WO2014167444A1

WO2014167444A1 - SUBSTITUTED BICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS

Info

Publication number: WO2014167444A1
Application number: PCT/IB2014/060122
Authority: WO
Inventors: Laxmikant Atmaram Gharat; Abhisek Banerjee; Neelima Khairatkar-Joshi; Vidya Ganapati Kattige
Original assignee: Glenmark Pharmaceuticals S.A.
Priority date: 2013-04-08
Filing date: 2014-03-25
Publication date: 2014-10-16

Abstract

The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.

Description

SUBSTITUTED BICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS

Related Applications

This application claims the benefit of Indian Provisional Application Nos. 1340/MUM/2013 filed on April 08, 2013; and 2507/MUM/2013 filed on July 29, 2013, each of which is hereby incorporated by reference in its entirety.

Technical Field

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

Background of the Invention

There are many diseases or disorders that are inflammatory in their nature. One of the major problems associated with existing treatments of inflammatory conditions 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 H₂ (PGH₂), which is further converted to other prostaglandins, including PGE₂, PGF_2a, PGD₂, prostacyclin and thromboxane A₂. 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 another that in most cells and tissues is induced by pro-inflammatory stimuli, such as cytokines, during an inflammatory response (COX-2).

Among all prostaglandin metabolites, PGE₂ is particularly known to be a strong pro-inflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE₂, 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 PGE₂. However, the inhibition of COXs has the disadvantage of reducing the formation of all metabolites of PGH₂, thereby decreasing the beneficial properties of some of the metabolites. In view of this, drugs which act by inhibition of COXs are 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 PGE₂ in inflammation. The conversion of PGH₂ to PGE₂ by prostaglandin E synthases (PGES) may, therefore, represent a pivotal step in the propagation of inflammatory stimuli. There are two microsomal prostaglandin E synthases (mPGES-1 and mPGES-2), and one cytosolic prostaglandin E synthase (cPGES). mPGES-1 is an inducible PGES after exposure to proinflammatory stimuli. mPGES-1 is induced in the periphery and CNS by inflammation, and represents therefore a target for acute and chronic inflammatory disorders. PGE₂ 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 PGH₂ which is a substrate for mPGES-1, the terminal enzyme transforming PGH₂ to the pro-inflammatory PGE₂.

Agents that are capable of inhibiting the action of mPGES-1, and thus reducing the formation of the specific arachidonic acid metabolite PGE₂, are beneficial 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 beneficial in the treatment of asthma and COPD.

Blocking the formation of PGE₂ 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 PGE₂ is involved in malignant growth. PGE₂ facilitates tumor progression by stimulation of cellular proliferation and angiogenesis and by modulation of immunosupression. In support of a role for PGE₂ in cancers, genetic deletion of mPGES-1 in mice suppresses 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 a 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 has 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).

International Publication Nos. WO 2006/063466, WO 2007/059610, WO 2010/034796, WO 2010/100249, WO 2012/055995, WO 2012/110860, WO 2013/038308 and WO/2013/072825 disclose numerous heterocyclic compounds which are stated to be the inhibitors of microsomal prostaglandin E synthase- 1 (mPGES-1) enzyme.

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

Summary of the Invention

aspect, the present invention relates to a compound of formula (I)

(I)

or a pharmaceutically acceptable salt thereof,

wherein,

Q¹, Q², Q³ and Q⁴, which may be same or different, are independently selected from N, CH and CR⁴; with a proviso that Q², Q³ and Q⁴ are not N simultaneously;

W is selected from Ci_-8alkyl, Ci_-8alkoxyCi_-8alkyl, haloCi_-8alkyl, hydroxyCi. 8alkyl, carboxylCi_-8alkyl, C_3-i₂cycloalkyl and 3 to 15 membered heterocyclyl;

R¹ is selected from Ci_-8alkyl, Ci_-8alkoxyCi_-8alkyl, haloCi_-8alkyl, hydroxyCi. ₈alkyl, carboxylCi_-8alkyl, C_3-i₂cycloalkyl, C₆-i₄ ryl, C₆-i₄arylCi_-8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_-8alkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_-8alkyl;

R² is selected from hydrogen, halogen, nitro, cyano, hydroxyl, Ci_-8alkyl, Ci. 8alkoxy, haloCi_-8alkyl, hydroxyCi_-8alkyl, C_3-i₂cycloalkyl and C_3-8cycloalkylCi_-8alkyl;

R³ is selected from hydrogen, halogen, nitro, cyano, hydroxyl, Ci_-8alkyl, Ci. 8alkoxy, haloCi_-8alkyl, hydroxyCi_-8alkyl, C_3-i₂cycloalkyl and C_3-8cycloalkylCi_-8alkyl; each occurrence of R⁴ is independently selected from halogen, nitro, cyano, hydroxyl, Ci_-8alkyl, Ci_-8alkoxy, Ci_-8alkoxyCi_-8alkyl, haloCi_-8alkyl, hydroxyCi_-8alkyl, C_3-i₂Cycloalkyl and C_3-8cycloalkylCi_-8alkyl;

each occurrence of R^x and R^y, which may be the same or different, are independently selected from hydrogen, Ci_-8alkyl and C₆-i₄arylCi_-8alkyl;

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

dotted line [— ] inside the ring represents an optional bond; with a proviso that when dotted line [— ] inside the ring represents a bond then R³ is absent.

The compounds of formula (I) may involve one or more embodiments. Embodiments of formula (I) include compounds of formula (II)), 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 Q¹ is CH or CR⁴ (according to an embodiment defined below), R² is hydrogen or methyl (according to another embodiment defined below), R^x is hydrogen (according to yet another embodiment defined below) and n is 1 (according to yet another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (I), in which Q¹ is CH or CR⁴.

According to another embodiment, specifically provided are compounds of formula (I), in which Q² is CH or CR⁴.

According to yet another embodiment, specifically provided are compounds of formula (I), in which Q³ is N or CH.

According to yet another embodiment, specifically provided are compounds of formula (I), in which Q⁴ is CH or CR⁴.

According to yet another embodiment, specifically provided are compounds of formula (I), in which Q¹ is CH or CR⁴, Q² is CH, Q³ is N or CH, and Q⁴ is CR⁴.

According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R⁴ is independently selected from halogen (e.g. F, CI or Br), Ci_-4alkyl (e.g. methyl or ethyl) and haloCi_-8alkyl (e.g. trifluoromethyl or difluoromethyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R⁴ is independently selected from CH₃, CF₃, CHF₂, CI and F.

