Related applications

This application claims benefit of Indian provisional application No(s). 3235/MUM/2011 filed on November 16, 2011; 1577/MUM/2012 filed on May 25, 2012; 2559/MUM/2012 filed on September 3, 2012 and US provisional application No(s). 61/576,813 filed on December 16, 2011; 61/665,279 filed on June 27, 2012; 61/707,842 filed on September 28, 2012. All of which are hereby incorporated by reference in their entirety.

Technical Field

The present patent application is directed to bicyclic compounds which may be useful as microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors.

Background

There are many diseases or disorders that are inflammatory in their nature. One of the major problems associated with existing treatments of inflammatory condition is inadequate efficacy and/or the prevalence of side effects. Inflammatory diseases that affect the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis. Inflammation is also a common cause of pain.

The enzyme cyclooxygenase (COX) converts arachidonic acid to an unstable intermediate, prostaglandin H ₂ (PGH ₂ ) which is further converted to other prostaglandins including PGE ₂ , PGF _2a , PGD ₂ , prostacyclin and thromboxane A ₂ . These arachidonic acid metabolites are known to have pronounced physiological and pathophysiological activity including pro-inflammatory effects. The COX enzyme exists in two forms, one that is constitutively expressed in many cells and tissues (COX-1), and other that in most cells and tissues are induced by pro-inflammatory stimuli, such as cytokines, during an inflammatory response (COX-2).

Among all prostaglandin metabolites, PGE ₂ is particularly known to be a strong proinflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE ₂ , including "NSAIDs" (non-steroidal anti-inflammatory drugs) and "coxibs" (selective COX-2 inhibitors). These drugs act predominantly by inhibition of COX-1 and/or COX-2, thereby reducing the formation of PGE ₂ . However, the inhibition of COXs has the disadvantage that it results in the reduction of the formation of all metabolites of PGH ₂ , thereby decreasing the beneficial properties of some of the metabolites. In view of this, drugs which act by inhibition of COXs are therefore known / suspected to cause adverse biological effects. For example, the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function. Even the selective inhibition of COX-2 by coxibs, whilst reducing such gastrointestinal side-effects, is believed to give rise to cardiovascular problems.

A combination of pharmacological, genetic and neutralizing antibody approaches demonstrates the importance of PGE ₂ in inflammation. The conversion of PGH ₂ to PGE ₂ by prostaglandin E synthases (PGES) may therefore represent a pivotal step in the propagation of inflammatory stimuli. Microsomal prostaglandin E synthase- 1 (mPGES-1) is an inducible PGES after exposure to pro-inflammatory stimuli. mPGES-1 is induced in the periphery and CNS by inflammation and represents therefore a target for acute and chronic inflammatory disorders. PGE ₂ is a major prostanoid, produced from arachidonic acid liberated by phospholipases (PLAs), which drives the inflammatory processes. Arachidonic acid is transformed by the action of prostaglandin H synthase (PGH synthase, cycloxygenase) into PGH ₂ which is a substrate for mPGES-1, which is the terminal enzyme transforming PGH ₂ to the pro-inflammatory PGE ₂ .

PGH ₂ may be transformed to PGE ₂ by prostaglandin E synthases (PGES). There are two microsomal prostaglandin E synthases (mPGES-1 and mPGES-2), and one cytosolic prostaglandin E synthase (cPGES). Thus, agents that are capable of inhibiting the action of mPGES-1, and thus reducing the formation of the specific arachidonic acid metabolite PGE ₂ , are likely to be of benefit in the treatment of inflammation. Further, agents that are capable of inhibiting the action of the proteins involved in the synthesis of the leukotrienes are also likely to be of benefit in the treatment of asthma and COPD.

Blocking the formation of PGE ₂ in animal models of inflammatory pain results in reduced inflammation, pain and fever response (Kojima et. al, The Journal of Immunology 2008, 180, 8361-6; Xu et. al., The Journal of Pharmacology and Experimental Therapeutics 2008, 326, 754-63). In abdominal aortic aneurism, inflammation leads to connective tissue degradation and smooth muscle apoptosis ultimately leading to aortic dilation and rupture. In animals lacking mPGES-1 a slower disease progression and disease severity has been demonstrated (Wang et. al, Circulation, 2008, 117, 1302-1309).

Several lines of evidence indicate that PGE ₂ is involved in malignant growth. PGE ₂ facilitates tumour progression by stimulation of cellular proliferation and angiogenesis and by modulation of immunosupression. In support of a role for PGE ₂ in cancers, genetic deletion of mPGES-1 in mice suppresses the intestinal tumourogenesis (Nakanishi et. al., Cancer Research 2008, 68(9), 3251-9). In human beings, mPGES-1 is also upregulated in cancers such as colorectal cancer {Schroder Journal of Lipid Research 2006, 47, 1071-80).

Myositis is chronic muscle disorder characterized by muscle weakness and fatigue. Proinflammatory cytokines and prostanoids have been implicated in the development of myositis. In skeletal muscle tissue from patients suffering from myositis an increase in cyclooxygenases and mPGES-1 has been demonstrated, implicating mPGES-1 as a target for treating this condition. (Korotkova Annals of the Rheumatic Diseases 2008, 67, 1596- 1602).

In atherosclerosis inflammation of the vasculature leads to atheroma formation that eventually may progress into infarction. In patients with carotid atherosclerosis an increase in mPGES-1 in plaque regions have been reported (Gomez -Hernandez Atherosclerosis 2006,187, 139-49). In an animal model of atherosclerosis, mice lacking the mPGES-1 receptor were found to show a retarded atherogenesis and a concomitant reduction in macrophage-derived foam cells together with an increase in vascular smooth muscle cells (Wang, Proceedings of National Academy of Sciences 2006, 103(39), 14507-12).

PCT publication numbers WO2006/063466, WO2007/059610, WO2010/034796, and WO2010/100249 disclose numerous heterocyclic compounds which are shown to be inhibitors of microsomal prostaglandin E synthase- 1 (mPGES-1) enzyme.

The present application is directed to compounds that may be inhibitors of the mPGES-1 enzyme and would therefore be useful for the treatment of pain and inflammation in a variety of diseases or conditions.

Summary

The present patent application is directed to compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein,

A is selected from C ₆ -i ₄ aryl, 5-14 membered heteroaryl and 3-15 membered heterocyclyl; G ¹ , G ² and G ³ , which may be same or different, are independently selected from nitrogen and CR ³ ;

L is a bond or selected from -(CR ^x R ^y ) _n NR ^x -, -(CR ^x R ^y ) _n C(0)NR ^x -, -(CR ^x R ^y ) _n C(0)0-, - (CR ^x R ^y ) _n NR ^x C(0)-, -(CR ^x R ^y ) _n NR ^x C(0)NR ^y -, -(CR ^x R ^y ) _n NR ^x C(0)0-, -(CR ^x R ^y ) _n NR ^x S0 ₂ -, - (CR ^x R ^y ) _n OC(0)-, -(CR ^x R ^y ) _n OC(0)0-, -(CR ^x R ^y ) _n OC(0)NR ^x -, -(CR ^x R ^y ) _n S(0)-, - (CR ^x R ^y ) _n S0 ₂ -, -(CR ^x R ^y ) _n S(0)NR ^x -, -(CR ^x R ^y ) _n S0 ₂ NR ^x - and -(CR ^x R ^y ) _n S-;

W is selected from hydrogen, substituted or unsubstituted Ci_ ₈ alkyl, substituted or unsubstituted C ₂ _ioalkenyl, substituted or unsubstituted C ₂ _ioalkynyl, substituted or unsubstituted Ci.galkoxyCi.galkyl, substituted or unsubstituted haloCi_galkyl, substituted or unsubstituted hydroxyCi_galkyl, substituted or unsubstituted C ₃ _i ₂ cycloalkyl, substituted or unsubstituted C ₃ _ ₈ cycloalkenyl, substituted or unsubstituted C ₆ _i ₄ aryl, substituted or unsubstituted 3 to 15 membered heterocyclyl, and substituted or unsubstituted 5 to 14 membered heteroaryl;

R ¹ is selected from hydrogen, substituted or unsubstituted Ci_galkyl, substituted or unsubstituted C ₂ _ioalkenyl, substituted or unsubstituted C ₂ _ioalkynyl, substituted or unsubstituted Ci_ ₈ alkoxyCi_ ₈ alkyl, substituted or unsubstituted haloCi_ ₈ alkyl, substituted or unsubstituted hydroxyCi_ ₈ alkyl, substituted or unsubstituted C ₃ -i ₂ cycloalkyl, substituted or unsubstituted C ₃ _ ₈ cycloalkylCi_ ₈ alkyl, substituted or unsubstituted C ₃ _ ₈ cycloalkenyl, substituted or unsubstituted C ₃ _ ₈ cycloalkenylCi_ ₈ alkyl, substituted or unsubstituted C ₆ -i ₄ aryl, substituted or unsubstituted C ₆ _i ₄ arylCi_ ₈ alkyl, substituted or unsubstituted 3-15 membered heterocyclyl, substituted or unsubstituted 3-15 membered heterocyclylCi_ ₈ alkyl, substituted or unsubstituted 5-14 membered heteroaryl and substituted or unsubstituted 5-14 membered heteroarylC i_ ₈ alkyl;

at each occurrence R ² and R ³ , which may be the same or different, are independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted Ci_ 8alkyl, substituted or unsubstituted C ₂ _ioalkenyl, substituted or unsubstituted C ₂ _ioalkynyl, substituted or unsubstituted Ci_ ₈ alkoxy, substituted or unsubstituted Ci_ ₈ alkoxyCi_ ₈ alkyl, substituted or unsubstituted haloCi_ ₈ alkyl, substituted or unsubstituted haloCi_ ₈ alkoxy, substituted or unsubstituted hydroxyCi_ ₈ alkyl, substituted or unsubstituted C ₃ _i ₂ cycloalkyl, substituted or unsubstituted C ₃ _ ₈ cycloalkylCi_ ₈ alkyl, substituted or unsubstituted C ₃ _ scycloalkenyl, substituted or unsubstituted C ₃ _gcycloalkenylCi_galkyl, substituted or unsubstituted C ₆ -i ₄ aryl, substituted or unsubstituted C ₆ -i ₄ aryloxy, substituted or unsubstituted C ₆ -i ₄ arylCi_galkyl, substituted or unsubstituted 3-15 membered heterocyclyl, substituted or unsubstituted 3-15 membered heterocyclylCi_ ₈ alkyl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 5-14 membered heteroarylCi_ ₈ alkyl, - C(0)R ^a , -C(0)NR ^a R ^b , -C(0)OR ^a , -NR ^a R ^b , -NR ^a C(0)R ^b , -NR ^a C(0)NR ^a R ^b , -NR ^a C(0)OR ^b , - N(R ^a )S0 ₂ R ^b , -OC(0)R ^a , -OC(0)OR ^a , -OC(0)NR ^a R ^b , -S(0)R ^a , -S0 ₂ R ^a , -S(0)NR ^a R ^b , - S0 ₂ NR ^a R ^b and -SR ^a ;

at each occurrence R ⁴ , is selected from halogen, nitro, cyano, hydroxyl, substituted or unsubstituted Ci_ ₈ alkyl, substituted or unsubstituted C ₂ _i ₀ alkenyl, substituted or unsubstituted C ₂ _i ₀ alkynyl, substituted or unsubstituted Ci_ ₈ alkoxy, substituted or unsubstituted Ci_ galkoxyCi.galkyl, substituted or unsubstituted haloCi_ ₈ alkyl, substituted or unsubstituted haloCi.galkoxy, substituted or unsubstituted hydroxyCi_galkyl, substituted or unsubstituted C ₃ _ i ₂ cycloalkyl, substituted or unsubstituted C ₃ _gcycloalkylCi_galkyl, substituted or unsubstituted C ₃ _ ₈ cycloalkenyl, substituted or unsubstituted C ₃ _ ₈ cycloalkenylCi_ ₈ alkyl, substituted or unsubstituted C ₆ _i ₄ aryl, C ₆ _i ₄ aryloxy, substituted or unsubstituted C ₆ -i ₄ arylCi_ ₈ alkyl, substituted or unsubstituted 3-15 membered heterocyclyl, substituted or unsubstituted 3-15 membered heterocyclylCi_ ₈ alkyl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 5-14 membered heteroarylCi_ ₈ alkyl, -C(0)R ^a , -C(0)NR ^a R ^b , - C(0)OR ^a , -NR ^a R ^b , -NR ^a C(0)R ^b , -NR ^a C(0)NR ^a R ^b , -NR ^a C(0)OR ^b , -N(R ^a )S0 ₂ R ^b , -OC(0)R ^a , - OC(0)OR ^a , -OC(0)NR ^a R ^b , -S(0)R ^a , -S0 ₂ R ^a , -S(0)NR ^a R ^b , -S0 ₂ NR ^a R ^b and -SR ^a ;

at each occurrence, R ^a and R ^b , which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted Ci_ ₈ alkyl, substituted or unsubstituted Ci_ ₈ alkoxyCi_ ₈ alkyl, substituted or unsubstituted haloCi_ ₈ alkyl, substituted or unsubstituted hydroxyCi_ ₈ alkyl, substituted or unsubstituted C ₃ _i ₂ cycloalkyl, substituted or unsubstituted C ₃ _ ₈ cycloalkylCi_ ₈ alkyl, substituted or unsubstituted C ₆ -i ₄ aryl, substituted or unsubstituted C ₆ _ i ₄ arylCi_ ₈ alkyl, substituted or unsubstituted 3-15 membered heterocyclyl, substituted or unsubstituted 3-15 membered heterocyclylCi_ ₈ alkyl, substituted or unsubstituted 5-14 membered heteroaryl and substituted or unsubstituted 5-14 membered heteroarylCi_ ₈ alkyl; or R ^a and R ^b together with the atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;

at each occurrence, R ^x and R ^y , which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted Ci_ ₈ alkyl, substituted or unsubstituted Ci_ ₈ alkoxyCi_ ₈ alkyl, substituted or unsubstituted haloCi_ ₈ alkyl, substituted or unsubstituted hydroxyCi_ ₈ alkyl, substituted or unsubstituted C ₃ _i ₂ cycloalkyl, substituted or unsubstituted C ₃ _ ₈ cycloalkylCi_ ₈ alkyl, substituted or unsubstituted C ₆ -i ₄ aryl, substituted or unsubstituted C ₆ _ i ₄ arylCi_ ₈ alkyl, substituted or unsubstituted 3-15 membered heterocyclyl, substituted or unsubstituted 3-15 membered heterocyclylCi_ ₈ alkyl, substituted or unsubstituted 5-14 membered heteroaryl and substituted or unsubstituted 5-14 membered heteroarylCi.galkyl; or R ^x and R ^y together with the atom to which they are attached, form a cyclic ring which is substituted or unsubstituted and wherein the cyclic ring optionally contains one or more hetero atoms selected from O, N or S;

'm' is an integer ranging from 0 to 4, both inclusive; and

'n' is an integer ranging from 0 to 6, both inclusive.

The compounds of formula (I) may involve one or more embodiments. Embodiments of formula (I) include compounds of formula (II) and (III), as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above wherein R ² is hydrogen (according to an embodiment defined below) and R ³ is hydrogen (according to another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (I), in which G ¹ , G ² and G ³ are CR ³ .

According to another embodiment, specifically provided are compounds of formula

(I), in which one of the G ¹ , G ² or G ³ is N.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ³ is hydrogen.

According to yet another embodiment, specifically provided are compounds of formula (I), in which G ¹ , G ² and G ³ are CH.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ² is hydrogen.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is hydrogen, substituted or unsubstituted Ci.galkyl (e.g. methyl, isopropyl, hexyl), substituted or unsubstituted haloCi_ ₈ alkyl (e.g. 2,2,2-trifluoroethyl), substituted or unsubstituted C ₃ _i ₂ cycloalkyl (e.g. cyclobutyl, cyclohexyl, 4,4- dimethylcyclohexyl, ( 15 ^, ,45 ^, )-4-(trifluoromethyl)cyclohexyl, ( 1 r,4r)-4-

(trifluoromethyl)cyclohexyl), substituted or unsubstituted C ₃ - ₈ cycloalkylCi_galkyl (e.g. cyclopropylmethyl, cyclohexylmethyl) or substituted or unsubstituted C ₆ _i ₄ aryl (e.g. 4- (trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4- fluorophenyl, 2,4-difluorophenyl, 4-isopropylphenyl, 4-bromophenyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is substituted or unsubstituted Ci.galkyl, preferably unsubstituted Ci_ ₆ alkyl (e.g. methyl, isopropyl, hexyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is substituted or unsubstituted haloCi_ ₈ alkyl, preferably unsubstituted haloCi_ ₄ alkyl (e.g. 2,2,2-trifluoroethyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is substituted or unsubstituted C ₃ _i ₂ cycloalkyl, preferably substituted or unsubstituted C ₃ _ ₆ cycloalkyl (e.g. cyclohexyl, cyclobutyl). In this embodiment, substituent(s) on C ₃ _i ₂ cycloalkyl or C ₃ _ ₆ cycloalkyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl) and haloCi.galkyl (e.g. trifluoromethy 1) .

According to another embodiment, specifically provided are compounds of formula

(I), in which R ¹ is cyclobutyl or cyclohexyl optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl) and haloCi_ ₈ alkyl (e.g. trifluoromethy 1).

According to another embodiment, specifically provided are compounds of formula (I), in which R ¹ is substituted or unsubstituted C ₃ _8CycloalkylCi_galkyl, preferably C ₃ _

₆ cycloalkylCi_ ₄ alkyl (e.g. cyclopropylmethyl, cyclohexylmethyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is substituted or unsubstituted C6 _-14 aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl.

According to another embodiment, specifically provided are compounds of formula

(I), in which R ¹ is substituted phenyl. In this embodiment, substituent(s) on phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl, isopropyl) and haloCi-salkyl (e.g. trifluoromethy 1).

According to another embodiment, specifically provided are compounds of formula (I), in which R ¹ is phenyl optionally substituted with one or more substituents selected from halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl, isopropyl) and haloCi.galkyl (e.g. trifluoromethy 1) .

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is hydrogen, methyl, isopropyl, hexyl, 2,2,2-trifluoroethyl, cyclobutyl, cyclohexyl, 4,4-dimethylcyclohexyl, (l5',45')-4-(trifluoromethyl)cyclohexyl, (lr,4r)-4-(trifluoromethyl)cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, 4-

(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4- fluorophenyl, 2,4-difluorophenyl, 4-isopropylphenyl or 4-bromophenyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which A is C ₆ _i ₄ aryl, preferably phenyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which A is 5-14 membered heteroaryl, preferably pyridinyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ⁴ is halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl) or Ci.galkoxy (e.g. methoxy).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ⁴ is CI, F, CH ₃ or OCH ₃ .

According to yet another embodiment, specifically provided are compounds of formula (I), in which m is 1 or 2.

According to yet another embodiment, specifically provided are compounds of formula (I), in which L is a bond and W is substituted or unsubstituted hydroxyC i.galkyl (e.g. 3-hydroxy-3-methylbutyl, 2-hydroxypropan-2-yl) or substituted or unsubstituted 5 to 14 membered heteroaryl (e.g. 5 -methyl- lH-pyrazol-3-yl, lH-l,2,3-triazol-4-yl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which L is a bond and W is 3-hydroxy-3-methylbutyl, 2-hydroxypropan-2-yl, 5 -methyl- lH-pyrazol-3-yl or lH-l,2,3-triazol-4-yl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which L is -(CR ^x R ^y ) _n NR ^x -, -(CR ^x R ^y ) _n NR ^x C(0)-, or -(CR ^x R ^y ) _n C(0)NR ^x -. In this embodiment R ^x and R ^y are independently selected from hydrogen, Ci_ ₄ alkyl (e.g. methyl) and n is 1 or 2.

According to yet another embodiment, specifically provided are compounds of formula (I), in which L is -CH ₂ NH-, -CH ₂ NHC(0)-, -CH ₂ NCH ₃ C(0)-, or -(CH ₂ ) ₂ C(0)NH-.

According to yet another embodiment, specifically provided are compounds of formula (I), in which W is hydrogen, substituted or unsubstituted Ci_ ₈ alkyl (e.g. methyl, tert- butyl, isopropyl), substituted or unsubstituted C ₃ _i ₂ cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted 3-15 membered heterocyclyl (e.g. 3-oxabicyclo[3.1.0]hexane) According to yet another embodiment, specifically provided are compounds of formula (I), in which W is hydrogen, methyl, tert-butyl, isopropyl, cyclopropyl or 3- oxabicyclo[3.1.0]hexanyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which L is -CH ₂ NHC(0)- or -CH ₂ NCH ₃ C(0)- and W is tert-butyl, isopropyl, cyclopropyl or 3-oxabicyclo[3.1.0]hexanyl.

According to an embodiment, specifically provided are compounds of formula (I) with an IC ₅₀ value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to mPGES-1 activity.

Further embodiments relating to groups R ¹ , L and W (and groups defined therein) are described hereinafter in relation to the compounds of formula (II). It is to be understood that these embodiments are not limited to use in conjunction with formula (II), but apply independently and individually to the compounds of formula (I). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (II) in which L is -(CH ₂ ) _n NR ^x C(0)-, and consequently there is also provided a compound of formula (I) in which L is -(CH ₂ ) _n NR ^x C(0)-.

The invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).

