF (4 ml), intermediate 11 (149 mg, 0.48 mmol), DIPEA (286 mg, 2.22 mmol) and HBTU (202 mg, 0.53 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Pale-brown solid. Yield: 150 mg. % Yield: 61. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.52 (s, 1H), 8.74 (s, 2H), 8.28 (dd, J 8.0,1.2, 1H), 8.01 (d, J 7.6, 1H), 7.96 (dt, J 7.2,1.6, 1H), 7.87 (dt, J 8.0,1.2, 1H), 7.30-7.21 (m, 5H), 4.56 (d, J 11.6, 1H), 4.51 (dd, J 8.0,4.4, 1H), 4.36 (d, J 12.0, 1H), 3.97-3.81 (m, 4H), 3.73-3.57 (m, 4H), 3.51-2.99 (m, 2H), 2.21-1.98 (m, 2H). MS (m/z): 553.20 ([M+H] ⁺ ). Intermediate 53: ethyl 4-(3-oxoisobenzofuran-1(3H)-ylidene)pentanoate [225] Following the general procedure 1, the titled compound was synthesized from Intermediate 2 (3.95 g, 8.32 mmol), THF (15 ml), ethyl 4-oxopentanoate (1.0 g, 6.93 mmol) and potassium tert-butoxide (1.55 g, 13.87 mmol). Purification: Combi-Flash. Eluent: Ethyl acetate and petroleum ether (10:90) as eluent. Appearance: Pale yellow liquid (0.90 g). Yield: 48%. MS (m/z): 360.90([M] ⁺ ). Intermediate 54: ethyl 4-(4-oxo-3,4-dihydrophthalazin-1-yl)pentanoate [226] Following the general procedure 2, the titled compound was synthesized from intermediate 53 (0.90 g, 3.46 mmol), ethanol (15 ml), and hydrazine hydrate (260 mg, 5.19 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2:98) as eluent. Appearance: Pale-brown solid (100 mg). Yield: 10%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.24 (s, 1H), 8.50 (td, J 7.6,0.8, 1H), 7.94 (d, J, 8.0, 1H), 7.87 (dt, J 7.2,1.6, 1H), 7.80 (dt, J 8.0,1.6, 1H), 4.14 (q, J 7.2, 2H), 3.50-3.42 (m, 1H), 2.48-2.22 (m, 3H), 1.97-1.88 (m, 1H), 1.35 (t, J 6.8, 3H), 1.24 (t, J 7.2, 3H). MS (m/z): 275.15 ([M+H] ⁺ ). Intermediate 55: 4-(4-oxo-3,4-dihydrophthalazin-1-yl)pentanoic acid [227] Following the general procedure 3, the titled compound was synthesized from Intermediate 54 (0.100 g, 0.38 mmol), THF (3 ml), water (1 ml) and NaOH (0.43 g, 10.8 mmol). Appearance: Pale-brown solid (60 mg). Yield: 63%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.51 (s, 1H), 12.04 (s, 1H), 8.29 (dd, J 7.6,0.8, 1H), 8.08 (d, J 8.0, 1H), 7.96 (dt, J 7.6,1.6, 1H), 7.86 (dt, J 8.0, 0.8, 1H), 3.51 (dd, J 9.6,6.8, 1H), 2.30-2.25 (m, 2H), 2.09-2.01 (m, 1H), 1.81-1.72 (m, 1H), 1.25 (d, J 6.8, 3H).. MS (m/z): 247.25 ([M+H] ⁺ ). Intermediate 56: tert-butyl 4-(5-(difluoromethoxy)pyridin-2-yl)piperazine-1-carboxylate [228] To 2-chloro-5-(difluoromethoxy)pyridine (500 mg, 2.78 mmol) in toluene (10 ml), tert- butyl piperazine-1-carboxylate (519 mg, 2.78 mmol), sodium tert-butoxide (321 mg, 3.34 mmol) were added at room temperature. BINAP (86.7 mg, 0.13 mmol) and Pd ₂ (dba) ₃ (128 mg, 0.13 mmol) were added and purged under nitrogen for10 min. The reaction mixture was heated to 80°C and stirred for 16h. After 16h the reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (15:85) as eluent to obtain the title compound as a pale-brown solid (300 mg). Yield: 32%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.03 (d, J 2.8, 1H), 7.48 (dd, J 9.2,2.8, 1H), 7.24(t, J 74.4, 1H), 6.90 (d, J 9.2, 1H), 3.46-3.40 (m, 8H).1.41 (s, 9H). MS (m/z): 330.01 ([M+H] ⁺ ). Intermediate 57: 1-(5-(difluoromethoxy)pyridin-2-yl)piperazine dihydrochloride [229] Following the general procedure 5, the titled compound was synthesized from intermediate 56 (0.30 g, 0.911 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done. Appearance: Off-white solid (270 mg). Yield: 98%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.43 (s, 2H), 8.67 (s, 1H), 8.07(d, J 7.2, 1H), 7.57(dd, J 9.2,2.8, 1H), 7.29 (t, J 74.4, 1H), 7.02 (d, J 9.2, 1H), 3.74 (t, J 5.2, 4H), 3.19-3.11 (m, 4H). MS (m/z): 230.14 ([M-2HCl+H] ⁺ ). Intermediate 58: tert-butyl 5-(trifluoromethyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)- carboxylate [230] To 2-chloro-5-(trifluoromethyl)pyridine (500 mg, 2.8 mmol) in toluene (8 ml), and water (0.8 ml), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydopy ridine- 1(2H)-carboxylate (1.50 g, 5.0 mmol), sodium carbonate (0.59 g, 5.5 mmol) were added at room temperature. Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (220 mg, 0.28 mmol) were added and purged under nitrogen for 20 min. The reaction mixture was heated to 100°C and stirred for 16h. After 16h, the reaction mixture was filtered through cealite bed and washed with ethyl acetate (30 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (6:94) as eluent to obtain the title compound as a off-white gel (400 mg). Yield: 44%. MS (m/z): 327.40 ([M- H] ⁺ ). Intermediate 59: tert-butyl 4-(5-(trifluoromethyl)pyridin-2-yl)piperidine-1-carboxylate [231] To intermediate 58 (480 mg, 1.8 mmol) in methanol (20 ml) in an autoclave, 5% Pd/C (125 mg) was added and hydrogenated under atmospheric pressure for 2h. After 2h, the reaction mixture was filtered through cealite bed and washed with dichloromethane (200 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (11:89) as eluent to obtain the title compound as a brown gel (200 mg). Yield: 41%. ¹ H-NMR (δ ppm, DMSO- d6, 400 MHz): 8.89 (dd, J 1.2,0.8, 1H), 8.14 (dt, J 8.0,2.0, 1H), 7.56 (d, J 8.0, 1H), 4.08 (d, J 12.0, 2H), 3.02-2.96 (m, 1H), 2.82-2.71 (m, 2H), 1.85 (dd, 14.0,2.0, 2H), 1.64-1.55 (m, 2H), 1.41 (s, 9H). MS (m/z): 231.19 ([M-Boc+H] ⁺ ). Intermediate 60: 2-(piperidin-4-yl)-5-(trifluoromethyl)pyridine dihydrochloride [232] Following the general procedure 5, the titled compound was synthesized from intermediate 59 (0.18 g, 0.54 mmol) and 2M HCl in dioxan (4 ml). Purification: Not done. Appearance: Brown solid (150 mg). Yield: 100%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.09 (s,1H), 8.93 (t, J 1.6, 1H), 8.85 (s, 1H), 8.19 (dd, J 8.4,2.0, 1H), 7.56 (d, J 8.4, 1H), 3.39- 3.34 (m, 2H), 3.18-3.12 (m, 1H), 3.05-2.96 (m, 2H), 2.06-1.91 (m, 4H). MS (m/z): 231.19 ([M-2HCl+H] ⁺ ). Intermediate 61: tert-butyl tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate [233] To 2-chloro-5-(trifluoromethyl)pyrimidine (500 mg, 2.7 mmol) in 1,4-dioxane (40 ml), and water (10 ml), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydopyridine-1(2H)-carboxylate (0.74 g, 2.4 mmol), potassium carbonate (0.67 g, 4.9 mmol) were added at room temperature. Tetrakis triphenylphosphine palladium (0) (160 mg, 0.14 mmol) were added and purged under nitrogen for 20 min. The reaction mixture was heated to 110°C and stirred for 20h. After 20h, the reaction mixture was filtered through cealite bed and washed with ethyl acetate (100 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (4:96) as eluent to obtain the title compound as a off-white solid (550 mg). Yield: 61%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.22 (s,2H), 7.37 (s, 1H), 4.14 (s, 2H), 3.56 (t, J 5.6, 2H), 2.63-2.58 (m, 2H), 1.49 (s, 9H). MS (m/z): 230.12 ([M-Boc+H] ⁺ ). Intermediate 62: tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-1-carboxylat e [234] To intermediate 61 (530 mg, 1.61 mmol) in methanol (20 ml) in an autoclave 5% Pd/C (250 mg) was added and hydrogenated under atmospheric pressure for 2h. After 2h, the reaction mixture was filtered through cealite bed and washed with dichloromethane (200 ml). The organic layer was distilled under reduced pressure using rotavap to obtain the title compound as a pale-brown solid (510 mg). Yield: 95%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.23 (s,2H), 4.04 (d, J 10.0, 2H), 3.24-3.11 (m, 1H), 2.96-2.81 (m, 2H), 1.98 (dd, J 13.2,2.4, 2H), 1.69-1.58 (m, 2H), 1.41 (s, 9H). MS (m/z): 232.26 ([M-Boc+-H] ⁺ ). Intermediate 63: 2-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidine dihydrochloride [235] Following the general procedure 5, the titled compound was synthesized from intermediate 62 (0.51 g, 1.50 mmol) and 2M HCl in dioxan (10.2 ml). Purification: Not done. Appearance: Pale-brown solid (400 mg). Yield: 97. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.26 (s,2H), 8.96 (s, 1H), 8.71 (s, 1H), 3.33-3.26 (m, 3H), 3.10-3.01 (m, 2H), 2.19-2.12 (m, 2H), 2.04-1.94 (m, 2H). MS (m/z): 232.23 ([M-2HCl+H] ⁺ ). Intermediate 64: tert-butyl 4-(6-(trifluoromethyl)pyridazin-3-yl)piperazine-1-carboxylat e [236] Following the general procedure 4, the titled compound was synthesized from 3-chloro- 6-(trifluoromethyl)pyridazine (0.50 g, 2.70 mmol), tert-butyl piperazine-1-carboxylate (0.51 g 2.70 mmol), N-Methylpyrrolidone (5 ml), and potassium carbonate (0.76 g, 5.50 mmol). Purification: Not done. Appearance: Off-white solid (820 mg). Yield: 90%. ¹ H-NMR (δ ppm, DMS-d6, 400 MHz): 7.84 (d, J 9.6, 1H), 7.41 (d, J 9.6, 1H), 3.75-3.72 (m, 4H), 3.48 (t, J 5.6, 4H), 1.43 (s, 9H) MS (m/z): 233.32 ([M-Boc+H] ⁺ ). Intermediate 65: 3-(piperazin-1-yl)-6-(trifluoromethyl)pyridazine dihydrochloride [237] Following the general procedure 5, the titled compound was synthesized from intermediate 64 (0.81 g, 2.43 mmol) and 2M HCl in dioxan (20 ml). Purification: Not done. Appearance: Pale-brown solid (620 mg). Yield: 83%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.41 (s, 2H), 7.92 (d, J 9.6, 1H), 7.52 (d, J 9.6, 1H), 4.98 (s, 1H), 4.00 (t, J 5.2, 4H), 3.25-3.19 (m, 4H. MS (m/z): 233.21 ([M-2HCl+H] ⁺ ). Intermediate 66: tert-butyl 4-(5-(difluoromethoxy)pyrimidin-2-yl)piperazine-1-carboxylat e [238] To 2-chloro-5-(difluoromethoxy)pyrimidine (900 mg, 4.99 mmol) in toluene (20 ml), tert-butyl piperazine-1-carboxylate (929 mg, 4.99 mmol), sodium tert-butoxide (575 mg, 5.98 mmol) were added at room temperature. BINAP (155 mg, 0.24 mmol) and Pd ₂ (dba) ₃ (228 mg, 0.24 mmol) were added and purged under nitrogen for10 min. The reaction mixture was heated to 80°C and stirred for 12h. After 12h the reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (8:92) as eluent to obtain the title compound as an off-white solid (330 mg). Yield: 30%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.35 (s, 2H), 7.25 (t, J 73.6, 1H), 3.71-3.68 (m, 4H), 3.41 (t, J 5.6, 4H), 1.42 (s, 9H). MS (m/z): 231.14 ([M-Boc+H] ⁺ ). Intermediate 67: 5-(difluoromethoxy)-2-(piperazin-1-yl)pyrimidine dihydrochloride [239] Following the general procedure 5, the titled compound was synthesized from intermediate 66 (0.50 g, 1.51 mmol) and 2M HCl in dioxan (15 ml). Purification: Not done. Appearance: Off-white solid (400 mg). Yield: 87%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.39 (s, 2H), 8.64 (s, 1H), 8.41 (s, 2H), 7.36 (t, J 73.6, 1H), 3.96 (t, J 5.2, 4H), 3.18-3.11 (m, 4H). MS (m/z): 231.12 ([M-2HCl+H] ⁺ ). Intermediate 68: tert-butyl 4-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl)piperazine-1 - carboxylate [240] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (300 mg, 1.29 mmol), DMF (5 ml), tert-butyl piperazine-1-carboxylate (265 mg, 1.42 mmol), DIPEA (835 mg, 6.46 mmol) and HBTU (588 mg, 1.55 mmol). Purification: Not done. Appearance: Pale-brown solid. Yield: 350 mg. % Yield: 67. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 12.46 (s, 1H), 8.27 (dd, J 7.6,0.8, 1H), 8.08 (d, J 8.0, 1H), 7.96 (dt, J 7.2,1.6, 1H), 7.86 (dt, J 8.0,1.2, 1H), 3.49-3.41 (m, 4H), 3.43-3.28 (m, 4H), 2.95 (t, J 7.6, 2H), 2.49- 2.44 (m, 2H), 1.95-1.88 (m, 2H), 1.41 (s, 9H). MS (m/z): 401.29 ([M+H] ⁺ ). Intermediate 69: 4-(4-oxo-4-(piperazin-1-yl)butyl)phthalazin-1(2H)-one hydrochloride [241] Following the general procedure 5, the titled compound was synthesized from intermediate 68 (0.350 g, 0.87 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done. Appearance: Off-white solid 320mg). Yield: >100%(crude). ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 9.46 (s, 2H), 8.27 (dd, J 7.6,0.8, 1H), 8.08 (d, J 8.0, 1H), 7.97 (dt, J 7.2,1.6, 1H), 7.87 (dt, J 8.0,1.2, 1H), 3.69 (br s, 4H), 3.12-3.01 (m, 4H), 2.96 (t, J 7.2, 2H), 2.50-2.49 (m, 2H), 1.96-1.89 (m, 2H), MS (m/z): 301.24 ([M-HCl+H] ⁺ ). Intermediate 70: tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)-1,4-diazepane-1-carbox ylate [242] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(trifluoromethyl)pyrimidine (0.50 g, 2.70 mmol), tert-butyl 1,4-diazepane-1-carboxylate (0.55 g 2.70 mmol), N-Methylpyrrolidone (5 ml), and potassium carbonate (0.76 g, 5.50 mmol). Purification: Not done. Appearance: Off-white solid (800 mg). Yield: 84%. ¹ H-NMR (δ ppm, DMS-d6, 400 MHz): 8.70 (t, J 4.4, 2H), 3.91 (t, J 6.0, 2H), 3.80 (q, J 5.6, 2H), 3.57 (t, J 6.0, 1H), 3.51 (t, J 5.6, 1H), 3.34-3.27 (m, 2H), 1.80-1.71 (m, 2H), 1.28 (s, 9H). MS (m/z): 247.24 ([M-Boc+H] ⁺ ). Intermediate 71: 1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,4-diazepane dihydrochloride [243] Following the general procedure 5, the titled compound was synthesized from intermediate 70 (0.75 g, 2.2 mmol) and 2M HCl in dioxan (20 ml). Purification: Not done. Appearance: Off-white solid (600 mg). Yield: 90%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.28 (s, 2H), 8.75 (s, 2H), 6.75 (s, 1H), 4.06 (t, J 5.2, 2H), 3.91 (t, J 6.0, 2H), 3.34-3.14 (m, 4H), 2.10-2.04 (m, 2H). MS (m/z): 247.20 ([M-2HCl+H] ⁺ ). Intermediate 72: 4-(6-fluoro-3-oxoisobenzofuran-1(3H)-ylidene)butanenitrile [244] Following the general procedure 1, the titled compound was synthesized from 6-fluoro- 3-oxo-1,3-dihydroisobenzofuran-1-yl)triphenylphosphonium bromide (4.7 g, 9.6 mmol), dichloromethane (80 ml), 4-oxobutanenitrile (800 mg, 9.6 mmol) and triethylamine (1.9 g, 19.0 mmol). Purification: Combi-Flash. Eluent: Ethyl acetate and petroleum ether (18:82) as eluent. Appearance: Yellow solid (1.00 g). Yield: 48%. MS (m/z): 218.23 ([M+H] ⁺ ). Intermediate 73: 4-(7-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)butanenitrile [245] Following the general procedure 2, the titled compound was synthesized from Intermediate 72 (0.95 g, 4.4 mmol), ethanol (15 ml), and hydrazine hydrate (0.33 g, 6.6 mmol). Purification: Not done. Appearance: Off-white solid (1.0 g). Yield: 99%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.59 (s, 1H), 8.34 (dd, J 8.8, 6.0, 1H), 7.85 (dd, J 10.0,2.4, 1H), 7.73 (dt, J 8.8,2.4, 1H), 3.01 (t, 7.6, 2H), 2.64 (t, J 7.2, 2H), 2.03-1.95 (m, 2H). MS (m/z): 232.26 ([M+H] ⁺ ). Intermediate 74: 4-(7-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)butanoic acid [246] To intermediate 73 (0.95 g, 4.1 mmol), water (25 ml) and NaOH (066 g, 16.0 mmol) were added and heated to 100°C. After 6h, the reaction mixture was cooled to room temperature, acidified to pH 2 with con. HCl, the solid precipitated was filtered, washed with water (20 ml) and dried under vacuum. The solid was stirred with dichloromethane (10 ml), filtered and dried under vacuum to obtain the title compound as an off-white solid (900 mg). Yield: 88%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.54 (s, 1H), 12.09 (s, 1H), 8.34 (dd, J 8.8, 6.0, 1H), 7.86 (dd, J 10.0,2.4, 1H), 7.72 (dt, J 8.8,2.4, 1H), 2.92 (t, 7.6, 2H), 2.38 (t, J 7.2, 2H),1.92-1.85 (m, 2H). MS (m/z): 251.25 ([M+H] ⁺ ). Intermediate 75: tert-butyl 4-(5-(trifluoromethoxy)pyridin-2-yl)piperazine-1-carboxylate [247] To 2-chloro-5-(trifluoromethoxy)pyridine (500 mg, 2.5 mmol) in toluene (12 ml), tert- butyl piperazine-1-carboxylate (470 mg, 2.5 mmol), sodium tert-butoxide (290 mg, 3.0 mmol) were added at room temperature. BINAP (79 mg, 0.13 mmol) and Pd2(dba)3 (120 mg, 0.13 mmol) were added and purged under nitrogen for10 min. The reaction mixture was heated to 80°C and stirred for 10h. After 10h the reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (15:85) as eluent to obtain the title compound as a brown gel (500 mg). Yield: 57%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.16 (d, J 2.8, 1H), 7.63-7.60 (m, 1H), 6.92 (d, J 9.2, 1H), 3.52-3.49 (m, 4H), 3.45-3.40 (m, 4H), 1.42 (s, 9H). MS (m/z): 248.22 ([M- Boc+H] ⁺ ). Intermediate 76: 1-(5-(trifluoromethoxy)pyridin-2-yl)piperazine dihydrochloride [248] Following the general procedure 5, the titled compound was synthesized from intermediate 75 (0.48 g, 1.38 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done. Appearance: Off-white solid (400 mg). Yield: 90%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.48 (s, 2H), 8.21 (d, J 3.2, 1H), 8.17 (s, 1H), 7.71-7.67 (m, 1H), 7.03 (d, J 8.8, 1H), 3.79 (t, J 5.2, 4H), 3.19-3.11 (m, 4H). MS (m/z): 248.18 ([M-2HCl+H] ⁺ ). Intermediate 77: 2-(3-bromopropyl)-1,3-dioxolane [249] To ethyl 4-bromobutanoate (10 g, 51.2 mmol) in dichloromethane (750 ml) cooled to - 78°C, DIBAL-H (76.9 ml, 1M in toluene, 76.9 mmol) was added and stirred for 8h. After 8h, the reaction mixture was slowly quenched with 1N HCl (150 ml), extracted with dichloromethane (3 x 200 ml) and the organic layer was distilled under reduced pressure. To the residue, 4-methylbezenesulphonic acid (296 mg, 1.56 mmol), ethylene glycol (2.32 g, 37.4 mmol and toluene (50 ml) were added and heated to 140°C for 4h using Den-Stork apparatus to remove water. After 4h, the reaction mass was cooled to room temperature and diluted with toluene (100 ml), washed with sodium bicarbonate solution (50 ml), water (2 x 50 ml) and concentrated under reduced pressure to obtain the title compound as a yellow liquid (2.10 g). Yield: 21%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 4.91 (t, J 4.4, 1H), 3.98-3.95 (m, 2H), 3.87- 3.83 (m, 2H), 3.47 (t, J 6.8, 2H), 2.04-1.97 (m, 2H), 1.84-1.79 (m, 2H). MS (m/z): 195.14 ([M] ⁺ ). Intermediate 78: 3-(1,3-dioxolan-2-yl)propyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine- 1-carboxylate [250] To intermediate 11 (500mg, 1.6 mmol) in DMSO (10 ml), cesium carbonate (1.6 g, 4.9 mmol) was added and stirred at room temperature for 30 min. Intermediate 77 (640 mg, 3.3 mmol) was added and heated to 90°C for 8h. After 8h, the reaction mass cooled to room temperature and quenched with water (150 ml). The solid precipitated was filtered, washed with water (50 ml) and dried under vacuum to obtain the title compound as a pale-brown solid (520 mg). Yield: 83%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.72 (s, 2H), 4.82 (t, J 4.4, 1H), 4.06 (t, J 6.4, 2H), 3.89-3.80 (m, 6H), 3.77-3.74 (m, 2H), 3.48 (t, J 5.2, 4H), 1.68-1.61 (m, 4H). MS (m/z): 391.26 ([M] ⁺ ). Intermediate 79: 4-oxobutyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylat e [251] To intermediate 78 (500mg, 1.3 mmol) in THF (10 ml) cooled to 0°C, 6N HCl (10 ml) was added stirred at room temperature for 4h. After 4h, the reaction mass pH was adjusted to 7-8 by sodium bicarbonate solution (100 ml) and extracted with dichloromethane (3 x 50 ml). The organic layer was washed with water (2 x 100 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the title compound as a pale-brown solid (420 mg). Yield: 95%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.62 (s, 1H), 8.72 (s, 2H), 4.05 (t, J 6.4, 2H), 3.85-3.83 (m, 4H), 3.48 (t, J 5.2, 2H), 2.55-2.48 (m, 4H), 1.89-1.82 (m, 2H). MS (m/z): 347.23 ([M+H] ⁺ ). Intermediate 80: 4-(3-oxoisobenzofuran-1(3H)-ylidene)butyl 4-(5-(trifluoromethyl)pyrimidin- 2-yl)piperazine-1-carboxylate [252] Following the general procedure 1, the titled compound was synthesized from intermediate 2 (0.55 g, 1.2 mmol), dichloromethane (80 ml), intermediate 79 (0.400 g, 1.2 mmol) and triethylamine (230 mg, 2.3 mmol). Purification: Combi-Flash. Eluent: Ethyl acetate and petroleum ether (30:70) as eluent. Appearance: Pale-yellow gel (380 mg). Yield: 71%. MS (m/z): 463.36 ([M+H] ⁺ ). Intermediate 81: 2-(4-(3-(1,3-dioxolan-2-yl)propyl)piperazin-1-yl)-5- (trifluoromethyl)pyrimidine [253] To intermediate 11 (500mg, 1.6 mmol) in acetonitrile (10 ml), cesium carbonate (1.6 g, 4.9 mmol) was added and stirred at room temperature for 30 min. Intermediate 77 (640 mg, 3.3 mmol) was added and heated to 90°C for 4h. After 4h, the reaction mass cooled to room temperature, quenched with water (50 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was washed with water (30 ml), brine solution (30 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (2.5:97.5) as eluent to obtain the title compound as a colourless liquid (210 mg). Yield: 37%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.65 (s, 2H), 4.81 (t, J 4.8, 1H), 3.89-3.85 (m, 2H), 3.82-3.79 (m, 4H), 3.77-3.73 (m, 2H), 2.42 (t, J 5.2, 4H), 2.34 (t, J 7.2, 2H), 1.60-1.50 (m, 4H). MS (m/z): 347.37 ([M] ⁺ ). Intermediate 82: 4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butan al [254] To intermediate 81 (250mg, 0.72 mmol) in THF (6 ml) cooled to 0°C, 6N HCl (5.7 ml) was added stirred at room temperature for 4h. After 4h, the reaction mass pH was adjusted to 7-8 by sodium bicarbonate solution (100 ml) and extracted with dichloromethane (3 x 50 ml). The organic layer was washed with water (2 x 100 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the title compound as a pale-yellow liquid (210 mg). Yield: 96%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.68 (s, 1H), 8.68 (s, 2H), 3.81 (t, J 4.8, 4H), 2.46-2.40 (m, 6H), 2.33 (t, J 6.8, 