According to yet another embodiment, specifically provided are compounds of formula (I), in which Q¹ is CH or CR⁴, Q² is CH, Q³ is N or CH, and Q⁴ is CR⁴. In this embodiment, R⁴ is CH₃, CF₃, CHF₂, CI or F.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R¹ is Ci_-8alkyl (e.g. methyl, ethyl, isopropyl, ie/t-butyl, 2,4,4- trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3- dimethylbutan-2-yl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R¹ is cyclohexyl optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI or Br),

(e.g. methyl) and haloCi_-8alkyl (e.g. trifiuoromethyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R is cyclohexyl optionally substituted with one or more substituents independently selected from CH₃ and CF₃.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R¹ is phenyl optionally substituted with trifiuoromethyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R¹ is pyridine optionally substituted with trifiuoromethyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R¹ is Ci_-8alkyl (e.g. methyl, ethyl, isopropyl, ie/t-butyl, 2,4,4- trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3- dimethylbutan-2-yl), C_3-i₂cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, 4- (trifluoromethyl)cyclohexyl or (ls,4s)-4-(trifluoromethyl)cyclohexyl), C6-i₄ ryl (e.g. 4-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl) or 5-14 membered heteroaryl (e.g. 6-(trifluoromethyl)pyridin-3-yl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R¹ is isopropyl, ie/t-butyl, 2,4,4-trimethylpentan-2-yl, 3,3- dimethylbutan-2-yl, ( ?)-3,3-dimethylbutan-2-yl, (S)-3,3-dimethylbutan-2-yl, cyclohexyl, 4,4-dimethylcyclohexyl, 4-(trifluoromethyl)cyclohexyl, (ls,4s)-4- (trifluoromethyl)cyclohexyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl or 6-(trifluoromethyl)pyridin-3-yl.

According to yet another e 1

According to yet another embodiment, specifically provided are compounds of formula (I), in which R² is hydrogen or

(e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R² is hydrogen or methyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which dotted line [— ] inside the ring represent a bond and R³ is absent. According to yet another embodiment, specifically provided are compounds of formula (I), in which R³ is hydrogen or Ci_-4alkyl (e.g. methyl) and dotted line [— ] inside the ring does not represent a bond.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R³ is hydrogen, Ci_-4alkyl (e.g. methyl) or absent.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R³ is methyl or absent.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R² and R³ are methyl.

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

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

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which R^x and R^y are hydrogen.

According to yet another embodiment specifically provided are compounds of formula (I), in which W is Ci-salkyl (e.g. methyl, ethyl, isopropyl or tert-buty\) or haloCi-salkyl (e.g. l-fluoro-2-methylpropan-2-yl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which W is isopropyl, ie/ -butyl or l-fluoro-2-methylpropan-2-yl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which W is f or A

According to yet another embodiment, specifically provided are compounds of formula (I), in which:

Q¹ is CH or CR⁴; Q² is CH; Q³ is N or CH; Q⁴ is CR⁴;

R¹ is Ci-salkyl (e.g. methyl, ethyl, isopropyl, tert-butyl, 2,4,4-trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3-dimethylbutan-2-yl), C3-i₂cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, 4-

(trifluoromethyl)cyclohexyl or (ls,4s)-4-(trifluoromethyl)cyclohexyl), C6-i₄ ryl (e.g. 4-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl) or 5-14 membered heteroaryl (e.g. 6-(trifluoromethyl)pyridin-3-yl); R² is hydrogen or Ci_-4alkyl (e.g. methyl);

R³ is hydrogen, Ci_-4alkyl (e.g. methyl) or absent;

each occurrence of R⁴ is independently halogen (e.g. F, CI or Br), Ci_-4alkyl (e.g. methyl or ethyl) or haloCi-salkyl (e.g. trifluoromethyl or difluoromethyl);

n is 1 ;

R^x is hydrogen;

R^y is hydrogen; and

W is Ci-salkyl (e.g. methyl, ethyl, isopropyl or ie/ -butyl) or haloCi-salkyl (e.g. 1- fluoro-2-methylpropan-2-yl).

Q¹ is CH or CR⁴;

Q² is CH;

Q³ is N or CH;

Q⁴ is CR⁴;

R¹ is isopropyl, tert-butyl, 2,4,4-trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (R)-3,3-dimethylbutan-2-yl, (S)-3,3-dimethylbutan-2-yl, cyclohexyl, 4,4- dimethylcyclohexyl, 4-(trifluoromethyl)cyclohexyl, (ls,4s)-4-

(trifluoromethyl)cyclohexyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl or 6-(trifluoromethyl)pyridin-3-yl;

R² is hydrogen or methyl;

R³ is methyl or absent;

each occurrence of R⁴ is independently CH₃, CF₃, CHF₂, CI or F;

n is 1 ;

R^x is hydrogen;

R^y is hydrogen; and

W is isopropyl, ie/ -butyl or l-fluoro-2-methylpropan-2-yl.

According to an embodiment, specifically provided are compounds of formula (I) that exhibit an IC50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to mPGES-1 inhibition.

1 2 3 1 2 3 4

Further embodiments relating to groups R , R , R , Q , Q , Q , Q and W 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) wherein R² and R³ are methyl and consequently there is also provided a compound of formula (I) wherein R² and R³ are methyl.

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

Accordingly the invention provides a compound of formula (II)

(Π)

or a pharmaceutically acceptable salt thereof,

wherein,

W is selected from Ci_-8alkyl, Ci_-8alkoxyCi_-8alkyl, haloCi_-8alkyl, hydroxyCi.

₈alkyl, carboxylCi_-8alkyl, C3-i₂cycloalkyl and 3 to 15 membered heterocyclyl;

R¹ is selected from Ci_-8alkyl, Ci_-8alkoxyCi_-8alkyl, haloCi_-8alkyl, hydroxyCi. ₈alkyl, carboxylCi_-8alkyl, C_3-i₂cycloalkyl, C_6-i₄aryl, C_6-i₄arylCi_-8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_-8alkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_-8alkyl;

R² is selected from hydrogen, and Ci_-8alkyl;

R³ is selected from hydrogen and Ci_-8alkyl; and

each occurrence of R⁴ is independently selected from halogen, nitro, cyano, hydroxyl, Ci_-8alkyl, Ci_-8alkoxy, Ci_-8alkoxyCi_-8alkyl, haloCi_-8alkyl, hydroxyCi_-8alkyl, C_3-i₂cycloalkyl and C_3-8cycloalkylCi_-8alkyl.

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, 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 Q¹ is CH or CR⁴ (according to an embodiment defined below), Q² is CH or CR⁴ (according to another embodiment defined below), Q³ is N or CH (according to yet another embodiment defined below) and R² and R³ are methyl (according to yet another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (II), in which Q¹ is CH or CR⁴.