Accordingly the present patent application provides the compound of formula (II):

or a pharmaceutically acceptable salt thereof,

wherein,

Q ¹ , Q ² , Q ³ and Q ⁴ are selected from N, CH and CR ⁴ , with a proviso that Q ² , Q ³ and Q ⁴ are not N simultaneously;

L is a bond or selected from -(CR ^x R ^y ) _n NR ^x -, -(CR ^x R ^y ) _n C(0)NR ^x -, and -

(CR ^x R ^y ) _n NR ^x C(0)-;

W is selected from hydrogen, substituted or unsubstituted Ci.galkyl, substituted or unsubstituted Ci_galkoxyCi_galkyl, substituted or unsubstituted haloCi_galkyl, substituted or unsubstituted hydroxyCi_ ₈ alkyl, substituted or unsubstituted C ₃ _i ₂ cycloalkyl, substituted or unsubstituted C6 _-14 aryl, substituted or unsubstituted 3 to 15 membered heterocyclyl, and substituted or unsubstituted 5 to 14 membered heteroaryl; with a proviso that when L is a bond then W is hydroxyCi_ ₈ alkyl or 5 to 14 membered heteroaryl;

R ¹ is selected from substituted or unsubstituted Ci_ ₈ alkyl, substituted or unsubstituted Ci-galkoxyCi.galkyl, substituted or unsubstituted haloCi_ ₈ alkyl, substituted or unsubstituted hydroxyCi.galkyl, substituted or unsubstituted C ₃ _i ₂ cycloalkyl, substituted or unsubstituted C ₃ _ gcycloalkylCi_ ₈ alkyl, substituted or unsubstituted C ₆ _i ₄ aryl, substituted or unsubstituted C ₆ _ i ₄ arylCi_ ₈ alkyl, substituted or unsubstituted 3-15 membered heterocyclyl, substituted or unsubstituted 3-15 membered heterocyclylCi_ ₈ alkyl, substituted or unsubstituted 5-14 membered heteroaryl and substituted or unsubstituted 5-14 membered heteroarylCi_ ₈ alkyl; at each occurrence R ⁴ is selected from halogen, cyano, hydroxyl, substituted or unsubstituted Ci_ ₈ alkyl, substituted or unsubstituted Ci_ ₈ alkoxy, substituted or unsubstituted Ci_ ₈ alkoxyCi_ ₈ alkyl, substituted or unsubstituted haloCi_ ₈ alkyl and substituted or unsubstituted hydroxyCi_ ₈ alkyl;

at each occurrence, R ^x and R ^y which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted Ci_ ₈ alkyl, substituted or unsubstituted C ₃ _ i ₂ cycloalkyl, substituted or unsubstituted C ₆ -i ₄ aryl and substituted or unsubstituted C ₆ _i ₄ arylCi_ ₈ alkyl; and

'n' is an integer ranging from 1 to 6, both inclusive.

The compounds of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, or any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (II) as defined above wherein Q ² is N or CH (according to an embodiment defined below), Q ³ is CH (according to another embodiment defined below) and Q ⁴ is CH or CR ⁴ (according to an embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (II), in which R ¹ is substituted or unsubstituted Ci_ ₈ alkyl (e.g. methyl, isopropyl, hexyl), substituted or unsubstituted haloCi_ ₈ alkyl (e.g. 2,2,2-trifluoroethyl), substituted or unsubstituted C ₃ _ i ₂ cycloalkyl (e.g. cyclobutyl, cyclohexyl, 4,4-dimethylcyclohexyl, (ls,4s)-4- (trifluoromethyl)cyclohexyl, (lr,4r)-4-(trifluoromethyl)cyclohexyl), substituted or unsubstituted C ₃ _ ₈ cycloalkylCi_ ₈ alkyl (e.g. cyclopropylmethyl, cyclohexylmethyl) or substituted or unsubstituted C ₆ _i ₄ aryl (e.g. 4-(trifluoromethyl)phenyl, 3- (trifluoromethyl)phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-isopropylphenyl) .

According to another embodiment, specifically provided are compounds of formula (II), in which R ¹ is substituted or unsubstituted Ci.galkyl, preferably unsubstituted Ci_ ₆ alkyl

(e.g. methyl, isopropyl, hexyl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ¹ is substituted or unsubstituted haloCi.galkyl, preferably unsubstituted haloCi_ ₄ alkyl (e.g. 2,2,2-trifluoroethyl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ¹ is substituted or unsubstituted C ₃ _i ₂ cycloalkyl, preferably substituted or unsubstituted C ₃ _ ₆ cycloalkyl (e.g. cyclohexyl, cyclobutyl). In this embodiment, substituent(s) on C ₃ _i ₂ cycloalkyl or C ₃ _ ₆ cycloalkyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl) and haloCi.galkyl (e.g. trifluoromethy 1) .

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ¹ is cyclobutyl or cyclohexyl optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl) and haloCi_ ₈ alkyl (e.g. trifluoromethy 1).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ¹ is substituted or unsubstituted C ₃ _ ₈ cycloalkylCi_ ₈ alkyl, preferably C ₃ _

₆ CycloalkylCi_ ₄ alkyl (e.g. cyclopropylmethyl, cyclohexylmethyl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ¹ is substituted or unsubstituted C6 _-14 aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl.

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ¹ is substituted phenyl. In this embodiment, substituent(s) on phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_ ₄ alkyl

(e.g. methyl, isopropyl) and haloCi.galkyl (e.g. trifluoromethy 1).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ¹ is phenyl optionally substituted with one or more substituents selected from halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl, isopropyl) and haloCi.galkyl

(e.g. trifluoromethy 1). According to yet another embodiment, specifically provided are compounds of formula (II), in which R ¹ is methyl, isopropyl, hexyl, 2,2,2-trifluoroethyl, cyclobutyl, cyclohexyl, 4,4-dimethylcyclo hexyl, (^^^-(trifluoromethy^cyclohexyl, (lr,4r)-4- (trifluoromethyl)cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, 4- (trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4- fluorophenyl, 2,4-difluorophenyl or 4-isopropylphenyl.

According to yet another embodiment, specifically provided are compounds of formula (II), in which Q ¹ is N, CH or CR ⁴ .

According to yet another embodiment, specifically provided are compounds of formula (II), in which Q ² is N or CH.

According to yet another embodiment, specifically provided are compounds of formula (II), in which Q ³ is CH.

According to yet another embodiment, specifically provided are compounds of formula (II), in which Q ⁴ is CH or CR ⁴ .

According to yet another embodiment, specifically provided are compounds of formula (II), in which Q ¹ is N, CH or CR ⁴ , Q ² is N or CH, Q ³ is CH and Q ⁴ is CR ⁴ .

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ⁴ is halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl) or Ci.galkoxy (e.g. methoxy).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ⁴ is CI, F, CH ₃ or OCH ₃ .

According to yet another embodiment, specifically provided are compounds of formula (II), in which L is a bond and W is substituted or unsubstituted hydroxyCi.galkyl (e.g. 3-hydroxy-3-methylbutyl, 2-hydroxypropan-2-yl) or substituted or unsubstituted 5 to 14 membered heteroaryl (e.g. 5 -methyl- lH-pyrazol-3-yl, lH-l ,2,3-triazol-4-yl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which L is a bond and W is 3-hydroxy-3-methylbutyl, 2-hydroxypropan-2-yl, 5 -methyl- lH-pyrazol-3-yl or lH-l ,2,3-triazol-4-yl.

According to yet another embodiment, specifically provided are compounds of formula (II), in which L is -(CR ^x R ^y ) _n NR ^x -, -(CR ^x R ^y ) _n NR ^x C(0)-, or -(CR ^x R ^y ) _n C(0)NR ^x -. In this embodiment R ^x and R ^y are independently selected from hydrogen, Ci_ ₄ alkyl (e.g. methyl) and n is 1 or 2.

According to yet another embodiment, specifically provided are compounds of formula (II), in which L is -(CH ₂ )„NR ^x C(0)-. According to yet another embodiment, specifically provided are compounds of formula (II), in which L is -CH ₂ NH-, -CH ₂ NHC(0)-, -CH ₂ NCH ₃ C(0)-, or -(CH ₂ ) ₂ C(0)NH-.

According to yet another embodiment, specifically provided are compounds of formula (II), in which W is hydrogen, substituted or unsubstituted Ci.galkyl (e.g. methyl, tert- butyl, isopropyl), substituted or unsubstituted C ₃ -i ₂ cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted 3-15 membered heterocyclyl (e.g. 3-oxabicyclo[3.1.0]hexane)

According to yet another embodiment, specifically provided are compounds of formula (II), in which W is hydrogen, methyl, ie/t-butyl, isopropyl, cyclopropyl or 3- oxabicyclo[3.1.0]hexanyl.

According to yet another embodiment, specifically provided are compounds of formula (II), in which L is -CH ₂ NHC(0)- or -CH ₂ NCH ₃ C(0)- and W is ierf-butyl, isopropyl, cyclopropyl or 3-oxabicyclo[3.1.0]hexanyl.

According to an embodiment, specifically provided are compounds of formula (II) with an IC ₅₀ value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to mPGES-1 activity.

Further embodiments relating to groups R ¹ , R ⁴ , R ^x , n and W (and groups defined therein) are described hereinafter in relation to the compounds of formula (III). It is to be understood that these embodiments are not limited to use in conjunction with formula (III), but apply independently and individually to the compounds of formula (I) and (II). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (III) in which n is 1, and consequently there is also provided a compound of formula (I) or (II) in which n is 1.

The invention also provides a compound of formula (III), which is an embodiment of a compound of formula (I).

Accordingly the present patent application provides the compound of formula (III):

(III)

or a pharmaceutically acceptable salt thereof,

wherein, W is selected from hydrogen, substituted or unsubstituted Ci_ ₈ alkyl, substituted or unsubstituted C ₃ _i ₂ cycloalkyl and substituted or unsubstituted 3 to 15 membered heterocyclyl;

R ¹ is selected from substituted or unsubstituted Ci_ ₈ alkyl, substituted or unsubstituted Ci-galkoxyCi.galkyl, substituted or unsubstituted haloCi_ ₈ alkyl, substituted or unsubstituted hydroxyCi.galkyl, substituted or unsubstituted C ₃ _i ₂ cycloalkyl, substituted or unsubstituted C ₃ _ gcycloalkylCi_ ₈ alkyl, substituted or unsubstituted C ₆ _i ₄ aryl, substituted or unsubstituted C ₆ _ i ₄ arylCi_ ₈ alkyl, substituted or unsubstituted 3-15 membered heterocyclyl and substituted or unsubstituted 5-14 membered heteroaryl;

at each occurrence R ⁴ is selected from halogen, cyano, hydroxyl, substituted or unsubstituted Ci_ ₈ alkyl, substituted or unsubstituted Ci_ ₈ alkoxy, substituted or unsubstituted Ci_ ₈ alkoxyCi_ ₈ alkyl, substituted or unsubstituted haloCi_ ₈ alkyl and substituted or unsubstituted hydroxyCi_ ₈ alkyl;

R ^x is selected from hydrogen or substituted or unsubstituted Ci_ ₈ alkyl;

'm' is an integer ranging from 0 to 4, both inclusive; and

'n' is an integer ranging from 1 to 4, both inclusive;

The compounds of formula (III) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (III) as defined above wherein n is 1 (according to an embodiment defined below) and R ^x is hydrogen or methyl (according to another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (III), in which R ¹ is substituted or unsubstituted Ci_ ₈ alkyl (e.g. methyl, isopropyl, hexyl), substituted or unsubstituted haloCi_ ₈ alkyl (e.g. 2,2,2-trifluoroethyl), substituted or unsubstituted C ₃ -i ₂ cycloalkyl (e.g. cyclobutyl, cyclohexyl, 4,4-dimethylcyclohexyl, (ls,4s)-4- (trifluoromethyl)cyclohexyl, (lr,4r)-4-(trifluoromethyl)cyclohexyl), substituted or unsubstituted C ₃ _ ₈ cycloalkylCi_ ₈ alkyl (e.g. cyclopropylmethyl, cyclohexylmethyl) or substituted or unsubstituted C ₆ -i ₄ aryl (e.g. 4-(trifluoromethyl)phenyl, 3- (trifluoromethyl)phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-isopropylphenyl) . According to another embodiment, specifically provided are compounds of formula (III), in which R ¹ is substituted or unsubstituted Ci_galkyl, preferably unsubstituted Ci_ ₆ alkyl (e.g. methyl, isopropyl, hexyl).

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ¹ is substituted or unsubstituted haloCi.galkyl, preferably unsubstituted haloCi_ ₄ alkyl (e.g. 2,2,2-trifluoroethyl).

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ¹ is substituted or unsubstituted C ₃ -i ₂ cycloalkyl, preferably substituted or unsubstituted C ₃ - ₆ cycloalkyl (e.g. cyclohexyl, cyclobutyl). In this embodiment, substituent(s) on C ₃ _i ₂ cycloalkyl or C ₃ - ₆ cycloalkyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl) and haloCi_ ₈ alkyl (e.g. trifluoromethy 1) .

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ¹ is cyclobutyl or cyclohexyl optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl) and haloCi_galkyl (e.g. trifluoromethy 1).

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ¹ is substituted cyclohexyl and substituent(s) are independently selected from methyl and trifluoromethy 1.

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ¹ is substituted or unsubstituted C ₃ _ ₈ cycloalkylCi_ ₈ alkyl, preferably

C ₃ _ ₆ cycloalkylCi_ ₄ alkyl (e.g. cyclopropylmethyl, cyclohexylmethyl).

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ¹ is substituted or unsubstituted C ₆ -i ₄ aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl.

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ¹ is substituted phenyl. In this embodiment, substituent(s) on phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_ ₄ alkyl

(e.g. methyl, isopropyl) and haloCi.galkyl (e.g. trifluoromethy 1).

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ¹ is phenyl optionally substituted with one or more substituents selected from halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl, isopropyl) and haloCi.galkyl

(e.g. trifluoromethy 1). According to yet another embodiment, specifically provided are compounds of formula (III), in which R ¹ is substituted phenyl and substituent(s) are independently selected from fluoro, methyl, isopropyl and trifluoromethyl.

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ¹ is methyl, isopropyl, hexyl, 2,2,2-trifluoroethyl, cyclobutyl, cyclohexyl, 4,4-dimethylcyclo hexyl, (^^^^-(trifluoromethy^cyclohexyl, (lr,4r)-4- (trifluoromethyl)cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, 4-

(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4- fluorophenyl, 2,4-difluorophenyl or 4-isopropylphenyl.

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ⁴ is halogen (e.g. F, CI or Br), Ci_ ₄ alkyl (e.g. methyl) or Ci_ ₈ alkoxy (e.g. methoxy).

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ⁴ is CI, F, CH ₃ or OCH ₃ .

According to yet another embodiment, specifically provided are compounds of formula (III), in which m is 1 or 2.

According to yet another embodiment, specifically provided are compounds of formula (III), in which n is 1.

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ^x is hydrogen or Ci_ ₄ alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ^x is hydrogen or methyl.

According to yet another embodiment, specifically provided are compounds of formula (III), in which W is substituted or unsubstituted Ci.galkyl (e.g. iert-butyl, isopropyl), substituted or unsubstituted C ₃ _i ₂ cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted 3- 15 membered heterocyclyl (e.g. 3-oxabicyclo[3.1.0]hexane).

According to yet another embodiment, specifically provided are compounds of formula (III), in which W is tert-butyl, isopropyl, cyclopropyl or 3-oxabicyclo[3.1.0]hexanyl.

According to an embodiment, specifically provided are compounds of formula (III) with an IC ₅₀ value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to mPGES-1 activity.

It should be understood that the formulas (I), (II) and (III), structurally encompasses all geometrical isomers, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.

The present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipients (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described in the present patent application may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.

The compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of mPGES-1 , which is believed to be related to a variety of disease states.

The present patent application further provides a method of inhibiting mPGES-1 in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor.

Detailed Description

Definitions

The invention is defined by the claims and not limited by the description provided herein below. The terms used in the appended claims are defined herein in this glossary section, with the proviso that the claim terms may be used in a different manner if so defined by express recitation.

The terms "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine

(bromo), or iodine (iodo).

The term "alkyl" refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci.galkyl), 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 "Ci_ ₆ alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. The term "Ci_ ₄ alkyl" refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e. C ₂ _ioalkenyl) and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), z ^' sopropenyl, 2- methyl-l-propenyl, 1-butenyl, and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkynyl" refers to a hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred i.e. C2_ioalkynyl). Non-limiting examples of alkynyl groups include ethynyl, propynyl, and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. Ci_ ₈ alkoxy). Representative examples of such groups are -OCH ₃ and - OC ₂ H ₅ . Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkoxyalkyl" or "alkyloxyalkyl" refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. Ci.galkoxyCi.galkyl or Ci_ ₈ alkyloxyCi_galkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, - CH ₂ OCH ₃ and -CH ₂ OC ₂ H ₅ . Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "haloalkyl" refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e.haloCi-salkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e.haloCi_galkoxy). Examples of "haloalkoxy" include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy. Unless set forth or recited to the contrary, all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "hydroxy alkyl" refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi_ ₈ alkyl). Examples of hydroxyalkyl moiety include, but are not limited to -CH ₂ OH, -C ₂ H ₄ OH and -CH(OH)C ₂ H ₄ OH. The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, for example C ₃ _i ₂ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. The term "C ₃ _6cycloalkyl" refers to the cyclic ring having 3 to 6 carbon atoms. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group, for example C ₃ _ ₈ CycloalkylCi_ ₈ alkyl. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, for example C ₃ _gcycloalkenyl, such as cyclopropenyl, cyclobutenyl, and cyclop entenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.

The term "cycloalkenylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group, for example C ₃ _ ₈ CycloalkenylCi_ ₈ alkyl. The cycloalkenylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all cycloalkenylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C ₆ _ i ₄ aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.

The term "aryloxy" refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C ₆ -i ₄ aryloxy). Examples of aryloxy moiety include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted. The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C ₆ -i ₄ arylCi_ ₈ alkyl, such as -CH ₂ C ₆ H ₅ and -C ₂ H ₄ C ₆ H ₅ . Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "heterocyclic ring" or "heterocyclyl" unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic 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; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefmic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxabicyclo[3.1.0]hexane. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.

The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. heterocyclylCi-salkyl). The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "heteroaryl" unless otherwise specified refers to substituted or unsubstituted

5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S. The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl. Unless set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be substituted or unsubstituted.

The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group (i.e. heterarylCi-salkyl). The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.

Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyl alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -C(0)OR ^x' , -C(0)R ^x' , -C(S)R ^X' , -C(0)NR ^x R , -C(0)ONR ^x R , - NR ^x CONR R ^z' , -N(R ^x )SOR , -N(R ^x )S0 ₂ R , -(=N-N(R ^x )R ), -NR ^x C(0)OR , -NR ^x R ^y , - NR ^x C(0)R , -NR ^x C(S)R , -NR ^x' C(S)NR ^y' R ^z' , -SONR ^x R ^y , -S0 ₂ NR ^x R , -OR ^x' , - OC(0)NR R ^z' , -OC(0)OR , -OC(0)R ^x' , -OC(0)NR ^x R , -SR ^X' , -SOR ^x' , -S0 ₂ R ^x' , and -ON0 ₂ , wherein R ^x ' R ^y and R ^z are independently selected from 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 cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, and substituted or unsubstituted heterocyclic ring. 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" can be unsubstituted alkenyl but cannot be "substituted alkenyl".

The term "pharmaceutically acceptable salt" includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc.

The term "treating" or "treatment" of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).

A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated. The term "acute pain" is usually self-limiting. The sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to this harmful stimulus are termed as "nociceptors". Nociceptors are primary sensory afferent (C and Αδ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH<6) modalities. Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain.

The term "chronic pain" usually refers to pain which persists for 3 months or longer and can lead to significant changes in a patient's personality; lifestyle, functional ability and overall quality of life. Chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. The pain is typically well localized, constant, and often with an aching or throbbing quality. Visceral pain is the subtype of nociceptive pain that involves the internal organs. It tends to be episodic and poorly localized. Nociceptive pain is usually time limited, meaning when the tissue damage heals, the pain typically resolves (arthritis is a notable exception in that it is not time limited).

The compound described in the present patent application may form salts. Non- limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids. Certain compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the general formula (I) the present patent application extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the present patent application may be separated from one another by the method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated. It is also to be understood that compounds of the invention may exist in solvated forms (such as hydrates) as well as unsolvated forms, and that the invention encompasses all such forms. Pharmaceutical Compositions

The compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.

Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.

The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.

Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted routes of administration of pharmaceutical compositions. The route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.

Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.

The pharmaceutical compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 ^th Ed., 2003 (Lippincott Williams & Wilkins).

Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.

Methods of Treatment

Compounds of the present invention are particularly useful because they may selectively inhibit the activity of prostaglandin E synthases {and particularly microsomal prostaglandin E synthase-1 (mPGES-1)}, i.e., they prevent the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit mPGES-1 modulating effect. Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1, is required.

Compounds of the invention are thus expected to be useful in the treatment of inflammation. The term "inflammation" will be understood by those skilled in the art to include any condition characterized by a localized or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow.

The term "inflammation" is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, and necrotic inflammation, and other forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever.

The compounds of the present invention may also be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, chronic pain, acute pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections (e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g. breast cancer, colon cancer, and prostate cancer), hyperprostaglandin E syndrome, classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, autoimmune diseases, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.

Compounds of the invention may also have effects that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases.

By virtue of the mPGES-1 inhibitory activity of compounds of the present invention, the compounds of Formula (I), (II) or (III) are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, migraine (acute and prophylactic treatment), toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, juvenile rheumatoid arthritis, degenerative joint diseases (osteoarthritis), acute gout and ankylosing spondylitis, acute, subacute and chronic musculoskeletal pain syndromes such as bursitis, burns, injuries, and pain following surgical (post-operative pain) and dental procedures as well as the preemptive treatment of surgical pain. The pain may be mild pain, moderate pain, severe pain, musculoskeletal pain, complex regional pain syndrome, neuropathic pain, back pain such as acute visceral pain, neuropathies, acute trauma, chemotherapy - induced mononeuropathy pain states, polyneuropathy pain states (such as diabetic peripheral neuropathy & chemotherapy induced neuropathy), autonomic neuropathy pain states, pheriphaeral nervous system (PNS) lesion or central nervous system (CNS) lesion or disease related pain states, polyradiculopathies of cervical, lumbar or sciatica type, cauda equina syndrome, piriformis syndrome, paraplegia, quadriplegia, pain states related to various Polyneuritis conditions underlying various infections, chemical injuries, radiation exposure, underlying disease or deficiency conditions (such as beriberi, vitamin deficiencies, hypothyroidism, porphyria, cancer, HIV, autoimmune disease like multiple sclerosis and spinal-cord injury, fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, stomach duodenal ulcer, muscle pain, pain due to colicky and referred pain. In addition, such a compound may inhibit cellular neoplastic transformations and metastic tumour growth and hence can be used in the treatment of cancer. Compounds of Formula (I), (II) or (III) may also be useful for the treatment or prevention of endometriosis, hemophilic arthropathy and Parkinson's disease.