2H), 1.75-1.70 (m, 2H). MS (m/z): 303.44 ([M+H] ⁺ ). Intermediate 83: 3-(4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1- yl)butylidene)isobenzofuran-1(3H)-one [255] Following the general procedure 1, the titled compound was synthesized from intermediate 2 (0.34 g, 0.66 mmol), dichloromethane (20 ml), intermediate 82 (0.200 g, 0.66 mmol) and triethylamine (134 mg, 1.32 mmol). Purification: Not done. Appearance: Pale- yellow gel (250 mg). Yield: 90%. MS (m/z): 419.49 ([M+H] ⁺ ). Intermediate 84: tert-butyl 4-(5-chloropyridin-2-yl)piperazine-1-carboxylate [256] To 2-bromo-5-chloropyridine (517 mg, 2.68 mmol) in toluene (10 ml), tert-butyl piperazine-1-carboxylate (500 mg, 2.68 mmol), sodium tert-butoxide (310 mg, 3.22 mmol) were added at room temperature. BINAP (83.6 mg, 0.13 mmol) and Pd ₂ (dba) ₃ (123 mg, 0.13 mmol) were added and purged under nitrogen for10 min. The reaction mixture was heated to 80°C and stirred for 2h. After 2h, the reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (7:93) as eluent to obtain the title compound as a pale-yellow solid (500 mg). Yield: 62%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.11 (d, J 2.4, 1H), 7.63 (dd, J 8.8,2.4, 1H), 6.88 (d, J 9.2, 1H), 3.48-3.45 (m, 4H), 3.4c1-3.39 (m, 4H), 1.41 (s, 9H). MS (m/z): 198.10 ([M-Boc+H] ⁺ ). Intermediate 85: 1-(5-chloropyridin-2-yl)piperazine dihydrochloride [257] Following the general procedure 5, the titled compound was synthesized from intermediate 84 (0.500 g, 1.68 mmol) and 2M HCl in dioxan (5 ml). Purification: Not done. Appearance: Off-white solid (450 mg). Yield: 99%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.47 (s, 2H), 8.16 (d, J 2.4, 1H), 7.71 (dd, J 9.2,2.8, 1H), 6.99 (d, J 9.2, 1H), 5.51 (s, 1H), 3.75 (t, J 5.2, 4H), 3.18-3.10 (m, 4H). MS (m/z): 198.15 ([M-2HCl+H] ⁺ ). Intermediate 86: tert-butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate [258] Following the general procedure 4, the titled compound was synthesized from 6- chloronicotinonitrile (0.30 g, 2.17 mmol), tert-butyl piperazine-1-carboxylate (0.44 g, 2.38 mmol), N-Methylpyrrolidone (5 ml), and potassium carbonate (0.89g, 6.50 mmol). Purification: Not done. Appearance: Pale-brown solid (500 mg). Yield: 80%. ¹ H-NMR (δ ppm, DMS-d6, 400 MHz): 8.50 (dd, J 2.2,0.8, 1H), 7.89 (dd, J 9.2,2.4, 1H), 6.93 (dd, J 9.2,0.8, 1H), 3.67-3.64 (m, 4H), 3.43 (t, J 5.2, 4H), 1.42 (s, 9H). MS (m/z): 189.18 ([M-Boc+H] ⁺ ). Intermediate 87: 6-(piperazin-1-yl)nicotinonitrile dihydrochloride [259] Following the general procedure 5, the titled compound was synthesized from intermediate 86 (0.45 g, 1.56 mmol) and 2M HCl in dioxan (7.8 ml). Purification: Not done. Appearance: Pale-brown solid (395 mg). Yield: 96%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.57 (s, 2H), 8.53 (dd, J 2.2,0.8, 1H), 8.01 (s, 1H), 7.96 (dd, J 9.2,2.4, 1H), 7.04 (d, J 9.2, 1H), 6.75 (s, 1H), 3.93 (t, J 5.2, 4H), 3.19-3.10 (m, 4H). MS (m/z): 189.11 ([M-2HCl+H] ⁺ ). Intermediate 88: 3-((4-chlorophthalazin-1-yl)oxy)propan-1-ol [260] To propane-1,3-diol (714 mg, 9.39 mmol) in THF (25 ml), sodium hydroxide (680 mg, 17.08 mmol), tetrabutylammonium bromide (550 mg, 1.70 mmol) were added at room temperature.1,4-dichlorophthalazine (1.70 g, 8.54 mmol) was added and heated to 50°C. After 24h, the reaction mixture was quenched with water (50 ml), pH adjusted to 6 with dilute HCl, extracted with 5% MeOH in dichloromethane (3 x 50 ml). The organic layer was washed with saturated sodium carbonate solution (50 ml), water (50 ml), brine solution (50 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi- flash using methanol and dichloromethane (2:98) as eluent to obtain the title compound as an off-white solid (850 mg). Yield: 41%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.25-8.19 (m, 2H), 8.16-8.09 (m, 2H), 4.66-4.60 (m, 3H), 3.68-3.63 (m, 2H), 2.06-1.95 (m,2H). MS (m/z): 239.14 ([M+H] ⁺ ). Intermediate 89: 3-((4-chlorophthalazin-1-yl)oxy)propanoic acid [261] To intermediate 88 (700 mg, 2.93 mmol) in acetonitrile (12 ml) and water (8 ml) at 0°C, TEMPO (2,2,6,6-tetramethylpiperidin-1-olate; 229 mg, 1.47 mmol) was added at room temperature. After 1h at room temperature, the reaction mixture was concentrated under reduced pressure, water (50 ml) was added to the residue and solid precipitated was filtered. The solid was washed with water (20 ml) and diethyl ether (20 ml) to obtain the crude. Crude product was purified by combi-flash using methanol and dichloromethane (7:93) as eluent to obtain the title compound as an off-white solid (360 mg). Yield: 48%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.44 (s, 1H), 8.22-8.11 (m, 4H), 4.78 (t, J 6.0, 2H), 2.90 (t, J 6.0, 2H). MS (m/z): 253.12 ([M+H] ⁺ ). Intermediate 90: 3-((4-chlorophthalazin-1-yl)oxy)-1-(4-(5-(trifluoromethyl)py rimidin-2- yl)piperazin-1-yl)propan-1-one [262] Following the general procedure 6, the titled compound was synthesized from intermediate 89 (290 mg, 1.15 mmol), DMF (5 ml), intermediate 11 (385 mg, 1.26 mmol), DIPEA (742 mg, 5.74 mmol) and HBTU (566 mg, 1.49 mmol). Purification: Combi-Flash. Eluent: Ethyl acetate and petroleum ether (65:35) as eluent. Appearance: Off-white solid (130 mg). Yield: 24%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.73 (s, 2H), 8.22-8.18 (m, 2H), 8.16-8.08 (m, 2H), 4.86 (t, J 6.4, 2H), 3.92 (t, J 4.8, 2H), 3.85 (t, J 4.8, 2H), 3.67 (t, J 5.2, 2H), 3.63 (t, J 5.2, 2H), 3.09 (t, J 6.4, 2H). MS (m/z): 467.20 ([M+H] ⁺ ). Intermediate 91: tert-butyl (1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl)piperidin-4 - yl)carbamate [263] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (300 mg, 1.29 mmol), DMF (5 ml), tert-butyl piperidin-4-ylcarbamate (259 mg, 1.29 mmol), DIPEA (835 mg, 6.46 mmol) and HBTU (588 mg, 1.55 mmol). Purification: Combi-Flash. Eluent: Methanol and dichloromethane (3.5:96.5) as eluent. Appearance: Off- white solid (400 mg). Yield: 74%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.44 (s, 1H), 8.27 (d, J 7.6, 1H), 8.08 (d, J 8.0, 1H), 7.96 (t, J 7.2, 1H), 7.86 (t, J 7.6, 1H), 6.85 (d, J 7.2, 1H), 4.26 (t, J 12.4, 1H), 3.81 (d, J 13.2, 1H), 3.49-3.41 (m, 1H), 3.06 (t, J 12.0, 1H), 2.94 (t, J 7.2, 2H), 2.69 (t, J 12.4, 1H), 2.45 (t, J 7.2, 2H), 1.93-1.86 (m, 2H), 1.78-1.60 (m, 2H), 1.38 (s, 9H), 1.27- 1.13 (m, 2H). MS (m/z): 415.24 ([M+H] ⁺ ). Intermediate 92: 4-(4-(4-aminopiperidin-1-yl)-4-oxobutyl)phthalazin-1(2H)-one hydrochloride [264] Following the general procedure 5, the titled compound was synthesized from intermediate 91 (0.40 g, 0.96 mmol) and 2M HCl in dioxan (5 ml). Purification: Not done. Appearance: Off-white gummy solid (300 mg). Yield: 88%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.47 (s, 1H), 8.27-8.20 (m, 4H), 8.09 (d, J 7.6, 1H), 7.97 (dt, J 7.2,1.2, 1H), 7.87 (dt, J 8.0,1.2, 1H), 4.41 (t, J 13.2, 1H), 3.94 (d, J 13.6, 1H), 3.29-3.20 (m, 1H), 3.08 (t, J 12.0, 1H), 2.95 (t, J 7.2, 2H), 2.67-2.60 (m, 1H), 2.50-2.45 (m, 2H), 1.97-1.87 (m, 4H), 1.50-1.20 (m, 2H). MS (m/z): 315.28 ([M-HCl+H] ⁺ ). Intermediate 93: 4-(5-chloropyrimidin-2-yl)piperazin-2-one [265] Following the general procedure 4, the titled compound was synthesized from 2,5- dichloropyrimidine (750 mg, 5.03 mmol), piperazin-2-one (504 mg, 5.03 mmol), N- Methylpyrrolidone (10 ml), and DIPEA (1.95 g, 15.1 mmol). Purification: Not done. Appearance: Pale-brown solid (948 mg). Yield: 88%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.47 (s, 2H), 8.11 (s, 1H), 4.13 (s, 2H), 3.88 (t, J 5.6, 2H), 3.31-3.26 (m, 2H). MS (m/z): 213.08 ([M+H] ⁺ ). Intermediate 94: 1-(3-(1,3-dioxolan-2-yl)propyl)-4-(5-chloropyrimidin-2-yl)pi perazin-2-one [266] To intermediate 93 (700 mg, 3.29 mmol) in DMSO (5 ml), cesium carbonate (3.22 g, 9.88 mmol) was added and stirred at room temperature for 30 min. Intermediate 77 (706 mg, 3.62 mmol) was added and heated to 90°C for 5h. After 5h, the reaction mass cooled to room temperature, quenched with water (50 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was washed with water (30 ml), brine solution (30 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and petroleum ether (8:92) as eluent to obtain the title compound as an off-white solid (380 mg). Yield: 35%. MS (m/z): 327.37 ([M] ⁺ ). Intermediate 95: 4-(4-(5-chloropyrimidin-2-yl)-2-oxopiperazin-1-yl)butanal [267] To intermediate 94 (380 mg, 1.21 mmol) in THF (10 ml) cooled to 0°C, 6N HCl (8 ml) was added stirred at room temperature for 5h. After 5h, the reaction mass pH was adjusted to 7-8 by sodium bicarbonate solution (100 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was washed with water (2 x 100 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the title compound as a pale-brown liquid (260 mg). Yield: 79%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.65 (s, 1H), 8.48 (s, 2H), 4.19 (d, J 5.2, 2H), 3.94 (t, J 5.2, 2H), 3.43 (t, J 5.2, 2H), 3.38 (t, J 7.2, 2H), 2.46-2.42 (m, 2H), 1.78- 1.71 (m, 2H). MS (m/z): 283.22 ([M+H] ⁺ ). Intermediate 96: 4-(5-chloropyrimidin-2-yl)-1-(4-(3-oxoisobenzofuran-1(3H)- ylidene)butyl)piperazin-2-one [268] Following the general procedure 1, the titled compound was synthesized from intermediate 2 (0.25 g, 0.88 mmol), dichloromethane (7.5 ml), intermediate 95 (0.250 g, 0.88 mmol) and triethylamine (179 mg, 1.77 mmol). Purification: Not done. Appearance: Dark- yellow solid (900 mg). Yield: >100%(crude). MS (m/z): 399.35 ([M+H] ⁺ ). Intermediate 97: 4-(5-chloropyrimidin-2-yl)-1-(3-methoxypropyl)piperazin-2-on e [269] To intermediate 93 (5.0 g, 23.5 mmol) in DMSO (100 ml), cesium carbonate (13.32 g, 47.0 mmol) was added and stirred at room temperature for 30 min. 1-bromo-3- methoxypropane (7.19 g, 47.0 mmol) was added and heated to 85°C for 24h. After 24h, the reaction mass cooled to room temperature, quenched with water (75 ml) and extracted with 5% methanol in dichloromethane (3 x 150 ml). The organic layer was washed with water (75 ml), brine solution (75 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and petroleum ether (50:50) as eluent to obtain the title compound as a pale-yellow oil (2.2 g). Yield: 33%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.48 (s, 2H), 4.19 (s, 2H), 3.94 (t, J 5.2, 2H), 3.43 (t, J 5.6, 2H), 3.39 (t, J 7.2, 2H), 3.32-3.31 (m, 2H), 3.21 (s, 3H), 1.75-1.68 (m, 2H). MS (m/z): 285.28 ([M] ⁺ ). Intermediate 98: 4-(5-chloropyrimidin-2-yl)-1-(3-hydroxypropyl)piperazin-2-on e [270] To intermediate 97 (500 mg, 1.76 mmol) in Dichloromethane (10 ml) cooled to 05°C, boron tribromide (1M in dichloromethane; 2.63 ml, 2.63 mmol) was added and stirred at room temperature for 2h. After 2h, the reaction mixture was quenched with saturated sodium bicarbonate solution (20 ml) and extracted with 5% methanol in dichloromethane (2 x 30 ml). The organic layer was washed with water (20 ml), brine solution (20 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (3.6:96.4) as eluent to obtain the title compound as a pale-yellow solid (200 mg). Yield: 42%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.49 (s, 2H), 4.46 (t, J 5.2, 1H), 4.19 (s, 2H), 3.94 (t, J 5.2, 2H), 3.44-3.36 (m, 6H), 1.67- 1.60 (m, 2H). MS (m/z): 271.24 ([M] ⁺ ). Intermediate 99: 3-(4-(5-chloropyrimidin-2-yl)-2-oxopiperazin-1-yl)propanal [271] To intermediate 98 (180 mg, 0.66 mmol) in Dichloromethane (50 ml), Dess-Martin periodinane (620 mg, 1.46 mmol) was added and stirred at room temperature for 3h. After 3h, the reaction mixture was passed through cealite bed, washed with saturated sodium bicarbonate solution (20 ml) and concentrated under reduced pressure to obtain the title compound as an off-white solid (179 mg). Yield: 100%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.66 (s, 1H), 8.48 (s, 2H), 4.19 (s, 2H), 3.97 (t, J 5.6, 2H), 3.61 (t, J 6.8, 2H), 3.46 (t, J 5.6, 2H), 2.72-2.67 (m, 2H). MS (m/z): 271.24 ([M] ⁺ ). Intermediate 100: 4-(5-chloropyrimidin-2-yl)-1-(3-(3-oxoisobenzofuran-1(3H)- ylidene)propyl)piperazin-2-one [272] Following the general procedure 1, the titled compound was synthesized from intermediate 2 (0.708 g, 1.49 mmol), dichloromethane (30 ml), intermediate 99 (0.200 g, 0.74 mmol) and triethylamine (310 mg, 2.98 mmol). Purification: Not done. Appearance: Pale- yellow semi solid (250 mg). Yield: 87%. MS (m/z): 385.39 ([M+H] ⁺ ). Intermediate 101: tert-butyl 4-(5-chloro-4-methylpyrimidin-2-yl)piperazine-1-carboxylate [273] Following the general procedure 4, the titled compound was synthesized from 2,5- dichloro-4-methylpyrimidine (0.50 g, 3.07 mmol), tert-butyl piperazine-1-carboxylate (0.57 g, 3.01 mmol), N-Methylpyrrolidone (10 ml), and potassium carbonate (0.84g, 6.13 mmol). Purification: Combi-Flash. Eluent: ethyl acetate and petroleum ether (10:90) as eluent. Appearance: Off-white solid (850 mg). Yield: 88%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.30 (s, 1H), 3.70 (t, J 5.6, 4H), 3.39 (t, J 5.2, 4H), 2.37 (s, 3H), 1.41 (3, 9H). MS (m/z): 213.23 ([M-Boc+H] ⁺ ). Intermediate 102: 5-chloro-4-methyl-2-(piperazin-1-yl)pyrimidine dihydrochloride [274] Following the general procedure 5, the titled compound was synthesized from intermediate 101 (085 g, 2.71 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done. Appearance: Off-white solid (750 mg). Yield: 96%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.51 (s, 2H), 8.37 (s, 1H), 5.90 (s, 1H), 3.56 (t, J 5.2, 4H), 3.17-3.08 (m, 4H), 2.39 (s, 3H). MS (m/z): 213.20 ([M-2HCl+H] ⁺ ). Intermediate 103: tert-butyl 4-(5-chloro-4-methylpyridin-2-yl)piperazine-1-carboxylate [275] To 2,5-dichloro-4-methylpyridine (500 mg, 3.1 mmol) in toluene (10 ml), tert-butyl piperazine-1-carboxylate (500 mg, 2.68 mmol), sodium tert-butoxide (570 mg, 3.1 mmol) were added at room temperature. BINAP (96 mg, 0.15 mmol) and Pd2(dba)3 (140 mg, 0.15 mmol) were added and purged under nitrogen for10 min. The reaction mixture was heated to 90°C and stirred for 16h. After 16h, the reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (6.5:93.5) as eluent to obtain the title compound as a pale-brown solid (320 mg). Yield: 33%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.04 (s, 1H), 6.87 (s, 1H), 3.478- 3.46 (m, 4H), 3.40-3.38 (m, 4H), 1.41 (s, 9H). MS (m/z): 212.25 ([M-Boc+H] ⁺ ). Intermediate 104: 1-(5-chloro-4-methylpyridin-2-yl)piperazine dihydrochloride [276] Following the general procedure 5, the titled compound was synthesized from intermediate 103 (0.360 g, 1.20 mmol) and 2M HCl in dioxan (5 ml). Purification: Combi- Flash. Not done. Appearance: Pale-pink solid (350 mg). Yield: >100%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.46 (s, 2H), 8.10 (s, 1H), 7.02 (s, 1H), 6.39 (s, 1H), 3.56 (t, J 5.2, 4H), 3.18-3.09 (m, 4H), 2.29 (s, 3H). MS (m/z): 212.29 ([M-2HCl+H] ⁺ ). Intermediate 105: ethyl 3-(3-oxoisobenzofuran-1(3H)-ylidene)propanoate [277] To ethyl 3,3-diethoxypropanoate (1.30 g, 6.83 mmol) in dichloromethane cooled to 0°C, TFA (3.89 g, 34.14 mmol) and water (2 ml) were added and stirred at room temperature for 2h. After 2h, the reaction mixture was quenched with saturated sodium carbonate solution (30 ml), extracted with dichloromethane (3 x 30 ml), washed with water (30 ml) and concentrated under reduced pressure to obtain ethyl 3-oxopropanoate. By following the general procedure 1, the titled compound was synthesized from intermediate 2 (3.07 g, 6.46 mmol), dichloromethane (20 ml), ethyl 3-oxopropanoate (0.750 g, 6.46 mmol) and triethylamine (654 mg, 6.46 mmol). Purification: Not done. Appearance: Dark-red solid (1.40 mg). Yield: 94%. MS (m/z): 231.27 ([M-H] ⁺ ). Intermediate 106: ethyl 3-(4-oxo-3,4-dihydrophthalazin-1-yl)propanoate

[278] Following the general procedure 2, the titled compound was synthesized from Intermediate 105 (1.40 g, 6.02 mmol), ethanol (19 ml), and hydrazine hydrate (452 mg, 9.04 mmol). Purification: Not done. Appearance: Pale-yellow gummy solid (1.25 g). Yield: 84%. MS (m/z): 247.38 ([M+H] ⁺ ). Intermediate 107: 3-(4-oxo-3,4-dihydrophthalazin-1-yl)propanoic acid [279] Following the general procedure 3, the titled compound was synthesized from Intermediate 106 (1.25 g, 5.07 mmol), THF (31 ml), water (12 ml) and NaOH (0.43 g, 10.8 mmol). Appearance: Pale-brown solid (110 mg). Yield: 10%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.49 (s, 1H), 12.15 (s, 1H), 8.27 (dd, J 7.6,0.8, 1H), 8.02 (d, J 7.6, 1H), 7.97 (dt, J 7.2,1.6, 1H), 7.87 (dt, J 8.4, 1.2, 1H), 3.19 (t, J ,6.8, 2H), 2.73 (t, J 6.8, 2H). MS (m/z): 219.26 ([M+H] ⁺ ). Intermediate 108: 1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)prop-2-en-1-one [280] To intermediate 28 (2.0 g, 7.4 mmol) in dichloromethane (60 ml) cooled to -40°C, acrylic anhydride (1.0 g, 8.1 mmol and triethylamine (2.50 g, 24 mmol) were added. After 1h, the reaction mixture was quenched with water (400 ml) at -40°C, warmed to room temperature and extracted with dichloromethane (3 x 70 ml). The organic layer was washed with water (100 ml), brine solution (100 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (31:69) as eluent to obtain the title compound as an off-white solid (1.5 g). Yield: 81%. ¹ H- NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.46 (s, 2H), 6.87 (dd, J 16.8,2.4, 1H), 6.17 (dd, J 16.4,2.4, 1H), 5.73 (dd, J 10.4,2.4, 1H), 3.79-3.71 (m, 4H), 3.69-3.59 (m, 4H). MS (m/z): 253.25 ([M+H] ⁺ ). Intermediate 109: ethyl 4-oxo-3,4-dihydrophthalazine-1-carboxylate [281] To 4-oxo-3,4-dihydrophthalazine-1-carboxylic acid (4.5 g, 23.7 mmol) in ethanol (68 ml), sulphuric acid (13.5 ml) was added and heated to 100°C for 16h. After 16h, the reaction mixture was concentrated to remove ethanol. To the residue, water (50 ml) was added, extracted with ethyl acetate (3 x 50 ml), washed with water (100 ml), brine solution (100 ml) and distilled under reduced pressure to obtain the title compound as an off-white solid (4.1 g). Yield: 79%. MS (m/z): 219.19 ([M+H] ⁺ ). Intermediate 110: ethyl 3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazine-1-carboxyla te [282] To intermediate 109 (500 mg, 2.3 mmol) in DMF (5 ml) cooled to 0°C, sodium hydride (66 mg, 2.7 mmol was added and stirred for 20 min. 4-Methoxybenzyl chloride (430 mg, 2.7 mmol) was added and stirred at room temperature for 4h. After 4h, the reaction mixture was quenched with water (20 ml), extracted with ethyl acetate (3 x 30 ml). The organic layer was washed with water (50 ml), brine solution (50 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (15:85) as eluent to obtain the title compound as a colourless liquid (500 mg). Yield: 64%. MS (m/z): 339.18 ([M+H] ⁺ ). Intermediate 111: 4-(hydroxymethyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one [283] To intermediate 110 (480 mg, 1.4 mmol) in methanol (5 ml) and water (5 ml) cooled to 0°C, sodium borohydride (270 mg, 7.1 mmol) was added and stirred at room temperature for 1h. After 1h, the reaction mixture was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (38:62) as eluent to obtain the title compound as an off-white solid (300 mg). Yield: 71%. ¹ H- NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.31 (dd, J 8.0,0.8, 1H), 8.15 (d, J 8.0, 1H), 7.96 (dt, J 7.2,1.2, 1H), 7.88 (dt, J 8.0, 1.2, 1H), 7.30 (dd, J 6.8, 2.0, 2H), 6.89 (dd, J 6.8,2.0, 2H), 5.55 (t, J 5.6, 1H), 5.23 (s, 2H), 4.71 (d, J 5.6, 2H), 3.71 (s, 3H). MS (m/z): 297.44 ([M+H] ⁺ ). Intermediate 112: 4-((3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropox y)methyl)- 2-(4-methoxybenzyl)phthalazin-1(2H)-one [284] To intermediate 111 (280 mg, 0.95 mmol) in acetonitrile (15 ml), intermediate 108 (200 mg, 0.79 mmol) and cesium carbonate (310 mg, 0.95 mmol) were added and heated to 90°C for 24h. After 24h, the reaction mixture was cooled to room temperature, quenched with water (50 ml), extracted with ethyl acetate (3 x 50 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (66:34) as eluent to obtain the title compound as an off-white solid (100 mg). Yield: 23%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.43 (s, 2H), 8.27 (dd, J 8.0,0.8, 1H), 8.06 (d, J 7.6, 1H), 7.94 (dt, J 8.4,1.2, 1H), 7.87 (dt, J 8.0, 1.2, 1H), 7.28 (d, J 8.8, 2H), 6.88 (d, J 8.8, 2H), 5.24 (s, 2H), 4.71 (s, 2H), 3.80 (t, J 6.4, 2H), 3.70 (s, 3H), 3.62-3.59 (m, 4H), 3.50- 3.48 (m, 4H), 2.66 (6, J 6.4, 2H). MS (m/z): 549.47 ([M+H] ⁺ ). Intermediate 113: 1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop- 2-en-1-one [285] To intermediate 11 (2.0 g, 6.6 mmol) in dichloromethane (60 ml) cooled to -40°C, acrylic anhydride (0.91 g, 7.2 mmol and triethylamine (2.20 g, 22 mmol) were added. After 1h, the reaction mixture was quenched with water (400 ml) at -40°C, warmed to room temperature, extracted with dichloromethane (3 x 70 ml). The organic layer was washed with water (100 ml), brine solution (100 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (31:69) as eluent to obtain the title compound as an off-white solid (1.5 g). Yield: 80%. ¹ H- NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.74 (s, 2H), 6.87 (dd, J 16.8,2.4, 1H), 6.17 (dd, J 16.4,2.0, 1H), 5.73 (dd, J 10.4,2.4, 1H), 3.88-3.81 (m, 4H), 3.70-3.61 (m, 4H). Intermediate 114: 2-(4-methoxybenzyl)-4-((3-oxo-3-(4-(5-(trifluoromethyl)pyrim idin-2- yl)piperazin-1-yl)propoxy)methyl)phthalazin-1(2H)-one [286] To intermediate 111 (370 mg, 1.3 mmol) in acetonitrile (20 ml), intermediate 113 (300 mg, 1.0 mmol) and cesium carbonate (410 mg, 1.3 mmol) were added and heated to 90°C for 40h. After 40h, the reaction mixture was cooled to room temperature, quenched with water (50 ml), extracted with ethyl acetate (3 x 50 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (63:37) as eluent to obtain the title compound as an off-white solid (160 mg). Yield: 27%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.71 (s, 2H), 8.28 (dd, J 8.0,0.8, 1H), 8.06 (d, J 8.0, 1H), 7.93 (dt, J 7.2,1.2, 1H), 7.87 (dt, J 8.0, 1.2, 1H), 7.28 (dd, J 8.8,2.0, 2H), 6.88 (dd, J 6.8,2.0, 2H), 5.24 (s, 2H), 4.72 (s, 2H), 3.81 (t, J 6.4, 2H), 3.74-3.72 (m, 4H), 3.70 (s, 3H), 3.54-3.50 (m, 4H), 2.67 (6, J 6.8, 2H). MS (m/z): 583.37 ([M+H] ⁺ ). Intermediate 115: ethyl 2-((3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazin-1- yl)methoxy)acetate [287] To intermediate 111 (400 mg, 1.58 mmol) in DMF (5 ml) cooled to 0°C, sodium hydride (75 mg, 3.16 mmol) was added and stirred for 30 min. Ethyl bromoacetate (396 mg, 2.37 mmol) was added and stirred at room temperature for 2h. After 2h, quenched with water (10 ml), extracted with ethyl acetate (3 x 20 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (30:70) as eluent to obtain the title compound as a colourless liquid (320 mg). Yield: 60%. MS (m/z): 383.23 ([M+H] ⁺ ). Intermediate 116: 2-((3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)met hoxy)acetic acid [288] Following the general procedure 3, the titled compound was synthesized from Intermediate 115 (300 g, 0.78 mmol), THF (1 ml), water (3 ml) and NaOH (0.24 g, 6.0 mmol). Appearance: Off-white solid (240 mg). Yield: 86%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.80 (s, 1H), 8.31-8.27 (m, 2H), 7.98 (dt, J 7.2,0.8, 1H), 7.90 (dt, J 8.4, 1.2, 1H), 7.29 (d, J 8.8, 2H), 6.89 (d, J 8.8, 2H), 5.25 (s, 2H), 4.79 (s, 2H), 4.17 (s, 2H), 3.71 (s,3H). MS (m/z): 355.22 ([M+H] ⁺ ). Intermediate 117: 2-(4-methoxybenzyl)-4-((3-oxo-3-(4-(5-(trifluoromethyl)pyrim idin-2- yl)piperazin-1-yl)propoxy)methyl)phthalazin-1(2H)-one [289] Following the general procedure 6, the titled compound was synthesized from intermediate 116 (200 mg, 0.56 mmol), DMF (4 ml), intermediate 11 (189 mg, 0.62 mmol), DIPEA (365 mg, 2.8 mmol) and HBTU (257 mg, 0.67 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (1:99) as eluent. Appearance: Pale-brown solid. Yield: 220 mg. % Yield: 69. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.73 (s, 2H), 8.43 (d, J 8.0, 1H), 8.31 (d, J 7.2, 1H), 7.97 (t, J 7.21H), 7.90 (t, J 7.6, 1H), 7.30 (d, J 8.8, 2H), 6.88 (dd, J 8.8, 2H), 5.25 (s, 2H), 4.80 (s, 2H), 4.38 (s, 2H), 3.84-3.81 (m, 4H), 3.69 (s, 3H), 3.58-3.52 (m, 2H), 3.46-3.41 (m, 2H). MS (m/z): 569.36 ([M+H] ⁺ ). Intermediate 118: tert-butyl 4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1- carboxylate

[290] Following the general procedure 4, the titled compound was synthesized from 2,3- difluoro-5-(trifluoromethyl)pyridine (0.50 g, 2.7 mmol), tert-butyl piperazine-1-carboxylate (0.51 g, 2.7 mmol), DMSO (3 ml), and DIPEA (0.71, 5.5 mmol). Purification: Not done. Appearance: Off-white solid (800 mg). Yield: 84%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.35 (t, J 0.8, 1H), 7.98 (dd, J 14.0, 2.0, 1H), 3.59-3.57 (m, 4H), 3.46-3.44 (m, 4H), 1.42 (3, 9H). MS (m/z): 250.19 ([M-Boc+H] ⁺ ). Intermediate 119: 1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazine diihydrochloride [291] Following the general procedure 5, the titled compound was synthesized from intermediate 118 (0.80 g, 2.3 mmol) and 2M HCl in dioxan (6.7 ml). Purification: Not done. Appearance: Off-white solid (550 mg). Yield: 75%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.42 (s, 2H), 8.41 (t, J 0.8, 1H), 8.06 (dd, J 13.2,2.0, 1H), 4.59 (s, 2H), 3.83 (t, J 4.8, 4H), 3.23- 3.13 (m, 4H). MS (m/z): 250.16 ([M-2HCl+H] ⁺ ). Intermediate 120: tert-butyl 4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1- carboxylate [292] Following the general procedure 4, the titled compound was synthesized from 2,3- dichloro-5-(trifluoromethyl)pyridine (1.0 g, 4.63 mmol), tert-butyl piperazine-1-carboxylate (0.86 g, 4.63 mmol), N-methylpyrrolidone (8 ml), and K ₂ CO ₃ (1.28, 9.26 mmol). Purification: Not done. Appearance: Off-white solid (1.30 g). Yield: 77%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.57 (dd, J 2.0,1.2, 1H), 8.22 (d, J 2.0, 1H), 3.48-3.41 (m, 8H), 1.42 (3, 9H). MS (m/z): 266.24 ([M-Boc+H] ⁺ ). Intermediate 121: 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine dihydrochloride [293] Following the general procedure 5, the titled compound was synthesized from intermediate 120 (1.30 g, 3.55 mmol) and 2M HCl in dioxan (10.4 ml). Purification: Not done. Appearance: Off-white solid (1.0 g). Yield: 83%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.32 (s, 2H), 8.61 (s, 1H), 8.28 (s, 1H), 4.54 (s, 1H), 3.68 (t, J 4.4, 4H), 3.24 (t, J 4.4, 4H). MS (m/z): 266.22 ([M-2HCl+H] ⁺ ). Intermediate 122: (3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl methanesulfonate [294] To intermediate 111 (1.0 g, 3.37 mmol) in dichloromethane (20 ml), triethylamine (683 mg, 6.75 mmol) was added and cooled to 0°C. Methane sulfonyl chloride (464 mg, 4.04 mmol) was added and stirred at 0°C for 45 min. The reaction mixture was quenched with water (50 ml), extracted with dichloromethane (3 x 30 ml). The organic layer was washed with water (50 ml), brine solution (50 ml) and distilled under reduced pressure using rotavap to obtain a crude. The crude product was stirred with petroleum ether (20 ml) for 30 min. filtered, washed with petroleum ether (20 mL) and dried under vacuum to obtain the title compound as an off-white solid (1.1 g). Yield: 87%. MS (m/z): 375.06 ([M+H] ⁺ ). Intermediate 123: 4-(azidomethyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one [295] To intermediate 122 (1.10 g, 2.94 mmol) in DMF (11 ml), sodium azide (382 mg, 5.88 mmol) was added and heated to 85°C. After 1.5, the reaction mixture cooled to room temperature, quenched with water (110 ml), the solid precipitated was filtered, washed with water (100 ml) and dried under vacuum at 55°C for 30 min. to obtain the title compound as an off-white solid (0.87 g). Yield: 92%. MS (m/z): 322.08 ([M+H] ⁺ ). Intermediate 124: 4-(aminomethyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one [296] To intermediate 123 (0.87 g, 2.7 mmol) in THF (17.4 ml), triphenylphosphine (1.40 g, 5.4 mmol) was added stirred for 75 min. Water (2.4 ml) was added and heated to 85°C. After 16h, the reaction mixture cooled to room temperature, quenched with water (50 ml), extracted with dichloromethane (3 x 50ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (1.1:98.9) as eluent to obtain the title compound as an off-white solid (600 mg). Yield: 75%. ¹ H- NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.30 (dd, J 8.0,1.2, 1H), 8.13 (d, J 7.6, 1H), 7.94 (dt, J 7.2,1.6, 1H), 7.87 (dt, J 8.0, 1.2, 1H), 7.31 (dd, J 6.8,2.0, 2H), 6.88 (dd, J 6.8,2.0, 2H), 5.23 (s, 2H), 4.02 (s, 2H), 3.71 (s, 3H), 1.78 (d, J 8.4, 2H). MS (m/z): 296.06 ([M+H] ⁺ ). Intermediate 125: ethyl 3-(((3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazin-1- yl)methyl)amino)propanoate

[297] To intermediate 124 (100 mg, 0.34 mmol) in acetonitrile (4 ml), ethyl acrylate (30 mg, 0.30 mmol) and DBU (43 mg, 0.28 mmol) were added and heated to 80°C. After 16h, the reaction mixture cooled to room temperature, quenched with water (50 ml), extracted with 10% methanol in dichloromethane (3 x 30ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (1.7:98.3) as eluent to obtain the title compound as a colourless liquid (50 mg). Yield: 40%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.26 (dd, J 8.0,1.2, 1H), 8.14 (d, J 8.0, 1H), 7.92 (dt, J 7.2,1.6, 1H), 7.86 (dt, J 8.0, 1.2, 1H), 7.30 (d, J 8.8, 2H), 6.87 (d, J 8.8, 2H), 5.23 (s, 2H), 4.00 (q, J 7.2, 2H), 3.98 (s, 2H), 3.70 (s, 3H), 2.82 (t, J 6.8, 2H), 2.43 (t, J 6.8, 2H).1.22 (t, J 7.2, 3H). MS (m/z): 396.27 ([M+H] ⁺ ). Intermediate 126: 3-(((3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazin-1- yl)methyl)amino)propanoic acid [298] To intermediate 125 (150 mg, 0.38 mmol) in THF (3 ml) cooled to °C, Lithium hydroxide (48 mg, 1.1 mmol) in water (0.75 ml) was added stirred at room temperature. After 16h, the reaction mixture cooled to °C, the reaction mass pH was adjusted to 5 with 2N HCl, concentrated under reduced pressure and co-distilled with toluene to afford the crude product. The crude product was stirred with 10% methanol in dichloromethane (50 ml) for 30 min and filtered. The filtrate was concentrated to obtain the title compound as an off-white solid (130 mg). Yield: 93%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.55 (s, 1H), 8.32 (dd, J 8.0,1.2, 1H), 8.05 (d, J 7.6, 1H), 8.00 (dt, J 7.2,1.6, 1H), 7.94 (dt, J 8.4, 1.2, 1H), 7.44 (d, J 8.4, 2H), 6.87 (d, J 8.4, 2H), 5.26 (s, 2H), 4.58 (s, 2H), 4.19 (s, 1H), 3.71 (s, 3H), 3.23 (t, J 7.6, 2H), 2.88 (t, J 7.6, 2H). MS (m/z): 368.26 ([M+H] ⁺ ). Intermediate 127: 2-(4-methoxybenzyl)-4-(((3-oxo-3-(4-(5-(trifluoromethyl)pyri midin-2- yl)piperazin-1-yl)propyl)amino)methyl)phthalazin-1(2H)-one [299] Following the general procedure 6, the titled compound was synthesized from intermediate 126 (120 mg, 0.33 mmol), DMF (2.5 ml), intermediate 11 (100 mg, 0.33 mmol), DIPEA (210 mg, 1.6 mmol) and HBTU (150 mg, 0.39 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3.2:96.8) as eluent. Appearance: Pale-yellow solid. Yield: 40 mg. % Yield: 22. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.72 (s, 2H), 8.28 (d, J 7.2, 1H), 8.15 (d, J 8.0, 1H), 7.94 (dt, J 8.0,1.21H), 7.86 (t, J 8.0, 1H), 7.31 (d, J 8.4, 2H), 6.88 (d, J 8.8, 2H), 5.24 (s, 2H), 4.07 (s, 2H), 3.83-3.72 (m, 4H), 3.70 (s, 3H), 3.58-3.49 (m, 4H), 2.87 (t, J 6.8, 2H), 2.58 (t, J 6.4, 2H). MS (m/z): 582.55 ([M+H] ⁺ ). Intermediate 128: 3-Bromo-6-fluoroisobenzofuran-1(3H)-on7-bromofuro[3,4-b]pyri din- 5(7H)-onee [300] 7-bromofuro[3,4-b]pyridin-5(7H)-one (1.0 g, 7.04mmol) was suspended in benzotrifluoride (15 ml) and added N-Bromosuccinimide (1.97 g, 11.10 mmol). Reaction mixture heated to 120°C and azobisisobutyronitrile (AIBN) (20 mg, 0.12 mmol) was added to the reaction mixture. After 5 h, the reaction mixture was cooled to room temperature. Reaction mixture was quenched with water and separated the organic layer. The aqueous layer was extracted with dichloromethane (3 x 50 ml) and the combined organic layers were dried on anhydrous Na ₂ SO ₄ and concentrated under vacuum to obtain the crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (25:75) as eluent to obtain the title compound as a colourless liquid (320 mg). layer evaporated to obtain the titled compound as a pale-brown solid (750 mg). Yield: 49%. ¹ H-NMR (δ ppm, CDCl3, 400 MHz): 9.01 (dd, J 4.8,1.2, 1H), 8.27 (dd, J 7.6,1.2, 1H), 7.60 (dd, J 7.6,0.8, 1H), 7.39 (s, 1H). MS (m/z): 214.11 ([M] ⁺ ). Intermediate 129 (5-oxo-5,7-dihydrofuro[3,4-b]pyridin-7-yl)triphenylphosphoni um bromide [301] To intermediate 128 (750 mg, 3.50 mmol) suspended in acetonitrile (5 ml), triphenylphosphine (919 mg, 3.50 mmol) was added and heated to 90°C. After 3h, the reaction mixture was cooled to 0°C, diethyl ether (20 ml) was added and stirred for 1h. The solid was filtered, washed with diethyl ether (5 ml), dried under vacuum for 1 hr to obtain the titled compound as a pale-brown solid (1.1 g). Yield: 66%. MS (m/z): 396.30 ([M-Br] ⁺ ). Intermediate 130: 4-(5-oxofuro[3,4-b]pyridin-7(5H)-ylidene)butanenitrile [302] Following the general procedure 1, the titled compound was synthesized from intermediate 129 (1.0 g, 2.10 mmol), dichloromethane (20 ml), 4-oxobutanenitrile (174 mg, 2.10 mmol) and triethylamine (425 mg, 4.20 mmol). Purification: Not done. Appearance: Black gummy solid (0.42 g). Yield: 100%. MS (m/z): 201.22 ([M+H] ⁺ ). Intermediate 131: 4-(5-oxo-5,6-dihydropyrido[2,3-d]pyridazin-8-yl)butanenitril e [303] Following the general procedure 2, the titled compound was synthesized from Intermediate 130 (0.40 g, 2.0 mmol), ethanol 8 ml), and hydrazine hydrate (0.20 g, 4.0 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (0.5:99.5) as eluent. Appearance: Off-white solid (300 mg). Yield: 70%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.76 (s, 1H), 9.16 (dd, J 4.8, 2.0, 1H), 8.60 (dd, J 8.0, 1.6, 1H), 7.87 (dd, J 8.0,4.4, 1H), 3.15 (t, 7.2, 2H), 2.63 (t, J 7.2, 2H), 2.08-2.01 (m, 2H). MS (m/z): 215.27 ([M+H] ⁺ ). Intermediate 132: 4-(5-oxo-5,6-dihydropyrido[2,3-d]pyridazin-8-yl)butanoic acid [304] To intermediate 131 (0.28 g, 1.3 mmol), water (4 ml) and NaOH (0.21 g, 5.2 mmol) were added and heated to 100°C. After 2.5 h, the reaction mixture was cooled to room temperature, acidified to pH 2 with con. HCl, the solid precipitated was filtered, washed with water (7 ml) and dried under vacuum. The solid was co-distilled with toluene and dried under vacuum to obtain the title compound as an off-white solid (120 mg). Yield: 39%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.72 (s, 1H), 12.02 (s, 1H), 9.15 (dd, J 4.8,2.0, 1H), 8.60 (dd, J 8.0, 1.6, 1H), 7.86 (dd, J 8.0,4.4, 1H), 3.06 (t, 7.2, 2H), 2.34 (t, J 7.2, 2H),1.98-1.91(m, 2H). MS (m/z): 234.16 ([M+H] ⁺ ). Intermediate 133: ethyl 5-(5-oxofuro[3,4-b]pyridin-7(5H)-ylidene)pentanoate [305] Following the general procedure 1, the titled compound was synthesized from intermediate 129 (4.36 g, 9.16 mmol), Dichloromethane (15 ml), intermediate 42 (1.20 g, 8.32 mmol) and triethylamine (1.68 g, 16.6 mmol). Purification: Combi-Flash. Eluent: Ethyl acetate and petroleum ether (20:80) as eluent. Appearance: Pale yellow liquid (1.05 g). Yield: 48%. MS (m/z): 262.10([M+H] ⁺ ). Intermediate 134: ethyl 5-(5-oxo-5,6-dihydropyrido[2,3-d]pyridazin-8-yl)pentanoate [306] Following the general procedure 2, the titled compound was synthesized from intermediate 133 (1.00 g,3.83 mmol), ethanol (15 ml), and hydrazine hydrate (0.29 g, 5.74 mmol). Purification: Combi-Flash. Eluent: ethyl acetate and petroleum ether (40:60) as eluent. Appearance: Off-white solid (0.52 g). Yield: 52%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.71 (s, 1H), 9.16 (dd, J 4.8, 2.0, 1H), 8.60 (dd, J 8.0,1.6, 1H), 7.86 (dt, J 8.0,4.4, 1H), 4.05 (q, J 7.6, 2H), 3.03 (t, J 7.2, 2H), 2.35 (t, J 7.2, 2H), 1.75-1.69 (m, 2H), 1.65-1.60 (m, 2H), 1.16 (t, J 7.2, 3H). MS (m/z): 276.21 ([M+H] ⁺ ). Intermediate 135: 5-(5-oxo-5,6-dihydropyrido[2,3-d]pyridazin-8-yl)pentanoic acid [307] Following the general procedure 3, the titled compound was synthesized from intermediate 134 (0.240 g, 0.87 mmol), THF (4.4 ml), water (2.2 ml) and NaOH (0.192 g, 4.79 mmol). Appearance: Off-white solid (0.17 g). Yield: 78%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.71 (s, 1H), 11.98 (s, 1H), 9.16 (dd, J 4.8,2.0, 1H), 8.60 (dd, J 8.0,1.6, 1H), 7.86 (dd, J 8.0,4.4, 1H), 3.03 (t, J 7.6, 2H), 2.27 (t, J 7.2, 2H), 1.77-1.69 (m, 2H), 1.63-1.56 (m, 2H). MS (m/z): 248.16 ([M+H] ⁺ ). Intermediate 136: 2-(4-methoxybenzyl)-4-((methylamino)methyl)phthalazin-1(2H)- one [308] To intermediate 122 (1.00 g, 2.67 mmol), methylamine in THF (13.4 ml, 2M in THF, 26.8 mmol) was added and stirred at room temperature. After 3h, the reaction mixture was quenched with water (100 ml), extracted with dichloromethane (3 x 100 ml). The organic layer was washed with water (100 ml), brine solution (100 ml), dried with anhydrous sodium sulphate and concentrated under reduced pressure to obtain the crude. Crude product was purified by combi-flash using methanol and dichloromethane (2.8:97.2) as eluent to obtain the title compound as an off-white solid (480 mg). Yield: 58%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.29 (dd, J 8.0,1.2, 1H), 8.16 (d, J 8.0, 1H), 7.93 (dt, J 7.2,1.6, 1H), 7.86 (dt, J 8.0,1.2, 1H), 7.30 (dd, J 6.8,2.0, 2H), 6.88 (dd, J 6.6,2.0, 2H), 5.23 (s, 2H), 3.93 (s, 2H), 3.70 (s, 3H), 2.30 (s, 3H), 2.21 (s, 1H). MS (m/z): 310.17 ([M+H] ⁺ ). Intermediate 137: ethyl 3-(((3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazin-1- yl)methyl)(methyl)amino)propanoate [309] To intermediate 136 (480 mg, 1.63 mmol) in acetonitrile (15 ml), ethyl acrylate (163 mg 163 mmol) and DBU (247 mg 1.63 mmol) were added and heated to 80°C. After 16h, the reaction mixture cooled to room temperature, quenched with water (50 ml), extracted with 10% methanol in dichloromethane (3 x 30ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (1.4:98.6) as eluent to obtain the title compound as a colourless liquid (480 mg). Yield: 45%. MS (m/z): 410.31 ([M+H] ⁺ ). Intermediate 138: 3-(((3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazin-1- yl)methyl)(methyl)amino)propanoic acid [310] To intermediate 137 (480 mg, 1.17 mmol) in THF (8 ml) cooled to °C, Lithium hydroxide (148 mg, 3.52 mmol) in water (2.5 ml) was added stirred at room temperature. After 16h, the reaction mixture cooled to °C, the reaction mass pH was adjusted to 5 with 2N HCl, concentrated under reduced pressure and co-distilled with toluene to afford the crude product. The crude product was stirred with 10% methanol in dichloromethane (50 ml) for 30 min and filtered. The filtrate was concentrated to obtain the title compound as an off-white solid (380 mg). Yield: 85%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.66 (s, 1H), 8.34 (dd, J 8.0,1.2, 1H), 8.10 (d, J 8.0, 1H), 8.01 (dt, J 8.0,1.2, 1H), 7.97 (dt, J 7.6, 1.2, 1H), 7.37 (d, J 8.4, 2H), 6.89 (d, J 9.2, 2H), 5.28 (s, 2H), 4.67 (s, 2H), 3.71 (s, 3H), 3.33 (s, 3H), 2.85-2.72 (m, 4H). MS (m/z): 382.36 ([M+H] ⁺ ). Intermediate 139: 2-(4-methoxybenzyl)-4-((methyl(3-oxo-3-(4-(5-(trifluoromethy l)pyrimidin- 2-yl)piperazin-1-yl)propyl)amino)methyl)phthalazin-1(2H)-one