According to another embodiment, specifically provided are compounds of formula (II), in which Q² is CH or CR⁴.

According to yet another embodiment, specifically provided are compounds of formula (II), in which Q³ is N or CH.

According to yet another embodiment, specifically provided are compounds of formula (II), in which Q⁴ is CH or CR⁴.

According to yet another embodiment, specifically provided are compounds of formula (II), in which Q¹ is CH or CR⁴, Q² is CH, Q³ is N or CH, and Q⁴ is CR⁴.

According to yet another embodiment, specifically provided are compounds of formula (II), in which each occurrence of R⁴ is independently selected from halogen (e.g. F, CI or Br),

(e.g. methyl or ethyl) and haloCi-salkyl (e.g. trifiuoromethyl or difluoromethyl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which each occurrence of R⁴ is independently selected from CH₃, CF₃, CHF₂, CI and F.

According to yet another embodiment, specifically provided are compounds of formula (II), in which Q¹ is CH or CR⁴, Q² is CH, Q³ is N or CH, and Q⁴ is CR⁴. In this embodiment, R⁴ is CH₃, CF₃, CHF₂, CI or F.

According to yet another embodiment, specifically provided are compounds of formula (II), in which R¹ is Ci-salkyl (e.g. methyl, ethyl, isopropyl, tert-butyl, 2,4,4- trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3- dimethylbutan-2-yl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R¹ is C_3-i₂cycloalkyl, preferably C_3-6Cycloalkyl, and more preferably substituted or unsubstituted cyclohexyl. In this embodiment, substituent(s) on C₃-i₂cycloalkyl, C₃-₆cycloalkyl or cyclohexyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_-4alkyl (e.g. methyl) and haloCi-salkyl (e.g. trifluoromethyl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R¹ is cyclohexyl optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI or Br), Ci_-4alkyl (e.g. methyl) and haloCi_-8alkyl (e.g. trifluoromethyl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R¹ is cyclohexyl optionally substituted with one or more substituents independently selected from CH₃ and CF₃.

According to yet another embodiment, specifically provided are compounds of formula (II), in which R¹ is C₆-i₄aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl. In this embodiment, substituent(s) on C₆-i₄ ryl or phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_-4alkyl (e.g. methyl, isopropyl) and haloCi_-8alkyl (e.g. trifluoromethyl).

According to another embodiment, specifically provided are compounds of formula (II), in which R¹ is phenyl optionally substituted with trifluoromethyl.

According to yet another embodiment, specifically provided are compounds of formula (II), in which R¹ is 5-14 membered heteroaryl, preferably substituted or unsubstituted pyridine, more preferably substituted pyridine. In this embodiment, substituent(s) on 5-14 membered heteroaryl or pyridine may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_-4alkyl (e.g. methyl, isopropyl) and haloCi_-8alkyl (e.g. trifluoromethyl).

According to another embodiment, specifically provided are compounds of formula (II), in which R¹ is pyridine optionally substituted with trifluoromethyl.

According to yet another embodiment, specifically provided are compounds of formula (II), in which R¹ is Ci_-8alkyl (e.g. methyl, ethyl, isopropyl, tert-butyl, 2,4,4- trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3- dimethylbutan-2-yl), C_3-i₂cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, 4- (trifluoromethyl)cyclohexyl or (ls,4s)-4-(trifluoromethyl)cyclohexyl), C_6-i₄aryl (e.g. 4-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl) or 5-14 membered heteroaryl (e.g. 6-(trifluoromethyl)pyridin-3-yl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R¹ is isopropyl, ie/ -butyl, 2,4,4-trimethylpentan-2-yl, 3,3- dimethylbutan-2-yl, ( ?)-3,3-dimethylbutan-2-yl, (S)-3,3-dimethylbutan-2-yl, cyclohexyl, 4,4-dimethylcyclohexyl, 4-(trifluoromethyl)cyclohexyl, (ls,4s)-4- (trifluoromethyl)cyclohexyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl or 6-(trifluoromethyl)pyridin-3-yl.

According to yet another embodiment, specifically provided are compounds of

According to yet another embodiment, specifically provided are compounds of formula (II), in which R² is hydrogen or Ci_-4alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R³ is hydrogen or Ci_-4alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R² and R³ are methyl.

According to yet another embodiment specifically provided are compounds of formula (II), in which W is Ci_-8alkyl (e.g. methyl, ethyl, isopropyl or tert-buty\) or haloCi_-8alkyl (e.g. l-fluoro-2-methylpropan-2-yl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which W is isopropyl, ie/t-butyl or l-fluoro-2-methylpropan-2-yl.

According to yet another embodiment, specifically provided are compounds of formula (II), in which W

According to yet another embodiment, specifically provided are compounds of formula (II), in which:

Q¹ is CH or CR⁴; Q² is CH; Q³ is N or CH; Q⁴ is CR⁴;

R¹ is Ci_-8alkyl (e.g. methyl, ethyl, isopropyl, tert-butyl, 2,4,4-trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3-dimethylbutan-2-yl), C3-i₂cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, 4-

(trifluoromethyl)cyclohexyl or (ls,4s)-4-(trifluoromethyl)cyclohexyl), C_6-i₄aryl (e.g. 4-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl) or 5-14 membered heteroaryl (e.g. 6-(trifluoromethyl)pyridin-3-yl);

R² is hydrogen or Ci_-4alkyl (e.g. methyl);

R³ is hydrogen or Ci_-4alkyl (e.g. methyl); each occurrence of R⁴ is independently halogen (e.g. F, CI or Br),

(e.g. methyl or ethyl) or haloCi_-8alkyl (e.g. trifluoromethyl or difluoromethyl); and

W is Ci_-8alkyl (e.g. methyl, ethyl, isopropyl or ie/ -butyl) or haloCi_-8alkyl (e.g. 1- fluoro-2-methylpropan-2-yl).

Q¹ is CH or CR⁴;

Q² is CH;

Q³ is N or CH;

Q⁴ is CR⁴;

R² is methyl;

R³ is methyl;

each occurrence of R⁴ is independently CH₃, CF₃, CHF₂, CI or F; and

W is isopropyl, ie/ -butyl or l-fluoro-2-methylpropan-2-yl.

According to an embodiment, specifically provided are compounds of formula (II) which exhibit an IC₅₀ value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to mPGES-1 inhibition.

Compounds of the present invention include the compounds in Examples 1 -

22.