Compounds of Formula (I), (II) or (III) will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma.

In addition, the compound of the present invention may inhibit cellular neoplastic transformations and metastic tumour growth and hence can be used in the treatment of cancer. The cancer includes Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adolescents Cancer, Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, Astrocytomas, Atypical Teratoid, Basal Cell Carcinoma, Bile Duct Cancer, Extrahepatic, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumor, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Cardiac (Heart) Tumors, Central Nervous System tumors, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma, Duct Bile Extrahepatic cancer, Ductal Carcinoma In Situ, Embryonal Tumors, Central Nervous System cancer, Endometrial Cancer, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gall bladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors, Germ Cell Tumor, Gestational Trophoblastic Tumor, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma, Kidney cancer, Langerhans Cell Histiocytosis, Laryngeal Cancer, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Hairy Cell Leukemia, Lip and Oral Cavity Cancer, Liver Cancer, Lobular Carcinoma In Situ, Lung Cancer, AIDS-Related Lymphoma, Cutaneous T-Cell Lymphoma, Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Primary Central Nervous System (CNS) Lymphoma, Macroglobulinemia, Waldenstrom, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Merkel Cell Carcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplasia Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia, Chronic, Myeloid Leukemia Acute, Multiple Myeloma, Chronic Myeloproliferative Disorders, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and, Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer, Pancreatic Cancer, Papillomatosis, Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Ewing Sarcoma, Kaposi Sarcoma, Osteosarcoma, Rhadomyosarcoma, Soft Tissue Sarcoma, Uterine Sarcoma, Sezary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic, Stomach (Gastric) Cancer, T-Cell Lymphoma, Cutaneous, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor, Gestational, Unknown Primary, Carcinoma of, Ureter and Renal Pelvis, Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenstrom , Macroglobulinemia, Wilms Tumor and Women's Cancers.

Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of the invention may be in the range from 0.05 mg/kg to 100 mg/kg.

General Methods of Preparation

The compounds described herein, including compounds of Formula (I), (II), (III) and specific examples are prepared using techniques known to one skilled in the art through the reaction sequences depicted in schemes provided below, as well as by other methods. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained by using the general reaction sequences may be of insufficient purity. These compounds can be purified by using any of the methods for purification of organic compounds known to person skilled in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.

The starting materials for the below reaction schemes are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, intermediates and compounds of the present application may be prepared using the reaction scheme as follows, wherein all symbols are as defined above.

Synthetic scheme 1

The synthesis of the compounds of formula (I) (wherein A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁴ , m, L and W are as defined above for the compounds of formula (I)) can be performed as described in Synthetic scheme 1 , which involves the treatment of amine compound of formula (1) with appropriate acyl compound of formula (2), wherein LG represent OH or CI or Br or O-alkyl or O-aryl or 0(C=0)-alkyl. When LG represents OH the reaction can be performed with a suitable coupling reagent known to those skilled in the art for example, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) in a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) in the temperature range of 0-120°C, optionally in the presence of a suitable base such as N,N-diisoporpylethylamine (DIPEA). Alternatively, the reaction can be performed using a suitable reagent such as isobutyl chloroformate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA. When, LG represents CI the reaction can be performed in a suitable solvent such as DMF or THF in the temperature range of 0-120°C, optionally in the presence of a suitable base such as DIPEA. Furthermore, when LG represents O-alkyl or O- aryl or 0(C=0)-alkyl the reaction can be performed with a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.

Synthetic scheme 2

(3)

(I I)

The synthesis of the compounds of formula (II) (wherein Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , L and W are as defined above for the compounds of formula (II)) can be performed as described in Synthetic scheme 2, which involves the treatment of amine compound of formula (3) with appropriate acyl compound of formula (4), wherein LG represent OH or CI or Br or O-alkyl or O-aryl or 0(C=0)-alkyl. When LG represents OH the reaction can be performed with a suitable coupling reagent known to those skilled in the art for example, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) in a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) in the temperature range of 0-120°C, optionally in the presence of a suitable base such as N,N-diisoporpylethylamine (DIPEA). Alternatively, the reaction can be performed using a suitable reagent such as isobutyl chloroformate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA. When LG represents CI the reaction can be performed in a suitable solvent such as DMF or THF in the temperature range of 0-120°C, optionally in the presence of a suitable base such as DIPEA. Furthermore, when LG represents O-alkyl or O- aryl or 0(C=0)-alkyl the reaction can be performed with a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.

Synthetic scheme 3

The synthesis of the compounds of formula (III) (wherein R ¹ , R ⁴ , R ^x , m, n and W are as defined above for the compounds of formula (III)) can be performed as described in Synthetic scheme 3, which involves the treatment of amine compound of formula (3) with appropriate acyl compound of formula (5), wherein LG represent OH or CI or Br or O-alkyl or O-aryl or 0(C=0)-alkyl. When LG represents OH the reaction can be performed with a suitable coupling reagent known to those skilled in the art for example, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) in a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) in the temperature range of 0-120°C, optionally in the presence of a suitable base such as N,N-diisoporpylethylamine (DIPEA). Alternatively, the reaction can be performed using a suitable reagent such as isobutyl chloroformate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA. When LG represents CI the reaction can be performed in a suitable solvent such as DMF or THF in the temperature range of 0-120°C, optionally in the presence of a suitable base such as DIPEA. Furthermore, when LG represents O-alkyl or O- aryl or 0(C=0)-alkyl the reaction can be performed with a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF. Synthetic scheme 4

(II I) (8)

The synthesis of the compound of formula (III) (wherein R ¹ , R ⁴ , R ^x , m, n and W are as defined above in the compound of formula (III)) can be performed as described in synthetic scheme 4. The coupling of compound of formula (3) with compound of formula (6) (wherein LG represents OH or CI or O-alkyl or O-aryl or 0(C=0)-alkyl) provides compound of formula (7). Further deprotection of compound of formula (7) using a suitable deprotecting agent (e.g. HC1) provides compound of formula (8). Coupling of compound of (8) with compound of formula (9) (wherein LG represents OH or CI or O-alkyl or O-aryl or 0(C=0)- alkyl) can provide compound of formula (III) under the conditions as described in the scheme 1.

Synthetic scheme 5

The synthesis of the compound of formula (3) can be performed as described in synthetic scheme 5. The reaction of the phthalide compound (10) with the appropriate nitrating agent such as potassium nitrate or cone, nitric acid in cone, sulphuric acid or acetic acid in the temperature range -10 to 100°C can provide the compound of formula (11). Subsequently, the bromination of the compound of formula (11) with appropriate brominating agent such as N-bromosuccinimide and azobisisobutyronitrile in a suitable solvent such as carbon tetrachloride in the temperature range 0-150°C can provide the compound of formula (12). Then the reaction of the compound of formula (12) under acidic conditions provides an intermediate which upon reaction with an appropriate hydrazine of formula (13) can provide the compound of formula (14). Alternatively, the reaction of the compound of formula (12) under acidic conditions with hydrazine hydrate can provide the phthalazine derivative, which can then be appropriately substituted under the conditions known to those skilled in the art or disclosed herein to provide the compound of formula (14). The nitro group of the compound of formula (14) can be reduced to provide the compound of formula (3) under the conditions known to those skilled in the art such as using iron powder in presence of ammonium chloride or hydrochloric acid in a suitable solvent such as methanol or ethanol in the temperature range 0-100°C.

Experimental

Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate (Na ₂ S0 ₄ ), filtration and evaporation of the solvent under reduced pressure. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, in suitable solvents of a suitable polarity as the mobile phase. Abbreviations used in the text that are as follows: DMSO-<i6: Hexadeuterodimethyl sulfoxide; CDC1 ₃ : deuterated chloroform; DMSO: dimethyl sulfoxide; DMF: N,N- Dimethylformamide; DMA: dimethylacetamide; DCM: dichloromethane; DIPEA: N,N- diisopropylethylamine; EDCI: l-ethyl-3-(3-dimethylaminopropyl)carbodiimide); HOBt: hydroxybenzotriazole; /: Coupling constant in units of Hz; RT or rt: room temperature (22- 26°C); aq.: aqueous; equiv. or eq.: equivalents; cone. : concentrated; i.e. : that is; h : hours; /: coupling constant in units of Hz.

Preparation of Intermediates

Intermediate- 1

3-Bromo-6-nitroisobenzofuran-l(3H)- ne

Step 1 : Preparation of 6-nitroisobenzofuran-l 3H -

To a solution of phthalide (2.5 g, 18.65 mmol) in conc.H ₂ S0 ₄ was added a solution of potassium nitrate (2.22 g, 18.65 mmol) in cone. H ₂ S0 ₄ . The reaction mixture was stirred at 0°C for 30 minutes and quenched with water and filtered. The filtrate was concentrated and purified by column chromatography to afford 1.00 g of the title product. 1H NMR (300 MHz, DMSO-Je): δ 5.45 (s, 2H), 7.72 (d, / = 8.4 Hz, 1H), 8.58 (d, / = 8.1 Hz, 1H), 8.78 (s, 1H). Step-2: Preparation of 3-bromo-6-nitroisobenzofuran-l(3H)-one

To a solution of 6-nitroisobenzofuran-l(3H)-one (1.0 g, 4.67 mmol) in CCI ₄ were added N- bromosuccinimide (1.66 g, 9.34 mmol) and azobisisobutyronitrile (38 mg, 0.233 mmol). The reaction mass was heated at reflux for 24 h. The reaction mass was filtered and the filtrate was concentrated and purified by column chromatography to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 7.48 (s, 1H), 7.84 (d, / = 8.1 Hz, 1H), 8.65 (d, / = 8.1 Hz, 1H), 8.77 (s, 1H).

Intermediate-2

7-Amino-2-(4-bromophenyl)phthalazin- 1 (2H)-one

Step 1 : Preparation of 2-(4-bromophenyl)-7-nitrophthalazin-l(2H)-one

A solution of 3-bromo-6-nitroisobenzofuran-l(3H)-one (Intermediate- 1 , 200 mg, 0.775 mmol) in 5% aq. HC1 (3.0 mL) was heated at reflux temperature for 1-2 h. Then 4- bromophenylhydrazine hydrate (208 mg, 0.930 mmol) was added at rt and the reaction mass was stirred for 2-3 h. The reaction mass was diluted with water and filtered. The filtered cake was dissolved in methanol (3 mL) and the solution was heated at reflux for 1 h. The reaction mass was neutralized with saturated aq. NaHC0 ₃ solution and was extracted with chloroform. The organic layer was separated, dried, filtered and concentrated to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 8.93 (s, 1H), 8.78-8.73 (m, 2H), 8.29 (d, / = 9.0 Hz, 1H), 7.74 (d, / = 8.7 Hz, 2H), 7.62 (d, / = 8.1 Hz, 2H); MS [M+H] ⁺ :347.07.

Step 2: Preparation of 7-amino-2-(4-bromophenyl)phthalazin-l(2H)-one

To a solution of 2-(4-bromophenyl)-7-nitrophthalazin-l(2H)-one (180 mg, 0.520 mmol) in a mixture of ethanokwater (2: 1 , 3.0 mL) were added iron powder (291 mg, 5.2 mmol), and ammonium chloride (222 mg, 4.16 mmol). The reaction mass was heated at reflux temperature for 2 h before it was filtered at rt. The filtrate was concentrated to afford 140 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 8.23 (s, 1H), 7.68-7.58 (m, 3H), 7.56 (d, / = 8.4 Hz, 2H), 7.33 (s, 1H), 7.17 (d 2H), 6.36 (br s, 2H); MS [M] ⁺ : 316.06.

Intermediate-3

7-Amino-2-(4-(trifluoromethyl)phenyl)phthalazin- 1 (2H)-one

Step 1 : Preparation of 7-nitro-2- -(trifluoromethyl)phenyl)phthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 1 of Intermediate-2 using 3-bromo-6-nitroisobenzofuran-l(3H)-one (Intermediate- 1 , 200 mg, 0.775 mmol), 4-(trifluoromethyl)phenyl)hydrazine (163 mg, 0.926 mmol), 5% aq. HC1 (3.0 mL) and MeOH (3 mL) to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 8.94 (s, 1H), 8.82 (s, 1H), 8.75 (d, / = 8.7 Hz, 1H), 8.31 (d, / = 8.1 Hz, 1H), 7.93(s, 4H); MS [M+H] ⁺ :336.13.

Step 2: Preparation of 7-amino-2-(4-(trifluoromethyl)phenyl)phthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 7-nitro-2-(4-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (150 mg, 0.447 mmol), iron powder (250 mg, 4.46 mmol) and ammonium chloride (238 mg, 4.44 mmol) in EtOH (2 mL) and H ₂ 0 (1 mL) to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO-Je): δ 8.28 (s, 1H), 7.86 (m, 4H), 7.65 (d, / = 9.0 Hz, 1H), 7.35 (s, 1H), 7.15 (d, 1H), 6.40 (br s, 2H); MS [M+H] ⁺ : 306.31.

Intermediate-4

Methyl 2-chloro-5-((N-methylpivalamido)methyl)benzoate

Step 1 : Preparation of 2-chloro-5- {[(trifluoroacetyl)amino]methyl}benzoic acid: To a solution of 2-chloro benzoic acid (500 mg, 3.49 mmol) in cone. H ₂ S0 ₄ (3 mL) was added 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (547 mg, 3.49 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was poured into ice-water and stirred for 2 h. The precipitate was collected by filtration. The filter cake was re-crystallized from toulene:butan- 2-one (7: 1) to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 13.47 (br s, 1H), 10.06 (br s, 1H), 7.71 (s, 1H), 7.54 (d, / = 8.4 Hz, 1H), 7.43 (d, / = 9.9 Hz, 1H), 4.42 (d, / = 6.0 Hz, 2H); MS (m/z): 280.18 (M-H) ^~ .

Step 2: Preparation of methyl 2-chloro-5-((2,2,2-trifluoro-N- methylacetamido)methyl)benzoate

To the solution of 2-chloro-5-{[(trifluoroacetyl)amino]methyl}benzoic acid (1.0 g, 3.18 mmol) in DMF (10 mL) were added potassium carbonate (878 mg, 6.36 mmol) and methyl iodide (451 mg, 3.18 mmol). The reaction mass was stirred at rt for 4 h before it was quenched with IN HCl and was extracted with EtOAc. The organic layer was washed with water, separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 500 mg of the title product.

Step 3: Preparation of 5-(((ieri-butoxycarbonyl)(methyl)amino)methyl)-2-chlorobenzo ic acid

The solution of methyl 2-chloro-5-((2,2,2-trifluoro-N-methylacetamido)methyl)benzoa te (800 mg, 2.84 mmol) in cone. HCl (5 mL) and dioxane (1 mL) was heated at reflux for 12 h. The reaction mixture was concentrated and the residue was dissolved in THF (10 mL). Then the solution were treated with a solution of NaOH (284 mg, 7.10 mmol) in H ₂ 0 (1 mL) at 0°C followed by di-iert-butyl dicarbonate (840 mg, 3.00 mmol). The reaction mixture was stirred at rt for 16 h before it was quenched with IN HCl and was extracted with 5% MeOH in CHCI ₃ . The organic layer was separated, dried, filtered and concentrated to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 13.40 (br s, 1H), 7.64 (s, 1H), 7.52 (d, / = 7.8 Hz, 1H), 7.36 (d, / = 7.8 Hz, 1H), 4.38 (s, 2H), 2.76 (s, 3H), 1.38 (s, 9H).

Step 4: Preparation of methyl 5-(((iert-butoxycarbonyl)(methyl)amino)methyl)-2- chlorobenzoate

To a solution of 5-(((iert-butoxycarbonyl)(methyl)amino)methyl)-2-chlorobenzo ic acid (160 mg, 0.534 mmol) and K ₂ C0 ₃ (184 mg, 1.335 mmol) in DMF (1.5 mL) was added methyl iodide (189 mg, 1.335 mmol) at rt. The reaction mixture was stirred at rt for 2-3 h before it was quenched with IN HC1 and was extracted with EtOAc. The organic layer was washed with water, separated, dried, filtered and concentrated to afford 160 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 7.67 (br s, 1H), 7.57 (d, / = 7.8 Hz, 1H), 7.41 (d, / = 7.8 Hz, 1H), 4.39 (s, 2H), 3.85 (s, 3H), 2.77 (s, 3H), 1.38 (s, 9H).

Step 5 : Preparation of methyl 2-chloro-5-((N-methylpivalamido)methyl)benzoate

A solution of methyl 5-(((iert-butoxycarbonyl)(methyl)amino)methyl)-2-chlorobenzo ate (160 mg, 0.510 mmol) in EtOAc saturated with HC1 (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated. To a solution of the concentrate in CH ₂ C1 ₂ (2 mL) were added DIPEA (329 mg, 2.55 mmol) followed by pivaloyl chloride (123 mg, 1.02 mmol) at 0-5°C. The reaction mixture was stirred at rt for 1 h before it was quenched with IN HC1 and was extracted with CHC1 ₃ . The organic layer was washed with water, separated, dried, filtered and concentrated to afford 90 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 7.61 (s, 1H), 7.55 (d, / = 8.4 Hz, 1H), 7.36 (d, / = 8.7 Hz, 1H), 4.57 (s, 2H), 3.85 (s, 3H), 2.97 (s, 3H), 1.22 (s, 9H).

Intermediate-5

Methyl 2-chloro-5-(pivalamidomethyl)benzoate

Step 1 : Preparation of 5- {[(iert-butoxycarbonyl)amino]methyl}-2-chlorobenzoic acid

A solution of 2-chloro-5- {[(trifluoroacetyl)amino]methyl}benzoic acid (Intermediate -4, step 1 , 800 mg, 2.84 mmol) in cone. HC1 (5 mL) and dioxane (1 mL) was heated at reflux for 12 h. The reaction mixture was concentrated and the residue was dissolved in THF (10 mL). The solution were treated with a solution of NaOH (284 mg, 7.10 mmol) in H ₂ 0 (1 mL) at 0°C followed by di-iert-butyl dicarbonate (840 mg, 3.00 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was acidified with IN HC1 and the pH was adjusted to 2-3. The reaction mixture was extracted with 5% MeOH in CHCI ₃ . The organic layer was separated, dried, filtered and concentrated. The concentrate was recrystallized from toluene/butan-2-one (7: 1) to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 13.1 (br s, 1H), 7.64 (s, 1H), 7.49 (d, / = 8.1 Hz, 1H), 7.37 (d, / = 7.8 Hz, 1H), 4.13 (d, J = 5.1 Hz, 2H), 1.38 (s, 9H); MS (m/z): 283.94 (M-H) ^~ .

Step 2: Preparation of methyl 5-(((iert-butoxycarbonyl)amino)methyl)-2-chlorobenzoate

To a solution of 5-{[(ieri-butoxycarbonyl)amino]methyl}-2-chlorobenzoic acid (1.0 g, 3.50 mmol) in DMF (5.0 mL) were added methyl iodide (496 mg, 3.50 mmol) and potassium carbonate (966 mg, 7.00 mmol). The reaction mass was stirred at rt for 18 h. The reaction mass was diluted with EtOAc and the organic layer was washed with water and brine. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 440 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 7.66 (s, 1H), 7.49-7.52 (m, 2H), 7.42 (d, / = 6.3 Hz, 1H), 4.13 (d, / = 5.7 Hz, 2H), 3.85 (s, 3H), 1.38(s, 9H).

Step 3 : Preparation of methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride

A solution of methyl 5-(((iert-butoxycarbonyl)amino)methyl)-2-chlorobenzoate (100 mg, 0.334 mmol) in EtOAc saturated with HC1 (1 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and was triturated with pentane to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 8.20 (br s, 3H), 7.95 (s, 1H), 7.67 (s, 2H), 4.00 (s, 2H), 3.88(s, 3H).

Step 4: Preparation of methyl 2-chloro-5-(pivalamidomethyl)benzoate

To a solution of methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (1.80 g, 6.00 mmol) in CH ₂ C1 ₂ were added DIPEA (3.096 g, 2.4 mmol ) followed by pivaloyl chloride (1.2 mL, 9.0 mmol) at 0-5°C and the reaction mixture was stirred at rt for lh before it was quenched with water and was extracted with chloroform. The organic layer was separated, dried, filtered and concentrated to afford 2.0 g of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 8.16 (m, 1H), 7.65 (s, 1H), 7.53 (d, / = 8.4 Hz, 1H), 7.41 (d, / = 8.4 Hz, 1H), 4.25 (d, / = 5.7 Hz, 2H), 3.85 (s, 3H), 1.15 (s, 9H). Intermediate-6

7-Amino-2-cyclohexylphthalazin- 1 (2H)-one

Step 1 : Preparation of 2-cyclohexyl- -nitrophthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 1 of Intermediate-2 using 3-bromo-6-nitroisobenzofuran-l(3H)-one (Intermediate- 1 , 300 mg, 1.024), cyclohexylhydrazine hydrate (81 mg, 1.627 mmol), 5% aq. HC1 (4 mL) and MeOH (4 mL) to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 8.80 (s, 1H), 8.68- 8.66 (m, 2H), 8.20 (d, / = 9.0 Hz, 1H), 4.87 (m, 1H), 1.80- 1.67 (m, 6H), 1.45- 1.41 (m, 2H), 1.22-1.17 (m, 2H).