[311] Following the general procedure 6, the titled compound was synthesized from intermediate 138 (200 mg, 0.52 mmol), DMF (4 ml), intermediate 11 (176 mg, 0.57 mmol), DIPEA (339 mg, 2.62 mmol) and HBTU (239 mg, 0.63 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.6:97.4) as eluent. Appearance: Pale-yellow solid. Yield: 200 mg. % Yield: 64. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.72 (s, 2H), 8.24 (dd, J 8.0,1.2, 1H), 8.19 (d, J 8.0, 1H), 7.89 (dt, J 7.6,1.6, 1H), 7.81 (dt, J 8.0,1.2, 1H), 7.28 (d, J 8.8, 2H), 6.87 (dd, J 6.8,2.0, 2H), 5.23 (s, 2H), 3.73-3.71 (m, 6H), 3.69 (s, 3H), 3.49-3.41 (m, 4H), 2.74 (t, J 7.2, 2H), 2.57 (t, J 7.6, 2H), 2.20 (s, 3H). MS (m/z): 596.52 ([M+H] ⁺ ). Intermediate 140: tert-butyl 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [312] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(trifluoromethyl) pyrimidine (215 mg, 1.18 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (250 mg, 1.18 mmol), N-Methylpyrrolidone (5 ml) and DIPEA (458 mg, 3.54 mmol). Purification: Not done Appearance: Off-white (400 mg). Yield: 94%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.48 (s, 2H), 4.51 (t, J 2.0, 1H), 4.47 (t, J 2.0, 1H), 4.34 (br s, 2H), 3.20 (d, J 10.4, 2H), 1.95 (m, 2H), 1.68 (m, 2H), 1.49 (s, 9H). MS (m/z): 259.33 ([M-Boc+H] ⁺ ). Intermediate 141: 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1 ]octane dihydrochloride [313] Following the general procedure 5, the titled compound was synthesized from intermediate 140 (375 mg, 1.05 mmol) and 2M HCl in dioxan (15 ml). Purification: Not done. Appearance: Off-white solid (257 mg). Yield: 74%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.65 (s, 1H), 9.44 (s, 1H), 8.78 (s, 2H), 4.52 (d, J 12.6, 2H), 4.15 (s, 2H), 3.47 (d, J 13.6, 2H), 3.40 (s, 1H), 1.98 (m, 2H), 1.73 (m, 2H). MS (m/z): 259.20 ([M-2HCl+H] ⁺ ). Intermediate 142: tert-butyl 6-(5-(trifluoromethyl)pyrimidin-2-yl)-2,6-diazaspiro[3.3]hep tane- 2-carboxylate [314] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(trifluoromethyl) pyrimidine (500 mg, 2.70 mmol), 2,6-Diazaspiro[3.3]heptane-2-carboxylic acid, 1,1-dimethylethyl ester, ethanedioate (2:1) (1.0 g, 2.1 mmol), N-Methylpyrrolidone (10ml) and potassium carbonate (1.10 g, 8.2 mmol). Purification: Not done Appearance: Off- white (350 mg). Yield: 37%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.47 (s, 2H), 4.25 (s, 4H), 4.04 (s, 4H), 1.37 (s, 9H). MS (m/z): 245.31([M-Boc+H] ⁺ ). Intermediate 143: 2-(5-(trifluoromethyl)pyrimidin-2-yl)-2,6-diazaspiro[3.3]hep tane dihydrochloride [315] Following the general procedure 5, the titled compound was synthesized from intermediate 142 (300 mg, 0.87 mmol) and 2M HCl in dioxan (7.5 ml). Purification: Not done. Appearance: Off-white solid (280 mg). Yield: 100%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.72 (s, 2H), 8.44 (s, 3H), 4.16 (d, J 9.6, 2H), 4.11 (s, 2H), 3.96 (d, J 9.6, 2H), 3.25 (q, J 5.6, 2H). MS (m/z): 245.25 ([M-2HCl+H] ⁺ ). Intermediate 144: tert-butyl 8-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate [316] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(trifluoromethyl) pyrimidine (215 mg, 1.18 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane- 3-carboxylate (250 mg, 1.18 mmol), N-Methylpyrrolidone (5 ml) and DIPEA (457 mg, 3.53 mmol). Purification: Not done Appearance: Off-white (396 mg). Yield: 94%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.48 (s, 2H), 4.84 (t, J 16.4, 2H), 3.96 (d, J 12.4, 1H), 3.80 (d, J 12.4, 1H), 3.15 (d, J 12.4, 1H), 3.05 (d, J 12.4, 1H), 2.02-1.84 (m, 4H), 1.46 (s, 9H). MS (m/z): 259.37 ([M-Boc+H] ⁺ ). Intermediate 145: 8-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1 ]octane dihydrochloride [317] Following the general procedure 5, the titled compound was synthesized from intermediate 144 (366 mg, 1.02 mmol) and 2M HCl in dioxan (15.3 ml). Purification: Not done. Appearance: Off-white solid (309 mg). Yield: 91%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.78 (s, 1H), 9.48 (s, 1H), 8.79 (s, 2H), 7.89 (s, 1H), 4.84 (d, J 2.0, 2H), 3.19-3.06 (m, 4H), 2.21-2.03 (m, 4H).MS (m/z): 259.25 ([M-2HCl+H] ⁺ ). Intermediate 146: tert-butyl (±)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate [318] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(trifluoromethyl) pyrimidine (215 mg, 1.18 mmol), tert-butyl (±)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (250 mg, 1.18 mmol), N-Methylpyrrolidone (5 ml) and DIPEA (457 mg, 3.53 mmol). Purification: Not done Appearance: Off-white solid (293 mg). Yield: 69%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.52 (s, 1H), 8.45 (s, 1H), 5.07 (d, J 18.4, 1H), 4.46 and 4.30 (s, 1H), 3.84 (m, 1H), 3.65 (m, 2H), 3.53 (dt, J 11.2,2.0, 1H), 2.12 (m, 2H), 1.92 (m, 2H), 1.47 (s, 9H). MS (m/z): 259.35 ([M-Boc+H] ⁺ ). Intermediate 147: (±)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-2,5-diazabicyclo[ 2.2.2]octane dihydrochloride [319] Following the general procedure 5, the titled compound was synthesized from intermediate 146 (250 mg, 0.69 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done. Appearance: Pale-yellow gel (170 mg). Yield: 74%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.37 (s, 2H), 8.80 (d, J 2.8, 1H), 8.74 (d, J 2.8, 1H), 4.93 (d, J 2.0, 1H), 3.89 (d, J 2.4, 2H), 3.71 (m, 2H), 3.37 (m, 2H), 2.17 (m, 1H), 1.99 (m, 3H). MS (m/z): 259.25 ([M-2HCl+H] ⁺ ). Intermediate 148: tert-butyl (±)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate [320] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(trifluoromethyl) pyrimidine (230 mg, 1.26 mmol), tert-butyl (±)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (250 mg, 1.26 mmol), N-Methylpyrrolidone (5 ml) and DIPEA (489 mg, 3.78 mmol). Purification: Not done Appearance: Off-white solid (410 mg). Yield: 94%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.47 (s, 2H), 5.04 (s, 1H), 4.70 (d, 21.6, 1H), 3.67-3.33 (m, 4H), 2.02 (m, 2H), 1.47 (s, 9H). MS (m/z): 245.32 ([M-Boc+H] ⁺ ). Intermediate 149: (±)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-2,5-diazabicyclo[ 2.2.1]heptane dihydrochloride [321] Following the general procedure 5, the titled compound was synthesized from intermediate 148 (360 mg, 1.05 mmol) and 2M HCl in dioxan (16 ml). Purification: Not done. Appearance: Off-white solid (300 mg). Yield: 90%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 10.05 (s, 1H), 9.40 (s, 1H), 8.77 (d, J 7.6, 1H), 8.68 (d, J 5.2, 1H), 8.62 (s, 1H), 5.01 (s, 1H), 4.49 (s, 1H), 3.88 (d, J 11.6, 1H), 3.63 (d, J 12.0, 1H), 3.30-3.17 (m, 2H), 2.16 (d, J 10.8, 1H), 1.99 (d J 10.8, 1H). MS (m/z): 245.18 ([M-2HCl+H] ⁺ ). Intermediate 150: tert-butyl 3-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [322] Following the general procedure 4, the titled compound was synthesized from 2,5- dichloro pyrimidine (175 mg, 1.18 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (250 mg, 1.18 mmol), N-Methylpyrrolidone (5 ml) and potassium carbonate (325 mg, 2.36 mmol). Purification: Not done Appearance: Off-white solid (300 mg). Yield: 78%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.49 (s, 2H), 4.24 (m, 4H), 3.03 (dd, J 12.8,1.6, 2H), 1.82 (t, J 4.0, 2H), 1.57 (m, 2H), 1.42 (s, 9H). Intermediate 151: 3-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane dihydrochloride [323] Following the general procedure 5, the titled compound was synthesized from intermediate 150 (300 mg, 0.92 mmol) and 2M HCl in dioxan (5 ml). Purification: Not done. Appearance: Off-white solid (270 mg). Yield: 98%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.68 (s, 1H), 9.51 (s, 1H), 8.50 (t, J 5.6, 2H), 6.16 (s, 1H), 4.37 (d, J 13.6, 2H), 4.12 (s, 2H), 3.04 (d, J 13.2, 2H), 1.97 (m, 2H), 1.73 (m, 2H). MS (m/z): 225.24 ([M-2HCl+H] ⁺ ). Intermediate 152: tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]o ctane- 8-carboxylate [324] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(trifluoromethyl)pyridine (214 mg, 1.18 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (250 mg, 1.18 mmol), N-Methylpyrrolidone (5 ml) and potassium carbonate (325 mg, 2.36 mmol). Purification: Not done Appearance: Off-white solid (250 mg). Yield: 59%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.41 (dd, J 1.6,0.8, 1H), 7.82 (dd, J 9.2,2.4, 1H), 6.89 (d, J 8.8, 1H), 4.24 (s, 2H), 4.10 (d, J 12.4, 2H), 3.01 (d, J 11.2, 2H), 1.85 (t, J 4.0, 2H), 1.62 (t, J 7.6, 2H), 1.42 (s, 9H). Intermediate 153: 3-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]o ctane dihydrochloride [325] Following the general procedure 5, the titled compound was synthesized from intermediate 152 (250 mg, 0.70 mmol) and 2M HCl in dioxan (4 ml). Purification: Not done. Appearance: Off-white solid (230 mg). Yield: 99%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.74 (s, 1H), 9.59 (s, 1H), 8.45 (t, J 0.8, 1H), 8.20 (s, 1H), 7.90 (dd, J 9.2,2.4, 1H), 6.98 (d, J 9.2, 1H), 4.23 (d, J 13.6, 2H), 4.14 (s, 2H), 3.38 (d, J 12.8, 2H), 1.99 (m, 2H), 1.80 (m, 2H). MS (m/z): 258.25 ([M-2HCl+H] ⁺ ). Intermediate 154: tert-butyl 3-(5-cyanopyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [326] Following the general procedure 4, the titled compound was synthesized from 2- chloropyrimidine-5-carbonitrile (164 mg, 1.18 mmol), tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 1.18 mmol), N-Methylpyrrolidone (5 ml) and potassium carbonate (325 mg, 2.36 mmol). Purification: Not done Appearance: Off-white solid (300 mg). Yield: 80%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.77 (s, 2H), 4.46 (d, J 12.8, 2H), 4.24 (s, 2H), 3.12 (d, J 12.8, 2H), 1.83 (t, J 4.0, 2H), 1.52 (m, 2H), 1.42 (s, 9H). 216.24 ([M-Boc+H] ⁺ ). Intermediate 155: 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidine-5-carbonitri le dihydrochloride [327] Following the general procedure 5, the titled compound was synthesized from intermediate 154 (300 mg, 1.34 mmol) and 2M HCl in dioxan (5 ml). Purification: Not done. Appearance: Off-white solid (270 mg). Yield: 98%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.80 (s, 1H), 9.56 (s, 1H), 8.83 (s, 2H), 4.54 (d, J 13.6, 2H), 4.19 (s, 1H), 4.15 (d, J 18.4, 2H), 3.51 (d, J 12.8, 2H), 1.97 (m, 2H), 1.71 (m, 2H). MS (m/z): 216.19 ([M-2HCl+H] ⁺ ). Intermediate 156: tert-butyl 3-(5-cyanopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [328] Following the general procedure 4, the titled compound was synthesized from 6- chloronicotinonitrile (163 mg, 1.18 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (250 mg, 1.18 mmol), N-Methylpyrrolidone (5 ml) and potassium carbonate (325 mg, 2.36 mmol). Purification: Not done Appearance: Off-white solid (250 mg). Yield: 67%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.49 (d, J 2.0, 1H), 7.88 (dd, J 9.2,2.4, 1H), 6.87 (d, J 9.2, 1H), 4.24 (s, 2H), 4.13 (d, J 12.4, 2H), 3.03 (d, J 11.2, 2H), 1.84 (m, 2H), 1.59 (m, 2H), 1.42 (s, 9H).215.24 ([M-Boc+H] ⁺ ). Intermediate 157: 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile dihydrochloride [329] Following the general procedure 5, the titled compound was synthesized from intermediate 156 (250 mg, 1.10 mmol) and 2M HCl in dioxan (5 ml). Purification: Not done. Appearance: Off-white solid (200 mg). Yield: 87%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.68 (s, 1H), 9.50 (s, 1H), 8.54 (d, J 2.0, 1H), 7.96 (dd, J 8.8,2.4, 1H), 6.96 (d, J 9.2, 1H), 4.63 (s, 1H), 4.26 (d, J 13.6, 2H), 4.14 (s, 2H), 3.38 (d, J 12.0, 2H), 1.98 (m, 2H), 1.77 (m, 2H). MS (m/z): 215.20 ([M-2HCl+H] ⁺ ). Intermediate 158: tert-butyl 3-(5-chloropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [330] To 2-bromo-5-chloropyridine (227 mg, 1.18 mmol) in toluene (5 ml), 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 1.18 mmol), potassium tert-butoxide (136 mg, 1.31 mmol) were added at room temperature. BINAP (36.7 mg, 0.06 mmol) and Pd2(dba)3 53.9 mg, 0.06 mmol) were added and purged under nitrogen for10 min. The reaction mixture was heated to 80°C and stirred for 2h. After 2h the reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (10:90) as eluent to obtain the title compound as a yellow solid (150 mg). Yield: 39%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.10 (d, J 2.4, 1H), 7.61 (dd, J 9.2,2.4, 1H), 6.79 (d, J 9.2, 1H), 4.22 (s, 2H), 3.92 (d, J 10.8, 2H), 2.91 (dd, J 12.4,1.6, 2H), 1.84 (m, 2H), 1.64 (m, 2H), 1.41 (s, 9H).324.02 ([M+H] ⁺ ). Intermediate 159: 3-(5-chloropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane dihydrochloride [331] Following the general procedure 5, the titled compound was synthesized from intermediate 158 (150 mg, 0.46 mmol) and 2M HCl in dioxan (5 ml). Purification: Not done. Appearance: Off-white solid (120 mg). Yield: 87%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.66 (s, 1H), 9.56 (s, 1H), 8.15 (d, J 2.4, 1H), 7.69 (dd, J 9.2,2.8, 1H), 6.93 (s, 1H), 6.88 (d, J 9.2, 1H), 4.12 (s, 2H), 4.05 (d, J 13.2, 2H), 3.28 (d, J 12.4, 2H), 1.99 (m, 2H), 1.81 (m, 2H). MS (m/z): 224.22 ([M-2HCl+H] ⁺ ). Intermediate 160: tert-butyl 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate [332] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(trifluoromethyl)pyrimidine (230 mg, 1.26 mmol), tert-butyl 3,6-diazabicyclo[3.1.1]heptane- 6-carboxylate (250 mg, 1.26 mmol) N-Methylpyrrolidone (5 ml), and DIPEA (489 mg, 3.78 mmol). Purification: Not done Appearance: Off-white solid (370 mg). Yield: 85%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.78 (s, 2H), 4.21 (d, J 6.4, 2H), 4.14 (s, 2H), 3.59 (d, J 12.8, 2H), 2.56 (m, 1H), 1.51 (d, J 8.8, 1H), 1.26 (s, 9H).245.20 ([M-Boc+H] ⁺ ). Intermediate 161: 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-diazabicyclo[3.1.1 ]heptane dihydrochloride [333] Following the general procedure 5, the titled compound was synthesized from intermediate 160 (370 mg, 1.07 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done. Appearance: Off-white solid (273 mg). Yield: 80%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.93 (s, 1H), 8.86 (s, 2H), 8.48 (s, 1H), 4.52 (s, 1H), 4.48 (d, J 4.8, 2H), 4.10 (d, J 13.6, 2H), 4.03 (d, JJ 13.6, 2H), 2.93 (m, 1H), 1.88 (dd, J 12.0,6.0, 1H). MS (m/z): 245.15 ([M- 2HCl+H] ⁺ ). Intermediate 162: tert-butyl 6-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6- diazabicyclo[3.1.1]heptane-3-carboxylate [334] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(trifluoromethyl)pyrimidine (230 mg, 1.26 mmol), tert-butyl 3,6-diazabicyclo[3.1.1]heptane- 3-carboxylate (250 mg, 1.26 mmol) N-Methylpyrrolidone (5 ml), and DIPEA (489 mg, 3.78 mmol). Purification: Not done Appearance: Off-white solid (300 mg). Yield: 73%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.78 (s, 2H), 4.51(m, 2H), 3.89 (m, 2H), 3.42-3.33 (m, 2H), 2.74 (m, 1H), 1.60 (d, J 8.8, 1H), 1.30 (s, 9H).245.23 ([M-Boc+H] ⁺ ). Intermediate 163: 6-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-diazabicyclo[3.1.1 ]heptane dihydrochloride [335] Following the general procedure 5, the titled compound was synthesized from intermediate 162 (300 mg, 0.87 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done. Appearance: Off-white solid (250 mg). Yield: 90%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.39 (s, 1H), 9.58 (s, 1H), 9.18 (s, 1H), 8.85 (s, 2H), 4.54 (d, J 6.4, 2H), 3.60 (m, 2H), 3.40 (m, 2H), 2.86 (m, 1H), 2.17 (dd, J 9.6, 1H). MS (m/z): 245.14 ([M-2HCl+H] ⁺ ). Intermediate 164: tert-butyl 3-(5-(difluoromethyl)pyrimidin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [336] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-(difluoromethyl)pyrimidine (194 mg, 1.18 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (250 mg, 1.26 mmol), N-Methylpyrrolidone (5 ml) and K2CO3 (325 mg, 2.36 mmol). Purification: Not done Appearance: Off-white solid (320 mg). Yield: 79%. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.56 t, J 1.2, 2H), 7.11 (t, J 15.6, 1H), 4.43 (dd, J 12.8,1.6, 2H), 4.23 (s, 2H), 3.07 (d, J 12.4, 2H), 1.83 (m, 2H), 1.54 (m, 2H), 1.43 (s, 9H). Intermediate 165: 3-(5-(difluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1] octane dihydrochloride [337] Following the general procedure 5, the titled compound was synthesized from intermediate 164 (320 mg, 1.33 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done. Appearance: Off-white solid (280 mg). Yield: 67%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.70 (s, 1H), 9.51 (s, 1H), 8.63 (t, J 1.2, 2H), 7.15 (t, J 15.2, 1H), 5.97 (s, 1H), 4.51 (d, J 13.6, 2H), 4.13 (s, 2H), 3.45 (d, J 13.6, 2H), 1.98 (m, 2H), 1.74 (m, 2H). MS (m/z): 241.21 ([M- 2HCl+H] ⁺ ). Intermediate 166: 2-chloro-5-(difluoromethyl)pyridine [338] To a solution of 2-chloropyridine-5-carbaldehyde (1.0 g, 7.06 mmol) in chloroform (20 mL), (diethylamino)sulfur trifluoride (1.13 g, 7.06 mmol) was added and heated to reflux. After 2h cooled to room temperature, quenched with water (30 ml) and the aqueous layer was extracted with dichloromethane (3 x 50 ml). The organic layer was distilled under vacuum to afford the crude. The crude product was purified by combi-flash using a mixture of ethyl acetate and petroleum ether (8:92) as eluent to obtain the title compound as a brown liquid (0.50 g). Yield: 43%. ¹ H-NMR (δ ppm, CDCl3, 400 MHz): 8.54 (d, J 1.2, 1H), 7.83-7.80 (m, 1H), 7.46 (dd, J 8.4,0.4, 1H), 6.85 (t, J 55.6, 1H). MS (m/z): 164.04 ([M+H] ⁺ ). Intermediate 167: tert-butyl 3-(5-(difluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]oc tane- 8-carboxylate [339] To intermediate 166 (270 mg, 1.65 mmol) in toluene (10 ml), 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 1.65 mmol), sodium tert-butoxide (190 mg, 1.98 mmol) were added at room temperature. BINAP (51.3 mg, 0.08 mmol) and Pd ₂ (dba) ₃ (75.5 mg, 0.08 mmol) were added and purged under nitrogen for10 min. The reaction mixture was heated to 80°C and stirred for 2h. After 2h the reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (7:93) as eluent to obtain the title compound as a pale-yellow solid (150 mg). Yield: 27%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.26 (d, J 2.0, 1H), 7.70 (dd, J 8.8,2.4, 1H), 7.01(t, J 56.0, 1H), 6.85 (d, J 9.2, 1H), 4.23 (s, 2H), 4.05 (d, J 11.6, 2H), 2.96 (d, J 11.6, 2H), 1.84-1.82 (m, 2H), 1.64-1.59 (m, 2H), 1.42 (s, 9H). MS (m/z): 340.08 ([M+H] ⁺ ). Intermediate 168: 3-(5-(difluoromethyl)pyrimid-2-yl)-3,8-diazabicyclo[3.2.1]oc tane dihydrochloride [340] Following the general procedure 5, the titled compound was synthesized from intermediate 167 (240 mg, 0.70 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done. Appearance: Pale-brown solid (200 mg). Yield: 90%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.63 (s, 1H), 9.52 (s, 1H), 8.31 (d, J 1.6, 1H), 7.80 (d, J 8.8, 1H), 7.11 (t, J 55.6, 1H), 6.97 (d, J 9.2, 1H), 6.09 (s, 1H), 4.20-4.12 (m, 4H), 3.34 (d, J 12.8, 2H), 1.98-1.96 (m, 2H), 1.82-1.78 (m, 2H). Intermediate 169: tert-butyl 3-(5-(methoxycarbonyl)pyrimidin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [341] Following the general procedure 4, the titled compound was synthesized from methyl 2-chloropyrimidine-5-carboxylate (406 mg, 2.36 mmol), tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.36 mmol), N-Methylpyrrolidone (10 ml) and DIPEA (913 mg, 7.07 mmol). Purification: Not done Appearance: Off-white solid (700 mg). Yield: 85%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.79 (s, 2H), 4.50 (dd, J 12.8,1.6, 2H), 4.24 (s, 2H), 3.80 (s, 3H), 3.11 (dd, J 13.2,1.6, 2H), 1.83-1.81 (m, 2H), 1.54-1.50 (m, 2H), 1.41 (s, 9H). MS (m/z): 249.31 ([M-Boc+H] ⁺ ). Intermediate 170: tert-butyl tert-butyl 3-(5-(methylcarbamoyl)pyrimidin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [342] To a sealed tube intermediate 169 (500 mg, 1.44 mmol) and 25% methylamine in methanol 15 ml) were added and heated to 60°C for 12h. After 12h, cooled to room temperature, concentrated under reduced pressure. The residue was stirred with diethyl ether (10 ml), filtered and dried under vacuum to obtain the title compound as an off-white solid (450 mg). Yield: 90%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.74 (s, 2H), 8.31 (q, J 4.4, 1H), 4.45 (d, J 12.8, 2H), 4.23 (s, 2H), 3.07 (d, J 12.0, 2H), 2.76 (d, J 4.8, 3H), 1.82-1.80 (m, 2H), 1.58-1.49 (m, 2H), 1.43 (s, 9H). MS (m/z): 370.12 ([M-Boc+Na] ⁺ ). Intermediate 171: 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-methylpyrimidine-5-c arboxamide dihydrochloride [343] Following the general procedure 5, the titled compound was synthesized from intermediate 170 (400 mg, 1.15 mmol) and 2M HCl in dioxan (10 ml). Purification: Not done. Appearance: Off-white solid (350 mg). Yield: 94%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.71 (s, 1H), 9.54 (s, 1H), 8.21 (s, 2H), 8.48 (q, J 4.4, 1H), 8.63 (t, J 1.2, 2H), 6.14 (s, 1H), 4.53 (d, J 13.6, 2H), 4.13 (s, 2H), 3.48 (d, J 12.8, 2H), 2.76 (d, J 4.4, 3H), 1.97-1.94 (m, 2H), 1.72- 1.67 (m, 2H). MS (m/z): 248.20 ([M-2HCl+H] ⁺ ). Intermediate 172: 2-chloro-5-(methylsulfinyl)pyrimidine [344] To a solution of 2-chloro-5-(methylthio)pyrimidine (500 mg, 3.11 mmol) in dichloromethane (20 ml) cooled to -20°C, m-chloroperbezoic acid (806 mg, 4.67) was added and stirred for 1h. After 1h, the reaction mixture was quenched with saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (2 x 30 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (80:20) as eluent to obtain the title compound as an off-white solid (350 mg). Yield: 63%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.03 (s, 2H), 2.97 (s, 3H). MS (m/z): 177.07 ([M +H] ⁺ ). Intermediate 173: 2-chloro-5-(methylsulfinyl)pyrimidine [345] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (782 mg, 3.06 mmol), DMF (10 ml), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3- carboxylate (650 mg, 3.06 mmol), DIPEA (1.98 g, 15.3 mmol) and HBTU (1.51 g, 3.98 mmol). Purification: Not done. Appearance: Pale-yellow liquid (1.25 g). Yield: 95%. MS (m/z): 427.22 ([M+H] ⁺ ). Intermediate 174: 4-(4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4-oxobutyl)phthalaz in-1(2H)-one [346] Following the general procedure 5, the titled compound was synthesized from intermediate 173 (2.1 g, 4.9 mmol) and 2M HCl in dioxan (25 ml). The reaction mixture was concentrated, adjusted the pH to 10 with saturated sodium bicarbonate solution and extracted with 5% methanol in dichloromethane (6 x 100 ml). The organic layer was dried with anhydrous sodium sulphate and concentrated under reduced pressure to obtain the title compound as a Pale-green solid (705 mg). Yield: 36%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.27 (dd, J 7.6,0.8, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt, J 7.2,1.2, 1H), 7.86 (dt, J 8.0,0.8, 1H), 4.37 (d, J 6.8, 1H), 4.11 (d, J 4.4, 1H), 2.96 (t, J, 7.6, 2H), 2.75-2.57 (m, 5H), 2.49-2.37 (m, 2H), 1.96-1.86 (m, 2H), 1.84-1.68 (m, 4H). MS (m/z): 327.26 ([M+H] ⁺ ). Intermediate 175: 2-chloro-5-(methylsulfonyl)pyrimidine [347] To a solution of 2-chloro-5-(methylthio)pyrimidine (500 mg, 3.11 mmol) in dichloromethane (20 ml) cooled to -20°C, m-chloroperbezoic acid (1.61 g, 9.31) was added and stirred for 1h. After 1h, the reaction mixture was quenched with saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (2 x 30 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (32:68) as eluent to obtain the title compound as a