It should be understood that the formulas (I) and (II), structurally encompass 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 excipient (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 herein 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 related to a variety of disease states.

The present invention 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 an amount effective to cause inhibition of such receptor. Detailed Description of the Invention

Definitions

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_-8alkyl), 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, ft-pentyl and 1, 1-dimethylethyl (i-butyl). The term "Ci_-6 alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. The term

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. C2-ioalkenyl) and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), z^'so-propenyl, 2-methyl- 1-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. C_2-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 -OCH₃ and -OC₂H₅. 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. ₈alkoxyCi_-8alkyl or Ci_-8alkyloxyCi_-8alkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, -CH₂OCH₃ and -CH₂OC₂H₅. 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_-8alkyl). 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_-8alkoxy). 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 "haloalkoxyalkyl" refers to haloalkoxy group as defined above directly bonded to an alkyl group as defined above (i.e. haloCi_-8alkoxyCi_-8alkyl). Examples of "haloCi_-8alkoxyCi_-8alkyl" include but are not limited to (2,2,2- trifluoroethoxy )m ethyl or (2,2-difluoroethoxy)m ethyl. Unless set forth or recited to the contrary, all haloalkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "hydroxyalkyl" 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_-8alkyl). Examples of hydroxyalkyl moieties include, but are not limited to -CH₂OH, -C₂H₄OH and -CH(OH)C₂H₄OH. Unless set forth or recited to the contrary, all hydroxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "carboxyl" means the group -COOH.

The term "carboxylalkyl" refers to an Ci_-8alkyl group as defined above wherein at least one of the hydrogen atoms of the Ci_-8alkyl group is replaced by a carboxyl group (i.e. "carboxylCi_-8alkyl"). Examples of carboxylalkyl moieties include, but are not limited to carboxylmethyl (-CH₂-COOH), carboxylethyl (-CH₂- CH₂-COOH), carboxylisopropyl (-C(CH₃)₂-COOH) and carboxyltertbutyl (- C(CH₃)₂CH₂-COOH). Unless set forth or recited to the contrary, all carboxylalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e. C_3-i₂cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, 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 non-aromatic cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group (i.e. C_3- ₈cycloalkylCi_-8alkyl). 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 ccyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, (i.e. C_3- ₈cycloalkenyl). Examples of "cycloalkenyl" include but are not limited to cyclopropenyl, cyclobutenyl, and cyclopentenyl. 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 non-aromatic 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, (i.e. Cs-scycloalkenylCi-salkyl). 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-i₄aryl), 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. C₆-i₄aryloxy). Examples of aryloxy moieties 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.

such as -CH₂C₆H₅ and - C₂H₄C₆H₅. 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 (i.e. 3 to 15 membered heterocyclyl) 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 olefinic 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 or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. 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. 3 to 15 membered heterocyclylCi-salkyl). 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 (i.e. 5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi- or tricyclic ring system. 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. 5 to 14 membered heterarylCi-salkyl). 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 cycloalkylalkyl, 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, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR^x', -C(0)R^x', -C(S)R^X', -C(0) R^xR^y', -C(0)O R^xR^y', - R^xCO R^yR^z, -N(R^x')SOR^y', -N(R^x')S0₂R^y', -(=N-N(R^x)R^y), - R^x'C(0)OR^y', - R^xR^y , -NR^xC(0)R^y', - R^xC(S)R^y', - R^x'C(S) R^y'R^z', -SO R^xR^y, -S0₂ R^xR^y', - OR^x', -OC(0) R^yR^z', -OC(0)OR^y', -OC(0)R^x', -OC(0) R^xR^y', -SR^X', -SOR^x', - S0₂R^x, and -ON0₂, wherein each occurrence of 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 cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl, 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, methyl sulfate, 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" may 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 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).

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 invention extends to all these stereoisomeric forms and to mixtures thereof. The different stereoisomeric forms of the compounds described herein may be separated from one another by the methods 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 described herein 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 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, and solvents.

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 inhibit the activity of prostaglandin E synthases {and particularly microsomal prostaglandin E synthase- 1 (mPGES-1)}, i.e., they prevent, inhibit, or suppress 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 are thus 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 procedures, dental procedures or condition (e.g. dental surgery, tooth removal, toothache, dental pain or postsurgical dental pain), 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, Parkinson'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 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) procedure and dental procedures or conditions such as dental surgery, tooth removal, toothache, dental pain or postsurgical dental pain 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 such as 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. Compounds of the present invention may also be useful for the treatment or prevention of endometriosis, hemophilic arthropathy and Parkinson's disease.

Compounds of the present invention 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 compounds of the present invention may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer, and pain associated with cancer. Furthermore, the present invention provides preferred embodiments of the methods and uses as described herein, in which 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, Myelodysplastic 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.

In an embodiment, the compounds of the present invention may be useful in the treatment of disease, disorder, syndrome or condition selected from the group consisting of inflammation, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, pain, inflammatory pain, chronic pain, acute pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections, influenza, common cold, herpes zoster, hepatitis C, AIDS, bacterial infections, fungal infections, dysmenorrhea, burns, pains assoicted with surgical and dental procedures, dental pain, malignancies hyperprostaglandin E syndrome, classic Bartter syndrome, synovitis, 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, cancer, neurodegenerative disorders, autoimmune diseases, multiple sclerosis, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary heart disease, and sarcoidosis.

In another embodiment, the compounds of the present invention may be useful in the treatment of pain, chronic pain, acute pain, rheumatoid arthritic pain, osteoarthritic pain or dental pain.

In yet another embodiment, the compounds of the present invention may be useful in the treatment of pain.

In yet another embodiment, the compounds of the present invention may be useful in the treatment of chronic pain or acute pain.

In yet another embodiment, the compounds of the present invention may be useful in the treatment of rheumatoid arthritic pain, osteoarthritic pain or dental pain.

In yet another embodiment, the compounds of the present invention may be useful in the treatment of pain associated with dental procedures or condition selected from dental surgery, tooth removal, toothache, dental pain and postsurgical dental pain. In yet another embodiment, the compounds of the present invention may be useful in the treatment of toothache, dental pain, postsurgical dental pain, dental surgery or tooth removal.

In yet another embodiment, the compounds of the present invention may be useful in the treatment of inflammation, asthma or chronic obstructive pulmonary disease.

In yet another embodiment, the compounds of the present invention may be useful in the treatment of neurodegenerative disorders selected from Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis.

In yet another embodiment, the compounds of the present invention may be useful in the treatment prevention or management of the cancer.