Step 2: Preparation of 7-amino-2-cyclohexylphthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-cyclohexyl-7-nitrophthalazin-l(2H)-one (200 mg, 0.732 mmol), iron powder (328 mg, 5.86 mmol) and ammonium chloride (391 mg, 7.32 mmol) in EtOH (3 mL) and water (1 mL) to afford 100 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 8.10 (s, 1H), 7.54 (d, / = 8.7 Hz, 1H),7.27 (s, 1H), 7.05 (d, / = 9.9 Hz, 1H), 6.21 (br s, 2H), 4.82 (m, 1H), 1.83- 1.69 (m, 6H), 1.41- 1.37 (m, 2H), 1.23- 1.14 (m, 2H); MS [M+H] ⁺ : 244.13.

Intermediate-7

Methyl 2-chloro-5-(2-hydroxypropan-2-yl)benzoate

To a solution of methyl 5-acetyl-2-chlorobenzoate (50 mg, 0.235 mmol) in THF (5.0 mL) was added a 3M solution of methylmagnesium bromide in ether (0.390 mL, 1.176 mmol) at -60°C. The reaction mass was slowly warmed up to rt and stirred for 1-2 h. The reaction mass was quenched with ice-water and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 7.89 (s, 1H), 7.63 (d, / = 9.0 Hz, 1H), 7.49 (d, / = 8.4 Hz, 1H), 4.10 (m, 1H), 3.85 (s, 3H), 1.41 (s, 6H).

Intermediate- 8

Ethyl 2-chloro-5 -(5 -methyl- 1 H-pyrazol-3 -yl)benzoate

Step 1 : Preparation of 2-chloro-5 -(5 -methyl- 1 H-pyrazol-3 -yl)benzohydrazide

To a solution of methyl 5-acetyl-2-chlorobenzoate (300 mg, 1.41 1 mmol) in DMF (1.0 mL) was added N,N-dimethylacetamide dimethylacetal (375 mg, 2.823 mmol). The reaction mass was heated at 100°C for 5-6 h. The reaction mass was concentrated and diluted with ethanol. Then hydrazine hydrate (0.5 mL) was added to reaction mixture and it was stirred at rt overnight. The reaction mass was quenched with water and the precipitate was filtered and dried to afford 280 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 12.70 (br s, 1H), 9.62 (s, 1H), 7.80- 7.74 (m, 2H), 7.48 (d, / = 8.4 Hz, 1H), 6.50 (s, 1H), 4.51 (br s, 2H), 2.25 (s, 3H).

Step 2: Preparation of ethyl 2-chloro-5 -(5 -methyl- 1 H-pyrazol-3 -yl)benzoate

To a solution of 2-chloro-5 -(5 -methyl- 1 H-pyrazol-3 -yl)benzohydrazide (300 mg, 1.28 mmol) in ethanol (2.0 mL) was added copper (II) chloride (300 mg, 2.23 mmol). The reaction mass was heated at reflux for 1 h. Then the reaction mass was diluted with chloroform and was filtered through celite bed. The filtrate was concentrated and dissolved in ethanol. Then the solution was treated with cone. H ₂ SO ₄ (0.5 mL) and was heated at reflux for 12 h. The reaction mass was quenched with water and was extracted with chloroform. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 12.73 (br s, 1H), 8.14 (s, 1H), 7.89 (m, 1H), 7.57 (m, 1H), 6.53 (s, 1H), 4.34 (m, 2H), 2.26 (s,3H), 1.33 (m, 3H).

Intermediate-9

Methyl 2-chloro-5-(2H-l ,2,3-triazol-4-yl)benzoate To a solution of methyl 2-chloro-5-ethynylbenzoate (400 mg, 2.05 mmol) in n-butanol (5.0 mL) were added cuprous iodide (19 mg, 0.102 mmol) and azidotrimethylsilane (591 mg, 5.14 mmol). The reaction mass was heated at 100-120°C for 24 h in a sealed tube. The reaction mass was concentrated and purified by column chromatography to afford 160 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 15.18 (br s, 1H), 8.38 (br s, 1H), 8.29 (s, 1H), 8.06 (d, / = 8.4 Hz, 1H), 7.68 (d, / = 9.0 Hz, 1H), 3.90 (s, 3H); MS [M-H] ^~ : 236.06.

Intermediate- 10

7-Amino-2-(cyclopropylmethyl)phthalazin- 1 (2H)-one

Step 1 : Preparation of 7-nitrophthalazin- 1 (2H)-one

O

^Η Υ ΤΥ ^Ν ° ²

The title compound was prepared following the procedure described in Step 1 of Intermediate-2 using 3-bromo-6-nitroisobenzofuran-l(3H)-one (Intermediate- 1 , 300 mg, 1.024), hydrazine hydrate (42 mg, 1.48 mmol), 5% aq. HC1 (4 mL) and MeOH (4 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 13.07 (br s, 1H), 8.83 (s, 1H), 8.66 (d, / = 8.7 Hz, 1H), 8.54 (s, 1H), 8.19 (d, / = 6.3 Hz, 1H).

Step 2: Preparation of 2-(cyclopropylmethyl)-7-nitrophthalazin-l(2H)-one

To a solution of 7-nitrophthalazin- l(2H)-one (100 mg, 0.534 mmol) in DMF (1.5 mL) were added cyclopropylmethyl bromide (182 mg, 1.35 mmol) and K ₂ CO ₃ (191 mg, 1.44 mmol). The reaction mass was heated at 50°C for 12-14 h before it was quenched with water and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 100 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 8.89 (s, 1H), 8.69- 8.64 (m, 2H), 8.22 (d, / = 8.7 Hz, 1H), 4.04 (d, / = 7.5 Hz, 2H), 1.27 (m, 1H), 0.53-0.40 (m, 4H).

Step 3 : Preparation of 7-amino-2-(cyclopropylmethyl)phthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of

Intermediate-2 using, 2-(cyclopropylmethyl)-7-nitrophthalazin-l(2H)-one(150 mg, 0.568 mmol), iron powder (254 mg, 4.545 mmol) and ammonium chloride (303 mg, 5.68 mmol) in EtOH (3 mL) and water (1 mL) to afford 100 mg of the title product. 1H NMR (300 MHz, DMSO-Je): δ 8.07 (s, 1H), 7.56 (d, / = 8.7 Hz, 1H), 7.26 (s, 1H), 7.06 (d, / = 8.4 Hz, 1H), 6.24 (br s, 2H), 3.91 (d, / = 7.2 Hz, 2H), 1.23 (m, 1H), 0.45- 0.35 (m, 4H); MS [M+H] ⁺ : 216.03.

Intermediate- 11

Methyl 5-(3-amino-3-oxopropyl)-2-chlorobenzoate

Step 1 : Preparation of methyl 5-(3-(iert-butoxy)-3-oxoprop-l-en-l-yl)-2-chlorobenzoate

To a solution of methyl 5-bromo-2-chlorobenzoate (500 mg, 2.00 mmol) in DMF (2.5 mL) were added iert-butyl acrylate (641 mg, 5.00 mmol), K ₂ CO ₃ (828 mg, 6.00 mmol) and Pd(PPh ₃ ) ₄ (46 mg, 0.04 mmol). The reaction mass was heated at 80-90 °C for 8-10 h before it was filtered through a celite bed. The filtrate was concentrated and purified by column chromatography to afford 500 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 7.96 (s, 1H), 7.67 (m, 1H), 7.53 (d, / = 8.4 Hz, 1H), 7.32 (d, / = 8.4 Hz, 1H), 6.38 (d, / = 16.2 Hz, 1H), 3.94 (s, 3H), 1.53 (s, 9H).

Step 2: Preparation of methyl 5-(3-(iert-butoxy)-3-oxopropyl)-2-chlorobenzoate

To a solution of methyl 5-(3-(ieri-butoxy)-3-oxoprop-l-en-l-yl)-2-chlorobenzoate (500 mg, 1.68 mmol) in methanol (10 mL) was added 10% Pd/C (200 mg). The reaction mass was hydrogenated at 30-40 psi for 10 h. The reaction mass was filtered through a celite bed. The filtrate was concentrated and purified by column chromatography to afford 103 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 7.66 (s, 1H), 7.36 (d, / = 6.6 Hz, 1H), 7.26 (s, 1H), 3.92 (s, 3H), 2.90 (t, / = 7.8 Hz, 2H), 2.53 (t, 7 = 7.8 Hz, 2H), 1.41(s, 9H).

Step 3 : Preparation of 3-(4-chloro-3-(methoxycarbonyl)phenyl)propanoic acid

To a solution of methyl 5-(3-(iert-butoxy)-3-oxopropyl)-2-chlorobenzoate (100 mg, 0.33 mmol) in THF (1 mL) was added trifluoroacetic acid (0.5 mL). The reaction mass was stirred at rt for 12-16 h. The reaction mass was quenched with water and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated to afford 90 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 7.66 (s, 1H), 7.47- 7.42 (m, 2H), 3.84 (s, 3H), 2.84 (t, / = 7.5 Hz, 2H), 2.55 (t, / = 7.2 Hz, 2H).

Step 4: Preparation of methyl 5-(3-amino-3-oxopropyl)-2-chlorobenzoate

To a solution of 3-(4-chloro-3-(methoxycarbonyl)phenyl)propanoic acid (90 mg, 0.37 mmol) in CH ₂ CI ₂ (5 mL) was added oxalyl chloride (0.5 mL). The reaction mass was stirred at rt for 2-3 h. The reaction mass was concentrated. The concentrate was dissolved in THF (2 mL) and was treated with a solution of aq. N¾ (1 mL) at 0°C and stirred at rt for 2-3 h. The reaction mass was concentrated and purified by column chromatography to afford 75 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 7.63 (s, 1H), 7.49- 7.40 (m, 2H), 7.28 (br s, 1H), 6.78 (br s, 1H), 3.84 (s, 3H), 2.83 (t, / = 7.5 Hz, 2H), 2.36 (t, / = 7.8 Hz, 2H); MS [M+H] ⁺ : 241.75.

Intermediate- 12

7-Amino-2-hexylphthalazin- 1 (2H -one

Step 1 : Preparation of 2-hexyl-7-nitrophthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate- 10 using 7-nitrophthalazin-l(2H)-one (Step 1, Intermediate- 10, 300 mg, 1.449 mmol), n-hexyl bromide (717 mg, 4.347 mmol) and K ₂ CO ₃ (765 mg, 5.797 mmol) in DMF (5 mL) to afford 290 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 8.88 (s, 1H), 8.69-8.65 (d, / = 8.7 Hz, 1H), 8.64 (s, 1H), 8.24-8.21 (d, / = 8.7 Hz, 1H), 4.18-4.14 (t, / = 7.5 Hz, 2H), 1.75 (t, / = 6.9 Hz, 2H), 1.28-1.22 (m, 6H), 0.84 (t, / = 6.3 Hz, 3H); MS [M+H] ⁺ : 275.93. Step 2: Preparation of 7-amino-2-hexylphthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-hexyl-7-nitrophthalazin-l(2H)-one (200 mg, 0.729 mmol), iron powder (327 mg, 5.839 mmol) and ammonium chloride (390 mg, 7.29 mmol) in EtOH (3 mL) and water (1 mL) to afford 170 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 8.05 (s, 1H), 7.53 (d, / = 8.1 Hz, 1H), 7.23 (s, 1H), 7.04 (d, / = 8.4 Hz, 1H), 6.21 (br s, 2H), 4.02 (t, / = 6.9 Hz, 2H), 1.67 (m, 2H), 1.25 (br s, 6H), 0.82 (m, 3H); MS [M+H] ⁺ : 265.06.

Intermediate- 13

7-Amino-2-(cyclohexylmethyl)phthalazin- 1 (2H)-one

Step 1 : Preparation of 2-(cyclohexylmethyl)-7-nitrophthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate- 10 using 7-nitrophthalazin-l(2H)-one (Step 1 , Intermediate- 10, 300 mg, 1.449 mmol), cyclohexylmethyl bromide (769 mg, 4.347 mmol), and K ₂ C0 ₃ (765 mg, 5.797 mmol) in DMF (5 mL) to afford 280 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 8.88 (s, 1H), 8.69- 8.62 (m, 2H), 8.21 (d, / = 8.7 Hz, 1H), 4.02 (d, / = 7.5 Hz, 2H), 1.90 (m, 1H), 1.62-1.59 (m, 6H), 1.23-1.05 (m, 4H); MS [M+H] ⁺ : 335.09.

Step 2: Preparation of 7-amino-2-(cyclohexylmethyl)phthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-(cyclohexylmethyl)-7-nitrophthalazin-l(2H)-one (200 mg, 0.696 mmol), iron powder (312 mg, 5.574 mmol) and ammonium chloride (372 mg, 6.96 mmol) in EtOH (3 mL) and water (1 mL) to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO-Je): δ 8.03 (s, 1H), 7.53 (d, / = 8.7 Hz, 1H), 7.23 (s, 1H), 7.04 (d, / = 8.4 Hz, 1H), 6.21 (br s, 2H), 3.88 (d, / = 7.5 Hz, 2H), 1.84 (m, 1H), 1.62- 1.51 (m, 6H), 1.13 (m, 4H); MS [M+H] ⁺ : 258.07.

Intermediate- 14

7- Amino-2-isopropylphthalazin- 1 (2H)-one

Step 1 : Preparation of 2-isopropyl-7-nitrophthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate- 10 using 7-nitrophthalazin-l(2H)-one (Step 1, Intermediate- 10, 350 mg, 1.83 mmol), isopropyl bromide (1.26 g, 9.16 mmol) and K ₂ CO ₃ (758 mg, 5.49 mmol) in DMF (6 mL) to afford 140 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 8.89 (s, 1H), 8.66 (s, 2H), 8.21 (d, / = 8.7 Hz, 1H), 5.27 (m, 1H), 1.34 (d, / = 6.6 Hz, 6H).

Step 2: Preparation of 7-amino-2-isopropylphthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-isopropyl-7-nitrophthalazin-l(2H)-one (140 mg, 0.60 mmol), iron powder (269 mg, 4.806 mmol) and ammonium chloride (321 mg, 6.00 mmol) in EtOH (3 mL) and water (1 mL) to afford 79 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 8.12 (s, 1H), 7.54 (d, / = 8.1 Hz, 1H), 7.26 (s, 1H), 7.05 (d, / = 8.4 Hz, 1H), 6.21 (br s, 2H), 5.28- 5.19 (m, 1H), 1.30- 1.23 (m, 6H).

Intermediate 15

7-Aminophthalazin- 1 (2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 7-nitrophthalazin-l(2H)-one (Step-1, Intermediate- 10, 350 mg, 1.83 mmol), iron powder (820 mg, 14.66 mmol) and ammonium chloride (970 mg, 18.32 mmol) in EtOH (7 mL) and water (3 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO-Je): δ 12.13 (br s, 1H), 7.99 (s, 1H), 7.53 (d, / = 8.1 Hz, 1H), 7.19 (s, 1H), 7.06 (d, 1H), 6.18 (bs, 2H).

Intermediate- 16

7-Amino-2-cyclobutylphthalazin- 1 (2H)-one

Step 1 : Preparation of 2-cyclobutyl-7-nitrophthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate- 10 using 7-nitrophthalazin-l(2H)-one (Step 1, Intermediate- 10, 350 mg, 1.83 mmol), cyclobutyl bromide (1.236 g, 9.16 mmol) and K ₂ CO ₃ (758 mg, 5.49 mmol) in DMF (6 mL) to afford 175 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 8.87 (s, 1H), 8.71- 8.66 (m, 2H), 8.22 (d, / = 8.7 Hz, 1H), 5.48-5.40 (m, 1H), 2.50- 2.45 (m, 2H), 2.30 (m, 2H), 1.89- 1.83 (m, 2H).

Step 2: Preparation of 7-amino-2-cyclobutylphthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-cyclobutyl-7-nitrophthalazin-l(2H)-one (175 mg, 0.71 mmol), iron powder (319 mg, 5.71 mmol) and ammonium chloride (378 mg, 7.14 mmol) in EtOH (3 mL) and water (1 mL) to afford 100 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 8.17 (s, 1H), 7.56 (d, / = 8.4 Hz, 1H), 7.24 (m, 1H), 7.06 (d, / = 8.4 Hz, 1H), 6.23 (br s, 2H), 5.48- 5.42 (m, 1H), 2.50- 2.39 (m, 2H), 2.21 (m, 2H), 1.80- 1.74 (m, 2H).

Intermediate- 17

7-Amino-2-methylphthalazin- 1 (2H)-one

Step 1 : Preparation of 2-methyl-7-nitrophthalazin- 1 (2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate- 10 using 7-nitrophthalazin-l(2H)-one (Step 1, Intermediate- 10, 350 mg, 1.83 mmol), methyl iodide (1.29 g, 9.16 mmol) and K ₂ C0 ₃ (758 mg, 5.49 mmol) in DMF (6 mL) to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 8.86 (m, 1H), 8.65 (d, / = 6.6 Hz, 1H), 8.58 (s, 1H), 8.20 (d, / = 8.7 Hz, 1H), 3.74 (s, 3H).

Step 2: Preparation of 7-amino-2-methylphthalazin-l(2H)-one The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-methyl-7-nitrophthalazin-l(2H)-one (150 mg, 0.73 mmol), iron powder (326 mg, 5.85 mmol) and ammonium chloride (387 mg, 7.31 mmol) in EtOH (3 mL) and water (1 mL) to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 8.05 (s, 1H), 7.55 (m, 1H), 7.25 (s, 1H), 7.07 (m, 1H), 6.23 (br s, 2H), 3.63 (s, 3H).

Intermediate- 18

7- Amino-2-(4-fluorophenyl)phthalazin- 1 2H)-one

Step 1 : Preparation of 2-(4-fluorophenyl)-7-nitrophthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 1 of Intermediate-2 using 3-bromo-6-nitroisobenzofuran-l(3H)-one (Intermediate- 1 , 500 mg, 1.937), (4-fluorophenyl)hydrazine hydrate (472 mg, 2.907 mmol), 5% aq. HCL (7 mL) and MeOH (7 mL) to afford 300 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 8.93 (m, 1H), 8.76- 8.73 (m, 2H), 8.30 (d, / = 8.4 Hz, 1H), 7.70- 7.66 (m, 2H), 7.38 (t, / = 8.7 Hz, 2H); MS [M+H] ⁺ : 286.02.

Step 2: Preparation of 7-amino-2-(4-fluorophenyl)phthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-(4-fluorophenyl)-7-nitrophthalazin-l(2H)-one (300 mg, 1.25 mmol), iron powder (56 mg, 10.00 mmol) and ammonium chloride (668 mg,12.5 mmol) in EtOH (6 mL) and water (1.5 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO- d ₆ ): δ 8.20 (s, 1H), 7.64- 7.56 (m, 3H), 7.32- 7.26 (m, 3H), 7.09 (dd, / = 6.3 Hz, 1H),6.34 (s, 2H).

Intermediate- 19

7-Amino-2-(2,2,2-trifluoroethyl)phthalazin- 1 (2H)-one

^F ₃ ^C - ^{N H*}

Step 1 : Preparation of 7-nitro-2-(2,2,2-trifluoroethyl)phthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 1 of lntermediate-2 using 3-bromo-6-nitroisobenzofuran-l(3H)-one (Intermediate- 1 , 500 mg, 1.937), (2,2,2-trifiuoroethyl)hydrazine hydrate (383 mg, 2.907 mmol), 5% aq. HC1 (7 mL) and MeOH (7 mL) to afford 350 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 8.89 (s, lH), 8.76- 8.72 (m, 2H), 8.26 (d, / = 9.0 Hz, 1H), 5.06 (q, / = 9.3 Hz, 2H).

Step 2: Preparation of 7-amino-2-(2,2,2-trifluoroethyl)phthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of lntermediate-2 using 7-nitro-2-(2,2,2-trifluoroethyl)phthalazin-l(2H)-one (300 mg, 0.804 mmol), iron powder (360 mg, 6.432 mmol) and ammonium chloride (426 mg, 8.04 mmol) in EtOH (4 mL) and water (1 mL) to afford 255 mg of the title product. 1H NMR (300 MHz, DMSO-Je): δ 8.15 (s, lH), 7.60 (d, / = 8.1 Hz, 1H), 7.28 (s, 1H), 7.10 (d, / = 8.4 Hz, 1H), 6.38 (bs, 2H),4.89 (q, / = 9.0 Hz, 2H).

Intermediate-20

7-Amino-2-(3-(trifluoromethyl)phenyl)phthalazin- 1 (2H)-one

Step 1 : Preparation of 7-nitro-2-(3-(trifluoromethyl)phenyl)phthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 1 of lntermediate-2 using 3-bromo-6-nitroisobenzofuran-l(3H)-one (Intermediate- 1 , 500 mg, 1.937), (3-(trifluoromethyl)phenyl)hydrazine hydrate (375 mg, 2.13 mmol), 5% aq. HC1 (7 mL) and MeOH (7 mL) to afford 530 mg of the title product. 1H NMR (300 MHz, DMSO- d ₆ ): δ 8.94 (s, 1H), 8.81 (s, 1H), 8.75 (d, / = 8.7 Hz, 1H), 8.32(d, / = 8.7 Hz, 1H), 8.06 (s, 1H), 8.00 (d, / = 7.8 Hz, 1H), 7.82-7.80 (m, 2H); MS [M+H] ⁺ : 336.04.