pale-brown solid (450 mg). Yield: 75%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.24 (s, 2H), 3.42 (s, 3H). Intermediate 176: 4-(4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4-oxobutyl)phthalaz in-1(2H)-one hydrochloride [348] Following the general procedure 5, the titled compound was synthesized from intermediate 173 (1.1 g, 2.6 mmol) and 2M HCl in dioxan (13 ml). Purification: Not done. Appearance: Pale-green solid (500 mg). Yield: 53%.MS (m/z): 327.44 ([M-HCl+H] ⁺ ). Intermediate 177: tert-butyl 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate [349] To 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg, 3.26 mmol) in THF (10 ml), triethylamine (494 mg, 4.88 mmol) and DMAP (39.8 mg, 0.326 mmol) were added at room temperature followed by Boc-anhydride (853 mg, 3.91 mmol). After 2h, the reaction mixture was quenched with water (10 ml), extracted with ethyl acetate (3 x 30 ml), washed with sodium bicarbonate solution (3 x 30 ml), water (3 x 30 ml). The organic layer was dried with anhydrous sodium sulphate and concentrated under reduced pressure to obtain the title compound as a Pale-brown solid (700 mg). Yield: 84%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.03 (s, 1H), 7.86 (d, J 4.0, 1H), 6.85 (d, J 4.4, 1H), 1.62 (s, 9H). MS (m/z): 154.01 ([M-Boc+H] ⁺ ). Intermediate 178: methyl 2-(bromomethyl)-6-fluorobenzoate [350] To methyl 2-fluoro-6-methylbenzoate (5 g, 29.73 mmol) Carbon tetrachloride (100 ml), N-Bromosuccinimide (5.29 g, 29.73 mol) was added and heated to 90°C. Azobisisobutyronitrile (AIBN) (4.88 g, 29.73 mmol) was added to the reaction mixture in lots. After 6 h, reaction mixture was cooled to room temperature, filtered and evaporated on rotavapor to obtain crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (1:99) as eluent to obtain the title compound as a colourless liquid (5.3 g). Yield: 72%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 7.59-7.54 (m, 1H), 7.42 (dd, J 7.6,0.8, 1H), 7.36-7.31 (m, 1H), 4.77 (s, 2H), 3.90 (s, 3H). Intermediate 179: 7-fluoroisobenzofuran-1(3H)-one [351] To intermediate 178 (5.3 g, 21 mmol) in 1,4-dioxane (100 ml) and water (100 ml), calcium carbonate (13 g, 130 mmol) was added and heated to 100°C. After 5h, the reaction mixture was cooled to room temperature. Filtered the solid and washed with dichloromethane (50 ml). The aqueous layer was extracted with dichloromethane (3 x 30 ml). The combined organic layers were concentrated under reduced pressure to obtain the title compound as an off- white solid (2.25 g). Yield: 69%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.84-7.79 (m, 1H), 7.50 (d, J 7.6, 1H), 7.39-7.34 (m, 1H), 5.24 (s, 2H). MS (m/z): 153.15([M+H] ⁺ ). Intermediate 180: 3-bromo-7-fluoroisobenzofuran-1(3H)-one [352] To intermediate 179 (400 mg, 2.63 mol) in Carbon tetrachloride (10 ml), N- Bromosuccinimide (468 mg, 2.63 mol) was added and heated to heated to 90°C. Azobisisobutyronitrile (AIBN) (432 mg, 2.63 mmol) was added to the reaction mixture. After 2h, the reaction mixture was cooled to room temperature, quenched with water (50 ml) and separated the organic layer. Aqueous layer was extracted with dichloromethane (2 x 50 ml), the combined organic layers were dried on anhydrous Na2SO4 and evaporated on rotavapor to obtain crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (20:80) as eluent to obtain the titled compound as a colourless liquid (400 mg). Yield: 65%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 7.87-7.84 (m, 1H), 7.15-7.43 (m, 2H), 6.66 (s, 1H). Intermediate 181: (4-fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl)triphenylphosp honium bromide [353] To intermediate 180 (2.40 g, 10.39 mmol) in acetonitrile (20 ml), triphenylphosphine (2.72 g, 10.39 mmol) was added and was heated to 90°C for 12h. After 12h, the reaction mixture was cooled to room to temperature and concentrated under reduced pressure. To the residue 2- propanol (20 ml) was added and heated to 90°C for 1h. Cooled to 0°C, diluted with diethyl ether (10 ml), filtered and washed with diethyl ether (10 ml). Solid was dried under vacuum for 30 mins to obtain the title compound as an off-white solid (4.7 g). Yield: 92%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.64 (s, 1H), 8.02-7.97 (m, 3 H), 7.90-7.71 (m, 13H), 7.60 (t, J 8.0, 1H), 6.79 (dt, J 7.6,1.2, 1H). Intermediate 182: 4-(4-fluoro-3-oxoisobenzofuran-1(3H)-ylidene)butanenitrile [354] Following the general procedure 1, the titled compound was synthesized from Intermediate 181 (2.97 g, 6.02 mmol), dichloromethane (30 ml), 4-oxobutanenitrile (500 mg, 6.02 mmol) and triethylamine (1.22 g, 12.0 mmol). Purification: Not done. Appearance: Dark yellow semi solid (2.50 g). Yield: >100%. The material was used as such for next step without any characterization. Intermediate 183: 4-(5-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)butanenitrile [355] Following the general procedure 2, the titled compound was synthesized from Intermediate 182 (1.30 g, 5.60 mmol), ethanol (19.5 ml), and hydrazine hydrate (0.42 g, 8.40 mmol). Purification: Combi-Flash. Eluent: Methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Pale-brown solid (1.27 g). Yield: 98%.232.30 ([M+H] ⁺ ). Intermediate 184: 4-(5-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)butanoic acid [356] To intermediate 183 (1.27 g, 5.52 mmol), water (15 ml) and NaOH (0.88 g, 22.11 mmol) were added and heated to 100°C. After 3h, the reaction mixture was cooled to room temperature and extracted with 5% methanol in dichloromethane (20 ml). The aqueous layer was acidified to pH 2 with con. HCl, the solid precipitated was filtered, washed with diethyl ether (10 ml) and dried under vacuum to obtain the title compound as a pale-brown solid (450 mg). Yield: 32%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.47 (s, 1H), 12.08 (s, 1H), 7.96 (dt, J 8.4, 5.2, 1H), 7.83 (d, J 8.0, 1H), 7.62 (dt, J 11.2,8.0, 1H), 2.92 (t, J 7.6, 2H), 2.38 (t, J 7.2, 2H), 1.93- 1.86 (m, 2H). MS (m/z): 251.18 ([M+H] ⁺ ). Intermediate 185: tert-butyl 3-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [357] Following the general procedure 4, the titled compound was synthesized from 2-chloro- 5-fluoropyrimidine (500 mg, 3.77 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (801 mg, 3.77 mmol), N-Methylpyrrolidone (5 ml) and potassium carbonate (1.56 g, 11.3 mmol). Purification: Not done Appearance: Pale-brown solid (1.0 g). Yield: 90%. ¹ H- NMR (δ ppm, DMSO-d6, 400 MHz): 8.45 (s, 2H), 4.23 (d, J 10.8, 4H), 3.01 (dd, J 12.8,2.0, 2H), 1.82-1.80 (m, 2H), 1.61-1.51(m, 2H), 1.42 (s, 9H). MS (m/z): 209.27 ([M-Boc+H] ⁺ ). Intermediate 186: 3-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane dihydrochloride [358] Following the general procedure 5, the titled compound was synthesized from intermediate 185 (1.0 g, 3.24 mmol) and 2M HCl in dioxan (8 ml). Purification: Not done. Appearance: Pale-brown solid (847 mg). Yield: 93%. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.82 (s, 1H), 9.66 (s, 1H), 8.51 (s, 2H), 7.67 (s, 1H), 4.31 (d, J 13.6, 2H), 4.11 (s, 2H), 3.41 (d, J 12.6, 2H), 1.99-1.90 (m, 2H), 1.75-1.70 (m, 2H). MS (m/z): 209.17 ([M-2HCl+H] ⁺ ). Intermediate 187: 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine [359] To 2-chloro-9H-purine (500 mg, 3.23 mol) in toluene (10 ml), 3,4-dihydro-2H-pyran (816 mg, 9.70 mol), 4-methylbenzenesulphonic acid (27.9 mg, 0.16 mmol) were added and heated to heated to 120°C. After 24h, the reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (30 ml), extracted with 5% methanol in dichloromethane (3 x 30 ml), the combined organic layers were dried on anhydrous Na ₂ SO ₄ and evaporated on rotavapor to obtain crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (40:60) as eluent to obtain the titled compound as a pale- brown liquid (430 mg). Yield: 55%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.13 (s, H), 8.88 (s, 1H), 5.76-5.73 (m, 1H), 4.05-4.00 (m, 1H), 3.77-3.70 (m, 1H), 2.34-2.24 (m, 1H), 2.02-1.96 (m, 2H), 1.81-1.70 (m, 1H), 1.65-1.57 (m, 2H). Intermediate 188: 4-(4-oxo-4-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl)-3 ,8- diazabicyclo[3.2.1]octan-8-yl)butyl)phthalazin-1(2H)-one [360] Following the general procedure 4, the titled compound was synthesized from intermediate 187 (359 mg, 1.50 mmol), intermediate 176 (500 mg, 1.25 mmol), n-butanol (10 ml) and DIPEA (647 mg, 5.01 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (6:94) as eluent. Appearance: Pale-brown solid. Yield: 130 mg. % Yield: 18. MS (m/z): 529.32 ([M+H] ⁺ ). Intermediate 189: 2-chloro-5-(methylsulfinyl)pyrimidine [361] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (5.7 g, 25 mmol), DMF (100 ml), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (5.0 g, 24 mmol), DIPEA (15 g, 120 mmol) and HBTU (11 g, 28 mmol). Purification: Not done. Appearance: Pale-brown solid (7.5 g). Yield: 75%. MS (m/z): 427.60 ([M+H] ⁺ ). Intermediate 190: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-4-oxobutyl)phthalaz in-1(2H)-one hydrochloride [362] Following the general procedure 5, the titled compound was synthesized from intermediate 189 (4.5 g, 10.6 mmol) and 2M HCl in ethyl acetate (54 ml). Purification: Not done. Appearance: Off-white solid (3.6 g). Yield: 85%. MS (m/z): 327.60 ([M-HCl+H] ⁺ ). Intermediate 191: tert-butyl 3-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [363] Following the general procedure 4, the titled compound was synthesized from 2,3- dichloro-5-(trifluoromethyl)pyridine (510 mg, 2.4 mmol), tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.4 mmol), N-Methylpyrrolidone (10 ml) and potassium carbonate 650 mg, 4.7 mmol). Purification: Not done Appearance: Brown solid (750 mg). Yield: 81%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.55 (dd, J 2.4,1.2, 1H), 8.18 (d, J 2.4, 1H), 4.21 (s, 2H), 3.83 (dd, J 12.0,1.6, 2H), 3.07 (d, J 11.6, 2H), 1.88-1.81 (m, 4H), 1.42 (s, 9H). MS (m/z): 392.10 ([M+H] ⁺ ). Intermediate 192: 3-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicycl o[3.2.1]octane dihydrochloride [364] Following the general procedure 5, the titled compound was synthesized from intermediate 191 (690 mg, 1.80 mmol) and 2M HCl in dioxan (5.1 ml). Purification: Not done. Appearance: Off-white solid (560 mg). Yield: 87%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.55 (s, 2H), 8.60 (dd, J 2.0,0.8, 1H), 8.26 (d, J 2.0, 1H), 6.00 (s, 1H), 4.13 (s, 2H), 3.90 (d, J 12.4, 2H), 3.44 (d, J 13.6, 2H), 2.08-1.97 (m, 4H). MS (m/z): 292.26 ([M-2HCl+H] ⁺ ). Intermediate 193: tert-butyl 3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate) [365] Following the general procedure 4, the titled compound was synthesized from 2,3- difluoro-5-(trifluoromethyl)pyridine (430 mg, 2.4 mmol), tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.4 mmol), DMSO (5 ml), DIPEA (610 mg, 4.7 mmol). Purification: Not done Appearance: Brown gummy liquid (700 mg). Yield: 79%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 8.33 (t, J 1.2, 1H), 7.94 (dd, J 14.0,2.0, 1H), 4.22 (s, 2H), 4.01 (dd, J 12.8,2.0, 2H), 3.15 (d, J 12.0, 2H), 1.86-1.79 (m, 2H), 1.75-1.69 (m, 2H), 1.42 (s, 9H). MS (m/z): 276.36 ([M-Boc+H] ⁺ ). Intermediate 194: 3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicycl o[3.2.1]octane dihydrochloride [366] Following the general procedure 5, the titled compound was synthesized from intermediate 193 (650 mg, 1.70 mmol) and 2M HCl in dioxan (5.0 ml). Purification: Not done. Appearance: Off-white solid (060 mg). Yield: 83%. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 9.41 (s, 1H), 9.28 (s, 1H), 8.38 (t, J 1.2, 1H), 8.04 (dd, J 13.6,1.6, 1H), 4.21-4.06 (s, 5H), 3.47 (d, J 13.6, 2H), 1.98-1.89 (m, 4H). MS (m/z): 276.19 ([M-2HCl+H] ⁺ ). Intermediate 195: 3-((tert-butoxycarbonyl)((3-(4-methoxybenzyl)-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)amino)propanoic acid

[367] To intermediate 126 (900 mg, 2.45 mmol) in THF (20 ml), sodium bicarbonate (521 mg, 6.20 mmol) was added followed by Boc-anhydride (519 mg, 2.38 mmol) and stirred at room temperature. After 16h, the reaction mixture cooled to °C, the reaction mass pH was adjusted to 5 with 2N HCl, extracted with 10% methanol in dichloromethane (2 x 50 ml), washed with water and concentrated under reduced pressure to obtain the title compound as an off-white solid (900 mg). Yield: 78%. MS (m/z): 368.20 ([M-Boc+H] ⁺ ). Intermediate 196: tert-butyl ((3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazin-1- yl)methyl)(3-oxo-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3, 8-diazabicyclo[3.2.1]octan-8- yl)propyl)carbamate [368] Following the general procedure 6, the titled compound was synthesized from intermediate 195 (218 mg, 0.46 mmol), DMF (6 ml), intermediate 141 (170 mg, 0.51 mmol), DIPEA (301 mg, 2.33 mmol) and HBTU (212 mg, 0.56 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.6:97.4) as eluent. Appearance: Off-white solid. Yield: 200 mg. % Yield: 60. MS (m/z): 708.21 ([M+H] ⁺ ). Intermediate 197: tert-butyl ((3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazin-1- yl)methyl)(3-oxo-3-(3-(5-(trifluoromethyl)pyridin-2-yl)-3,8- diazabicyclo[3.2.1]octan-8- yl)propyl)carbamate

[369] Following the general procedure 6, the titled compound was synthesized from intermediate 195 (300 mg, 0.64 mmol), DMF (8 ml), intermediate 153 (233 mg, 0.71 mmol), DIPEA (415 mg, 3.21 mmol) and HBTU (292 mg, 0.77 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (1.7:98.3) as eluent. Appearance: Yellow solid. Yield: 310 mg. % Yield: 68. MS (m/z): 707.24 ([M+H] ⁺ ). Example 1 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1 -yl)butyl)phthalazin-1(2H)- one [370] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (4 ml), intermediate 11 (131 mg, 0.43 mmol), pyridine (204 mg, 2.58 mmol) and T3P (Propylphosphonic anhydride) (411 mg, 1.29 mmol; 0.82 ml of 50% solution in ethyl acetate). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 50 mg. % Yield: 26. M.P.: 190-193 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.46 (s, 1H), 8.73 (s, 2H), 8.27 (d, J 7.6, 1H), 8.09 (d, J 8.0, 1H), 7.96 (t, J 7.2, 1H), 7.86 (t, J 7.2, 1H), 3.89-3.84 (m, 2H), 3.83- 3.81 (m, 2H), 3.59 (t, J 4.8, 4H), 2.98 (t, J 7.6, 2H), 2.52 (t, J 7.6, 2H), 1.99-1.92 (m, 2H). MS (m/z): 447.46 ([M+H] ⁺ ). Example 2 4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-4-oxobutyl)pht halazin-1(2H)-one [371] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (4 ml), intermediate 13 (108 mg, 0.43 mmol), DIPEA (55.7 mg, 0.43 mmol) and HBTU (163 mg, 0.43 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (5.3:94.7) as eluent. Appearance: Off-white solid. Yield: 70 mg. % Yield: 44. M.P.: 196-199 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.45 (s, 1H), 8.27 (dd, J 8.0,1.2, 1H), 8.08 (d, J 8.0, 1H), 7.96 (dt, J 7.2,1.2, 1H), 7.86 (dt, J 8.0,1.2, 1H), 3.66-3.35 (m, 8H), 2.97 (t, J 7.6, 2H), 2.50 (t, J, 7.2, 2H), 2.00-1.96 (m, 3H), 0.75-0.70 (m, 4H). MS (m/z): 369.31 ([M+H] ⁺ ). Example 3 4-(4-(4-(methylsulfonyl)piperazin-1-yl)-4-oxobutyl)phthalazi n-1(2H)-one [372] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (4 ml), intermediate 15 (135 mg, 0.51 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (5:95) as eluent. Appearance: Off-white solid. Yield: 80 mg. % Yield: 49. M.P.: 225-228 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.27 (dd, J 8.0,0.8, 1H), 8.08 (d, J 8.0, 1H), 7.97 (dt, J 7.6,1.6, 1H), 7.86 (dt, J 8.0,0.8, 1H), 3.58 (t, J 4.8, 4H), 3.12 (t, J 4.0, 2H), 3.08 (t, J 4.8, 2H), 2.96 (t, J 7.6, 2H), 2.88 (s, 3H), 2.48 (t, J 7.6, 2H), 1.97-1.90 (m, 2H). MS (m/z): 379.28 ([M+H] ⁺ ). Example 4 4-(4-oxo-4-(4-(pyrimidin-2-yl)piperazin-1-yl)butyl)phthalazi n-1(2H)-one [373] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2 ml), intermediate 17 (112 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (4.1:95.9) as eluent. Appearance: Pale brown solid. Yield: 100 mg. % Yield: 61. M.P.: 198-201 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.39 (d, J 4.4, 2H), 8.27 (dd, J 8.0,0.8, 1H), 8.10 (d, J 8.0, 1H), 7.96 (dt, J 7.6,1.6, 1H), 7.86 (dt, J 8.0,1.2, 1H), 6.67 (t, J 4.4, 1H), 3.78 (t, J 4.8, 2H), 3.72 (t, J 4.8, 2H), 3.54 (m, 4H), 2.98 (t, J 7.6, 2H), 2.53 (t, J 7.2, 2H), 1.98-1.91 (m, 2H). MS (m/z): 379.29 ([M+H] ⁺ ). Example 5 4-(4-oxo-4-(4-(pyrazin-2-yl)piperazin-1-yl)butyl)phthalazin- 1(2H)-one [374] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2 ml), intermediate 19 (112 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3.5:96.5) as eluent. Appearance: Off-white solid. Yield: 75 mg. % Yield: 46. M.P.: 193-196 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.33 (d, J 1.6, 1H), 8.27 (dd, J 8.0,0.8, 1H), 8.10-8.07 (m, 2H), 7.96 (dt, J 7.6,1.6, 1H), 7.86-7.82 (m, 2H), 3.62-3.52 (m, 8H), 2.98 (t, J 7.2, 2H), 2.53 (t, J 7.2, 2H), 1.98-1.91 (m, 2H). MS (m/z): 379.31 ([M+H] ⁺ ). Example 6 7-fluoro-4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)pi perazin-1- yl)butyl)phthalazin-1(2H)-one [375] Following the general procedure 6, the titled compound was synthesized from intermediate 22 (100 mg, 0.40 mmol), DMF (3 ml), intermediate 11 (134 mg, 0.40 mmol), DIPEA (258 mg, 2.0/0 mmol) and HBTU (182 mg, 0.48 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 80 mg. % Yield: 43. M.P.: 216-219 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.58 (s, 1H), 8.73 (s, 2H), 8.23 (dd, J 9.2,5.2, 1H), 7.94 (dd, J 8.8,2.8, 1H), 7.86 (dt, J 8.8,2.8, 1H), 3.89 (t, J, 4.4, 2H), 3.83 (t, J 4.4, 2H), 3.59 (t, J 5.2, 4H), 2.97 (t, J 7.6, 2H), 2.53 (t, J 7.2, 2H), 1.98- 1.90 (m, 2H). MS (m/z): 465.30 ([M+H] ⁺ ). Example 7 4-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-4-oxobutyl)p hthalazin-1(2H)-one [376] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2 ml), intermediate 24 (121 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (4:96) as eluent. Appearance: Pale brown solid. Yield: 80 mg. % Yield: 47. M.P.: 238-241 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.47 (s, 1H), 8.48 (s, 2H), 8.27 (dd, J 7.6,0.8, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt, J 7.6,1.6, 1H), 7.86 (dt, J 8.0,1.2, 1H), 3.73 (t, J 5.2, 2H), 3.68 (t, J 5.6, 2H), 3.55 (m, 4H), 2.97 (t, J 7.6, 2H), 2.53 (t, J 7.2, 2H), 1.98-1.91 (m, 2H). MS (m/z): 397.27 ([M+H] ⁺ ). Example 8 2-(4-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl)piperazin -1-yl)pyrimidine-5- carbonitrile [377] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2 ml), intermediate 26 (124 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2:98) as eluent. Appearance: Off-white solid. Yield: 30 mg. % Yield: 17. M.P.: 256-258 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.79 (s, 2H), 8.27 (dd, J 8.0,0.8, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt, J 7.6,1.6, 1H), 7.86 (dt, J 8.0,0.8, 1H), 3.89 (t, J 5.2, 2H), 3.82 (t, J 5.6, 2H), 3.59-3.56 (m, 4H), 2.98 (t, J 7.2, 2H), 2.53 (t, J 7.2, 2H), 1.98-1.91 (m, 2H). MS (m/z): 404.31 ([M+H] ⁺ ). Example 9 4-(4-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-4-oxobutyl)p hthalazin-1(2H)-one [378] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2 ml), intermediate 28 (129 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 105 mg. % Yield: 59. M.P.: 230-232 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.45 (s, 2H), 8.27 (dd, J 8.0,1.2, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt, J 7.6,1.6, 1H), 7.86 (dt, J 8.0,0.8, 1H), 3.76 (t, J 4.4, 2H), 3.71 (t, J 4.4, 2H), 3.58-3.52 (m, 4H), 2.97 (t, J 7.2, 2H), 2.52 (t, J 7.2, 2H), 1.98-1.91 (m, 2H). MS (m/z): 413.29 ([M+H] ⁺ ). Example 10 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-y l)butyl)phthalazin- 1(2H)-one [379] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2 ml), intermediate 30 (144 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 105 mg. % Yield: 54. M.P.: 208-211 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.43 (t, J 0.8, 1H), 8.27 (dd, J 8.0,1.2, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt, J 7.2,1.6, 1H), 7.86- 7.81 (m, 2H), 6.97 (d, J 8.8, 1H), 3.69-3.57 (m, 8H), 2.98 (t, J 7.6, 2H), 2.53 (t, J 7.2, 2H), 1.98- 1.91 (m, 2H). MS (m/z): 446.35 ([M+H] ⁺ ). Example 11 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazin-1-y l)butyl)phthalazin- 1(2H)-one [380] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2 ml), intermediate 32 (145 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 110 mg. % Yield: 57. M.P.: 239-241 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.51 (d, J 0.8, 1H), 8.43 (d, J 1.2, 1H), 8.27 (dd, J 8.0,0.8, 1H), 8.09 (d, J 8.0, 1H), 7.97 (dt, J 7.2,1.2, 1H), 7.86 (dt, J 8.0,1.2, 1H), 3.78 (t, J 5.6, 2H), 3.73 (t, J 4.8, 2H), 3.63-3.60 (m, 4H), 2.98 (t, J 7.6, 2H), 2.54 (t, J 7.2, 2H), 1.98-1.92 (m, 2H). MS (m/z): 447.34 ([M+H] ⁺ ). Example 12 4-(4-(4-(5-(difluoromethyl)pyrimidin-2-yl)piperazin-1-yl)-4- oxobutyl)phthalazin-1(2H)- one [381] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.431 mmol), DMF (2 ml), intermediate 37 (136 mg, 0.474 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 80 mg. % Yield: 43. M.P.: 212-214 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.58 (s, 2H), 8.27 (dd, J 8.0,1.2, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt, J 7.2,1.6, 1H), 7.88 (dt, J 8.0,0.8, 1H), 7.11 (t, J 55.2, 1H), 3.84-3.77 (m, 8H), 2.98 (t, J 7.2, 2H), 2.53 (t, J 7.2, 2H), 1.99- 1.91 (m, 2H). MS (m/z): 429.33 ([M+H] ⁺ ). Example 13 4-(4-oxo-4-(4-(pyridazin-3-yl)piperazin-1-yl)butyl)phthalazi n-1(2H)-one [382] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (80 mg, 0.34 mmol), DMF (2 ml), intermediate 34 (90 mg, 0.38 mmol), DIPEA (220 mg, 1.70 mmol) and HBTU (160 mg, 0.41 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (12:88) as eluent. Appearance: Pale-brown solid. Yield: 60 mg. % Yield: 46. M.P.: 221-224 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.46 (s, 1H), 8.58 (dd, J 4.4,1.2, 1H), 8.27 (dd, J 7.6,0.8, 1H), 8.10 (d, J 8.0, 1H), 7.97 (dt, J 7.2,1.6, 1H), 7.88 (dt, J 8.0,0.8, 1H), 7.42 (dd, J 9.2,4.4, 1H), 7.28 (dd, J 9.2,1.2, 1H), 3.65-3.58 (m, 8H), 2.98 (t, J 7.6, 2H), 2.54 (t, J 7.2, 2H), 1.99-1.91 (m, 2H). MS (m/z): 379.38 ([M+H] ⁺ ). Example 14 4-(4-(4-(5-isopropylpyrimidin-2-yl)piperazin-1-yl)-4-oxobuty l)phthalazin-1(2H)-one [383] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.431 mmol), DMF (3 ml), intermediate 41 (132 mg, 0.474 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield:60 mg. % Yield: 33. M.P.: 190-194 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.47 (s, 1H), 8.30 (s, 2H), 8.27 (d, J 8.0, 1H), 8.09 (d, J 8.0, 1H), 7.96 (t, J 7.6, 1H), 7.86 (t, J 7.6, 1H), 3.76- 3.64 (m, 4H), 3.57-3.51 (m, 4H), 2.97 (t, J 7.6, 2H), 2.81 (pentet, J 6.8, 1H), 2.51-2.47 (m, 2H), 1.96 (d, J 7.2, 2H), 1.19 (d, J 6.8, 6H). MS (m/z): 421.40 ([M+H] ⁺ ). Example 15 4-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1 -yl)pentyl)phthalazin- 1(2H)-one