Compounds of the present 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) and

(II), may be 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 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

(1 ) (I)

The synthesis of the compounds of formula (I) (wherein Q¹, Q², Q³, Q⁴, R¹, R², R³, R^x, R^y, n and W are as defined with respect to 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 and appropriate acyl compound of formula (2), wherein LG represent OH or CI or Br or O-alkyl or O-aiyl 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, (benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate) (PyBOP) 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-aiyl 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

The synthesis of the compounds of formula (II) (wherein Q¹, Q², Q³, Q⁴, R¹, R², R³ and W are as defined with respect to 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 an 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 then a compound of formula (3) is reacted with a compound of formula (4) using a suitable coupling reagent for example, (benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate) (PyBOP) in a suitable solvent such as DCM, dimethylformamide (DMF) or tetrahydrofuran (THF) optionally in the presence of a suitable base such as N,N-diisoporpylethylamine (DIPEA). A compound of formula (3) is reacted with a compound of formula (4) using PyBOP (benzotriazol- l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate and DIPEA in DMF. Alternatively, the reaction of a compound of formula (3) with a compound of formula (4) 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 or Et₃N.

When LG represents CI then the reaction of a compound of formula (3) with a compound of formula (4) 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 then the reaction of a compound of formula (3) with a compound of formula (4) 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.

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 (Na₂S0₄), 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 are as follows: DMSO-i : Hexadeuterodimethyl sulfoxide; CDC1₃: deuterated chloroform; DMSO: dimethyl sulfoxide; DMF: N,N- Dimethylformamide; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; EDCI: l-ethyl-3-(3-dimethylaminopropyl)carbodiimide); HOBt: hydroxybenzotriazole; BOP: Benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafiuorophosphate; PyBOP: Benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafiuorophosphate; Boc/BOC: ie/t-Butoxycarbonyl; BOC anhydride: Di-ie/t-butyl dicarbonate; EtOAc or EA: Ethyl acetate; MeOH: Methanol; EtOH: Ethanol; HC1: Hydrochloric acid; H₂SO₄: Sulfuric acid; AcOH: acetic acid; H₂0: water; Et₂0: Diethyl ether; Et₃N or TEA: Triethylamine; THF: Tetrahydofuran; TFA: trifiuoroacetic acid; LiOH: Lithium hydroxide; NaOH: Sodium hydroxide; NaH: Sodium hydride; nBuLi: n-Butyllithium; K₂C0₃: Potassium carbonate; NaHC0₃: Sodium bicarbonate; NH₄OAc: Ammonium acetate; NH₄CI: Ammonium chloride; PPh₃: Triphenylphosphine; Pd(OAc)₂ : Palladium(II) acetate or Palladium diacetate; Pd/C: Palladium on carbon; RT or rt: room temperature (22-26°C); aq.: aqueous; equiv. or eq. : equivalents; cone. : concentrated; e.g. : for example; i.e. : that is; h : hours; : coupling constant in units of Hz; 1H NMR: Proton Nuclear Magnetic Resonance; APCI-MS: Atmospheric Pressure Chemical Ionization Mass Spectrometry; MHz: Megahertz.

Preparation of Intermediates

Intermediate- 1

7-Amino-2-cyclohexyl-4,4-dimethyl-3,4-dihydroisoquinolin-l(2H)-one

Step 1 : Preparation of 2-bromo- -cyclohexyl-5-nitrobenzamide

To a solution of 2-bromo-5-nitrobenzoic acid (1.0 g, 4.06 mmol) in C¾CN (10 mL) were added N-[(dimethylamino)-lH-l,2,3-triazolo-[4,5-^]pyridin-l-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (1.54 g, 4.06 mmol), cyclohexylamine (442 mg, 4.47 mmol) and DIPEA (1.57 g, 12.18 mmol) and the reaction mixture was stirred at rt for 16 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 900 mg of the title product.

Step 2: Preparation of 2-bromo- -cyclohexyl-N-(2-methylallyl)-5-nitrobenzamide

A solution of 2-bromo-N-cyclohexyl-5-nitrobenzamide (700 mg, 2.14 mmol) in DMF (4 mL) was dropwise added to a suspension of NaH (171 mg, 4.28 mmol, 60% in mineral oil) in DMF (1 mL) at -78 °C. Then the reaction mixture was allowed to warm to 0 °C over 30 minutes and 3-bromo-2-methylpropene (577 mg, 4.28 mmol) was added to the reaction mixture. Then the reaction mixture was slowly warmed to rt over 1 h and stirred for additional 1 h at rt 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 500 mg of the title product. MS (m/z): 381 (M+H)⁺.

Step 3 : Preparation of 2-cyclohexyl-4,4-dimethyl-7-nitro-3,4-dihydroisoquinolin- l(2H)-one

To a solution of 2-bromo-N-cyclohexyl-N-(2-methylallyl)-5-nitrobenzamide (70 mg, 0.18 mmol) in DMF (1 mL) were added tetraethylammonium chloride (63 mg, 0.18 mmol), sodium formate (14 mg, 0.20 mmol) and sodium acetate (33 mg, 0.40 mmol) and the suspension was de-gassed for 10 minutes. Then Pd(OAc)₂ (4 mg, 0.02 mmol) was added to the reaction mixture and it was stirred at 70 °C for 4 h. Then the reaction mixture was filtered through a pad of celite and the filtrate was concentrated and purified by column chromatography to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.59 (d, = 2.7 Hz, 1H), 8.36-8.32 (dd, = 2.7, 7.8 Hz, 1H), 7.73-7.69 (d, J = 8.4 Hz, 1H), 4.49 (m, 1H), 3.16 (s, 2H), 1.78 (m, 2H), 1.59-1.40 (m, 8H), 1.30 (s, 6H); MS (m/z): 303 (M+H)⁺.

Step 4: Preparation of 7-amino-2-cyclohexyl-4,4-dimethyl-3,4-dihydroisoquinolin- l(2H)-one

To a solution of 2-cyclohexyl-4,4-dimethyl-7-nitro-3,4-dihydroisoquinolin-l(2H)-one (250 mg, 0.82 mmol) in a mixture of EtOH:H₂0 (2: 1, 6 mL) were added iron powder (457 mg, 8.20 mmol), and H₄C1 (353 mg, 6.55 mmol). The reaction mass was heated at reflux for 2 h and filtered. The filtrate was concentrated and the residue was purified by column chromatography to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO- e): δ 7.12 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.69-6.65 (dd, J = 2.4, 8.4 Hz, 1H), 5.13 (br s, 2H), 4.41 (m, 1H), 3.16 (s, 2H), 1.73-1.62 (m, 2H), 1.45-1.36 (m, 8H), 1.17 (s, 6H).