Step 2: Preparation of 7-amino-2-(3-(trifluoromethyl)phenyl)phthalazin- 1 (2H)-one

The title compound was prepared following the procedure described in Step 2 of lntermediate-2 using 7-nitro-2-(3-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (530 mg, 1.58 mmol), iron powder (886 mg, 15.8 mmol) and ammonium chloride (676 mg,12.6 mmol) in EtOH (7 mL) and water (2 mL) to afford 440 mg of the title product. 1H NMR (300 MHz, DMSO-Je): δ 8.28 (s, 1H), 7.99- 7.95 (m, 2H), 7.75- 7.65 (m, 3H), 7.35 (s, 1H), 7.12 (d, / = 6.6 Hz, 1H), 6.40 (br s, 2H). MS [M+H] ⁺ : 306.13.

Intermediate-21

7-Amino-2-(2,4-difluorophenyl)phthalazin- 1 2H)-one

Step 1 : Preparation of 2-(2,4-diflu rophenyl)-7-nitrophthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 1 of Intermediate-2 using 3-bromo-6-nitroisobenzofuran-l(3H)-one (Intermediate- 1 , 500 mg, 1.937), (2,4-difluorophenyl)hydrazine hydrate (524 mg, 2.907 mmol), 5% aq. HC1 (7 mL) and MeOH (7 mL) to afford 400 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 9.31 (s, 1H), 8.68 (dd, / = 6.6 Hz, 1H), 8.39 (s, 1H), 7.96 (d, / = 9.0 Hz, 1H), 7.54- 7.46 (m, 1H), 7.06- 7.01 (m, 2H).

Step 2: Preparation of 7-amino-2-(2,4-difluorophenyl)phthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-(2,4-difluorophenyl)-7-nitrophthalazin-l(2H)-one (300 mg, 1.15 mmol), iron powder (518 mg, 9.266 mmol) and ammonium chloride (613 mg,l 1.583 mmol) in EtOH (5 mL) and water (1 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO-Je): δ 8.20 (s, 1H), 7.65- 7.56 (m, 2H), 7.46 (t, / = 9.3 Hz, 1H), 7.28 (s, 1H), 7.22 (t, / = 7.2 Hz, 1H), 7.1 1(d, / = 6.9 Hz, 1H), 6.38 (s, 2H).

Intermediate-22

7- Amino-2-(2-fluorophenyl)phthalazin- 1 2H)-one

Step 1 : Preparation of 2-(2-fluorophenyl)-7-nitrophthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 1 of Intermediate-2 using 3-bromo-6-nitroisobenzofuran-l(3H)-one (Intermediate- 1 , 500 mg, 1.937), (2-fluorophenyl)hydrazine hydrate (472 mg, 2.907 mmol), 5% aq. HC1 (7 mL) and MeOH (7 mL) to afford 300 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 8.91 (s, 1H), 8.79-8.75 (m, 2H), 8.32 (d, / = 8.1 Hz, 1H), 7.67-7.38 (m, 4H).

Step 2: Preparation of 7-amino-2-(2-fluorophenyl)phthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-(2-fluorophenyl)-7-nitrophthalazin-l(2H)-one (300 mg, 1.25 mmol), iron powder (56 mg, 10.00 mmol) and ammonium chloride (668 mg,12.5 mmol) in EtOH (6 mL) and water (1 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 8.22 (s, 1H), 7.65 (d, / = 8.4 Hz, 1H), 7.56-7.31 (m, 5H), 7.12 (d, / = 6.0 Hz, 1H), 6.38 (br s, 2H).

Intermediate-23

7- Amino-2-(3 -fluorophenyl)phthalazin- 1 (2H)-one

Step 1 : Preparation of 2-(3-fluorophenyl)-7-nitrophthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 1 of Intermediate-2 using 3-bromo-6-nitroisobenzofuran-l(3H)-one (Intermediate- 1 , 500 mg, 1.937), (3-fluorophenyl)hydrazine hydrate (472 mg, 2.907 mmol), 5% aq. HC1 (7 mL) and MeOH (7 mL) to afford 300 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 8.93 (s, 1H), 8.79- 8.73 (m, 2H), 8.30 (d, / = 8.1 Hz, 1H), 7.61-7.43 (m, 3H), 7.32 (t, / = 7.2 Hz, 1H).

Step 2: Preparation of 7-amino-2-(3-fluorophenyl)phthalazin- 1 (2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-(3-fluorophenyl)-7-nitrophthalazin-l(2H)-one (300 mg, 1.25 mmol), iron powder (56 mg, 10.00 mmol) and ammonium chloride (668 mg,12.5 mmol) in EtOH (6 mL) and water (1 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 8.24 (s, 1H), 7.64 (d, / = 8.4 Hz, 1H), 7.56-7.46 (m, 3H), 7.34 (s, 1H), 7.23 (t, / = 7.20 Hz, 1H), 7.1 1(d, / = 6.3 Hz, 1H), 6.38 (br s, 2H).

Intermediate- 24

Methyl 2-fluoro-5 -(pivalamidometh l)benzoate

Step 1 : Preparation of 2-fluoro-5-((2,2,2-trifluoroacetamido)methyl)benzoic acid

The title compound was prepared following the procedure described in Step 1 of Intermediate-4 using 2-fluorobenzoic acid (1.00 g, 7.13 mmol), cone. H ₂ SO ₄ , 2,2,2-trifluoro- N-(hydroxymethyl)acetamide (1.2 g, 7.8 mmol) to afford 1.1 g of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 13.30 (br s, 1H), 10.03 (br s, 1H), 7.78 (m, 1H), 7.53 (m, 1H), 7.29 (t, / = 8.7 Hz, 1H), 4.40 (d, / = 6.3 Hz, 2H).

Step 2: Preparation of 5-(((ieri-butox carbonyl)amino)methyl)-2-fluorobenzoic acid

The title compound was prepared following the procedure described in Step 3 of Intermediate-4 using 2-fluoro-5-((2,2,2-trifluoroacetamido)methyl)benzoic acid (1.1 g, 5.7 mmol), cone. HC1 (5 mL), NaOH (1.0 g, 0.025 mmol), di-te/t-butyl dicarbonate (2.4 g, 1 1.14 mmol) to afford 800 mg of the title product.

Step 3 : Preparation of methyl 5-(( iert-butoxycarbonyl)amino)methyl)-2-fluorobenzoate

The title compound was prepared following the procedure described in Step 4 of Intermediate-4 using 5-(((iert-butoxycarbonyl)amino)methyl)-2-fluorobenzoic acid (200 mg, 0.743 mmol), K ₂ C0 ₃ (205 mg, 1.4 mmol), methyl iodide (104 mg,0.743 mmol) in DMF (3 mL) to afford 160 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 7.75 (d, / = 4.8 Hz, 1H), 7.48 (m, 2H), 7.29 (t, / = 8.4 Hz, 1H), 4.13 (d, / = 6.0 Hz, 2H),3.85 (s, 3H), 1.30 (s, 9H).

Step 4: Preparation of methyl 2-fluoro-5-(pivalamidomethyl)benzoate

The title compound was prepared following the procedure described in Step 5 of Intermediate-4 using methyl 5-(((iert-butoxycarbonyl)amino)methyl)-2-fluorobenzoate (160 mg, 0.565 mmol), EtOAc saturated with HC1 (2 riiL), DIPEA (155 mg, 19.0 mmol), pivaloyl chloride (1 18 mg, 0.983 mmol) and CH ₂ C1 ₂ (2 mL) to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 8.14 (m, 1H), 7.71 (d, / = 6.9 Hz, 1H), 7.47 (m, 1H), 7.27 (t, / = 8.7 Hz, 1H), 4.23 (d, / = 6.0 Hz, 2H), 3.82 (s, 3H), 1.10 (s, 9H).

Intermediate-25

7-Amino-2-(4-isopropylphenyl)phthalazin- 1 (2H)-one

Step 1 : Preparation of 2-(4-isopropylphenyl)-7-nitrophthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 1 of Intermediate-2 using 3-bromo-6-nitroisobenzofuran-l(3H)-one (Intermediate- 1 , 500 mg, 1.937), (4-isopropylphenyl)hydrazine hydrate (436 mg, 2.907 mmol), 5% aq. HC1 (7 mL) and MeOH (7 mL) to afford 350 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 8.29 (s, 1H), 8.75- 8.72 (m, 2H), 8.28 (d, / = 8.7 Hz, 1H), 7.53 (d, / = 7.8 Hz, 2H),7.40 (d, / = 8.4 Hz, 2H), 2.98 (m, 1H), 1.25 (d, / = 6.9 Hz, 6H).

Step 2: Preparation of 7-amino-2-(4-isopropylphenyl)phthalazin-l(2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-(4-isopropylphenyl)-7-nitrophthalazin-l(2H)-one (300 mg, 0.970 mmol), iron powder (434 mg, 7.766 mmol) and ammonium chloride (518 mg, 9.7 mmol) in EtOH (5 mL) and water (1 mL) to afford 255 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 8.20 (s, 1H), 7.63 (d, / = 8.7 Hz, 1H), 7.45 (d, / = 8.1 Hz, 2H), 7.35- 7.33 (m, 3H), 7.10 (dd, / = 6.3 Hz, 1H), 6.33 (s, 2H), 2.95(m, 1H), 1.24 (d, / = 6.9 Hz, 6H).

Intermediate- 26

Methyl 2-methyl-5 -(pivalamidomethyl)benzoate

Step 1 : Preparation of 2-methyl-5-((2,2,2-trifluoroacetamido)methyl)benzoic acid

The title compound was prepared following the procedure described in Step 1 of Intermediate-4 using 2-methyl benzoic acid (1.00 g, 7.34 mmol), cone. H ₂ SO ₄ , 2,2,2-trifluoro- N-(hydroxymethyl)acetamide (1.38 g, 8.8 mmol) to afford 1.0 g of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 10.03 (m, 1H), 7.75 (s, 1H), 7.36- 7.27 (m, 2H), 4.38 (d, / = 5.7 Hz, 2H), 2.55 (s, 3H).

Step 2: Preparation of 5-(((ieri-butox carbonyl)amino)methyl)-2-methylbenzoic acid

The title compound was prepared following the procedure described in Step 3 of Intermediate-4 using 2-methyl-5-((2,2,2-trifluoroacetamido)methyl)benzoic acid (1.0 g, 3.80 mmol), cone. HC1 (5 mL), dioxane (1.5 mL), NaOH (404 mg, 23.97 mmol), di-ie/t-butyl dicarbonate (3.13 g, 14.38 mmol), and water (1.5 mL) to afford 400 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 7.85 (br s, 1H), 7.31 (m, 1H), 7.18 (d, / = 7.8 Hz, 2H), 4.26 (m, 2H), 2.55 (s, 3H), 1.33 (s, 9H).

Step 3 : Preparation of methyl 5-(( iert-butoxycarbonyl)amino)methyl)-2-methylbenzoate

The title compound was prepared following the procedure described in Step 4 of Intermediate-4 using 5-(((ieri-butoxycarbonyl)amino)methyl)-2-methylbenzoic acid (400 mg, 1.465 mmol), K ₂ C0 ₃ (773 mg, 4.39 mmol), methyl iodide (624 mg, 5.86 mmol) in DMF (5 mL) to afford 400 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 7.81 (s, 1H), 7.32 (d, / = 7.8 Hz, 1H), 7.26- 7.19 (m, 2H), 4.29 (d, 2H), 3.88 (s, 3H), 2.57 (s, 3H), 1.48 (s, 9H).

Step 4: Preparation of methyl 2-methyl-5-(pivalamidomethyl)benzoate

The title compound was prepared following the procedure described in Step 5 of Intermediate-4 using methyl 5-(((ieri-butoxycarbonyl)amino)methyl)-2-methylbenzoate (400 mg, 2.23 mmol), EtOAc saturated with HCl (2 mL), DIPEA (1.37 g, 3.93 mmol), pivaloyl chloride (482 mg, 17.69 mmol) to afford 105 mg of the title product. 1H NMR (300 MHz, CDCls): δ 7.81 (s, 1H), 7.34-7.32 (d, / = 7.8 Hz, 1H), 7.26-7.20 (m, 3H), 4.29 (d, 2H), 3.89 (s, 3H), 2.57 (s, 3H), 1.48 (s, 9H).

Intermediate- 27

Methyl 2-chloro-5 -(3 -hydroxy-3 -methylbut- 1 -yn- 1 -yl)benzoate

To a solution of methyl 5-bromo-2-chlorobenzoate (250 mg, 1.004 mmol) in Et ₃ N (3 mL) were added 2-methylbut-3-yn-2-ol (135 mg, 1.606 mmol), triphenyl phosphine (5 mg, 0.020 mmol), Pd(PPh ₃ ) ₄ Cl ₂ (7 mg, 0.01 mmol), and Cul (4 mg, 0.02 mmol). The reaction mass was heated at 80-90 °C for 2 h before it was filtered through a celite bed and the bed was washed with EtOAc. The filtrate was washed with IN HCl, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 7.79 (s, 1H), 7.57 (s, 2H), 5.54 (s, 1H), 3.86 (s, 3H), 1.46 (s, 6H).

Intermediate- 28

Methyl 2-chloro-5 -(isobutyramidomethyl)benzoate

The title compound was prepared following the procedure described in Step 4 of Intermediate-5 using methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (Intermediate- 5, Step 3, 400 mg, 1.932 mmol), DIPEA (1 mL), isobutyryl chloride (307 mg, 2.898 mmol), CH ₂ CI ₂ (5 mL) to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 8.35 (m, 1H), 7.66 (s, 1H), 7.53 (d, / = 8.4 Hz, 1H), 7.41 (d, / = 8.1 Hz, 1H), 4.26 (d, / = 5.7 Hz, 2H), 3.85 (s, 3H), 2.41 (m, 1H), 1.02 (d, / = 6.9 Hz, 6H).

Intermediate 29

Methyl 5-chloro-2-(pivalamidomethyl)isonicotinate

Step 1 : Preparation of methyl 2,5-dichloroisonicotinate 3

To a solution of 2,5-dichloroisonicotinic acid (5.0 g, 18.47 mmol) in methanol (25 mL) was added cone. H ₂ SO ₄ (0.2 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated and the residue was slowly poured onto ice and the precipitate obtained was filtered, washed with sat. NaHC0 ₃ and was extracted with CH ₂ C1 ₂ . The organic layer was separated, dried, filtered and concentrated to afford 4.57 g of the of the title product .1H NMR (300 MHz, DMSO d ₆ ): δ 8.69 (s, 1H), 7.92(s, 1H), 3.90 (s, 3H).

Step 2: Preparation of methyl 5-chloro-2-meth lisonicotinate H3

To a cold solution of methyl 2,5-dichloroisonicotinate (500 mg, 2.42 mmol) in THF (15 mL) was added N-Methyl-2-pyrrolidone (1.4 mL), iron(III)acetyl acetone (43 mg, 0.12 mmol) and methyl magnesium bromide (36 mg, 0.305 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h and then at rt for 18 h. The reaction mixture was quenched with brine and was extracted with ethyl acetate. The organic layer was separated, dried, filtered and concentrated to afford 130 mg of the title product.1H NMR (300 MHz, DMSO d ₆ ): δ 8.46 (s, 1H), 7.74 (s,lH), 3.87 (s, 3H), 2.44 (s, 3H).

Step 3 : Preparation of methyl 2-(bromometh l)-5-chloroisonicotinate

To a solution of methyl 5-chloro-2-methylisonicotinate (1.00 g, 5.3 mmol) in CC1 ₄ (15 mL) was added 2,2-azobis(isobutronitrile) (89 mg, 0.542 mmol) and N-bromosuccinamide (1.16 g, 6.36 mmol). The reaction mixture was heated at reflux for 5 h before it was quenched with brine and was extracted with chloroform. The organic layer was separated, dried and concentrated. The concentrate was purified by column chromatography to afford 850 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 8.71 (s, 1H), 7.85 (s,lH), 4.95 (s, 2H), 3.92 (s, 3H).

Step 4: Preparation of methyl 2-(azidomethyl)-5-chloroisonicotinate

To a solution of methyl 2-(bromomethyl)-5-chloroisonicotinate (200 mg, 0.792 mmol) in DMSO (2 mL) was added sodium azide (102 mg, 1.58 mmol). The reaction mixture was heated at 70°C for 2 h. The reaction mixture was diluted with ethyl acetate and was washed with water. The organic layer was separated, dried, filtered and concentrated to afford 190 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 8.63 (s, 1H),7.87 (s,lH), 4.79 (s, 2H), 3.90 (s, 3H).

Step 5: Preparation of methyl 2-(((iert-butoxycarbonyl)amino)methyl)-5-chloroisonicotinate

To solution of methyl 2-(azidomethyl)-5-chloroisonicotinate (250 mg, 1.10 mmol) in methanol (5 mL) were added Pd/C (150 mg) and di-ie/t-butyl dicarbonate (502 mg, 2.20 mmol). The reaction mass was stirred under hydrogen atmosphere for 1 h. The reaction mass was filtered through celite and the filtrate was concentrated and purified by column chromatography to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 8.41 (s, 1H),7.44 (s,lH),7.38 (m, 1H), 4.37 (d, / = 5.4 Hz, 2H),3.86 (s, 3H), 1.36 (s, 9H).

Step 6: Preparation of methyl 5-chloro-2-(pivalamidomethyl)isonicotinate

A solution of methyl 2-(((iert-butoxycarbonyl)amino)methyl)-5-chloroisonicotinate (200 mg, 0.66 mmol) in ethyl acetate saturated with HC1 (1 mL) was stirred at rt for 1 h. The reaction mixture was concentrated and the concentrate was dissolved in CH ₂ CI ₂ (2 mL). The solution were treated with DIPEA (0.5 mL) followed by pivaloyl chloride (158 mg, 1.32 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc and was washed with H ₂ 0 and brine. The organic layer was separated, dried, filtered and concentrated to afford 225 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 8.37 (s, 1H),8.04 (m,lH),7.75 (s, 1H), 4.48 (d, / = 5.7 Hz, 2H),3.88 (s, 3H), 1.10 (s, 9H). Intermediate 30

Ethyl 6-chloro-2-fluoro-3 -(pivalamidomethyl)benzoate

Step 1 : Preparation of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate

To a solution DIPEA (6.6 mL, 46.0 mmol) in THF (15 mL) was addeed ⁿ BuLi (27 mL, 43.0 mmol, 1.6 M in hexane) at -78 °C and the reaction mixture was warmed to 0 °C over a period of 1 h. Then the reaction mixture was cooled to -78 °C and a solution of ethyl 2-chloro-6- fluorobenzoate (3.50 g, 19.0 mmol) in THF (56 mL) was added to the reaction mixture dropwise over 30 mins. The resulting mixture was stirred at -78 °C for 2 h before DMF (14 mL, 186 mmol) was added to the reaction mixture. The resulting mixture was stirred at -78 °C for 1 h and then gradually warmed to 0 °C over 1 h. The reaction mass was quenched with 10% aq. AcOH and was extracted with EtOAc. The organic layer was washed with water and brine, separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3- formylbenzoate. 1H NMR (300 MHz, DMSO-J ₆ ): δ 10.27 (s, 1H), 8.05-8.00 (t, / = 7.8 Hz, 1H), 7.72-7.69 (d, / = 8.4 Hz, 1H), 4.53-4.46 (q, / = 6.9, 14.4 Hz, 2H), 1.41-1.37 (t, / = 6.6 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-formylbenzoate (4.04 g, 17.52 mmol) and hydroxylamine (50% aq, solution, 4.29 mL, 70 mmol) in MeOH (60 mL) was stirred at 55 °C for 1.5 h. Then the mixture was concentrated and the residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate. 1H NMR (300 MHz, DMSO-Je): δ 11.89 (s, 1H), 8.20 (s, 1H), 7.88-7.83 (t, / = 8.1 Hz, 1H), 7.49-7.46 (d, / = 8.4 Hz, 1H), 4.44-4.37 (q, / = 7.5, 14.1 Hz, 2H), 1.34-1.29 (t, / = 7.2 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (4.21 g, 17.14 mmol), Zn (4.48 g, 68.56 mmol), and 10N HC1 in EtOH (51.42 mL, 514.2 mmol) in MeOH (200 mL) was heated at reflux for 3h. Additional Zn (2.24 g, 34.25 mmol) was added to the reaction mixture and it was heated at reflux for 2 h and then stirred at rt for 16 h. Then the reaction mixture was concentrated. The residue was diluted with EtOAc and was treated with a saturated solution of NaHC0 ₃ . The mixture was filtered and the organic layer was separated, dried, filtered and concentrated to provide 3.5 g of the title product. 1H NMR (300 MHz, CDCI ₃ ): δ 7.54 (t, / = 7.8 Hz, 1H), 7.28 (d, / = 7.8 Hz, 1H), 4.45 (q, / = 7.5, 14.1 Hz, 2H), 4.11 (d, / = 3.6 Hz, 2H), 3.37 (br s, 2H), 1.40 (t, / = 7.2 Hz, 3H).

Step 2: Preparation of ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate

To a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (70 mg, 0.3 mmol) in THF (3 mL) were added Et ₃ N (0.105 mL, 0.76 mmol) and pivaloyl chloride (38 μί, 0.31 mmol). The reaction mass was stirred at rt for 2 h before it was diluted with EtOAc and was washed with water, and brine. The organic layer was separated, dried, filtered and concentrated to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 8.15 (br t, 1H), 7.43 - 7.35 (m, 2H), 4.38 (q, / = 7.2 Hz, 2H), 4.26 (d, / = 5.7 Hz, 2H), 1.30 (t, / = 6.9 Hz, 3H), 1.1 l(s, 9H).