[384] Following the general procedure 6, the titled compound was synthesized from intermediate 45 (100 mg, 0.41 mmol), DMF (2 ml), intermediate 11 (140 mg, 0.45 mmol DIPEA (260 mg, 2.0 mmol) and HBTU (180 mg, 0.49 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 120 mg. % Yield: 64. M.P.: 217-220 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.72 (s, 2H), 8.26 (dd, J 7.6,0.8, 1H), 8.07 (d, J 8.0, 1H), 7.95 (dt, J 8.0,1.6, 1H), 7.86 (dt, J 8.0,1.2, 1H), 3.86 (t, J 5.2, 2H), 3.80 (t, J 5.2, 2H), 3.59-3.51 (m, 4H), 2.97 (t, J 6.8, 2H), 2.45 (t, J 7.2, 2H), 1.77-1.60 (m, 4H). MS (m/z): 461.54 ([M+H] ⁺ ). Example 16 4-(3-hydroxy-4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)p iperazin-1- yl)butyl)phthalazin-1(2H)-one [385] To intermediate 52 (150 mg, 0.27 mmol) in dichloromethane (10 ml) cooled to 0 ^o C, BCl ₃ (1M in dichloromethane, 5.5 ml) was added and stirred for 1h. After 1h, the reaction mixture was quenched with saturated sodium bicarbonate solution (5 ml), extracted with dichloromethane (3 x 50 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (2.5:97.5) as eluent to obtain the title compound as an off-white solid (70 mg). % Yield: 64. M.P.: 238-241 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.51 (s, 1H), 8.74 (s, 2H), 8.27 (dd, J 8.0,1.2, 1H), 8.04 (d, J 8.0, 1H), 7.97 (dt, J 7.2,1.2, 1H), 7.87 (dt, J 8.0,0.8, 1H), 5.11 (d, J 7.6, 1H), 4.51-4.46 (m, 1H), 3.95-3.71 (m, 4H), 3.67-3.52 (m, 4H), 3.09-3.00 (m, 2H), 2.14- 2.06 (m, 1H), 1.89-1.80 (m, 1H). MS (m/z): 463.33 ([M+H] ⁺ ). Example 17 4-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1 -yl)pentan-2-yl)phthalazin- 1(2H)-one [386] Following the general procedure 6, the titled compound was synthesized from intermediate 55 (60 mg, 0.24 mmol), DMF (2.5 ml), intermediate 11 (82 mg, 0.27 mmol DIPEA (160 mg, 1.2 mmol) and HBTU (110 mg, 0.29 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Pale-brown solid. Yield: 50 mg. % Yield: 45. M.P.: 211-215 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.52 (s, 1H), 8.72 (s, 2H), 8.29 (dd, J 7.6,0.8, 1H), 8.12 (d, J 8.0, 1H), 7.96 (dt, J 8.0,1.2, 1H), 7.85 (t, J 7.2, 1H), 3.82-3.74 (m, 4H), 3.55-3.49 (m, 5H), 2.45-2.35 (m, 2H), 2.15-2.06 (m, 1H), 1.80-1.71 (m, 1H), 1.27 (d, J 6.8, 3H). MS (m/z): 461.34 ([M+H] ⁺ ). Example 18 4-(4-(4-(5-(difluoromethoxy)pyridin-2-yl)piperazin-1-yl)-4-o xobutyl)phthalazin-1(2H)- one [387] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2.5 ml), intermediate 57 (143 mg, 0.47 mmol DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0519 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2:98) as eluent. Appearance: Off-white solid. Yield: 100 mg. % Yield: 52. M.P.: 167-170 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.46 (s, 1H), 8.27 (dd, J 7.6,0.8, 1H), 8.09 (d, J 7.6, 1H), 8.04 (d, J 3.6, 1H), 7.96 (dt, J 7.6,1.6, 1H), 7.86 (dt, J 8.0,1.2, 1H), 7.49 (dd, J 9.2,2.8, 1H), 7.24 (t, J 74, 1H), 6.99 (d, J 9.2, 1H), 3.59-3.55 (m, 4H), 3.52-3.45 (m, 4H), 2.97 (t, J 7.6, 2H), 2.51-2.47 (m, 2H), 1.98-1.91 (m, 2H). MS (m/z): 444.38 ([M+H] ⁺ ). Example 19 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperidin-1-y l)butyl)phthalazin-1(2H)-one [388] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2.5 ml), intermediate 60 (126 mg, 0.47 mmol DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0519 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 90 mg. % Yield: 46. M.P.: 162-165 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.46 (s, 1H), 8.89 (s, 1H), 8.27 (d, J 8.0, 1H), 8.15 (d, J 7.2, 1H), 8.10 (d, J 8.0, 1H), 7.96 (t, J 6.8, 1H), 7.86 (t, J 7.2, 1H), 7.56 (d, J 8.0, 1H), 4.57 (d, J 10.8, 1H), 4.02 (d, J 12.8, 1H), 3.17-3.08 (m, 2H), 2.97 (t, J 6.8, 2H), 2.69 (t, J 11.6, 1H), 2.50-2.47 (m, 2H), 1.98-1.82 (m, 4H), 1.71-1.54 (m, 2H).MS (m/z): 445.34 ([M+H] ⁺ ). Example 20 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-1 -yl)butyl)phthalazin-1(2H)- one [389] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2.5 ml), intermediate 63 (127 mg, 0.47 mmol DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.519 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 90 mg. % Yield: 47. M.P.: 183-186 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.45 (s, 1H), 9.22 (s, 2H), 8.27 (dd, J 8.0,0.8, 1H), 8.10 (d, J 8.0, 1H), 7.96 (dt, J 8.0,1.2, 1H), 7.86 (dt, J 8.0,0.8, 1H), 4.50 (d, J 12.8, 1H), 3.99 (d, J 14.0, 1H), 3.26-3.16 (m, 2H), 2.97 (t, J 6.8, 2H), 2.78 (t, J 7.2, 1H), 2.50-2.47 (m, 2H), 2.04-1.89 (m, 4H), 1.77-1.55 (m, 2H).MS (m/z): 44628 ([M+H] ⁺ ) Example 21 4-(4-oxo-4-(4-(6-(trifluoromethyl)pyridazin-3-yl)piperazin-1 -yl)butyl)phthalazin-1(2H)- one [390] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (80 mg, 0.34 mmol), DMF (2.5 ml), intermediate 65 (120 mg, 0.38 mmol), DIPEA (220 mg, 1.70 mmol) and HBTU (160 mg, 0.41 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 100 mg. % Yield: 65. M.P.: 229-232 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.27 (d, J 7.2, 1H), 8.10 (d, J 8.0, 1H), 7.97 (dt, J 8.0,0.8, 1H), 7.86-7.83 (m, 2H), 7.43 (d, J 9.6, 1H), 3.86-3.71 (m, 4H), 3.68-3.61 (m, 4H), 2.98 (t, J 7.6, 2H), 2.54-2.50 (m, 2H), 1.99-1.89 (m, 2H). MS (m/z): 447.23 ([M+H] ⁺ ). Example 22 4-(4-(4-(5-(difluoromethoxy)pyrimidin-2-yl)piperazin-1-yl)-4 -oxobutyl)phthalazin- 1(2H)-one [391] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (3 ml), intermediate 67 (144 mg, 0.38 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 80 mg. % Yield: 42. M.P.: 172-176 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.46 (s, 1H), 8.36 (s, 2H), 8.27 (dd, J 8.0,1.2, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt, J 7.6,1.6, 1H), 7.86 (dt, J 8.0,0.8, 1H), 7.26 (t, J 73.6, 1H), 3.75 (t, J 4.8, 2H), 3.71 (t, J 4.4, 2H), 3.59-3.51 (m, 4H), 2.98 (t, J 7.6, 2H), 2.53-2.50 (m, 2H), 1.98-1.91 (m, 2H). MS (m/z): 445.28 ([M+H] ⁺ ). Example 23 4-(4-(4-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazin-1-yl)-4- oxobutyl)phthalazin-1(2H)- one [392] Following the general procedure 4, the titled compound was synthesized from intermediate 69 (150 mg, 0.40 mmol), n-butanol (5 ml), 6-chloro-1H-pyrazolo[3,4- d]pyrimidine (62.1 mg, 0.40 mmol) and DIPEA (260 mg, 2.015 mmol). Purification: Combi- Flash. Eluent: methanol and dichloromethane (6.5:93.5) as eluent. Appearance: Pale-green solid. Yield: 50 mg. % Yield: 30. M.P.: 167-170 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.14 (s, 1H), 12.47 (s, 1H), 8.92 (s, 1H), 8.27 (dd, J 8.0,0.8, 1H), 8.10 (d, J 8.0, 1H), 7.99 (s, 1H), 7.97 (dt, J 7.2,1.6, 1H), 7.86 (dt, J 8.0,0.8, 1H), 3.89-3.77 (m, 4H), 3.62-3.52 (m, 4H), 2.98 (t, J 7.6, 2H), 2.54-2.51 (m, 2H), 1.99-1.92 (m, 2H). MS (m/z): 419.37 ([M+H] ⁺ ). Example 24 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)-1,4-diazep an-1-yl)butyl)phthalazin- 1(2H)-one [393] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2 ml), intermediate 71 (140 mg, 0.43 mmol), DIPEA (280 mg, 2.20 mmol) and HBTU (200 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 70 mg. % Yield: 35. M.P.: 166-169 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.44 (s, 1H), 8.68 (m, 2H), 8.26 (dd, J 7.6,1.2, 1H), 8.03 (dd, J 7.6,3.2, 1H), 7.95 (dt, J 78.0,1.2, 1H), 7.85 (t, J 7.6, 1H), 3.98 (t, J 5.6, 1H), 3.90 (t, J 5.2, 1H), 3.84-3.78 (m, 2H), 3.68 (t, J 5.2, 2H), 3.50-3.44 (m, 2H), 2.83-2.74 (m, 2H), 2.46 (t, J 7.6, 1H), 2.40 (t, J 7.2, 1H), 1.89-1.72 (m, 4H). MS (m/z): 461.40 ([M+H] ⁺ ). Example 25 6-fluoro-4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)pi perazin-1- yl)butyl)phthalazin-1(2H)-one [394] Following the general procedure 6, the titled compound was synthesized from intermediate 74 (100 mg, 0.40 mmol), DMF (3 ml), intermediate 11 (134 mg, 0.40 mmol), DIPEA (258 mg, 2.0 mmol) and HBTU (182 mg, 0.48 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2:98) as eluent. Appearance: Off-white solid. Yield: 105 mg. % Yield: 56. M.P.: 220-223 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.54 (s, 1H), 8.73 (s, 2H), 8.34 (dd, J 8.8,5.6, 1H), 7.95 (dd, J 10.0,3.6, 1H), 7.73 (dt, J 8.8,2.4, 1H), 3.86 (t, J, 5.2, 2H), 3.83 (t, J 5.6, 2H), 3.60 (t, J 5.6, 4H), 2.94 (t, J 7.2, 2H), 2.51-2.50 (m, 2H), 1.96- 1.89 (m, 2H). MS (m/z): 465.36 ([M+H] ⁺ ). Example 26 4-(4-oxo-4-(4-(5-(trifluoromethoxy)pyridin-2-yl)piperazin-1- yl)butyl)phthalazin-1(2H)- one

[395] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2 ml), intermediate 76 (140 mg, 0.43 mmol), DIPEA (280 mg, 2.20 mmol) and HBTU (200 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 80 mg. % Yield: 40. M.P.: 170-173 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.27 (dd, J 8.0,0.8, 1H), 8.17 (d, J 2.8, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt J 8.4,1.2, 1H), 7.86 (dt, J 8.0,0.8, 1H), 7.64 (dd, J 9.2,2.0, 1H), 6.94 (d, J 9.2, 1H), 3.61-3.49 (m, 8H), 2.97 (t, J 7.6, 2H), 2.52-2.50 (m, 2H), 1.98-1.90 (m, 2H). MS (m/z): 462.29 ([M+H] ⁺ ). Example 27 4-(4-oxo-3,4-dihydrophthalazin-1-yl)butyl 4-(5-(trifluoromethyl)pyrimidin-2- yl)piperazine-1-carboxylate [396] Following the general procedure 2, the titled compound was synthesized from Intermediate 80 (0.35 g, 0.76 mmol), 2-propanol (10 ml), and hydrazine hydrate (57 mg, 1.1 mmol). Purification: Combi-Flash. Eluent: ethyl acetate and petroleum ether (88:12) as eluent. Appearance: Off-white solid. Yield: 135 mg. % Yield: 37. M.P.: 165-168 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.72 (s, 2H), 8.27 (dd, J 8.0,0.8, 1H), 8.01 (d, J 7.6, 1H), 7.95 (dt J 7.2,1.6, 1H), 7.85 (dt, J 8.0,1.2, 1H), 4.11 (t, J 6.0, 2H), 3.83 (t, J 4.8, 4H), 3.46-3.43 (m, 4H), 2.98 (t, J 7.2, 2H), 1.81-1.70 (m, 4H). MS (m/z): 477.31 ([M+H] ⁺ ). Example 28 4-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperazin-1-yl)-4-o xobutyl)phthalazin-1(2H)- one [397] Following the general procedure 4, the titled compound was synthesized from intermediate 69 (1.0 g, 2.67 mmol), n-butanol (5 ml), 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (411 mg, 2.67 mmol) and DIPEA (1.73 g, 13.39 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (4:96) as eluent. Appearance: Pale-brown solid. Yield: 45 mg. % Yield: 4. M.P.: 232-235 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 11.36 (s, 1H), 8.62 (s, 1H), 8.27 (d, J 7.6, 1H), 8.10 (d, J 8.0, 1H), 7.95 (t, J 7.2, 1H), 7.86 (t, J 7.2, 1H), 7.10 (s, 1H), 6.33 (s, 1H), 3.79-3.61 (m, 4H), 3.56 (br s, 4H), 2.98 (t, J 7.2, 2H), 1.97 (t, J 7.2, 2H), 1.27 (t, J 6.0, 2H). MS (m/z): 418.35 ([M+H] ⁺ ). Example 29 4-(4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)bu tyl)phthalazin-1(2H)-one [398] Following the general procedure 2, the titled compound was synthesized from Intermediate 83 (0.23 g, 0.55 mmol), 2-propanol (10 ml), and hydrazine hydrate (41.3 mg, 0.82 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (5.2:94.8) as eluent. Appearance: Off-white solid. Yield: 100 mg. % Yield: 41. M.P.: 177-179 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.45 (s, 1H), 8.68 (s, 2H), 8.27 (dd, J 7.6,0.8, 1H), 8.04 (d, J 8.0, 1H), 7.96 (dt J 7.2,1.2, 1H), 7.86 (dt, J 8.0,0.8, 1H), 3.82 (t, J 4.8, 4H), 2.97 (t, J 7.2, 2H), 2.42 (t, J 4.8, 4H), 2.39 (t, J 7.2, 2H), 1.75-1.72 (m, 2H), 1.62-1.57 (m, 2H).. MS (m/z): 433.45 ([M+H] ⁺ ). Example 30 4-(4-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-4-oxobutyl)pht halazin-1(2H)-one

[399] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (5 ml), intermediate 85 (128 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Pale-brown solid. Yield: 100 mg. % Yield: 73. M.P.: 202-204 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.27 (dd, J 7.6,0.8, 1H), 8.13 (d, J 2.4, 1H), 8.09 (d, J 7.6, 1H), 7.96 (dt, J 7.2,1.2, 1H), 7.86 (dt, J 8.0,1.2, 1H), 7.64 (dd, J 9.2,2.8, 1H), 6.90 (d, J 9.2, 1H), 3.59-3.51(m, 6H), 3.50-3.43 (m, 2H), 2.97 (t, J 7.6, 2H), 2.52-2.50 (m, 2H), 1.98-1.90 (m, 2H). MS (m/z): 412.33 ([M+H] ⁺ ). Example 31 6-(4-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl)piperazin -1-yl)nicotinonitrile [400] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (5 ml), intermediate 87 (102 mg, 0.39 mmol), DIPEA (253 mg, 1.96 mmol) and HBTU (178 mg, 0.47 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (6:94) as eluent. Appearance: Off-white solid. Yield: 138 mg. % Yield: 87. M.P.: 234-238 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.51 (d, J 2.0, 1H), 8.27 (dd, J 8.0,0.8, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt, J 7.6,1.6, 1H), 7.90 (dd, J 8.8,2.4, 1H), 7.86 (dt, J 8.0,0.8, 1H), 6.95 (d, J 9.2, 1H), 3.72 (t, J 5.2, 2H), 3.68-3.62 (m, 2H), 3.59-3.66 (m, 4H), 2.97 (t, J 7.6, 2H), 2.52-2.50 (m, 2H), 1.98-1.91 (m, 2H). MS (m/z): 403.39 ([M+H] ⁺ ). Example 32 4-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1 -yl)propoxy)phthalazin- 1(2H)-one [401] To intermediate 90 (130 mg, 0.27 mmol) in acetic acid (5 ml), sodium acetate (50.3 mg, 0.61 mmol) was added and heated to 100 ^o C. After 90 min., the reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (30 ml), diluted with water (100 ml), extracted with 5% methanol in dichloromethane (3 x 30 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (3.6:96.4) as eluent to obtain the title compound as an off-white solid (100 mg). % Yield: 80. M.P.: 258-260 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 11.92 (s, 1H), 8.74 (s, 2H), 8.22 (dd, J 7.6,1.2, 1H), 7.93-7.86 (m, 3H), 4.53 (t, J 6.8, 2H), 3.92 (t, J 4.0, 2H), 3.85 (t, J 4.8, 2H), 3.66 (t, J 5.2, 2H), 3.62 (t, J 4.8, 2H), 3.00 (t, J 6.8, 2H). MS (m/z): 449.27 ([M+H] ⁺ ). Example 33 4-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)-4-oxo butyl)phthalazin-1(2H)-one [402] Following the general procedure 4, the titled compound was synthesized from intermediate 92 (200 mg, 0.57 mmol), N-methylpyrrolidone (5 ml), 2,5-dichloropyrimidine (93.2 mg, 0.62 mmol) and DIPEA (221 mg, 1.71 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3.5:96.5) as eluent. Appearance: Off-white solid. Yield: 35 mg. % Yield: 14. M.P.: 197-199 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.45 (s, 1H), 8.33 (s, 2H), 8.27 (d, J 7.6, 1H), 8.09 (d, J 8.0, 1H), 7.96 (t, J 7.2, 1H), 7.86 (t, J 7.6, 1H), 7.48 (d, J 7.6, 1H), 4.32 (d, J 11.6, 1H), 3.95-3.82 (m, 2H), 3.13 (t, J 12.0, 1H), 2.96 (t, J 7.2, 2H), 2.75- 2.63 (m, 1H), 2.59-2.51 (m, 2H), 1.93-1.83 (m, 4H), 1.40-1.23 (m, 2H). MS (m/z): 427.32 ([M- HCl+H] ⁺ ). Example 34 4-(4-(4-(5-chloropyrimidin-2-yl)-2-oxopiperazin-1-yl)butyl)p hthalazin-1(2H)-one [403] Following the general procedure 2, the titled compound was synthesized from Intermediate 96 (0.35 g, 0.87 mmol), ethanol (5 ml), and hydrazine hydrate (65.9 mg,1.32 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 130 mg. % Yield: 35. M.P.: 209-212 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.45 (s, 1H), 8.47 (s, 2H), 8.26 (d, J 7.6, 1H), 8.00 (d, J 8.0, 1H), 7.93 (t J 7.2, 1H), 7.85 (t, J 7.6, 1H), 4.19 (s, 2H), 3.93 (t, J 5.2, 2H), 3.46-3.39 (m, 4H), 2.96 (t, J 7.2, 2H), 1.69-1.52 (m, 4H). MS (m/z): 413.40 ([M+H] ⁺ ). Example 35 4-(3-(4-(5-chloropyrimidin-2-yl)-2-oxopiperazin-1-yl)propyl) phthalazin-1(2H)-one [404] Following the general procedure 2, the titled compound was synthesized from Intermediate 100 (0.280 g, 0.72 mmol), 2-propanol (10 ml), and hydrazine hydrate (146 mg, 2.9 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.9:97.1) as eluent. Appearance: Off-white solid. Yield: 110 mg. % Yield: 37. M.P.: 228-232 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.48 (s, 1H), 8.47 (s, 2H), 8.26 (d, J 7.6, 1H), 7.97-7.91 (m, 2H), 7.86 (dt, J 8.0,1.6, 1H), 4.19 (s, 2H), 3.95 (t, J 4.8, 2H), 3.50-3.45 (m, 4H), 2.93 (t, J 7.6, 2H), 1.98-1.912 (m, 2H). MS (m/z): 399.48 ([M+H] ⁺ ). Example 36 4-(4-(4-(5-chloro-4-methylpyrimidin-2-yl)piperazin-1-yl)-4-o xobutyl)phthalazin-1(2H)- one [405] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2.5 ml), intermediate 102 (135 mg, 0.39 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 65 mg. % Yield: 35. M.P.: 204-206 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.31 (s 1H), 8.27 (dd, J 8.0,0.8, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt, J 7.6,1.6, 1H), 7.86 (dt, J 8.0,1.2, 1H), 3.75 (t, J 5.2, 2H), 3.70 (t, J 6.0, 2H), 3.59-3.51 (m, 4H), 2.97 (t, J 7.6, 2H), 2.52- 2.50 (m, 2H), 2.38 (s, 3H), 1.98-1.91 (m, 2H). MS (m/z): 427.39 ([M+H] ⁺ ). Example 37 4-(4-(4-(5-chloro-4-methylpyridin-2-yl)piperazin-1-yl)-4-oxo butyl)phthalazin-1(2H)-one [406] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (140 mg, 0.60 mmol), DMF (5 ml), intermediate 104 (170 mg, 0.60 mmol), DIPEA (390 mg, 3.0 mmol) and HBTU (270 mg, 0.72 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.6:97.4) as eluent. Appearance: Off-white solid. Yield: 100 mg. % Yield: 39. M.P.: 210-212 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.27 (dd, J 8.0,0.8, 1H), 8.09 (d, J 8.0, 1H), 8.05 (s, 1H), 7.96 (dt, J 8.4,1.2, 1H), 7.86 (t, J 7.2, 1H), 6.88 (s 1H), 3.56-3.50 (m, 6H), 3.49-3.43 (m, 2H), 2.97 (t, J 7.2, 2H), 2.52-2.50 (m, 2H), 2.26 (s, 3H), 1.98-1.90 (m, 2H). MS (m/z): 426.40 ([M+H] ⁺ ). Example 38 4-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropyl) phthalazin-1(2H)-one [407] Following the general procedure 6, the titled compound was synthesized from intermediate 107 (100 mg, 0.45 mmol), DMF (5 ml), intermediate 28 (137 mg, 0.50 mmol), DIPEA (296 mg, 2.29 mmol) and HBTU (209 mg, 0.55 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 40 mg. % Yield: 22. M.P.: 236-240 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.48 (s, 1H), 8.45 (s, 2H), 8.27 (dd, J 8.0,0.8, 1H), 8.03 (d, J 8.0, 1H), 7.97 (dt, J 8.4,1.2, 1H), 7.87 (dt, J 8.0,0.8, 1H), 3.78 (t, J 5.2, 2H), 3.70 (t, J 5.2, 2H), 3.65-3.50 (m, 4H), 3.23 (t, J 6.8, 2H), 2.86 (t, J 7.2, 2H). MS (m/z): 399.32 ([M+H] ⁺ ). Example 39 4-(5-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-5-oxopentyl) phthalazin-1(2H)-one [408] Following the general procedure 6, the titled compound was synthesized from intermediate 45 (90 mg, 0.37 mmol), DMF (5 ml), intermediate 28 (1110 mg, 0.40 mmol), DIPEA (240 mg, 1.80 mmol) and HBTU (170 mg, 0.44 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (5.5:94.5) as eluent. Appearance: Off-white solid. Yield: 100 mg. % Yield: 64. M.P.: 220-224 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.44 (s, 2H), 8.26 (dd, J 8.0,1.2, 1H), 8.01 (d, J 8.0, 1H), 7.95 (dt, J 7.2,1.2, 1H), 7.86 (dt, J 8.0,1.2, 1H), 3.73 (t, J 4.4, 2H), 3.67 (t, J 4.4, 2H), 3.54-3.49 (m, 4H), 2.96 (t, J 7.2, 2H), 2.44 (t, J 7.6, 2H), 1.77-1.69 (m, 2H), 1.66-1.59 (m, 2H); MS (m/z): 427.55 ([M+H] ⁺ ). Example 40 4-((3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropox y)methyl)phthalazin- 1(2H)-one [409] To TFA (980 mg, 8.6 mmol) and trifluoromethanesulfonic acid (27 mg, 0.18 mmol) cooled to 0°C, intermediate 112 (100 mg, 0.18 mmol) was added and stirred at room temperature for 1h. After 1h, the reaction mixture was cooled to room temperature, quenched with water (50 ml), extracted with ethyl acetate (3 x 50 ml), washed with 10% aqueous potassium carbonate solution (3 x 30 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (3:97) as eluent to obtain the title compound as an off-white solid (40 mg). Yield: 50%. M.P.: 182-185 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.63 (s, 1H), 8.42 (s, 2H), 8.23 (d, J 7.6, 1H), 8.04 (d, J 8.0, 1H), 7.92 (dt, J 8.0,1.2, 1H), 7.84 (t, J 7.6, 1H), 4.69 (s, 2H), 3.78 (t, J 6.4, 2H), 3.64-3.51 (m, 4H), 3.50-3.43 (m, 4H), 2.66 (t, J 6.4, 2H). MS (m/z): 429.39 ([M+H] ⁺ ). Example 41 4-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin- 1- yl)propoxy)methyl)phthalazin-1(2H)-one [410] To TFA (1.50 g, 13.0 mmol) and trifluoromethanesulfonic acid (41 mg, 0.27 mmol) cooled to 0°C, intermediate 114 (160 mg, 0.27 mmol) was added and stirred at room temperature for 1h. After 1h, the reaction mixture was cooled to room temperature, quenched with water (50 ml), extracted with ethyl acetate (3 x 50 ml), washed with 10% aqueous potassium carbonate solution (3 x 30 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (3:97) as eluent to obtain the title compound as an off-white solid (40 mg). Yield: 30%. M.P.: 180-184 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.63 (s, 1H), 8.71 (s, 2H), 8.23 (dd, J 8.0,1.2, 1H), 8.05 (d, J 7.6, 1H), 7.93 (dt, J 7.2,1.2, 1H), 7.84 (dt, J 8.0,1.2, 1H), 4.70 (s, 2H), 3.79 (t, J 6.4, 2H), 3.75-3.73 (m, 4H), 3.53-3.49 (m, 4H), 2.67 (t, J 6.4, 2H). MS (m/z): 463.28 ([M+H] ⁺ ). Example 42 4-((2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin- 1- yl)ethoxy)methyl)phthalazin-1(2H)-one [411] To TFA (1.4 g, 12.0 mmol) and trifluoromethanesulfonic acid (52.0 mg, 0.35 mmol) cooled to 0°C, intermediate 117 (200 mg, 0.35 mmol) was added and stirred at room temperature for 1h. After 1h, the reaction mixture was cooled to room temperature, quenched with water (50 ml), extracted with ethyl acetate (3 x 50 ml), washed with 10% aqueous potassium carbonate solution (3 x 30 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (2.5:97.5) as eluent to obtain the title compound as an off-white solid (100 mg). Yield: 63%. M.P.: 212-214 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.65 (s, 1H), 8.73 (s, 2H), 8.41 (d, J 8.0, 1H), 8.26 (dd, J 7.2,0.8, 1H), 7.96 (dt, J 8.0,1.2, 1H), 7.83 (dt, J 8.0,1.2, 1H), 4.78 (s, 2H), 4.39 (s, 2H), 3.58 (t, J 4.8, 4H), 3.59-3.52 (m, 2H), 3.49-3.42 (m, 2H). MS (m/z): 449.31 ([M+H] ⁺ ). Example 43 4-(4-(4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazin- 1-yl)-4-oxobutyl)phthalazin- 1(2H)-one [412] Following the general procedure 6, the titled compound was synthesized from intermediate 119 (230 mg, 0.71 mmol), DMF (5 ml), intermediate 11 (150 mg, 0.65 mmol), DIPEA (500 mg, 3.9 mmol) and HBTU (290 mg, 0.78 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (1:99) as eluent. Appearance: Off-white solid. Yield: 150 mg. % Yield: 50. M.P.: 196-198 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.36 (s, 1H), 8.27 (dd, J 8.0,1.2, 1H), 8.09 (d, J, 8.0, 1H), 7.96-7.92 (m, 2H), 7.86 (dt, J 8.0,1.2, 1H), 3.68-3.52 (m, 8H), 2.98 (t, J 7.6, 2H), 2.52-2.50 (m, 2H), 1.98-1.91 (m, 2H). MS (m/z): 464.34 ([M+H] ⁺ ). Example 44 4-(5-(4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazin- 1-yl)-5- oxopentyl)phthalazin-1(2H)-one [413] Following the general procedure 6, the titled compound was synthesized from intermediate 119 (200 mg, 0.63 mmol), DMF (5 ml), intermediate 45 (140 mg, 0.57 mmol), DIPEA (440 mg, 3.4 mmol) and HBTU (260 mg, 0.68 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (1:99) as eluent. Appearance: Off-white solid. Yield: 100 mg. % Yield: 37. M.P.: 182-184 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.51 (s, 1H), 8.36 (t, J 0.8, 1H), 8.27 (dd, J 8.0,1.2, 1H), 8.02-7.92 (m, 3H), 7.86 (dt, J 8.0,0.8,1H), 3.62-3.51 (m, 8H), 2.97 (t, J 7.2, 2H), 2.44 (t, J 7.2, 2H), 1.75-1.62 (m, 4H). MS (m/z): 478.43 ([M+H] ⁺ ). Example 45 4-(4-(4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazin- 1-yl)-4-oxobutyl)phthalazin- 1(2H)-one [414] Following the general procedure 6, the titled compound was synthesized from intermediate 121 (240 mg, 0.71 mmol), DMF (5 ml), intermediate 11 (150 mg, 0.65 mmol), DIPEA (500 mg, 3.9 mmol) and HBTU (290 mg, 0.78 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.3:97.7) as eluent. Appearance: Pale-brown solid. Yield: 150 mg. % Yield: 48. M.P.: 212-214 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.57 (dd, J 2.4,1.2, 1H), 8.27 (dd, J 8.0,0.8, 1H), 8.26 (d, J 2.0, 1H), 8.10 (d, J, 8.0, 1H), 7.97 (dt, J 7.2,1.6, 1H), 7.86 (dt, J 8.0,0.8, 1H), 3.68-3.60 (m, 4H), 3.49-3.41 (m, 4H), 2.98 (t, J 7.6, 2H), 2.53-2.50 (m, 2H), 1.99-1.90 (m, 2H). MS (m/z): 480.36 ([M+H] ⁺ ). Example 46 4-(5-(4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazin- 1-yl)-5- oxopentyl)phthalazin-1(2H)-one [415] Following the general procedure 6, the titled compound was synthesized from intermediate 121 (170 mg, 0.49 mmol), DMF (4 ml), intermediate 45 (110 mg, 0.45 mmol), DIPEA (350 mg, 2.7 mmol) and HBTU (200 mg, 0.54 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 140 mg. % Yield: 63. M.P.: 179-181 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.57 (dd, J 2.0,0.8, 1H), 8.27 (dd, J 8.0,0.8, 1H), 8.23 (dd, J 2.0,0.4, 1H), 8.02 (d, J, 8.0, 1H), 7.94 (dt, J 8.0,1.6, 1H), 7.86 (dt, J 8.0, 1.2, 1H), 3.64-3.58 (m, 4H), 3.46-3.39 (m, 4H), 2.97 (t, J 7.2, 2H), 2.44 (t, J 7.2, 2H), 1.77-1.60 (m, 4H). MS (m/z): 494.44 ([M+H] ⁺ ). Example 47 4-(((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin -1- yl)propyl)amino)methyl)phthalazin-1(2H)-one [416] To TFA (1.5 g, 13.0 mmol) and trifluoromethanesulfonic acid (35.0 mg, 0.23 mmol) cooled to 0°C, intermediate 127 (136 mg, 0.23 mmol) was added and stirred at room temperature. After 2.5h, the reaction mixture was cooled to room temperature, quenched with water (30 ml), basified with aqueous sodium bicarbonate solution to pH 8, extracted with 10% methanol in dichloromethane (3 x 30 ml). The organic layer was washed with 10% aqueous potassium carbonate solution (30 ml), brine solution (30 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (6:94) as eluent to obtain the title compound as an off-white solid (24 mg). Yield: 22%. M.P.: 190-192 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.52 (s, 1H), 8.72 (s, 2H), 8.24 (dd, J 8.0,1.2, 1H), 8.15 (d, J 8.0, 1H), 7.92 (dt, J 8.0,1.2, 1H), 7.83 (dt, J 8.0,0.8, 1H), 3.99 (s, 2H), 3.85-3.76 (m, 4H), 3.55 (t, J 5.2, 4H), 2.84 (t, J 6.8, 2H), 2.56 (t, J 6.8, 2H). MS (m/z): 462.26 ([M+H] ⁺ ). Example 48 8-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1 -yl)butyl)pyrido[2,3- d]pyridazin-5(6H)-one [417] Following the general procedure 6, the titled compound was synthesized from intermediate 132 (110 mg, 0.47 mmol), DMF (5 ml), intermediate 11 (170 mg, 0.57 mmol), DIPEA (300 mg, 2.4 mmol) and HBTU (210 mg, 0.57 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (0.7:99.3) as eluent. Appearance: Off-white solid. Yield: 100 mg. % Yield: 47. M.P.: 229-231 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.73 (s, 1H), 9.15 (dd, J 4.4,2.0, 1H), 8.73 (s, 2H), 8.60 (dd, J, 8.0,2.0, 1H), 7.86 (dd, J 8.0,4.4, 1H), 3.87 (t, J 4.8, 2H), 3.81 (t, J 4.8, 2H), 3.56 (t, J 4.8, 4H), 3.08 (t, J 7.6, 2H), 2.50-2.46 (m, 2H), 2.04-1.96 (m, 2H). MS (m/z): 448.33 ([M+H] ⁺ ). Example 49 8-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1 -yl)pentyl)pyrido[2,3- d]pyridazin-5(6H)-one [418] Following the general procedure 6, the titled compound was synthesized from intermediate 135 (80 mg, 0.30 mmol), DMF (3 ml), intermediate 11 (100 mg, 0.30 mmol), DIPEA (200 mg, 2.0 mmol) and HBTU (100 mg, 0.40 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.8:97.2) as eluent. Appearance: Off-white solid. Yield: 90 mg. % Yield: 60. M.P.: 222-224 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.73 (s, 1H), 9.15 (dd, J 4.4,2.0, 1H), 8.73 (s, 2H), 8.60 (dd, J, 8.0,2.0, 1H), 7.86 (dd, J 8.0,4.4, 1H), 3.87 (t, J 4.8, 2H), 3.81 (t, J 4.8, 2H), 3.56 (t, J 4.8, 4H), 3.08 (t, J 7.6, 2H), 2.50-2.46 (m, 2H), 2.04-1.96 (m, 2H). MS (m/z): 448.33 ([M+H] ⁺ ). Example 50 4-((methyl(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)pip erazin-1- yl)propyl)amino)methyl)phthalazin-1(2H)-one [419] To TFA (2.11 g, 18.5 mmol) and trifluoromethanesulfonic acid (50.4 mg, 0.34 mmol) cooled to 0°C, intermediate 139 (200 mg, 0.34 mmol) was added and stirred at room temperature. After 2.5h, the reaction mixture was cooled to room temperature, quenched with water (30 ml), basified with aqueous sodium bicarbonate solution to pH 8, extracted with 10% methanol in dichloromethane (3 x 30 ml). The organic layer was washed with 10% aqueous potassium carbonate solution (30 ml), brine solution (30 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (4:96) as eluent to obtain the title compound as an off-white solid (60 mg). Yield: 38%. M.P.: 182-184 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.54 (s, 1H), 8.72 (s, 2H), 8.20-8.17 (m, 2H), 7.89 (dt, J 7.6,1.6, 1H), 7.81 (dt, J 8.0,1.2, 1H), 3.81- 3.71 (m, 6H), 3.53-3.47 (m, 4H), 2.72 (t, J 7.2, 2H), 2.59 (t, J 7.2, 2H), 2.21 (s, 3H). MS (m/z): 476.41 ([M+H] ⁺ ). Example 51 4-(4-oxo-4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazab icyclo[3.2.1]octan-8- yl)butyl)phthalazin-1(2H)-one

[420] Following the general procedure 6, the titled compound was synthesized from intermediate 9(100 mg, 0.43 mmol), DMF (4 ml), intermediate 141 (143 mg, 0.43 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (4:96) as eluent. Appearance: Off-white solid. Yield: 167 mg. % Yield: 82. M.P.: 204-208 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.72 (s, 2H), 8.27 (dd, J 8.0,1.2, 1H), 8.09 (d, J 7.6, 1H), 7.96 (dt, J 7.2,1.2, 1H), 7.85 (dt, J 8.0,1.2, 1H), 4.67 (d, J 6.8, 1H), 4.51-4.45 (m, 3H), 3.15 (d, J 12.0, 1H), 3.08 (d, J 12.8, 1H), 2.98 (t, J, 8.0, 2H), 2.55-2.50 (m, 2H), 2.00-1.88 (m, 3H), 1.80-1.74 (m, 1H), 1.65-1.50 (m, 2H). MS (m/z): 473.34 ([M+H] ⁺ ). Example 52 4-(4-oxo-4-(6-(5-(trifluoromethyl)pyrimidin-2-yl)-2,6-diazas piro[3.3]heptan-2- yl)butyl)phthalazin-1(2H)-one [421] Following the general procedure 6, the titled compound was synthesized from intermediate 9(100 mg, 0.43 mmol), DMF (2 ml), intermediate 143 (140 mg, 0.43 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3.5:96.5) as eluent. Appearance: Off-white solid. Yield: 45 mg. % Yield: 22. M.P.: 176-179 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.43 (s, 1H), 8.60 (s, 2H), 8.26 (d, J 7.6, 1H), 8.18 (t, J 6.4, 1H), 7.97 (m, 1H), 7.85 (dt, J 6.8,1.2, 1H), 4.00 (d, J 9.6, 2H), 3.93 (s, 2H), 3.89 (d, J 9.6, 2H), 3.48 (d, J 6.0, 2H), 2.85 (t, J 7.6, 2H), 2.26 (t, J, 7.2, 2H), 1.93 (m, 2H). MS (m/z): 459.45 ([M+H] ⁺ ). Example 53 4-(4-oxo-4-(8-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazab icyclo[3.2.1]octan-3- yl)butyl)phthalazin-1(2H)-one [422] Following the general procedure 6, the titled compound was synthesized from intermediate 9(100 mg, 0.43 mmol), DMF (5 ml), intermediate 145 (157 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (4:96) as eluent. Appearance: Off-white solid. Yield: 130 mg. % Yield: 64. M.P.: 225-229 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.45 (s, 1H), 8.73 (s, 2H), 8.27 (d, J 7.2, 1H), 8.08 (d, J 8.0, 1H), 7.95 (dt, J 8.4,1.2, 1H), 7.85 (t, J 7.6, 1H), 4.80 (s, 2H), 4.26 (d, J 12.4, 1H), 3.78 (d, J 12.4, 1H), 3.28 (d, J 12.4, 1H), 2.95 (t, J, 8.0, 2H), 2.81 (d, J 12.8, 1H), 2.60 (m, 1H), 2.41 (m, 1H), 1.94 (m, 4H), 1.82 (m, 1H), 1.66 (m, 1H). MS (m/z): 473.37 ([M+H] ⁺ ). Example 54 (±)-4-(4-oxo-4-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-2,5-d iazabicyclo[2.2.2]octan-2- yl)butyl)phthalazin-1(2H)-one [423] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (5 ml), intermediate 147 (160 mg, 0.47 mmol), DIPEA (280 mg, 2.20 mmol) and HBTU (200 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 70 mg. % Yield: 34. M.P.: 93-96 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.73 (d, J 2.4, 1H), 8.69 (d, J 2.8, 1H), 8.27 (m, 1H), 8.09 (dd, J 8.0,2.0, 1H), 7.96 (m, 1H), 7.86 (m, 1H), 5.00 (s, 1H) , 3.74-3.50 (m, 4H), 2.97 (m, 2H), 2.52 (m, 2H), 2.37 (s, 1H), 1.97 (m, 6H). MS (m/z): 473.41 ([M+H] ⁺ ). Example 55 (±)-4-(4-oxo-4-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-2,5-d iazabicyclo[2.2.1]heptan-2- yl)butyl)phthalazin-1(2H)-one [424] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (5 ml), intermediate 149 (150 mg, 0.47 mmol), DIPEA (280 mg, 2.20 mmol) and HBTU (200 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (6:94) as eluent. Appearance: Off-white solid. Yield: 75 mg. % Yield: 37. M.P.: 220-225 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.45 (s, 1H), 8.69 (d, J 2.8, 2H), 8.27 (dt, J 8.4,0.8, 1H), 8.09 (dt, J 8.4,2.8, 1H), 7.95 (m, 1H), 7.85 (m, 1H), 5.04 (d, J 18.8, 1H), 4.84 (d, J 33.2,1H), 3.64 (m, 2H), 3.44 (m, 2H), 2.96 (m, 2H), 2.63 (m, 1H), 2.36 (m, 1H), 1.98-1.85 (m, 4H). MS (m/z): 459.26 ([M+H] ⁺ ). Example 56 4-(4-(3-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octa n-8-yl)-4- oxobutyl)phthalazin-1(2H)-one [425] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (5 ml), intermediate 151 (147 mg, 0.47 mmol), DIPEA (280 mg, 2.20 mmol) and HBTU (200 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 110 mg. % Yield: 58. M.P.: 212-214 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.47 (s, 1H), 8.43 (s, 2H), 8.27 (d, J 7.2, 1H), 8.09 (d, J 8.0, 1H), 7.95 (dt, J 8.0,1.2, 1H), 7.85 (t, J 8.0, 1H), 4.65 (d, J 6.4, 1H), 4.44 (d, J 6.4,1H), 4.34 (t, J 12.0, 2H), 3.06-2.94 (m, 4H), 2.55- 2.45 (m, 2H), 1.95-1.88 (m, 3H), 1.76-1.74 (m, 1H), 1.63-1.54 (m, 2H). MS (m/z): 439.37 ([M+H] ⁺ ). Example 57 4-(4-oxo-4-(3-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabic yclo[3.2.1]octan-8- yl)butyl)phthalazin-1(2H)-one [426] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (5 ml), intermediate 153 (156 mg, 0.47 mmol), DIPEA (280 mg, 2.20 mmol) and HBTU (200 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 110 mg. % Yield: 54. M.P.: 205-208 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.43 (s, 1H), 8.41 (s, 1H), 8.27 (d, J 7.6, 1H), 8.08 (d, J 8.0, 1H), 7.95 (t, J 8.0, 1H), 7.85-7.80 (m, 2H), 6.89 (d, J 8.8, 1H), 4.68 (d, J 5.2, 1H), 4.47 (d, J 5.2,1H), 4.17-4.09 (m, 2H), 3.55-2.94 (m, 4H), 2.52-2.45 (m, 2H), 1.98-1.91 (m, 3H), 1.79-1.61 (m, 3H). MS (m/z): 472.42 ([M+H] ⁺ ). Example 58 2-(8-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl)-3,8-diaz abicyclo[3.2.1]octan-3- yl)pyrimidine-5-carbonitrile [427] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (5 ml), intermediate 155 (136 mg, 0.47 mmol), DIPEA (280 mg, 2.20 mmol) and HBTU (200 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 120 mg. % Yield: 64. M.P.: 220-223 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.77 (s, 2H), 8.27 (dd, J 8.0,1.2, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt, J 7.2,1.2, 1H), 7.86 (dt, J 8.0,0.8, 1H), 4.67 (d, J 6.8, 1H), 4.51 (m, 3H), 3.16 (d, J 7.6, 1H), 3.09 (d, J 12.0, 1H), 2.98 (t, J 6.8, 2H), 2.56 (m, 2H), 2.01-1.88 (m, 3H), 1.79 (m, 1H), 1.62-1.48 (m, 2H). MS (m/z): 430.39 ([M+H] ⁺ ). Example 59 6-(8-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl)-3,8-diaz abicyclo[3.2.1]octan-3- yl)nicotinonitrile [428] Following the general procedure 6, the titled compound was synthesized from intermediate 9(100 mg, 0.43 mmol), DMF (5 ml), intermediate 157 (136 mg, 0.47 mmol), DIPEA (280 mg, 2.20 mmol) and HBTU (200 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 60 mg. % Yield: 33. M.P.: 221-224 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.50 (d, J 2.0, 1H), 8.26 (d, J 7.2, 1H), 8.08 (d, J 8.0, 1H), 7.96 (dt, J 8.4,1.2, 1H), 7.89 (m, 2H), 6.87 (d, J 9.2, 1H), 4.66 (d, J 5.2, 1H), 4.46 (d, J 6.4, 1H), 4.19 (m, 2H), 3.07-2.94 (m, 4H), 2.56 (m, 2H), 1.98-1.89 (m, 3H), 1.80 (m, 1H), 1.66-1.54 (m, 2H). MS (m/z): 430.39 ([M+H] ⁺ ). Example 60 4-(4-(3-(5-chloropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan- 8-yl)-4-oxobutyl)phthalazin- 1(2H)-one [429] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (90 mg, 0.39 mmol), DMF (5 ml), intermediate 159 (130 mg, 0.43 mmol), DIPEA (250 mg, 1.90 mmol) and HBTU (180 mg, 0.47 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 60 mg. % Yield: 35. M.P.: 206-209 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.27 (dd, J 7.6,2.0, 1H), 8.10 (d, J 2.8, 1H), 8.08 (d, J 8.0, 1H), 7.94 (dt, J 8.0,1.2, 1H), 7.84 (t, J 7.2, 1H), 7.61 (dd, J 9.2,2.8, 1H), 6.78 (d, J 9.2, 1H), 4.66 (d, J 6.0, 1H), 4.44 (d, J 6.4, 1H), 3.99 (d, J 12.0, 1H), 3.94 (d, J 12.0, 1H), 2.97-2.86 (m, 4H), 2.57 (m, 2H), 1.99-1.87 (m, 3H), 1.80-1.61 (m, 3H). MS (m/z): 438.36 ([M+H] ⁺ ). Example 61 4-(4-oxo-4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-diazab icyclo[3.1.1]heptan-6- yl)butyl)phthalazin-1(2H)-one [430] Following the general procedure 6, the titled compound was synthesized from intermediate 9(100 mg, 0.43 mmol), DMF (5 ml), intermediate 161 (150 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (4.5:95.5) as eluent. Appearance: Off-white solid. Yield: 150 mg. % Yield: 76. M.P.: 168-170 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.44 (s, 1H), 8.74 (d, J 2.8, 1H), 8.71 (d, J 2.8, 1H), 8.25 (dd, J 7.6,0.8, 1H), 7.94 (d, J 8.0, 1H), 7.90 (dt, J 6.8,1.6, 1H), 7.83 (dt, J 8.0,1.2, 1H), 4.64 (s, 1H), 4.43 (d, J 1.6, 1H), 4.03 (d, J 11.6, 1H), 3.93 (d, J 12.8, 1H), 3.80 (d, J 13.2, 1H), 3.72 (d, J 12.0, 1H), 2.90 (m, 2H), 2.69 (m, 1H), 2.40 (m, 1H), 2.26 (m, 1H), 1.91 (m, 2H), 1.60 (d, J 8.8, 1H). MS (m/z): 459.28 ([M+H] ⁺ ). Example 62 4-(4-oxo-4-(6-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-diazab icyclo[3.1.1]heptan-3- yl)butyl)phthalazin-1(2H)-one [431] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (5 ml), intermediate 163 (150 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 120 mg. % Yield: 60. M.P.: 164-168 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.43 (s, 1H), 8.74 (s, 2H), 8.26 (dd, J 8.0,1.2, 1H), 8.03 (d, J 8.0, 1H), 7.93 (dt, J 7.2,1.2, 1H), 7.85 (dt, J 8.0,0.8, 1H), 4.56 (d, J 6.4, 2H), 4.01 (d, J 11.2, 1H), 3.85 (d, J 12.8, 1H), 3.68 (d, J 11.2, 1H), 3.53 (d, J 13.2, 1H), 2.86 (m, 2H), 2.78 (m, 1H), 2.43-2.27 (m, 2H), 1.84 (m, 2H), 1.64 (d, J 8.8, 1H). MS (m/z): 459.38 ([M+H] ⁺ ). Example 63 4-(4-(3-(5-(difluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[ 3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one [432] Following the general procedure 6, the titled compound was synthesized from intermediate 9(100 mg, 0.43 mmol), DMF (5 ml), intermediate 165 (148 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 130 mg. % Yield: 73. M.P.: 208-212 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.56 (s, 2H), 8.27 (dd, J 8.0,1.2, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt, J 7.2,1.2, 1H), 7.85 (dt, J 8.0,0.8, 1H), 7.11 (t, J 15.6, 1H), 4.67 (d, J 6.8, 1H), 4.49 (m, 3H), 3.11 (d, J 12.0, 1H), 3.04 (d, J 12.8, 1H), 2.98 (t, J 8.0, 2H), 2.57 (m, 2H), 2.00-1.83 (m, 3H), 1.75 (m, 1H), 1.64 (m, 2H). MS (m/z): 455.34 ([M+H] ⁺ ). Example 64 4-(4-(3-(5-(difluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3. 