Intermediate-2

2-Chloro-5-(pivalamidomethyl)benzoic acid

Step 1 : Preparation of 2-chloro- -{ [(trifluoroacetyl)amino]methyl}benzoic acid

To a solution of 2-chlorobenzoic acid (500 mg, 3.49 mmol) in cone. H₂S0₄ 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 the precipitate obtained, was collected by filtration, dried and the re-crystallized from toluene/butan-2-one (7: 1) to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 13.47 (br s, 1H), 10.06 (br s, 1H), 7.71 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 9.9 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H); MS (m/z): 280 (M-H)^".

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

A solution of 2-chloro-5-{[(trifluoroacetyl)amino]methyl}benzoic acid (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 concentrate was dissolved in THF (10 mL). The solution was treated with NaOH (284 mg, 7.10 mmol) in H₂0 (1 mL) at 0 °C followed by di-ie/ -butyl dicarbonate (840 mg, 3.00 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was acidified with IN HCl and the pH was adjusted to 2-3. The reaction mixture was extracted with 5% MeOH in CHC1₃. The organic layer was separated, dried, filtered and concentrated. The concentrate was re- crystallized from toluene/butan-2-one (7: 1) to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 13.1 (br s, 1H), 7.64 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.37 (d, 7 = 7.8 Hz, 1H), 4.13 (d, J = 5.7 Hz, 2H), 1.38 (s, 9H);MS (m/z): 284 (M-H)^". Step 3 : Preparation of methyl 5-(((ieri-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 K₂C0₃ (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-i¾): δ 7.66 (s, 1H), 7.49-7.52 (m, 2H), 7.42 (d, J = 6.3 Hz, 1H), 4.13 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H), 1.38 (s, 9H).

Step 4: Preparation of methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride

A solution of methyl 5-(((ieri-butoxycarbonyl)amino)methyl)-2-chlorobenzoate (100 mg, 0.334 mmol) in EtOAc saturated with HCl (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-i¾): δ 8.20 (br s, 3H), 7.95 (s, 1H), 7.67 (s, 2H), 4.00 (s,2H), 3.88 (s, 3H).

Step 5 : 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 THF (20 mL) were added DIPEA (3.096 g, 24.0 mmol) and pivaloyl chloride (1.2 mL, 9.0 mmol). The reaction mass was stirred at rt for 2 h, diluted with EtOAc and was washed with water, and brine. The organic layer was separated, dried, filtered and concentrated to afford 2.0 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.16 (m, 1H), 7.65 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 4.25 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H), 1.15 (s, 9H).

Step 6: Preparation of 2-chloro-5-(pivalamidomethyl)benzoic acid

To a solution of methyl 2-chloro-5-(pivalamidomethyl)benzoate (2.00 g, 7.05 mmol) in THF:MeOH:H₂0 (3 :2: 1 ; 6 mL), NaOH (564 mg, 14.1 mmol) was added. 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-i¾): 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, J = 6.0 Hz, 2H), 1.18 (s, 9H).

Intermediate-3

7-Amino-2-(4,4-dimethylcyclohexyl)-4,4-dimethyl-3,4-dihydroisoquinolin-l(2H)-one

Step 1 : Preparation of 2-bro -N-(4,4-dimethylcyclohexyl)-5-nitrobenzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-1 using 2-bromo-5-nitrobenzoic acid (500 mg, 2.04 mmol), N- [(dimethylamino)-lH-l,2,3-triazolo-[4,5-^]pyridin-l-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (775 mg, 2.04 mmol), 4,4- dimethylcyclohexylamine hydrochloride (500 mg, 3.06 mmol) and DIPEA (1.05 g, 8.16 mmol) in C¾CN (5 mL) to afford 480 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 8.54-8.52 (d, J = 8.1 Hz, 1H), 8.18-8.12 (m, 2H), 7.97-7.95 (d, = 8.1 Hz, 1H), 3.76 (m, 1H), 1.73-1.71 (m, 2H), 1.48-1.38 (m, 4H), 1.28-1.25 (m, 2H), 0.91 (s, 3H), 0.89 (s, 3H).

Step 2: Preparation of 2-bromo-N-(4,4-dimethylcyclohexyl)-N-(2-methylallyl)-5- nitrobenzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-2 using 2-bromo-N-(4,4-dimethylcyclohexyl)-5-nitrobenzamide (400 mg, 1.12 mmol), NaH (90 mg, 2.25 mmol, 60% mineral oil) and 3-bromo-2-methylpropene (302 mg, 2.24 mmol) in DMF (3 mL) to afford 500 mg of the title product.

Step 3 : Preparation of 2-(4,4-dimethylcyclohexyl)-4,4-dimethyl-7-nitro-3,4- dihydroisoquinolin-l(2H)-on

The title compound was prepared following the procedure described in Intermediate- 1, step-3 using 2-bromo-N-(4,4-dimethylcyclohexyl)-N-(2-methylallyl)-5- nitrobenzamide (312 mg, 0.91 mmol), tetraethyl ammonium chloride (150 mg, 0.91 mmol), sodium formate (68 mg, 0.97 mmol), sodium acetate (161 mg, 1.96 mmol) and Pd(OAc)₂ (20 mg, 0.09 mmol) in DMF (3 mL) to afford 235 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.59-8.58 (d, = 2.4 Hz, 1H), 8.36-8.32 (dd, J = 3.0, 8.7 Hz, 1H), 7.72-7.70 (d, J = 8.4 Hz, 1H), 4.30 (m, 1H), 3.37 (s, 2H), 1.75-1.72 (m, 2H), 1.43-1.39 (m, 6H), 1.32 (s, 6H), 0.98 (s, 3H), 0.93 (s, 3H); MS (m/z): 331 (M+H)⁺. Step 4: Preparation of 7-amino-2-(4,4-dimethylcyclohexyl)-4,4-dimethyl-3,4- dihydroisoquinolin-l(2H)-one

The title compound was prepared following the procedure described in Intermediate- 1, step-4 using 2-(4,4-dimethylcyclohexyl)-4,4-dimethyl-7-nitro-3,4- dihydroisoquinolin-l(2H)-one (232 mg, 0.70 mmol), iron powder (390 mg, 6.98 mmol), and H₄C1 (303 mg, 5.61 mmol) in EtOH:H₂0 (2: 1, 6 mL) to afford 220 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 7.12-7.1 1 (d, = 2.4 Hz, 1H), 7.02-6.99 (d, = 7.8 Hz, 1H), 6.69-6.65 (dd, = 2.4, 8.4 Hz, 1H), 5.14 (br s, 2H), 4.41 (m, 1H), 3.16 (s, 2H), 1.69-1.62 (m, 2H), 1.45-1.36 (m, 6H), 1.18 (s, 6H), 0.95 (s, 3H), 0.92 (s, 3H); MS (m/z): 301 (M+H)⁺.