Intermediate- 31

Ethyl 3 -chloro-6-(pivalamidomethyl)picolinate

Step 1 : Preparation of ethyl 3-chloro-6-iodopicolinate

To solution of 3,6-dichloropicolinic acid ethyl ester (5.0 g, 24 mmol) in CH ₃ CN (45 mL) was added Nal (10.0 g, 66.7 mmol) and acetyl chloride (2.5 mL). The reaction mass was heated in a sealed tube at 100 °C for 48 h. The reaction mass was diluted with ethyl acetate and was washed with an aq. saturated solutions of Na ₂ S20 ₃ and NaHC0 ₃ . The organic layer was separated, dried, filtered and concentrated to afford 2.0 g of the title product. 1H NMR (300 MHz, DMSO-Je): δ 8.04 (d, / = 8.4 Hz, 1H), 7.82 (d, / = 8.7 Hz, 1H), 4.38 (q, / = 7.5 Hz, 2H), 1.32 (t, / = 6.9 Hz, 3H).

Step 2: Preparation of ethyl 3-chloro-6-cyanopicolinate

To solution of ethyl 3-chloro-6-iodopicolinate (1.6 g, 5.38 mmol) in pyridine (40 mL) was added CuCN (480 mg, 5.36 mmol). The reaction mass was heated at 80 °C for 6 h. Then water was added to the reaction mass and it was extracted with ethyl acetate. The organic layer was separated, dried, filtered and concentrated to afford 850 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 8.44 (d, / = 8.1 Hz, 1H), 8.28 (d, / = 8.4 Hz, 1H), 4.42 (q, / = 7.2 Hz, 2H), 1.33 (t, / = 7.2 Hz, 3H).

Step 3: Preparation of ethyl 6-(((iert-butoxycarbonyl)amino)methyl)-3-chloropicolinate

To solution of ethyl 3-chloro-6-cyanopicolinate (1.0 g, 4.76 mmol) in ethanol (25 mL) were added Pt/C (1 g) and di-ie/t-butyl dicarbonate (1.037 g, 4.76 mmol). The reaction mass was hydrogenated at 60 psi for 18 h. The reaction mass was filtered through celite and the filtrate was concentrated to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 8.06 (d, / = 8.4 Hz, 1H), 7.56 (br t, 1H), 7.43 (d, / = 8.4 Hz, 1H), 4.36 (q, / = 6.9 Hz, 2H), 4.21 (d, / = 6.0 Hz, 2H), 1.39- 1.17 (m, 12H).

Step 4: Preparation of ethyl 3-chloro-6-(pivalamidomethyl)picolinate

A solution of ethyl 6-(((ieri-butoxycarbonyl)amino)methyl)-3-chloropicolinate (100 mg, 0.318 mmol) in ethyl acetate saturated with HC1 (1 mL) was stirred at rt for 1 h. The reaction mixture was concentrated and the concentrate was dissolved in CH ₂ CI ₂ (2 mL). The solution were treated with DIPEA (0.5 mL) followed by pivaloyl chloride (38 mg, 0.318 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc and was washed with H ₂ 0 and brine. The organic layer was separated, dried, filtered and concentrated to afford 85 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 8.26 (br t, 1H), 8.04 (d, / = 8.4 Hz, 1H), 7.35 (d, / = 8.1 Hz, 1H), 4.40- 4.31 (m, 4H), 1.33- 1.10 (m, 12H).

Intermediate- 32

Methyl 5-(((15 ^, ,55 ^, )-3-oxabicyclo[3.1.0]hexane-l-carboxamido)methyl)-2-ch lorobenzoate

Step 1 : Preparation of ( R^^-ethyl 2-o -3-oxabicyclo[3.1.0]hexane-l-carboxylate

To a cold solution of sodium (261 mg, 11.35 mmol) in ethanol (15 mL) was slowly added diethyl malonate (1.9 g, 11.89 mmol) at 0 °C. Then a solution of S-epichlorohydrine (1.0 g, 10.81 mmol) in ethanol was slowly added at rt and the reaction mixture was heated at reflux for 20 h. Then the reaction mixture was filtered and concentrated. The residue was dissolved in CH ₂ CI ₂ and was washed with water. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 850 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 4.36- 4.16 (m, 1H), 4.12- 3.83 (m, 3H), 1.92- 1.88 (m, 1H), 1.48- 1.45 (m, 1H), 1.31- 1.17 (m ,4H).

Step 2: Preparation of ( S^^-ethyl l ,2-bis(hydroxymethyl)cyclopropanecarboxylate

To a solution of ( R^^-ethyl 2-oxo-3-oxabicyclo[3.1.0]hexane-l-carboxylate

(200 mg, 1.17 mmol) in ethanol (5 mL) was added sodium borohydride (35 mg, 0.94 mmol) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with IN HCl and was extracted with ethyl acetate. The organic layer was washed with water and brine, separated, dried, filtered and concentrated to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 4.69 (t, / = 5.1 Hz, 1H), 4.59 (t, / = 5.4 Hz, 1H), 4.16- 4.00 (m, 4H), 3.84- 3.78 (m, 1H), 3.69- 3.59 (m, 1H), 1.17 (m, 1H), 1.21- 1.14 (m ,4H), 0.86- 0.82 (m, 1H). Step 3 : Preparation of ( S^^-ethyl 3-oxabicyclo[3.1.0]hexane-l-carboxylate

To a solution of ( S^^-ethyl l ,2-bis(hydroxymethyl)cyclopropanecarboxylate (500 mg, 2.87 mmol) in toluene (5 mL) was added p-toluene sulphonic acid (50 mg). The reaction mixture was heated at reflux for 4 h before it was quenched with water and was extracted in Et ₂ 0. The organic layer was separated, dried, filtered and concentrated to afford 220 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 4.16- 4.12 (m, 2H), 4.09- 3.64 (m, 4H), 2.12- 2.09 (m, 1H), 1.37- 1.23 (m, 1H), 1.22- 1.15 (m ,3H), 0.90- 0.83 (m, 1H).

Step 4: Preparation of (iS,5S)-3-oxabicyclo[3.1.0]hexane-l-carboxylic acid

To a solution of ( S^^-ethyl 3-oxabicyclo[3.1.0]hexane-l-carboxylate(200 mg, 1.28 mmol) in THF:H ₂ 0 (5 : 1 , 6 mL) was added LiOH (108 mg, 2.56 mmol). The reaction mixture was stirred at rt for 5-6 h. The reaction mixture was quenched with water and the organic impurities were extracted in Et ₂ 0. The aqueous layer was neutralized with IN HC1 and was extracted with CH ₂ C1 ₂ . The organic layer was separated, dried, filtered and concentrated to afford 130 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 12.32 (bs, 1H), 3.86- 3.63 (m, 4H), 2.05 (m, 1H), 1.34- 1.31 (m, 1H), 0.85- 0.81 (m ,1H).

Step 5 : Preparation of methyl 5-(((15 ^, ,55 ^, )-3-oxabicyclo[3.1.0]hexane-l-carboxamido)methyl)- 2-chlorobenzoate

A solution of (iS,5S)-3-oxabicyclo[3.1.0]hexane-l-carboxylic acid (200 mg, 1.72 mmol), methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (Intermediate-5, step-3; 488 mg, 2.06 mmol) benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (1.91 g, 4.31 mmol), DIPEA (665 mg, 5.16 mmol) in DMF (10 mL) was stirred at rt for 12h. Then the reaction mixture was diluted with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 8.18 (br t, 1H, NH), 7.67 (s, 1H), 7.54-7.52 (d, / = 7.8 Hz, 1H), 7.44-7.42 (d, / = 8.1 Hz, 1H), 4.29-4.27 (d, / = 6.3 Hz, 1H), 3.86- 3.63 (m, 4H), 2.05 (m, 1H), 1.34- 1.31 (m, 1H), 0.85- 0.81 (m ,lH).

Intermediate- 33

7-Amino-2-(4,4-dimethylcyclohexyl)phthalazin- 1 (2H)-one

Step 1 : Preparation of 2-(4,4-dimethylcyclohexyl)-7-nitrophthalazin- 1 (2H)-one

Method A: To a solution of 4,4-dimethylcyclohexanol (100 mg, 0.78 mmol) and Et ₃ N (201 mg, 1.56 mmol) in CH ₂ C1 ₂ (2 mL) was added methanesulfonyl chloride (178 mg, 1.56 mmol) at 0°C and the reaction mixture was stirred at rt for 2 h before it was quenched with water and was extracted with CH ₂ C1 ₂ . The organic layer was washed with brine, separated, dried, filtered and concentrated to afford 4,4-dimethylcyclohexyl methanesulfonate which was used without further purification. To a solution of 7-nitrophthalazin-l(2H)-one (Intermediate- 10, step-1 , 100 mg, 0.52 mmol) in THF (2 mL) was added NaH (41 mg, 1.02 mmol, 60% in mineral oil) at 0°C and stirred for 15 minutes. Then a solution of 4,4-dimethylcyclohexyl methanesulfonate in THF (1 mL) was slowly added to the reaction mixture at 0°C. Then the reaction mixture was heated at 80°C for 6 h before it was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 180 mg of the title product/H NMR (300 MHz, DMSO d ₆ ): δ 9.27 (s, 1H), 8.59-8.56 (d, / = 8.7 Hz, 1H), 8.30 (s, 1H), 7.88-7.85 (d, / = 8.7 Hz, 1H), 4.97-4.93 (m, 1H), 2.08-1.99 (m, 2H), 1.72-1.67 (m, 2H), 1.57-1.43 (m, 4H), 1.04 (s, 3H), 0.99 (s, 3H).

Method B: To a solution of 7-nitrophthalazin-l(2H)-one (Intermediate- 10, step-1 , 355 mg, 1.858 mmol) and 4,4-dimethylcyclohexanol (356 mg, 2.78 mmol) in THF (6 mL) were added PPh ₃ (1.22 g, 4.64 mmol) and diisopropyl azodicarboxylate (1.12 g, 5.57 mmol) and the reaction mixture was heated at reflux for 4 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 300 mg of the title product.

Step 2: Preparation of 7-amino-2-(4,4-dimethylcyclohexyl)phthalazin- 1 (2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 2-(4,4-dimethylcyclohexyl)-7-nitrophthalazin-l(2H)-one (180 mg, 0.59 mmol), iron powder (334 mg, 5.97 mmol) and ammonium chloride (253 mg, 4.77 mmol) in EtOH (3 mL) and water (1 mL) to afford 100 mg of the title product. 1H NMR (300 MHz, DMSO d ₆ ): δ 8.12 (s, 1H), 7.59-7.53 (d, / = 8.4 Hz, 1H), 7.27 (s, 1H), 7.07-7.05 (d, / = 8.1 Hz, 1H), 6.22 (s, 2H), 4.78 (m, 1H), 1.98-1.94 (m, 2H), 1.53-1.38 (m, 6H), 0.97 (s, 3H), 0.95 (s, 3H).

Intermediate- 34

6-Chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid

To a solution of ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (Intermediate-30, 100 mg, 0.317 mmol) in THF:MeOH:H ₂ 0 (3 :2: 1 ; 6 mL) was added NaOH (25 mg, 0.634 mmol). The reaction mass was stirred at rt for 3 h. The reaction mass was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 14.10 (s, 1H), 8.14 (br t, 1H), 7.38- 7.26 (m, 2H), 4.25 (d / = 5.4 Hz, 2H), 1.1 l(s, 9H). Intermediate- 35

2,6-Dimethyl-3-(pivalamidometh l)benzoic

Step 1 : Preparation of 2,6-dimeth l-3-((2,2,2-trifluoroacetamido)methyl)benzoic acid

To a solution of 2,6-dimethyl benzoic acid (2.0 g, 13.33 mmol) in cone. H ₂ SO ₄ (4 mL) was added 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (2.1 g, 13.33 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was poured into ice-water and stirred for 2 h. The precipitate was collected by filtration and dried to afford 3.2 g of the title product. 1H NMR (DMSO-Je): δ 9.92 (m, 2H), 7.15- 7.04 (m, 2H), 4.36 (s, 2H), 2.18 (m, 6H).

Step 2: Preparation of 2,6-dimethyl-3-(pivalamidomethyl)benzoic acid

To a solution of 2,6-dimethyl-3-((2,2,2-trifiuoroacetamido)methyl)benzoic acid (3.2 g, 11.63 mmol) in THF (15 mL) was added IN HC1 (15 mL) and the reaction mass was heated at reflux for 3 h. The reaction mixture was concentrated and the crude was co-distilled with toluene to afford 2.0 g of the 3-(aminomethyl)-2,6-dimethylbenzoic acid which was used in the next step without further purification. To a solution of 3-(aminomethyl)-2,6- dimethylbenzoic acid (500 mg, 2.46 mmol) in THF was added Ν,Ο- bis(trimethylsilyl)trifiuoroacetamide (948 mg, 3.69 mmol) and the reaction mass was heated at reflux for 20 minutes. The reaction mass was cooled to 0 °C and Et ₃ N (1.77 mL, 9.85 mmol) was added, followed by pivaloyl chloride (0.44 mL, 3.69 mmol). The reaction mixture was stirred at rt for 18 h before it was quenched with water and was extracted with chloroform. The organic layer was separated, dried, filtered and concentrated to afford 450 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 13.15 (br s, 1H), 7.93 (br t, 1H), 7.08- 7.01 (m, 2H), 4.19 (d, / = 5.7 Hz, 2H), 2.21 (s, 3H), 2.17 s, 3H), 1.12 (s, 9H).

Intermediate- 36

7-Amino-2-(( 15 ^, ,45 ^, )-4-(trifiuoromethyl)cyclohexyl)phthalazin- 1 (2H)-one

Intermediate- 37 7-Amino-2-(( 1 r,4r)-4-(trifluoromethyl)cyclohexyl)phthalazin- 1 (2H)-one

Step 1 : Preparation of 7-nitro-2- -(trifluoromethyl)cyclohexyl)phthalazin-l(2H)-one

The title compound was prepared following the procedure described in Intermediate-33, step- 1 , Method B using 7-nitrophthalazin-l(2H)-one (Intermediate- 10, step-1 , 500 mg, 2.61 mmol), 4-(trifluoromethyl)cyclohexanol (cis and trans mixture) (659 mg, 3.92 mmol), PPh ₃ (1.70 g, 6.52 mmol) and diisopropyl azodicarboxylate (1.31 g, 6.52 mmol) in THF (9 mL) to afford 500 mg of the title product as mixture of isomers. 1H NMR (300 MHz, DMSO d ₆ ): δ 8.90 (s, 1H), 8.67 (m, 2H), 8.22-8.19 (m, 1H), 5.03 (m, 1H), 2.38 (m, 1H), 1.99 (m, 2H), 1.90 (m, 2H), 1.82 (m, 2H), 1.56 (m, 2H).

Step 2: Preparation of 7-amino-2-((l5 ^, ,45 ^, )-4-(trifluoromethyl)cyclohexyl)phthalazin-l(2H)- one and 7-amino-2-(( 1 r,4r)-4-(trifluoromethyl)cyclohexyl)phthalazin- 1 (2H)-one

The title compound was prepared following the procedure described in Step 2 of Intermediate-2 using 7-nitro-2-(4-(trifluoromethyl)cyclohexyl)phthalazin-l(2H)-on e (500 mg, 1.46 mmol), iron powder (817 mg, 14.6 mmol) and ammonium chloride (621 mg, 14.6 mmol) in EtOH (6 mL) and water (1 mL) to afford 140 mg of the Intermediate-36 and 120 mg of Intermediate-37 after purification by column chromatography. Intermediate-36 : ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.1 1 (s, 1H), 7.54 (d, / = 8.7 Hz, 1H), 7.26 (s, 1H), 7.06 (d, / = 8.1 Hz, 1H), 6.23 (s, 2H), 4.92 (m, 1H), 1.98 (m, 4H), 1.77 (m, 2H), 1.73 (m, 3H); Intermediate- 37: 1H NMR (300 MHz, DMSO d ₆ ): δ 8.1 1 (s, 1H), 7.54 (d, 1H), 7.27 (s, 1H), 7.08 (d, 1H), 6.24 (s, 2H), 4.90 (m, 1H), 2.38 (m, 1H), 2.01-1.96 (m, 2H), 1.83 (m, 4H), 1.50 (m, 2H).

Intermediate- 38

2-Chloro-5-(pivalamidomethyl)benzoic acid

To a solution of methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 2.00 g, 7.05 mmol) in THF:MeOH:H ₂ 0 (9:6:3; 18 mL) was added NaOH (0.564 g, 14.1 mmol). The reaction mass was stirred at rt for 3 h. The reaction mass was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 1.8 g of the title product.1H NMR (300 MHz, DMSO d ₆ ): δ 12.3 (br s, 1H), 8.14 (br t, 1H), 7.61 (s, 1H), 7.47- 7.44 (d, / = 8.1 Hz, 1H), 7.34-7.32 (d, / = 7.8 Hz, 1H), 4.22 (d, / = 6.0 Hz, 2H), 1.18 (s, 9H).

Intermediate- 39

6-Chloro-2-methoxy-3-(pivalamidomethyl)benzoic acid

To a solution of ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (Intermediate-30; 1.00 g, 3.31 mmol) in THF:MeOH:H ₂ 0 (2:2: 1 ; 5 mL) was added KOH (0.930 g, 16.57 mmol). The reaction mass was heated in a sealed tube atlOO °C for 3 h. The reaction mass was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 700 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 13.65 (br s, 1H), 8.08 (t, 1H), 7.29-7.26 (d, / = 8.4 Hz, 1H), 7.22-7.19 (d, / = 8.7 Hz, 1H), 4.25 (d, / = 5.7 Hz, 2H), 3.79 (s, 3H), 1.13 (s, 9H); MS (m/z): 300.05 (M+H) ⁺ .

Examples

Example- 1

N-(3-(4-Bromophenyl)-4-oxo-3,4-dihydrophthalazin-6-yl)-2-chl oro-6-fluorobenzamide

To a solution of 2-chloro-6-fluorobenzoic acid (441 mg, 2.53 mmol) in CH ₂ C1 ₂ (4.0 mL) was added oxalyl chloride (956 mg, 7.58 mmol) and DMF (0.5 mL). The reaction mass was stirred at rt for 2 h before it was concentrated. The residue was dissolved in DMF (1 mL) and was added to a solution of 7-amino-2-(4-bromophenyl)phthalazin-l(2H)-one (Intermediate-2, 100 mg, 0.316 mmol) in DMF (2 mL) and pyridine (1.0 mL) at rt. The reaction mass was stirred at 80-90°C for 2-3 h. Then the reaction mass was concentrated and purified by column chromatography to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 1 1.44 (s, 1H), 8.76 (s, 1H), 8.55 (s, 1H), 8.15 (d, / = 8.4 Hz, 1H), 8.04 (d, / = 8.7 Hz, 1H), 7.71 (d, / = 8.7 Hz, 2H), 7.56-763 (m, 3H), 7.41 -7.51 (m, 2H), MS [M] ⁺ :474.15. Example-2

2-Chloro-5-((methylamino)methyl)-N-(4-oxo-3-(4-(trifiuoromet hyl)phi

dihydrophthalazin-6-yl)benzamide

To a solution of methyl 5-(((ieri-butoxycarbonyl)(methyl)amino)methyl)-2-chlorobenzo ate

(Intermediate -4, step 4, 1 12 mg, 0.374 mmol) and 7-amino-2-(4-

(trifiuoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-3, 100 mg, 0.327 mmol) in toluene (1 mL) was added a 2M solution of Me ₃ Al in toluene (0.5 mL). The reaction mixture was heated at reflux for 5-6 h before it was quenched with water and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 29 mg of the title product. 1H NMR (300 MHz, DMSO-Je): δ 1 1.10 (br s, 1H), 8.81 (s, 1H), 8.58 (s, 1H), 8.22 (d, / = 9.3 Hz, 1H), 8.04 (d, / = 8.4 Hz, 1H), 7.91 (m, 4H), 7.68 (s, 1H), 7.57 (d, / = 7.8 Hz, 2H), 3.88 (s, 2H), 2.38 (s, 3H); MS [M+H] ⁺ :557.39.

Example-3

2-Chloro-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydrop hthalazin-6-yl)-5- (pivalamidomethyl)benzamide

Step 1 : Preparation of 5-(aminomethyl)-2-chloro-N-(4-oxo-3-(4-(trifiuoromethyl)phi dihydrophthalazin-6-yl)benzamide

To a solution of methyl 5-(((ieri-butoxycarbonyl)amino)methyl)-2-chlorobenzoate (Intermediate-5 step-2, 180 mg, 0.603 mmol) and 7-amino-2-(4- (trifiuoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-3, 162 mg, 0.542 mmol) in toluene (2 mL) was added a 2M solution of Me ₃ Al in toluene (0.5 mL). The reaction mixture was heated at reflux for 2-3 h before it was quenched with water and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 280 mg of the title product.

Step 2: Preparation of 2-chloro-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4- dihydrophthalazin-6-yl)-5-(pivalamidomethyl)benzamide

To a solution of 5-(aminomethyl)-2-chloro-N-(4-oxo-3-(4-(trifluoromethyl)phen yl)-3,4- dihydrophthalazin-6-yl)benzamide (100 mg, 0.327 mmol) in THF (5.0 mL) was added pivaloyl chloride (59 mg, 0.491 mmol) and the reaction mass was stirred at rt for 1 h. The reaction mass was quenched with water and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 1 1.15 (s, 1H), 8.81 (s, 1H), 8.58 (s, 1H), 8.19 (m, 1H), 8.03 (d, / = 8.4 Hz, 1H), 7.91 (m, 4H), 7.54 (d, / = 8.4 Hz, 1H), 7.48 (s, 1H), 7.37 (d, / = 8.1 Hz, 1H), 4.30 (d, / = 6.0 Hz, 2H), 1.12 (s, 9H); MS [M+H] ⁺ : 557.39.