2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one [433] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (5 ml), intermediate 168 (148 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 110 mg. % Yield: 56. M.P.: 221-224 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.27 (s, 1H), 8.26 (dd, J 8.0,1.2, 1H), 8.08 (d, J 8.0, 1H), 7.94 (dt, J 7.2,1.2, 1H), 7.84 (dt, J 8.0,0.8, 1H), 7.71 (dd, J 8.8,2.4, 1H), 7.07 (t, J 55.6, 1H), 6.85 (d, J 9.2, 1H), 4.67 (d, J 6.4, 1H), 4.46 (d, J 6.4, 1H), 4.12 (d, J 11.2, 1H), 4.07 (d, J 11.2, 1H), 3.00-2.92 (m, 4H), 2.56- 2.45 (m, 2H), 1.99-1.89 (m, 3H), 1.79-1.62 (m, 3H). MS (m/z): 454.28 ([M+H] ⁺ ). Example 65 N-methyl-2-(8-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl) -3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidine-5-carboxamide [434] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (5 ml), intermediate 171 (152 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.52 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 100 mg. % Yield: 50. M.P.: 128-131 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.75 (s, 2H), 8.35 (q, J 4.4, 1H), 8.27 (dd, J 8.0,1.2, 1H), 8.09 (d, J 7.6, 1H), 7.96 (dt, J 7.2,1.2, 1H), 7.85 (dt, J 8.0,0.8, 1H), 4.66 (d, J 6.8, 1H), 4.51-4.48 (m, 3H), 3.15-3.01 (m, 3H), 2.98-2.94 (m, 2H), 2.76 (d, J 4.4, 3H), 2.56-2.45 (m, 1H), 2.00-1.87 (m, 3H), 1.76-1.74 (m, 1H), 1.64-1.50 (m, 2H). MS (m/z): 462.35 ([M+H] ⁺ ). Example 66 4-(4-(3-(5-(methylsulfinyl)pyrimidin-2-yl)-3,8-diazabicyclo[ 3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one [435] Following the general procedure 4, the titled compound was synthesized from intermediate 174 (100 mg, 0.30 mmol), intermediate 172 (59.5 mg, 0.33 mmol), N- Methylpyrrolidone (3 ml) and DIPEA (119 mg, 0.92 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (6.2:93.8) as eluent. Appearance: Pale-brown solid. Yield: 75 mg. % Yield: 52. M.P.: 192-194 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.47 (s, 1H), 8.65 (s, 2H), 8.27 (d, J 7.6, 1H), 8.09 (d, J 7.6, 1H), 7.95 (t, J 7.2, 1H), 7.85 (t, J 7.6, 1H), 4.67 (d, J 4.8, 1H), 4.51-4.46 (m, 3H), 3.13-2.92 (m, 5H), 2.85 (s, 3H), 1.95-1.90 (m, 4H), 1.79-1.67 (m, 1H), 1.62-1.54 (m, 2H). MS (m/z): 467.26 ([M+H] ⁺ ). Example 67 2-(8-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)butanoyl)-3,8-diaz abicyclo[3.2.1]octan-3-yl)- 5-(trifluoromethyl)pyridine 1-oxide [436] To example 57 (200 mg, 0.42 mmol) in dichloromethane, m-perchlorobenzoic acid (366 mg 212 mmol) was added and stirred at room temperature for 12h. After 12h, the reaction mixture was diluted with dichloromethane (50 ml), washed with saturated sodium bicarbonate solution (3 x 30 ml) and concentrated under reduced pressure to obtain the crude. Crude product was purified by combi-flash using methanol and dichloromethane (6.8:93.2) as eluent to obtain the title compound as an off-white solid. Yield: 15 mg. % Yield: 7. M.P.: 104-108 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.57 (s, 1H), 8.27 (d, J 7.2, 1H), 8.09 (d, J 8.0, 1H), 7.96 (t, J 7.6, 1H), 7.86 (t, J 7.2, 1H), 7.60 (d, J 7.2, 1H), 7.13 (d, J 8.8, 1H), 4.63 (d, J 6.8, 1H), 4.28 (d, J 6.0,1H), 4.09 (d, J 10.8, 1H), 3.91 (d, J 10.4, 1H), 2.98-2.88 (m, 4H), 2.54-2.48 (m, 2H), 2.08-2.06 (m, 1H), 2.02-1.82 (m, 4H), 1.78-1.71 (m, 1H). MS (m/z): 488.35 ([M+H] ⁺ ). Example 68 4-(4-(3-(5-(methylsulfonyl)pyrimidin-2-yl)-3,8-diazabicyclo[ 3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one [437] Following the general procedure 4, the titled compound was synthesized from intermediate 176 (200 mg, 0.55 mmol), intermediate 175 (117 mg, 0.60 mmol), N- Methylpyrrolidone (5 ml) and DIPEA (214 mg, 1.65 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3.5:96.5) as eluent. Appearance: Off-white solid. Yield: 120 mg. % Yield: 45. M.P.: 229-232 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.47 (s, 1H), 8.73 (s, 2H), 8.27 (dd, J 8.0,0.8, 1H), 8.09 (d, J 7.6, 1H), 7.94 (dt, J 8.0,1.2, 1H), 7.86 (dt, J 8.0,0.8, 1H), 4.68 (d, J 6.8, 1H), 4.55-4.46 (m, 3H), 3.24 (s, 3H), 3.18 (d, J, 12.8, 1H), 3.11 (d, J 12.0, 1H), 2.98-2.95 (m, 2H), 2.55-2.49 (m, 2H), 2.00-1.89 (m, 3H), 1.79-1.71 (m, 1H), 1.52- 1.49 (m, 2H). MS (m/z): 483.32 ([M+H] ⁺ ). Example 69 4-(4-(3-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,8-diazabicyclo[3 .2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one [438] Following the general procedure 4, the titled compound was synthesized from intermediate 176 (500 mg, 1.25 mmol), intermediate 177 (381 mg, 1.50 mmol), n-butanol (10 ml) and DIPEA (647 mg, 5.01 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (4.5:95.5) as eluent. Appearance: Pale-brown solid. Yield: 33 mg. % Yield: 6. M.P.: 171-175 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 11.33 (s, 1H), 8.59 (s, 1H), 8.26 (d, J 7.2, 1H), 8.09 (d, J 8.0, 1H), 7.95 (dt, J 8.0,1.2, 1H), 7.84 (t, J 7.6, 1H), 7.09 (dd, J 3.6,2.4, 1H), 6.31 (dd, J 3.2,1.6, 1H), 4.67 (d, J 6.0, 1H), 4.43-4.36 (m, 3H), 3.01-2.93 (m, 4H), 2.54-2.48 (m, 2H), 1.98-1.87 (m, 3H), 1.78-1.61 (m, 3H). MS (m/z): 444.42 ([M+H] ⁺ ). Example 70 4-(4-(3-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octa n-8-yl)-4-oxobutyl)-8- fluorophthalazin-1(2H)-one [439] Following the general procedure 6, the titled compound was synthesized from intermediate 184 (150 mg, 0.59 mmol), DMF (5 ml), intermediate 151 (196 mg, 0.66 mmol), DIPEA (387 mg, 3.00 mmol) and HBTU (296 mg, 0.77 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3.1:96.7) as eluent. Appearance: Off-white solid. Yield: 125 mg. % Yield: 43. M.P.: 250-252 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.44 (s, 1H), 8.43 (s, 2H), 7.96 (dd, J 8.4,5.2, 1H), 7.89 (d, J 7.2, 1H), 7.61 (dt, J 11.2,8.4, 1H), 4.64 (d, J 6.4, 1H), 4.44 (d, J 6.4, 1H), 4.34 (d, J 12.4, 1H), 4.31 (d, J 11.2, 1H), 3.06 (t, J 12.8, 2H), 2.96-2.80 (m, 2H), 2.57-2.42 (m, 2H), 1.97-1.86 (m, 3H), 1.78-1.71 (m, 1H), 1.65-1.51 (m, 2H). MS (m/z): 457.25 ([M+H] ⁺ ). Example 71 4-(4-(3-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octa n-8-yl)-4- oxobutyl)phthalazin-1(2H)-one [440] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (120 mg, 0.52 mmol), DMF (3 ml), intermediate 186 (145 mg, 0.52 mmol), DIPEA (334 mg, 2.58 mmol) and HBTU (225 mg, 0.62 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3.1:96.7) as eluent. Appearance: Pale-brown solid. Yield: 120 mg. % Yield: 55. M.P.: 185-187 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.47 (s, 1H), 8.45 (s, 2H), 8.27 (dd, J 8.0,1.2, 1H), 8.08 (d, J 8.0, 1H), 7.95 (dt, J 7.2,1.2, 1H), 7.85 (dt, J 8.0,0.8, 1H), 4.65 (d, J 6.8, 1H), 4.44 (d, J 6.4, 1H), 4.29 (d, J 11.2, 1H), 4.26 (d, J 10.0, 1H), 3.04 (d, J 12.4, 1H), 2.98-2.94 (m, 3H), 2.54-2.44 (m, 2H), 1.99-1.88 (m, 3H), 1.77-1.74 (m, 1H), 1.65-1.56 (m, 2H). MS (m/z): 423.32 ([M+H] ⁺ ). Example 72 4-(4-(3-(9H-purin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4 -oxobutyl)phthalazin-1(2H)- one [441] To intermediate 188 (130 mg, 0.25 mmol) in methanol (5 ml) cooled to 0 ^o C, 6N HCl (3.5 ml) was added and stirred at room temperature for 3h. After 3h, the reaction mixture was basified with saturated sodium bicarbonate solution (70 ml), extracted with 10% methanol in dichloromethane (3 x 50 ml). The organic layer was concentrated under reduced pressure to obtain the crude. Crude product was purified by combi-flash using methanol and dichloromethane (9.5:90.5) as eluent to obtain the title compound as an off-white solid. Yield: 30 mg. % Yield: 30. M.P.: 198-202 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.74 (s, 1H), 12.47 (s, 1H), 8.70 (s, 1H), 8.27 (dd, J 8.0,1.2, 1H), 8.11 (s, 1H), 8.09 (d, J 8.0, 1H), 7.95 (dt, J 7.2,1.2, 1H), 7.85 (dt, J 8.0,0.8, 1H), 4.67 (d, J 6.0, 1H), 4.45-4.36 (m, 3H), 3.05-2.94 (m, 4H), 2.55-2.46 (m, 2H), 2.00-1.86 (m, 3H), 1.77-1.58 (m, 3H). MS (m/z): 445.48 ([M+H] ⁺ ). Example 73 4-(4-(3-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,8-diazabicyclo[ 3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one [442] Following the general procedure 4, the titled compound was synthesized from intermediate 176 (646 mg, 1.62 mmol), 6-chloro-1H-pyrazolo[3,4-d] pyrimidine (250 mg, 1.62 mmol), n-butanol (10 ml) and DIPEA (1.05 g, 8.09 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (5:95) as eluent. Appearance: Pale-yellow solid. Yield: 43 mg. % Yield: 6. M.P.: 248-250 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.12 (s, 1H), 12.47 (s, 1H), 8.90 (s, 1H), 8.27 (dd, J 8.0,0.8, 1H), 8.09 (d, J 8.0, 1H), 7.99 (s, 1H), 7.95 (dt, J 8.4,1.2, 1H), 7.85 (t, J 7.6, 1H), 4.68 (d, J 6.4, 1H), 4.52-4.44 (m, 3H), 3.10 (d, J 12.4, 1H), 3.04 (d, J 12.8, 1H), 2.99 (t, J 7.2, 2H), 2.57-2.46 (m, 2H), 2.00-1.87 (m, 3H), 1.77-1.55 (m, 3H). MS (m/z): 445.40 ([M+H] ⁺ ). Example 74 4-(4-(8-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octa n-3-yl)-4- oxobutyl)phthalazin-1(2H)-one [443] Following the general procedure 4, the titled compound was synthesized from intermediate 190 (500 mg 125 mmol), 2,5-dichloropyrimidine (205 mg, 1.37 mmol), N- Methylpyrrolidone (7.5 ml) and K2CO3 (519 mg, 3.75 mmol). Purification: Not done. Appearance: Pale-brown solid. Yield: 180 mg. % Yield: 33. M.P.: 214-216 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.46 (s, 2H), 8.26 (d, J 7.6, 1H), 8.07 (d, J 8.0, 1H), 7.94 (t, J 7.2, 1H), 7.84 (t, J 7.2, 1H), 4.66 (s, 2H), 4.19 (d, J 12.8, 1H), 3.70 (d, J 12.4,1H), 3.26 (d, J 12.4, 2H), 2.93 (t, J 7.2, 2H), 2.79 (d, J 11.2, 1H), 2.40-2.33 (m, 1H), 1.92-1.89 (m, 4H), 1.79-1.70 (m, 1H), 1.62-1.58 (m, 1H). MS (m/z): 439.60 ([M+H] ⁺ ). Example 75 4-(4-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3,8-diaza bicyclo[3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one [444] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (120 mg, 0.52 mmol), DMF (3 ml), intermediate 192 (210 mg, 0.57 mmol), DIPEA (400 mg, 3.1 mmol) and HBTU (240 mg, 0.62 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.2:97.8) as eluent. Appearance: Pale-brown solid. Yield: 100 mg. % Yield: 38. M.P.: 181-183 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.55 (dd, J 2.4,1.2, 1H), 8.27 (dd, J 7.6,0.8, 1H), 8.19 (d, J 1.6, 1H), 8.09 (d, J 8.0, 1H), 7.96 (dt, J 7.2,1.6, 1H), 7.86 (dt, J 8.4,1.2, 1H), 4.63 (d, J 6.8, 1H), 4.43 (s, 1H), 3.88 (d, J 12.4, 2H), 3.12 (d, J 11.6, 1H), 3.04 (d, J 12.0, 1H), 2.98-2.94 (m, 2H), 2.51-2.50 (m, 2H), 1.99-1.82 (m, 5H), 1.79-1.71 (m, 1H). MS (m/z): 506.45 ([M+H] ⁺ ). Example 76 4-(5-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3,8-diaza bicyclo[3.2.1]octan-8-yl)-5- oxopentyl)phthalazin-1(2H)-one [445] Following the general procedure 6, the titled compound was synthesized from intermediate 45 (110 mg, 0.45 mmol), DMF 43 ml), intermediate 192 (180 mg, 0.49 mmol), DIPEA (350 mg, 2.7 mmol) and HBTU (200 mg, 0.54 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.6:97.4) as eluent. Appearance: Off-white solid. Yield: 120 mg. % Yield: 52. M.P.: 101-103 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.46 (s, 1H), 8.54 (s, 1H), 8.26 (d, J 7.6, 1H), 8.19 (s, 1H), 8.01 (d, J 8.0, 1H), 7.95 (t, J 7.2, 1H), 7.85 (t, J 7.2, 1H), 4.61 (d, J 5.2, 1H), 4.42 (s, 1H), 3.86 (d, J 12.0, 2H), 3.08 (d, J 12.0, 1H), 2.98-2.93 (m, 3H), 2.43-2.33 (m, 2H), 1.89-1.82 (m, 3H), 1.73-1.651 (m, 5H). MS (m/z): 520.53 ([M+H] ⁺ ). Example 77 4-((3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabi cyclo[3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one [446] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (120 mg, 0.52 mmol), DMF (4 ml), intermediate 194 (200 mg, 0.57 mmol), DIPEA (400 mg, 3.1 mmol) and HBTU (240 mg, 0.62 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 110 mg. % Yield: 43. M.P.: 177-179 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.47 (s, 1H), 8.33 (s, 1H), 8.27 (d, J 6,8, 1H), 8.09 (d, J 7.6, 1H), 7.95-7.91 (m, 2H), 7.85 (t, J 7.2, 1H), 4.65 (d, J 5.2, 1H), 4.44 (d, J 6.0, 1H), 4.06 (d, J 12.4, 2H), 3.20 (d, J 12.4, 1H), 3.12 (d, J 12.0, 1H), 2.98 (t, J 7.6, 2H), 2.53-2.50 (m, 2H), 1.98-1.22 (m, 3H), 1.79-1.74 (m, 3H). MS (m/z): 490.41 ([M+H] ⁺ ). Example 78 8-(3-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8 -yl)-5-oxopentyl)pyrido[2,3- d]pyridazin-5(6H)-one [447] Following the general procedure 6, the titled compound was synthesized from intermediate 135 (80 mg, 0.30 mmol), DMF (3 ml), intermediate 151 (100 mg, 0.30 mmol), DIPEA (200 mg, 2.00 mmol) and HBTU (100 mg, 0.4 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3.1:96.9) as eluent. Appearance: Pale-brown solid. Yield: 80 mg. % Yield: 43. M.P.: 220-222 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.72 (s, 1H), 9.14 (dd, J 4.4,1.6, 1H), 8.58 (dd, J 8.0,1.6, 1H), 8.42 (s, 2H), 7.85 (dd, J 8.0,4.4, 1H), 4.61 (d, J 6.8, 1H), 4.25 (d, J 6.4, 1H), 4.23 (t, J 11.6, 2H), 3.05-2.99 (m, 3H), 2.94 (d, J 12.0, 1H), 2.42-2.36 (m, 2H), 1.91-1.81 (m, 1H), 1.78-1.70 (m, 3H), 1.66-1.52 (m, 4H). MS (m/z): 454.42 ([M+H] ⁺ ). Example 79 4-(3-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1] octan-8-yl)-5- oxopentyl)phthalazin-1(2H)-one [448] Following the general procedure 6, the titled compound was synthesized from intermediate 45 (100 mg, 0.41 mmol), DMF (3 ml), intermediate 151 (120 mg, 0.41 mmol), DIPEA (260 mg, 2.00 mmol) and HBTU (180 mg, 0.49 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3.3:96.7) as eluent. Appearance: Off-white solid. Yield: 100 mg. % Yield: 54. M.P.: 230-232 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.47 (s, 1H), 8.42 (s, 2H), 8.26 (dd, J 8.0,1.2, 1H), 8.01 (d, J 7.6, 1H), 7.95 (dt, J 7.2,1.6, 1H), 7.85 (dt, J 8.0,1.2, 1H), 4.61 (d, J 6.8, 1H), 4.43 (d, J 6.4, 1H), 4.32 (t, J 12.8, 2H), 3.03 (d, J 12.4, 1H), 2.97-2.91 (m, 3H), 2.46-2.33 (m, 2H), 1.88-1.83 (m, 1H), 1.77-1.50 (m, 7H). MS (m/z): 453.32 ([M+H] ⁺ ). Example 80 4-(5-oxo-3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicy clo[3.2.1]octan-8- yl)pentyl)phthalazin-1(2H)-one [449] Following the general procedure 6, the titled compound was synthesized from intermediate 45 (100 mg, 0.41 mmol), DMF (3 ml), intermediate 141 (148 mg, 0.44 mmol), DIPEA (315 mg, 2.44 mmol) and HBTU (185 mg, 0.49 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.6:97.4) as eluent. Appearance: Off-white solid. Yield: 110 mg. % Yield: 52. M.P.: 222-224 ^o C. ¹ H-NMR (δ ppm, DMSO-d ₆ , 400 MHz): 12.46 (s, 1H), 8.71 (s, 2H), 8.26 (dd, J 8.0,1.2, 1H), 8.01 (d, J 7.6, 1H), 7.95 (dt, J 7.2,1.6, 1H), 7.85 (dt, J 8.0,1.2, 1H), 4.64 (d, J 6.8, 1H), 4.48-4.43 (m, 3H), 3.12 (d, J 12.4, 1H), 3.03 (d, J 12.4, 1H), 2.97 (t, J 6.8, 2H), 2.48-2.38 (m, 2H), 1.92-1.82 (m, 1H), 1.76-1.51 (m, 7H). MS (m/z): 487.26 ([M+H] ⁺ ). Example 81 8-(5-oxo-5-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazab icyclo[3.2.1]octan-8- yl)pentyl)pyrido[2,3-d]pyridazin-5(6H)-one [450] Following the general procedure 6, the titled compound was synthesized from intermediate 135 (100 mg, 0.40 mmol), DMF (3 ml), intermediate 141 (100 mg, 0.40 mmol), DIPEA (260 mg, 2.00 mmol) and HBTU (180 mg, 0.49 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 100 mg. % Yield: 51. M.P.: 207-209 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.72 (s, 1H), 9.15 (dd, J 4.8,2.0, 1H), 8.71 (s, 2H), 8.58 (dd, J 8.0,1.6, 1H), 7.85 (dd, J 8.0,4.8, 1H), 4.63 (d, J 6.8, 1H), 4.48-4.43 (m, 3H), 3.12 (d, J 12.4, 1H), 3.06-3.00 (m, 3H), 2.47-2.33 (m, 2H), 1.91- 180 ( 1H) 179170 ( 3H) 167-1.48 (m, 4H). MS (m/z): 488.43 ([M+H] ⁺ ). Example 82 4-(((3-oxo-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diaz abicyclo[3.2.1]octan-8- yl)propyl)amino)methyl)phthalazin-1(2H)-one [451] To TFA (1.77 g, 15.5 mmol) and trifluoromethanesulfonic acid (420 mg, 2.8 mmol) cooled to 0°C, intermediate 196 (200 mg, 0.28 mmol) was added and stirred at room temperature. After 2.5h, the reaction mixture was cooled to room temperature, quenched with water (30 ml), basified with aqueous sodium bicarbonate solution to pH 8, extracted with 10% methanol in dichloromethane (3 x 30 ml). The organic layer was washed with 10% aqueous potassium carbonate solution (30 ml), brine solution (30 ml) and distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (5.2:94.8) as eluent to obtain the title compound as an off-white solid (40 mg). Yield: 29%. M.P.: 180-182 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.50 (s, 1H), 8.69 (s, 2H), 8.20 (dd, J 8.0,0.8, 1H), 8.12 (d, J 8.0, 1H), 7.86 (dt, J 8.0,1.2, 1H), 7.78 (dt, J 8.0,0.8, 1H), 4.62 (d, J 6.8, 1H), 4.43-4.38 (m, 3H), 3.98 (s, 2H), 3.10 (d, J 12.4, 1H), 3.00 (d, J 12.4, 1H), 2.86 (t, J 6.4, 2H), 2.55-2.50 (m, 2H), 2.41-2.31 (m, 1H), 1.86-1.81 (m, 1H), 1.72-1.69 (m, 1H), 1.58-1.50 (m, 2H). MS (m/z): 488.41 ([M+H] ⁺ ). Example 83 4-(((3-oxo-3-(3-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazab icyclo[3.2.1]octan-8- yl)propyl)amino)methyl)phthalazin-1(2H)-one [452] To TFA (2.66 g, 23.3 mmol) and trifluoromethanesulfonic acid (63.7 mg, 0.42 mmol) cooled to 0°C, intermediate 197 (300 mg, 0.42 mmol) was added and stirred at room temperature. After 2.5h, the reaction mixture was cooled to room temperature, quenched with water (30 ml), basified with aqueous sodium bicarbonate solution to pH 8, extracted with 10% methanol in dichloromethane (3 x 30 ml). The organic layer was washed with 10% aqueous potassium carbonate solution (30 ml), brine solution (30 ml) and distilled under reduced pressure using rotavapor to obtain a crude. Crude product was purified by combi-flash using methanol and dichloromethane (5.8:94.2) as eluent to obtain the title compound as an off-white solid (100 mg). Yield: 48%. M.P.: 172-174 ^o C. ¹ H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.50 (s, 1H), 8.39 (s, 1H), 8.20 (d, J 7.6, 1H), 8.12 (d, J 8.0, 1H), 7.86-7.74 (m, 3H), 6.83 (d, J 8.0, 1H), 4.62 (d, J 6.0, 1H), 4.43 (d, J 5.6, 1H), 4.09 (dd, J 12.0,4.8, 2H), 3.98 (s, 2H), 3.00 (d, J 12.4, 1H), 2.92 (d, J 11.6, 1H), 2.85 (t, J 6.4, 2H), 2.50-2.48 (m, 2H), 2.39-2.31 (m, 1H), 1.91- 1.81 (m, 1H), 1.78-1.51 (m, 3H). MS (m/z): 487.46 ([M+H] ⁺ ). PARP Enzyme Assay Assay Protocol [453] A pre-coated histone 384-well plate was used for the assay. A ribosylation mixture containing substrate reaction mixture, DTT and water was prepared in 1X PARP assay buffer and 12.5 μL of this mixture was dispensed per well. The inhibitor was prepared in 1X PARP buffer. 2.5 μL (10X concentration) of 1X PARP buffer containing the inhibitor was added to each well. For the “Positive Control" and “Blank,” 2.5 μL of 1X buffer containing dimethyl sulfoxide (DMSO) was added. The final DMSO concentration in the well was 0.4%. PARP7 enzyme was prepared in 1X PARP buffer, and the reaction was initiated by adding 10 µL of diluted PARP7 enzyme to the designated wells. To the wells designated as "Blank," 10 μL of 1X PARP buffer was added. The plate was centrifuged for 30 seconds and incubated at room temperature for 60 minutes. The reaction mixture was discarded after 1 hour, and the plate was washed three times with 100 µL phosphate buffer saline (1 x PBS containing 0.05 % Tween-20 (PBST)) buffer. 25 µL of diluted (1:50 in blocking buffer) Streptavidin-Horseradish Peroxide (HRP) was added to each well. The plate was incubated for 30 minutes at room temperature. The plate was washed three times with 100 µL PBST buffer. Equal amounts of Enzyme Linked Immuno-Sorbent Assay (ELISA) Enhanced Chemiluminescence (ECL) Substrate-A and ELISA ECL Substrate-B were mixed and 50 µL was added per well. Immediately readings were recorded in a chemiluminescence setting in a plate-reader. % Inhibition Calculations [454] The “Blank well readings” were subtracted from the “Test compound well readings” and “DMSO well readings”, and the percent inhibition was calculated relative to a DMSO control sample. Formula [455] 100 - (Test compound well readings - Blank well readings) * 100 / (DMSO well readings - Blank well readings) IC50 Calculations [456] The “Blank well readings” were subtracted from the “Test compound well readings” and “DMSO well readings” and the percent inhibition was calculated relative to a DMSO control sample. The percent inhibition values were plotted in GraphPad Prism (Version 5.02) and IC ₅₀ values were determined. The results for percent inhibition and the IC ₅₀ values of exemplary compounds described herein are shown in Table 3 below. TABLE-3 [457] The compounds in Table 3 having a percent inhibition at 10 nM and 100 nM are categorised as follows: > 50 % inhibition as “+++” and 20% - 50% inhibition as “++”. IC50 values of the compounds in Table 3 are categorised as follows: IC50 ≤ 25 nM as “A”; IC50 between 25.01 nM and 50 nM as “B”; and IC50 > 50 nM as “C”. The symbol “_” represents that the compound was not tested. Cell Proliferation Assay Protocol in NCI-H1373 & Panc 03.27 Cancer Cell Lines [458] MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell proliferation assay in NCI-H1373 & Panc 03.27 cell lines was performed to determine GI50 values for compounds of the present invention. The cells were plated in 100 µl/well of their respective complete media in a 96-well plate in triplicate at the desired density and plates were incubated at 37 °C and 5% CO ₂ . The next day, cells in each well were treated with the inhibitor dilutions prepared in complete media, in triplicate, and plates were incubated at 37 °C and 5% CO ₂ for 144 hours. After 144 hours, 15 µL of 5 mg/mL of MTT was added to the test wells and mixed well. The plates were incubated at 37 °C and 5% CO2 for 3.5 hours. After incubation, the cells were pelleted down at 4000 rpm for 10 minutes. Media was aspirated and 150 µL of DMSO per well was added. Crystals were dissolved by repeated pipetting. Absorbance was read at A560 nM and A640 nm. GI ₅₀ values were calculated using GraphPad Prism. GI50 values for select compounds described herein are provided in Table 4. TABLE-4 [459] GI50 values of ≤ 1 µM and in the range of > 1 µM to 10 µM are categorised as “##” and “###” respectively. [460] All references, patents, and patent applications cited herein are hereby incorporated by reference.