Intermediate-4

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

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 ⁿBuLi (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 minutes. The resulting mixture was stirred at - 78 °C for 2 h and 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- e): 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 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- ₆): δ 11.89 (s, 1H), 8.20 (s, 1H), 7.88-7.83 (t, = 8.1 Hz, 1H), 7.49-7.46 (d, J = 8.4 Hz, 1H), 4.44-4.37 (q, J = 7.5 Hz, 2H), 1.34-1.29 (t, J = 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), ION 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 NaHC0₃. 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, CDC1₃): δ 7.54 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 4.45 (q, J = 7.5 Hz, 2H), 4.11 (d, J = 3.6 Hz, 2H), 3.37 (br s, 2H), 1.40 (t, = 7.2 Hz, 3H).

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

To a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (1.00 g, 4.32 mmol) in THF (30 mL) were added DIPEA (1.67 g, 12.96 mmol) and isobutyryl chloride (690 mg, 6.48 mmol). The reaction mass was stirred at rt for 2 h, diluted with EtOAc and was washed with water, and brine. The organic layer was separated, dried, filtered and concentrated to afford 1.0 g of the title product. 1H NMR (300 MHz, DMSO- e): δ 8.35 (t, 1H), 7.41 (m, 2H), 4.42-4.35 (q, J = 7.2 Hz, 2H), 4.28-4.26 (d, = 5.7 Hz, 2H), 2.40 (m, 1H), 1.00 (d, = 6.9 Hz, 6H).

Step 3 : Preparation of 6-chloro-2-fluoro-3-(isobutyramidomethyl)benzoic acid The title compound was prepared following the procedure described in step-6 of Intermediate-2 using ethyl 6-chloro-2-fluoro-3-(isobutyramidomethyl)benzoate (1.00 g, 3.31 mmol) and NaOH (530 mg, 13.26 mmol) in THF:MeOH:H₂0 (3 :2: 1; 12 mL) to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 14.10 (s, 1H), 8.32 (br t, 1H), 7.38- 7.29 (m, 2H), 4.25 (d, J = 5.1 Hz, 2H), 2.40 (m, 1H), 1.00 (d, J = 6.9 Hz, 6H).

Intermediate-5

2-(Difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid

Step 1 : Preparation of (Z)-ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate

To a freshly prepared solution of sodium ethoxide (prepared by addition of 1.1 1 g, 48.35 mmol Na metal in 8 mL EtOH) in EtOH was added a solution of ethyl difluoroacetate (5.0 g, 40.29 mmol) in EtOAc (9 mL) at rt and the reaction mixture was heated at 65 °C for 2 h. Then the reaction mixture was quenched with IN HCl at rt and the pH was adjusted to 6-7. Then the reaction mixture was extracted with EtOAc and the organic layer was washed with water and brine, separated, dried, filtered and concentrated to afford 5.5 g of ethyl 4,4-difluoro-3-oxobutanoate which was taken to the next step without further purification. To a mixture of ethyl 4,4- difluoro-3-oxobutanoate (5.5 g, 33.1 1 mmol) and triethyl orthoformate (12 mL, 66.26 mmol) was added acetic anhydride (27.0 g, 265.0 mmol) and the reaction mixture was heated at 100 °C for 12 h. Then the reaction mixture was concentrated to afford 5.5 g of the title product which was taken to the next step without further purification.

Step 2: Preparation of ethyl 5-cyano-2-(difluoromethyl)nicotinate

To a solution of cyanoacetic acid (2.0 g, 23.53 mmol) in 1,4-dioxane (10 mL) was added N,N-dimethylformamide dimethylacetal (3.35 g, 28.23 mmol) and the reaction mixture was heated at 80 °C for 4 h. Then the reaction mixture was concentrated, diluted with Et₂0 (diethyl ether) and filtered through a pad of silica. The filtrate was concentrated to afford 2.37 g of (E)-3-(dimethylamino)acrylonitrile which was taken to the next step without further purification. To a solution of (Z)-ethyl 2- (ethoxymethylene)-4,4-difluoro-3-oxobutanoate (5.5 g, 24.77 mmol) in DMF (15 mL) at 65 °C was added (E)-3-(dimethylamino)acrylonitrile (2.37 g, 24.77 mmol) dropwise and the reaction mixture was heated at the same temperature for 5 h. Then NH₄OAc (2.86 g, 37.15 mmol) was added to the reaction mixture and heating was continued for 12 h. Then the reaction mixture was quenched with water at rt and was extracted with Et₂0. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 1.3 g of the title product. 1H NMR (300 MHz, DMSO- e): δ 9.09 (s, 1H), 8.60 (s, 1H), 7.62-7.26 (t, 7 = 54 Hz, 1H), 4.51- 4.44 (q, 7 = 7.2 Hz, 2H), 1.46-1.42 (t, 7 = 7.2 Hz, 3H); MS (m/z): 227 (M+H)⁺.

Step 3 : Preparation of ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-2- (difluoromethyl)nicotinate

To a solution of ethyl 5-cyano-2-(difluoromethyl)nicotinate (500 mg, 2.21 mmol), Et₃N (0.4 mL, 2.87 mmol) and di-ie/t-butyl dicarbonate (963 mg, 4.42 mmol) in EtOH (2 mL) was added 10% Pd/C (300 mg) and the reaction mixture was hydrogenated at 40 psi for 2 h. Then the reaction mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography to afford 500 mg of the title product. 1H NMR (300 MHz, DMSO- d₆): δ 8.77 (s, 1H), 8.24 (s, 1H), 7.60-7.27 (t, 7 = 54 Hz, 1H), 4.48-4.41 (m, 4H), 1.47- 1.40 (m, 12H); MS (m/z): 331 (M+H)⁺.

Step 4: Preparation of ethyl -(difluoromethyl)-5-(isobutyramidomethyl)nicotinate

A solution of ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-2- (difluoromethyl)nicotinate (500 mg, 1.51 mmol) in HC1 in EtOH (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and the concentrate was dissolved in DMF (2 mL). The solution was treated with DIPEA (464 mg, 3.60 mmol) and isobutyryl chloride (1 15 mg, 1.08 mmol) at rt. The reaction mixture was stirred for 2 h and it was diluted with EtOAc and was washed with H₂0 and brine. The organic layer was 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- d₆): δ 8.75 (s, 1H), 8.48 (t, 1H), 8.14 (s, 1H), 7.59-7.24 (t, = 54 Hz, 1H), 4.39-4.32 (m, 4H), 2.44 (m, 1H), 1.35-1.29 (t, = 6.9 Hz, 3H), 1.04-1.02 (d, = 6.9 Hz, 6H); MS (m/z): 301 (M+H)⁺.