Example-4

2-Chloro-N-(3-cyclohexyl-4-oxo-3,4-dihydrophthalazin-6-yl )-5-(2-hydroxypropan-2- yl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-cyclohexylphthalazin-l(2H)-one (Intermediate-6, 25 mg, 0.102 mmol), methyl 2- chloro-5-(2-hydroxypropan-2-yl)benzoate (Intermediate-7, 24 mg, 0.102 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (0.5 mL) to afford 18 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.08 (s, 1H), 8.72 (s, 1H), 8.40 (s, 1H), 8.14 (d, / = 8.7 Hz, 1H), 7.92 (d, / = 8.4 Hz, 1H),7.68 (s, 1H), 7.61 (d, / = 8.4 Hz, 1H), 7.51 (d, / = 8.4 Hz, 1H), 5.62 (s, 1H), 4.87 (m, 1H), 1.86- 1.77 (m, 10 H), 1.45 (s, 6H); MS [M] ⁺ : 439.82.

Example-5

2-Chloro-N-(3-cyclohexyl-4-oxo-3,4-dihydrophthalazin-6-yl)-5 - (pivalamidomethyl)benzamide The title compound was prepared following the procedure described in Example-2 using 7- amino-2-cyclohexylphthalazin-l(2H)-one (Intermediate-6, 50 mg, 0.193 mmol), methyl 2- chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 82 mg, 0.289 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) to afford 24 mg of the title product. 1H NMR (300 MHz, DMSO-Je): δ 1 1.08 (s, 1H), 8.72 (s, 1H), 8.40 (s, 1H), 8.17-7.93 (m, 2H), 7.91 (d, / = 5.7 Hz, 1H), 7.53 (d, / = 9.9 Hz, 1H), 7.46 (s, 1H), 7.35 (d, / = 8.4 Hz, 1H), 4.87 (m, 1H), 4.29 (d, / = 9.0 Hz, 2H), 1.76 (m, 6H), 1.43 (m, 4H), 1.12 (s, 9H); MS [M+H] ⁺ : 495.09.

Example-6

2-Chloro-N-(3-cyclohexyl-4-oxo-3,4-dihydrophthalazin-6-yl)-5 -(5 -methyl- lH-pyrazol-3- yl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-cyclohexylphthalazin-l(2H)-one (Intermediate-6, 45 mg, 0.185 mmol), ethyl 2- chloro-5 -(5 -methyl- lH-pyrazol-3-yl)benzoate (Intermediate-8, 55 mg, 0.222 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) at rt to afford 13 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 12.72 (s, 1H), 1 1.12 (s, 1H), 8.74 (s, 1H), 8.41 (s, 1H), 8.14 (m, 1H), 7.99- 7.92 (m, 3H), 7.58 (d, / = 8.1 Hz, 1H), 6.58 (s, 1H), 4.86 (br s, 1H), 2.27(s, 3 H), 1.77 (m, 6H), 1.46 (s, 2H), 1.22 (s, 2H); MS [M+H] ⁺ : 462.05.

Example-7

2-Chloro-N-(3-cyclohexyl-4-oxo-3,4-dihydrophthalazin-6-yl)-5 -(lH-l ,2,3-triazol-4- yl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-cyclohexylphthalazin-l(2H)-one (Intermediate-6, 57 mg, 0.234 mmol), methyl 2- chloro-5-(2H-l ,2,3-triazol-4-yl)benzoate (Intermediate-9, 46 mg, 0.195 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) at rt to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 15.14 (s, 1H), 1 1.17 (s, 1H), 8.74 (s, 1H), 8.41 (s, 2H), 8.14 (br s, 2H), 8.03 (d, / = 8.7 Hz, 1H), 7.94 (d, / = 8.4 Hz, 1H), 7.69 (d, / = 8.1 Hz, 1H), 4.88 (m, 1H), 1.86-1.77 (m, 6H), 1.42 (m, 2H), 1.22 (m, 2H).

Example-8

2-Chloro-5-((N-methylpivalamido)methyl)-N-(4-oxo

dihydrophthalazin-6-yl benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(4-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-3, 50 mg, 0.164 mmol), methyl 2-chloro-5-((N-methylpivalamido)methyl)benzoate (Intermediate-4, 58 mg, 0.196 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (0.5 mL) at rt to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.18 (s, 1H), 8.80 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 8.04 (d, / = 8.1 Hz, 1H), 7.91 (m, 4H), 7.58(d, / = 7.8 Hz, 1H), 7.47 (s, 1H), 7. 32 (d, / = 8.4 Hz, 1H), 4.60 (s, 2H), 3.01 (s, 3H), 1.23 (s, 9H); MS [M] ⁺ : 470.98.

Example-9

2-Chloro-N-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydrophthalazi n-6-yl)-5- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(cyclopropylmethyl)phthalazin-l(2H)-one (Intermediate- 10, 100 mg, 0.465 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 158 mg, 0.558 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) at rt to afford 35 mg of the title product.1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.10 (s, 1H), 8.74 (s, 1H), 8.38 (s, 1H), 8.17- 8.10 (m, 2H), 7.95 (d, / = 8.1 Hz, 1H), 7.53 (d, / = 8.4 Hz, 1H), 7.47 (s, 1H), 7.36 (d, / = 8.4 Hz, 1H), 4.29 (d, / = 6.3 Hz, 2H), 4.01 (d, / = 6.9 Hz, 2H), 1.12 (s, 9H), 0.85 (m, 1H), 0.49- 0.39 (m, 4H); MS [M+H] ⁺ : 467.07.

Example- 10

5-(3-Amino-3-oxopropyl)-2-chloro-N-(4-oxo-3-(4-(trifluoromet hyl)phi

dihydrophthalazin-6-yl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(4-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-3, 75 mg, 0.248 mmol), methyl 5-(3-amino-3-oxopropyl)-2-chlorobenzoate (Intermediate-1 1 , 50 mg, 0.207 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) to afford 35 mg of the title product.1H NMR (300 MHz, DMSO- ): δ 1 1.12 (s, 1H), 8.79 (s, 1H), 8.56 (s, 1H), 8.20 (d, / = 8.1 Hz, 1H), 8.23 (d, / = 9.0 Hz, 1H), 7.90 (m, 3H), 7.48 (m, 2H), 7.39 (m, 1H), 7.30 (m, 1H), 6.79 (br s, 2H), 2.82 (t, / = 7.8 Hz, 2H), 2.30 (t, / = 7.2 Hz, 2H); MS [M+H] ⁺ : 515.01.

Example- 1 1

2-Chloro-N-(3-hexyl-4-oxo-3 4-dihydrophthalazin-6-yl)-5-(pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-hexylphthalazin-l(2H)-one (Intermediate- 12, 100 mg, 0.377 mmol), methyl 2- chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 106 mg, 0.377 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 39 mg of the title product H NMR (300 MHz, DMSO-Je): δ 1 1.09 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 8.17-8.09 (m, 2H), 7.93 (d, / = 8.4 Hz, 1H), 7.52 (m, 1H), 7.46 (s, 1H), 7.37 (m, 1H), 4.29 (br s, 2H), 4.12 (br s, 2H), 1.73 (br s, 2H), 1.28 (br s, 6H), 1.12 (s, 9H), 0.84 (s, 3H); MS [M+H] ⁺ : 497.12.

Example- 12

2-Chloro-N-(3-(cyclohexylmethyl)-4-oxo-3,4-dihydrophthalazin -6-yl)-5- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(cyclohexylmethyl)phthalazin-l(2H)-one (Intermediate- 13, 100 mg, 0.389 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 1 10 mg, 0.389 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 33 mg of the title product.1H NMR (300 MHz, DMSO- ): δ 1 1.09 (s, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 8.17-8.10 (m, 2H), 7.93 (d, / = 8.7 Hz, 1H), 7.53 (d, / = 8.4 Hz, 1H),7.46 (s, 1H), 7.36 (d, / = 7.8 Hz, 1H), 4.29 (d, / = 5.7 Hz, 2H), 3.98 (d, / = 7.5 Hz, 2H), 1.90 (m, 1H), 1.66- 1.56 (m, 6H), 1.33-1.12 (m, 13H); MS [M+H] ⁺ : 509.16.

Example- 13

2-Chloro-N-(3-isopropyl- -oxo-3,4-dihydrophthalazin-6-yl)-5-(pivalamidomethyl)benzami de

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-isopropylphthalazin-l(2H)-one (Intermediate- 14, 64 mg, 0.313 mmol), methyl 2- chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 88 mg, 0.313 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO-Je): δ 1 1.08 (s, 1H), 8.72 (s, 1H), 8.42 (s, 1H), 8.17- 8.10 (m, 2H), 7.92 (d, / = 6.3 Hz, 1H), 7.53 (d, / = 6.3 Hz, 1H), 7.46 (s, 1H), 7.36 (d, / = 6.9 Hz, 1H), 5.26 (m, 1H), 4.29 (d, / = 7.8 Hz, 2H), 1.33 7.92 (d, / = 8.7 Hz, 6H), 1.12 (s, 9H); MS [M+H] ⁺ : 455.08.

Example- 14

2-Chloro-N-(4-oxo-3,4-dihydrophthalazin-6-yl)-5-(pivalamidom ethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- aminophthalazin-l(2H)-one (Intermediate- 15, 90 mg, 0.56 mmol), methyl 2-chloro-5- (pivalamidomethyl)benzoate (Intermediate-5, 167 mg, 0.56 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (2 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-Je): δ 12.61 (s, 1H), 1 1.09 (s, 1H), 8.71 (s, 1H), 8.30 (s, 1H), 8.17 (m, 1H), 8.08 (d, / = 10.2 Hz, 1H), 7.92 (d, / = 8.7 Hz, 1H), 7.53 (d, / = 8.1 Hz, 1H), 7.46 (s, 1H), 7.36 (d, / = 7.8 Hz, 1H), 4.29 (d, / = 5.7 Hz, 2H), 1.12 (s, 9H); MS [M+H] ⁺ : 413.02.

Example- 15

2-Chloro-N-(3-cyclobutyl-4-oxo-3,4-dihydrophthalazin-6-yl)-5 - (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-cyclobutylphthalazin-l(2H)-one (Intermediate- 16, 80 mg, 0.37 mmol), methyl 2- chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 1 1 1 mg, 0.37 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 19 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 1 1.10 (s, 1H), 8.71 (s, 1H), 8.46 (s, 1H), 8.18-8.10 (m, 2H), 7.94 (d, / = 8.7 Hz, 1H), 7.53 (d, / = 8.4 Hz, 1H), 7.46 (s, 1H), 7.35 (d, / = 7.8 Hz, 1H), 5.48 (m, 1H), 4.29 (d, / = 5.7 Hz, 2H), 2.5 (m, 2H), 2.26 (m, 2H), 1.81 (m, 2H), 1.12 (s, 9H); MS [M+H] ⁺ : 467.06.

Example- 16

2-Chloro-N-(3-methyl-4-ox -3,4-dihydrophthalazin-6-yl)-5-(pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-methylphthalazin-l (2H)-one (Intermediate- 17, 85 mg, 0.485 mmol), methyl 2- chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 145 mg, 0.485 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 17 mg of the title product. 1H NMR (300 MHz, DMSO-Je): δ 1 1.10 (s, 1H), 8.73 (s, 1H), 8.35 (s, 1H), 8.17- 8.09 (m, 2H), 7.94 (d, / = 8.7 Hz, 1H), 7.53 (d, / = 8.1 Hz, 1H), 7.47 (s, 1H),7 .38 (m, 1H), 4.29 (d, / = 6.0 Hz, 2H), 3.72 (s, 3H), 1.12 (s, 9H); MS [M] ⁺ : 426.96.

Example- 17

2-Fluoro-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydrop hthalazin-6-yl)-5- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(4-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-3, 90 mg, 0.295 mmol), methyl 2-fluoro-5-(pivalamidomethyl)benzoate (Intermediate-24, 73 mg, 0.295 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 1 1.06 (s, 1H), 8.79 (s, 1H), 8.58 (s, 1H), 8.24 (d, / = 8.4 Hz, 1H), 8.17 (t, 1H), 8.03 (d, / = 8.7 Hz, 1H), 7.91 (m, 4H), 7.56 (d, / = 6.9 Hz, 1H), 7.44 (m, 1H), 7.34 (t, / = 9.0 Hz, 1H), 4.29 (d, / = 6.0 Hz, 2H), 1.12 (s, 9H); MS [M+H] ⁺ : 541.09.

Example- 18

2-Chloro-N-(3-(4-fluorophenyl)-4-oxo-3,4-dihydrophthalazin-6 -yl)-5- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(4-fiuorophenyl)phthalazin-l(2H)-one (Intermediate- 18, 80 mg, 0.380 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 162 mg, 0.457 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.16 (s, 1H), 8.78 (s, 1H), 8.51 (s, 1H), 8.20- 8.18 (m, 2H), 8.01 (d, / = 5.7 Hz, 1H), 7.66- 7.64 (m, 2H), 7.54 (d, / = 8.4 Hz, 1H), 7.48 (s, 1H),7 .38- 7.32 (m, 3H), 4.29 (d, / = 5.7 Hz, 2H), 1.12 (s, 9H); MS [M+H] ⁺ : 507.07.

Example- 19

2-Chloro-N-(4-oxo-3-(2,2,2-trifluoroethyl)-3,4-dihydrophthal azin-6-yl)-5- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(2,2,2-trifluoroethyl)phthalazin-l(2H)-one (Intermediate- 19, 100 mg, 0.41 1 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 139 mg, 0.493 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 25 mg of the title product.1H NMR (300 MHz, DMSO- ): δ 1 1.18 (s, 1H), 8.77 (s, 1H), 8.47 (s, 1H), 8.18- 8.15 (m, 2H),7.98 (d, / = 9.0 Hz, 1H), 7.54 (d, / = 8.4 Hz, 1H), 7.47 (s, 1H), 7.36 (d, / = 8.4 Hz, 1H),5.00 (q, / = 9.3 Hz, 2H), 4.29 (d, / = 5.7 Hz, 2H), 1.12 (s, 9H); MS [M+H] ⁺ : 495.05.

Example-20

2-Chloro-N-(4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydrop hthalazin-6-yl)-5- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(3-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-20, 50 mg, 0.163 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 51 mg, 0.180 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (0.5 mL) to afford 27 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 1 1.17 (s, 1H), 8.78 (s, 1H), 8.55 (s, 1H), 8.17 (m, 2H), 8.03- 7.97 (m, 3H), 7.77- 7.75 (m, 2H), 7.52 (d, / = 8.1 Hz, 1H), 7.46 (s, 1H), 7.35 (d, / = 8.1 Hz, 1H), 4.28 (d, / = 8.1 Hz, 1H), 4.28 (d, / = 6.0 Hz, 2H), 1.10 (s, 9H); MS [M+H] ⁺ : 557.1 1.

Example-21

2-Chloro-N-(3-(2,4-difluorophenyl)-4-oxo-3,4-dihydrophthalaz in-6-yl)-5- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(2,4-difluorophenyl)phthalazin-l(2H)-one (Intermediate-21 , 100 mg, 0.366 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 124 mg, 0.439 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 26 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.19 (s, 1H), 8.77 (s, 1H), 8.53 (s, 1H), 8.22- 8.19 (m, 2H), 8.04 (d, / = 6.0 Hz, 1H), 7.71- 7.66 (m, 1H), 7.56- 7.48 (m, 3H), 7.36 (d, / = 7.8 Hz, 1H), 7.29 (t, / = 8.7 Hz, 1H), 4.29 (d, / = 6.0 Hz, 2H), 1.12 (s, 9H); MS [M+H] ⁺ : 525.02.

Example-22

2-Chloro-N-(3-(2-fluorophenyl)-4-oxo-3,4-dihydrophthalazin-6 -yl)-5- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(2-fluorophenyl)phthalazin-l(2H)-one (Intermediate-22, 80 mg, 0.380 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 162 mg, 0.457 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 29 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.18 (s, 1H), 8.77 (s, 1H), 8.53 (s, 1H), 8.22-8.19 (m, 2H), 8.04 (d, / = 8.7 Hz, 1H), 7.64- 7.35 (m, 6H), 4.29 (d, / = 5.7 Hz, 2H), 1.12 (s, 9H); MS [M+H] ⁺ : 507.12.

Example-23

2-Chloro-N-(3-(3-fluorophenyl)-4-oxo-3,4-dihydrophthalazin-6 -yl)-5- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(3-fluorophenyl)phthalazin-l(2H)-one (Intermediate-23, 80 mg, 0.380 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 162 mg, 0.457 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 23 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.16 (s, 1H), 8.78 (s, 1H), 8.52 (s, 1H), 8.19- 8.17 (m, 2H), 8.00 (d, / = 8.4 Hz, 1H), 7.54- 7.46 (m, 5H), 7.35 (d, / = 7.8 Hz, 1H), 7.27 (t, / = 7.8 Hz, 1H), 4.27 (d, / = 5.7 Hz, 2H), 1.10 (s, 9H); MS [M+H] ⁺ : 507.07.

Example-24

2-Chloro-N-(3-(4-isopropylphenyl)-4-oxo-3,4-dihydrophthalazi n-6-yl)-5- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(4-isopropylphenyl)phthalazin-l(2H)-one (Intermediate-25, 80 mg, 0.286 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 97 mg, 0.344 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) to afford 23 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.15 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 8.18 (d, / = 6.3 Hz, 2H), 8.00 (d, / = 8.7 Hz, 2H), 7.56-7.48 (m, 3H), 7.37 (d, / = 7.8 Hz, 3H), 4.29 (d, / = 5.7 Hz, 2H), 2.94 (m, 1H), 1.25 (d, / = 6.9 Hz, 6H), 1.12 (s, 9H); MS [M-H] ^~ : 529.21. Example-25

2-Methyl-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydrop hth

(pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- Amino-2-(4-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-3, 90 mg, 0.295 mmol), methyl 2-methyl-5-(pivalamidomethyl)benzoate (Intermediate-26, 77 mg, 0.295 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) to afford 33 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 10.96 (s, 1H), 8.85 (s, 1H), 8.56 (s, 1H), 8.24 (d, / = 8.4 Hz, 1H), 8.10 (t, 1H), 8.02 (d, / = 8.1 Hz, 1H), 7.91 (br s, 4H), 7.38 (s, 1H), 7.27 (br s, 2H), 4.28 (d, / = 4.8 Hz, 2H), 2.37 (s, 3H), 1.12 (s, 9H); MS [M+H] ⁺ : 537.10.

Example-26

5-Chloro-N-(4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydrop hthalazin-6-yl)-2- (pivalamidomethyl)isonicotinamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(3-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-20, 70 mg, 0.229 mmol), methyl 5-chloro-2-(pivalamidomethyl)isonicotinate (Intermediate-29, 65 mg, 0.229 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) to afford 26 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 1 1.32 (s, 1H), 8.81 (s, 1H), 8.58 (s, 1H), 8.41 (s, 1H), 8.25-7.99 (m, 5H), 7.78 (m, 3H), 4.42-4.39 (d, / = 5.4 Hz, 2H), 1.04 (s, 9H); MS [M] ⁺ : 558.03.

Example-27

2-Chloro-5 -(3 -hydroxy-3 -methylbutyl)-N-(4-oxo-3 -(4-(trifluoromethyl)phenyl)-3 ,4- dihydrophthalazin-6-yl)benzamide Step 1 :- Preparation of 2-chloro-5 -(3 -hydroxy-3 -methylbut- 1 -yn- 1 -yl)-N-(4-oxo-3 -(4- (trifluoromethyl)phenyl)-3,4-dihydrophthalazin-6-yl)benzamid e

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(4-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-3, 136 mg, 0.537 mmol), methyl 2-chloro-5 -(3 -hydroxy-3 -methylbut- l-yn-l-yl)benzoate (Intermediate-27, 163 mg, 0.537 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (2 mL) at rt to afford 100 mg of the title product.

Step 2: -Preparation of 2-chloro-5 -(3 -hydroxy-3 -methylbutyl)-N-(4-oxo-3 -(4- (trifluoromethyl) phenyl)-3 ,4-dihydrophthalazin-6-yl)benzamide

To a solution of 2-chloro-5 -(3 -hydroxy-3 -methylbut- 1-yn-l -yl)-N-(4-oxo-3 -(4- (trifluoromethyl)phenyl)-3,4-dihydrophthalazin-6-yl)benzamid e (100 mg, 0.19 mmol) in MeOH (5.0 mL) was added Pd/C (70 mg). The reaction mass was hydrogenated at 40 psi for 4 hrs. The reaction mixture was filtered. The filtrate was concentrated and purified by column chromatography to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 10.80 (s, 1H), 8.84 (s, 1H), 8.57 (s, 1H), 8.43 (d, / = 8.7 Hz, 1H), 8.03 (d, / = 8.4 Hz, 1H), 7.91-7.86 (m, 5H), 7.47 (m, 2H), 4.32 (s, 1H), 2.73 (m, 2H), 1.69 (m, 2H), 1.16 (s, 6H); MS [M+H] ⁺ : 530.23.

Example-28

2-Chloro-N-(3-cyclohexyl-4-oxo-3,4-dihydrophthalazin-6-yl )-5- (isobutyramidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-cyclohexylphthalazin-l(2H)-one (Intermediate-6, 70 mg, 0.288 mmol), methyl 2- chloro-5-(isobutyramidomethyl)benzoate (Intermediate-28, 93 mg, 0.345 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) at rt to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.06 (s, 1H), 8.70 (s, 1H), 8.36 (m, 2H), 8.10 (d, / = 9.0 Hz, 1H), 7.90 (d, / = 9.0 Hz, 1H), 7.52 (d, / = 8.1 Hz, 1H), 7.46 (s, 1H), 7.35 (d, / = 8.4 Hz, 1H), 4.85 (m, 1H), 4.28 (d, / = 6.0 Hz, 2H), 2.43 (m, 1H), 1.77 (m, 6H), 1.40 (m, 2H), 1.19 (m, 2H), 1.00 (d, / = 6.9 Hz, 6H); MS [M+H] ⁺ : 481.09.

Example-29

(15,5 _l S ^, )-N-(4-Chloro-3-((3-cyclobutyl-4-oxo-3,4-dihydrophthal azin-6-yl)carbamoyl)bi 3-oxabicyclo[3.1.0]hexane- 1 -carboxamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-cyclobutylphthalazin-l(2H)-one (Intermediate- 16, 50 mg, 0.23 mmol), methyl 5- (((15 ^, ,55 ^, )-3-oxabicyclo[3.1.0]hexane-l-carboxamido)methyl)-2-ch lorobenzoate

(Intermediate-32, 65 mg, 0.23 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene

(1 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 1 1.09 (s, 1H), 8.71 (s, 1H), 8.46 (s, 1H), 8.21-8.1 1 (m, 2H), 7.96-7.93 (d, / = 8.4 Hz, 1H), 7.55-7.50 (m, 2H), 7.32-7.29 (d, / = 7.8 Hz, 1H), 5.48 (m, 1H), 4.32 (d, / = 5.7 Hz, 2H), 3.91-3.88 (m, 4H), 2.50 (m, 2H), 2.26 (m, 2H), 2.05 (m, 1H), 1.34- 1.31 (m, 1H), 1.81 (m, 2H), 0.85- 0.81 (m , 1H).

Example-30

6-Chloro-2-fluoro-N-(3-(3-fluorophenyl)-4-oxo-3,4-dihydropht halazin-6-yl)-3- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(3-fluorophenyl)phthalazin-l(2H)-one (Intermediate -23, 100 mg, 0.392 mmol), ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (lntermediate-30, 124 mg, 0.392 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1.5 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.48 (s, 1H), 8.78 (s, 1H), 8.56 (s, 1H), 8.21 (br t, 1H, NH), 8.17-8.15 (d, / = 7.2 Hz, 1H), 8.07-8.04 (d, / = 8.7 Hz, 1H), 7.58-7.29 (m, 6H), 4.32-4.30 (d, / = 6.0 Hz, 2H), 1.14 (s, 9H); MS [M+H] ⁺ : 525.03.

Example-31

3-Chloro-N-(3-(3-fluorophenyl)-4-oxo-3,4-dihydrophthalazin-6 -yl)-6- (pivalamidomethyl)picolinamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(3-fluorophenyl)phthalazin-l(2H)-one (Intermediate-23, 1 10 mg, 0.49 mmol), ethyl 3-chloro-6-(pivalamidomethyl)picolinate (Intermediate-31 , 134 mg, 0.49 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (2 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 1 1.29 (s, 1H), 8.83 (s, 1H), 8.55 9s, 1H), 8.28-8.25 (m, 2H), 8.10-8.04 (m, 2H), 7.58-7.54 (m, 3H), 7.41-7.38 (d, / = 8.1 Hz, 1H), 7.28 (m, 1H), 4.44-4.42 (d, / = 5.7 Hz, 2H), 1.16 (s, 9H); MS [M+H] ⁺ : 508.00.

Example-32

3-Chloro-N-(4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydrop hthalazin-6-yl)-6- (pivalamidomethyl)picolinamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(3-(trifluoromethyl)phenyl)phthalazin-l(2H)-one (Intermediate-20, 50 mg, 0.164 mmol), ethyl 3-chloro-6-(pivalamidomethyl)picolinate (Intermediate-31 , 46 mg, 0.164 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.31 (s, 1H), 8.34 (s, 1H), 8.58 (s, 1H), 8.30- 8.25 (m, 2H), 8.1 1-7.99 (m, 4H), 7.79 (m, 3H), 7.40-7.38 (d, / = 8.4 Hz, 1H), 4.44-4.42 (d, / = 6.0 Hz, 2H), 1.16 (s, 9H); MS [M+H] ⁺ : 557.89.

Example-33

2-Chloro-N-(3-(4,4-dimethylcyclohexyl)-4-oxo-3,4-dihydrophth alazin-6-yl)-5- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-2 using 7- amino-2-(4,4-dimethylcyclohexyl)phthalazin-l(2H)-one (Intermediate-33, 50 mg, 0.184 mmol), methyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-5, 78 mg, 0.276 mmol) and Me ₃ Al (0.5 mL, 2M solution in toluene) in toluene (1 mL) to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 1 1.08 (s, 1H), 8.72 (s, 1H), 8.42 (s, 1H), 8.17-8.10 (m, 2H), 7.94-7.91 (d, / = 8.7 Hz, 1H), 7.55-7.53 (d, / = 8.4 Hz, 1H), 7.47 (s, 1H), 7.37-7.35 (d, / = 7.5 Hz, 1H), 4.83 (m, 1H), 4.03-4.28 (d, / = 5.7 Hz, 2H), 1.99-1.95 (m, 2H), 1.60-1.40 (m, 6H), 1.12 (s, 9H), 0.99 (s, 3H), 0.97 (s, 3H); MS [M+H] ⁺ : 523.29.

Example-34

6-Chloro-N-(3-(4,4-dimethylcyclohexyl)-4-oxo-3,4-dihydrophth alazin-6-yl)-2-fluoro-3- (pivalamidomethyl)benzamide

To a solution of 6-chloro-2-fiuoro-3-(pivalamidomethyl)benzoic acid (Intermediate-34, 50 mg, 0.184 mmol) in CH ₂ C1 ₂ (1 mL) was added oxalyl chloride (52 mg, 0.414 mmol). The reaction mass was stirred at rt for 2 h before it was concentrated. The concentrate was dissolved in CH ₂ C1 ₂ (1 mL) and was added to a solution of 7-amino-2-(4,4- dimethylcyclohexyl)phthalazin-l(2H)-one (Intermediate-33, 80 mg, 0.276 mmol) in CH ₂ C1 ₂ (2 mL) and DIPEA (95 mg, 0.736 mmol) at 0 °C. The reaction mass was stirred at rt for 2 h before it was quenched with water and was extracted with chloroform. The organic layer was separated, dried, filtered, and concentrated. The residue was purified by column chromatography to afford 41 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 1 1.37 (s, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 8.19 (t, 1H), 8.09 (d, / = 8.4 Hz, 1H), 7.95 (d, / = 8.1 Hz, 1H), 7.43 (d, 1H), 7.36 (t, / = 7.8 Hz, 1H), 4.83 (m, 1H), 4.31 (d, 2H), 2.00 (m, 2H), 1.60 (m, 2H), 1.47 (m, 4H), 1.14 (s, 9H), 0.99 (s, 3H), 0.96 (s, 3H); MS (m/z): 573.13 (M+H) ⁺ .

Example-35

2-Chloro-5-(cyclopropanecarboxamidomethyl)-N-(3-(4,4-dimethy lcyclohexyl)-4-oxo-3,4- dihydrophthalazin-6-yl)benzamide

Step 1 : Preparation of iert-butyl 4-chloro-3-((3-(4,4-dimethylcyclohexyl)-4- dihydrophthalazin-6-yl)carbamoyl)benzylcarbamate The title compound was prepared following the procedure described in Example-34 using 7- amino-2-(4,4-dimethylcyclohexyl)phthalazin-l(2H)-one (Intermediate-33, 160 mg, 0.148 mmol) and 5-{[(ieri-butoxycarbonyl)amino]methyl}-2-chlorobenzoic acid (Intermediate-5, step-1, 252 mg, 0.885 mmol), oxalyl chloride (223 mg, 1.77 mmol), and DIPEA (57 mg, 0.444 mmol) in CH ₂ C1 ₂ (3 mL) to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 11.08 (s, 1H), 8.71 (s, 1H), 8.42 (s, 1H), 8.13 (d, / = 8.1 Hz, 1H), 7.93 (d, / = 8.7 Hz, 1H), 7.56-7.48 (m, 3H), 7.39 (d, / = 6.6 Hz, 1H), 4.83 (m, 1H), 4.17 (d, 2H), 1.99- 1.96 (m, 2H), 1.46 (m, 2H), 1.38 (s, 9H), 1.23 (m, 4H), 0.99 (s, 3H), 0.96 (s, 3H); MS [M+H ₂ 0] ⁺ : 557.21.

Step 2: Preparation of 2-chloro-5-(cyclopropanecarboxamidomethyl)-N-(3-(4,4- dimethylcyclohexyl)-4-oxo-3,4-dihydrophthalazin-6-yl)benzami de

A solution of tert-butyl 4-chloro-3-((3-(4,4-dimethylcyclohexyl)-4-oxo-3,4- dihydrophthalazin-6-yl)carbamoyl)benzylcarbamate (80 mg, 0.148 mmol) in HC1 in MeOH (5 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and the concentrate was dissolved in CH ₂ C1 ₂ (2 mL). The solution was treated with DIPEA (95 mg, 0.74 mmol), cyclopropylcarbonyl chloride (31 mg, 0.296 mmol) at 0-5°C. The reaction mixture was stirred for 2 h before it was diluted with EtOAc and was washed with H ₂ 0 and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 31 mg of the title product. 1H NMR (300 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 8.71 (s, 1H), 8.67 (t, 1H), 8.42 (s, 1H), 8.13 (d, / = 7.2 Hz, 1H), 7.93 (d, / = 9.0 Hz, 1H), 7.56-7.50 (m, 2H), 7.40 (d, / = 8.1 Hz, 1H), 4.83 (m, 1H), 4.33 (d, / = 6.0 Hz, 2H), 2.49 (m, 1H), 1.99-1.96 (m, 2H), 1.60 (m, 2H), 1.47 (m, 4H), 0.99 (s, 3H), 0.96 (s, 3H), 0.87-0.83 (m, 4H); MS [M+H] ⁺ : 507.45.

Example-36

N-(3-(4,4-Dimethylcyclohexyl)-4-oxo-3,4-dihydrophthalazin -6-yl)-2,6-dimethyl-3- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-34 using 7- amino-2-(4,4-dimethylcyclohexyl)phthalazin-l(2H)-one (Intermediate-33, 118 mg, 0.435 mmol) and 2,6-dimethyl-3-(pivalamidomethyl)benzoic acid (Intermediate-35, 229 mg, 0.87 mmol), oxalyl chloride (219 mg, 1.74 mmol), and DIPEA (169 mg, 1.31 mmol) in CH ₂ C1 ₂ (5 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 10.98 (s, 1H), 8.79 (s, 1H), 8.41 (s, 1H), 8.10 (d, / = 8.7 Hz, 1H), 7.98 (t, 1H), 7.91 (d, / = 8.1 Hz, 1H), 7.16-7.09 (m, 2H), 4.83 (m, 1H), 4.23 (d, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 2.00-1.95 (m, 2H), 1.59-1.55 (m, 2H), 1.47-1.41 (m, 4H), 1.14 (s, 9H), 0.99 (s, 3H), 0.96 (s, 3H); MS [M+H] ⁺ :

517.32.

Example-37

6-Chloro-2-fluoro-N-(4-oxo-3-((l5',45')-4-(trifluoromethyl)c yclohexyl)-3,4-dihydrophthalazin- 6-yl)-3-(pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-34 using 7- amino-2-(( 15 ^, ,45 ^, )-4-(trifluoromethyl)cyclohexyl)phthalazin- 1 (2H)-one (Intermediate-36, 140 mg, 0.45 mmol) and 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-34, 193 mg, 0.675 mmol), oxalyl chloride (170 mg, 1.35 mmol), and DIPEA (174 mg, 1.35 mmol) in CH ₂ C1 ₂ (5 mL) to afford 31 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.37 (s, 1H), 8.72 (s, 1H), 8.43 (s, 1H), 8.18 (t, 1H), 8.08 (d, / = 8.7 Hz, 1H), 7.95 (d, / = 9.0 Hz, 1H), 7.45 (d, / = 8.4 Hz, 1H), 7.36 (t, / = 7.8 Hz, 1H), 4.98 (m, 1H), 4.30 (d, / = 5.4 Hz, 2H), 2.41 (m, 1H), 2.02-1.98 (m, 4H), 1.79 (m, 4H), 1.14 (s, 9H); MS [M+H] ⁺ : 581.21.

Example-38

6-Chloro-2-fluoro-N-(4-oxo-3-((lr,4r)-4-(trifluoromethyl)cyc lohexyl)-3,4-dihydrophthalazin- 6-yl)-3 -(pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-34 using 7- amino-2-(( 1 r,4r)-4-(trifluoromethyl)cyclohexyl)phthalazin- 1 (2H)-one (Intermediate-37, 140 mg, 0.45 mmol) and 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-34,

193 mg, 0.675 mmol), oxalyl chloride (170 mg, 1.35 mmol), and DIPEA (174 mg, 1.35 mmol) in CH ₂ C1 ₂ (5 mL) to afford 33 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 1 1.38 (s, 1H), 8.72 (s, 1H), 8.43 (s, 1H), 8.18 (t, 1H), 8.09 (d, / = 9.0 Hz, 1H), 7.96 (d, / = 8.1 Hz, 1H), 7.45 (d, / = 9.0 Hz, 1H), 7.36 (t, / = 7.8 Hz, 1H), 4.91 (m, 1H), 4.30 (d, / = 5.7 Hz, 2H), 2.40 (m, 1H), 2.03-1.99 (m, 2H), 1.89 (m, 4H), 1.51 (m, 2H), 1.14 (s, 9H); MS [M+H] ⁺ : 581.23.

Example-39

2-Chloro-N-(4-oxo-3-((lr,4r)-4-(trifluoromethyl)cyclohexyl)- 3,4-dihydrophthalazin-6-yl^ (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-34 using 7- amino-2-(( 1 r,4r)-4-(trifluoromethyl)cyclohexyl)phthalazin- 1 (2H)-one (Intermediate-37, 60 mg, 0.192 mmol) and 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-38, 77 mg, 0.289 mmol), oxalyl chloride (73 mg, 0.578 mmol), and DIPEA (74 mg, 0.576 mmol) in CH ₂ C1 ₂ (2 mL) to afford 23 mg of the title product. 1H NMR (300 MHz, CD ₃ OD): δ 8.70 (s, 1H), 8.34 (s, 1H), 8.21-8.19 (m, 2H), 7.89 (d, / = 8.7 Hz, 1H), 7.48 (d, /= 8.4 Hz, 2H), 7.40 (d, / = 8.4 Hz, 1H), 4.60 (m, 1H), 4.38 (d, / = 5.7 Hz, 2H), 2.37 (m, 1H), 2.15-2.10 (m, 2H), 2.00 (m, 4H), 1.59 (m, 2H), 1.20 (s, 9H); MS [M+H] ⁺ : 563.18.

Example-40

2-Chloro-N-(4-oxo-3-((l5',45')-4-(trifluoromethyl)cyclohexyl )-3,4-dihydrophthalazin-6-yl)-5- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-34 using 7- amino-2-((l5',45')-4-(trifluoromethyl)cyclohexyl)phthalazin- l(2H)-one (Intermediate-36, 80 mg, 0.257 mmol) and 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-38, 103 mg, 0.385 mmol), oxalyl chloride (97 mg, 0.77 mmol), and DIPEA (100 mg, 0.77 mmol) in CH2CI2 (3 mL) to afford 17 mg of the title product. 1H NMR (300 MHz, DMSO-J ₆ ): δ 1 1.09 (s, 1H), 8.73 (s, 1H), 8.41 (s, 1H), 8.17-8.10 (m, 2H), 7.92 (d, / = 8.4 Hz, 1H), 7.54 (d, / = 7.8 Hz, 1H), 7.46 (s, 1H), 7.36 (d, / = 8.7 Hz, 1H), 4.97 (m, 1H), 4.29 (d, / = 6.0 Hz, 2H), 2.40 (m, 1H), 1.98 (m, 4H), 1.78 (m, 4H), 1.12 (s, 9H); MS [M+H] ⁺ : 563.22.

Example-41

6-Chloro-N-(3-(4,4-dimethylcyclohexyl)-4-oxo-3,4-dihydrophth alazin-6-yl)-2-methoxy-3- (pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example-34 using 7- amino-2-(4,4-dimethylcyclohexyl)phthalazin-l(2H)-one (Intermediate-33, 90 mg, 0.332 mmol) and 6-chloro-2-methoxy-3-(pivalamidomethyl)benzoic acid (Intermediate-39, 149 mg, 0.498 mmol), oxalyl chloride (125 mg, 0.996 mmol), and DIPEA (128 mg, 0.996 mmol) in CH ₂ C1 ₂ (2 mL) to afford 32 mg of the title product. 1H NMR (400 MHz, DMSO-J ₆ ): δ 11.16 (s, 1H), 8.73 (d, / = 1.6 Hz, 1H), 8.41 (s, 1H), 8.12-8.06 (m, 2H), 7.92 (d, / = 8.4 Hz, 1H), 7.34-7.27 (dd, / = 20.4, 12.0, 8.0 Hz, 2H), 4.83-4.79 (m, 1H), 4.29 (d, / = 6.0 Hz, 2H), 3.81 (s, 3H), 1.99-1.93 (m, 2H), 1.59-1.57 (m, 2H), 1.48-1.37 (m, 4H), 1.14 (s, 9H), 0.99 (s, 3H), 0.96 (s, 3H); MS [M+H] ⁺ : 553.30.

Pharmacological activity

In-vitro protocol for screening of mPGES-1 inhibitors:

mPGES-1 (microsomal prostaglandin E synthase- 1) is a microsomal enzyme that converts endoperoxide substrate PGH ₂ (prostaglandin H ₂ ) to product PGE ₂ (prostaglandin E ₂ ) by isomerization in the presence of reduced glutathione (GSH). mPGES-1 inhibitors were screened by assessing their ability to inhibit formation of PGE ₂ from PGH ₂ in presence of mPGES-1 using anti-PGE ₂ antibody based detection method. Recombinant human mPGES-1 was generated in-house by expressing in CHO cells (Ouellet M et al. (2002), Protein Expression and Purification 26: 489 - 495). Assay was set up using crude microsomal fractions at protein concentration of 40-60 μg/mL. Test compounds were prepared in 100 % dimethyl sulfoxide (DMSO) to obtain 20 mM stock solution and then diluted using assay buffer comprising 0.1 M Potassium phosphate buffer with 2 mM EDTA. Final concentration of DMSO in reaction was 0.5 % (v/v). Negative controls comprised of all assay reagents except the enzyme. Positive controls comprised of enzyme reaction in the absence of any inhibitor. Test compounds were incubated for 10 minutes in assay buffer containing 2.5 mM GSH and mPGES-1 enzyme followed by addition of PGH ₂ at a concentration of 15 μΜ for 1 minute. Reaction was stopped by addition of Stannous chloride (1 lmg/ml) and PGE ₂ levels were measured (Masse F et al. (2005), Journal of Biomolecular Screening 10(6) 599 - 605., Goedken RE et al. (2008), Journal of Biomolecular Screening 13(7): 619 - 625) by HTRF kit (CisBio). Inhibition of mPGES-1 enzyme activity was measured using percent of reaction occurring in the positive control. Concentration response curves were plotted using percent inhibition of maximum enzyme reaction. IC ₅₀ value was calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software.

The compounds prepared were tested using the above assay procedure and the results obtained are given in Table 1. Percentage inhibition at concentrations of 1.0 μΜ and 10.0 μΜ are given in the table along with IC ₅₀ (nM) details for selected examples. The compounds prepared were tested using the above assay procedure and were found to have IC ₅₀ less than 200nM, preferably less than lOOnM, more preferably less than 50nM or most preferably less than 20nM. The IC ₅₀ (nM) values of the compounds are set forth in Table 1 wherein "A" refers to an IC ₅₀ value of less than 50 nM, "B" refers to IC ₅₀ value in range of 50.01 to 100.0 nM and "C" refers to IC ₅₀ values more than 100 nM.

Table 1 :

Sr. No. Example No. Percentage inhibition at ICso (nM)

1 μΜ 10 μΜ

19 Example- 19 84.33 98.6 C

20 Example-20 96.78 99.16 A

21 Example-21 100 100 A

22 Example-22 94.87 97.2 B

23 Example-23 99.72 100 A

24 Example-24 100 96.95 A

25 Example-25 89.34 100 A

26 Example-26 39.02 72.56 -

27 Example-27 87.3 94.67 C

28 Example-28 97.8 98.99 A

29 Example-29 60.87 92.01 -

30 Example-30 99.68 100 A

31 Example-31 85.38 97.32 C

32 Example-32 94.1 95.25 A

33 Example-33 98.54 100 A

34 Example-34 97.28 97.91 A

35 Example-35 97.48 97.40 A

36 Example-36 95.29 96.29 A

37 Example-37 98.10 96.79 A

38 Example-38 97.76 95.16 A

39 Example-39 100.00 97.87 A

40 Example-40 95.42 97.35 A

41 Example-41 97.65 99.74 A

Screening for mPGES-1 inhibitors using the A549 cell based assay

The inhibition of mPGES-1 enzyme in A549 cell line was monitored as inhibition of IL-Ιβ induced PGE ₂ release. A549 cells were maintained in DMEM medium with 10% FBS and 1%) Penicillin-Streptomycin Solution in 5% C0 ₂ at 37°C. Cells were seeded 24 h prior to the assay in 96 well plates in DMEM containing 1% Penicillin- Streptomycin and 2% FBS so as to get ~ 40,000 cells per well on the day of experiment. Assay was carried out in a total volume of 200 μί. Test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare 2 mM stock solution and then diluted using plain DMEM. Final concentration of DMSO in the reaction was 0.55% (v/v). Cells were treated with test compounds for 30 minutes followed by addition of IL-Ιβ at a final concentration of 10 ng/mL for 16-20 h. Plates were then centrifuged at 1000 rpm for 10 min at 4°C. Supernatants were collected & analyzed by the addition of PGE ₂ -D2 & anti-PGE ₂ cryptate conjugate supplied by the CisBio HTRF kit in a 96 well half area blackwell EIA/PJA plate. The assay plate was incubated overnight at 4-5° C before being read in Artemis (K-101) (Japan) HTRF plate reader and levels of PGE ₂ calculated by extrapolation from the standard curve.

Concentration response curves were plotted as % of maximal response obtained in the absence of test antagonist. IC ₅₀ value was calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software.