Step 5 : Preparation of 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid To a solution of ethyl 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinate (200 mg, 0.66 mmol) in 1,4-Dioxane (2 mL) was added a solution of Li OH (70 mg, 1.66 mmol) in H₂0 (0.5 mL) and the reaction mixture was stirred at rt for 1 h. Then the reaction mixture was quenched with IN HCl and the precipitated solid was filtered and dried to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 13.98 (br s, 1H), 8.72 (s, 1H), 8.45 (t, 1H), 8.17 (s, 1H), 7.67-7.32 (t, = 54 Hz, 1H), 4.39-4.37 (d, J = 5.7 Hz, 2H), 2.43 (m, 1H), 1.04-1.02 (d, J = 6.6 Hz, 6H).

Intermediate-6

6-Chloro-2-fluoro-3-((3-fluoro-2,2-dimethylpropanamido)methyl)benzoic acid

O F O

Step 1 : Preparation of ethyl 6-chloro-2-fluoro-3-((3-hydroxy-2,2- dimethylpropanamido)methyl)benzoate

To a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (Intermediate-4, step-1 product, 800 mg, 3.45 mmol) and 3-hydroxy-2,2-dimethylpropanoic acid (591 mg, 5.00 mmol) in DMF (5 mL) were added (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (2.29 g, 5.18 mmol) and DIPEA (1.29 g, 10.0 mmol). Then reaction mixture was stirred at rt for 12 h and diluted with EtOAc and was washed with H₂0 and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 700 mg of the title product. 1H NMR (400 MHz, DMSO- d₆): δ 8.09-8.06 (t, = 8.0 Hz, 1H), 7.45-7.38 (m, 2H), 4.91-4.88 (t, = 5.2 Hz, 1H), 4.42-4.37 (q, J = 8.0 Hz, 2H), 4.29-4.28 (d, J = 5.6 Hz, 2H), 3.48 (m, 2H), 1.33-1.29 (t, 7 = 8.0 Hz, 3H), 1.05 (s, 6H). Step 2: Preparation of ethyl 6-chloro-2-fluoro-3-((3-fluoro-2,2- dimethylpropanamido)methyl)benzoate

To a solution of ethyl 6-chloro-2-fluoro-3-((3-hydroxy-2,2- dimethylpropanamido)methyl) benzoate (200 mg, 0.60 mmol) in THF (2 mL) was added diethylaminosulfur trifluoride (146 mg, 0.90 mmol) and the reaction mixture was stirred at rt for 12 h. Then the reaction mixture was quenched with water and was extracted with CHC1₃. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 104 mg of the title product. 1H NMR (300 MHz, OMSO-d₆): δ 8.32 (t, 1H), 7.44-7.36 (m, 2H), 4.47-4.29 (m, 6H), 1.33-1.29 (t, = 6.9 Hz, 3H), 1.14 (s, 6H). Step 3 : Preparation of 6-Chloro-2-fluoro-3-((3-fluoro-2,2- dimethylpropanamido)methyl)benzoic acid

The title compound was prepared following the procedure described in step-6 of Intermediate-2 using ethyl 6-chloro-2-fluoro-3-((3-fluoro-2,2- dimethylpropanamido)methyl)benzoate (100 mg, 0.30 mmol) and NaOH (24 mg, 0.60 mmol) in THF:MeOH:H₂0 (3 :2: 1 ; 6 mL) to afford 84 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.30 (t, 1H), 7.39-7.29 (m, 2H), 4.47-4.28 (m, 4H), 1.14 (s, 6H).

Intermediate-7

5-(Isobutyramidomethyl)-2-methylnicotinic acid

Step 1 : Preparation of (Z)-ethyl 2-(ethoxymethylene)-3-oxobutanoate

To a mixture of ethyl 3-oxobutanoate (2.0 g, 15.37 mmol) and triethyl orthoformate (4.55 g, 30.74 mmol) was added acetic anhydride (12.55 g, 122.96 mmol) and the reaction mixture was heated at 100 °C for 12 h. Then the reaction mixture was concentrated to afford 2.0 g of the title product which was taken to the next step without further purification.

Step 2: Preparation of ethyl 5-cyano-2-methylnicotinate

The title compound was prepared following the procedure described in Intermediate- 5, step-2 using (Z)-ethyl 2-(ethoxymethylene)-3-oxobutanoate (2.0 g, 10.74 mmol), (E)-3-(dimethylamino)acrylonitrile (1.09 g, 1 1.29 mmol) and H₄OAc (1.24 g, 16.1 1 mmol) in DMF (7 mL) to afford 300 mg of the title product. 1H NMR (300 MHz, CDC1₃): δ 8.88-8.87 (d, J = 2.1 Hz, 1H), 8.48-8.47 (d, J = 2.1 Hz, 1H), 4.46-4.39 (q, J = 7.5 Hz, 2H), 2.93 (s, 3H), 1.46-1.41 (t, J = 7.5 Hz, 3H); MS (m/z): 191 (M+H)⁺. Step 3 : Preparation of ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-2- methylnicotinate

The title compound was prepared following the procedure described in Intermediate- 5, step-3 using ethyl 5-cyano-2-methylnicotinate (300 mg, 1.58 mmol), Et₃N (205 mg, 2.05 mmol) and di-ferf-butyl dicarbonate (689 mg, 3.16 mmol), 10% Pd/C (180 mg) in EtOH (5 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO- d₆): δ 8.49 (s, 1H), 8.03 (s, 1H), 7.50 (t, 1H), 4.35-4.28 (q, J = 7.5 Hz, 2H), 4.16-4.15 (d, J = 5.4 Hz, 2H), 2.68 (s, 3H), 1.39 (s, 9H), 1.34-1.29 (t, J = 7.5 Hz, 3H).

Step 4: Preparation of ethyl 5-(isobutyramidomethyl)-2-methylnicotinate

The title compound was prepared following the procedure described in Intermediate- 5, step-4 using ethyl 5-(((ieri-butoxycarbonyl)amino)methyl)-2-methylnicotinate (250 mg, 0.85 mmol), HC1 in EtOH (2 mL), isobutyryl chloride (1 18 mg, 1.10 mmol), DIPEA (329 mg, 2.55 mmol) in DMF (2 mL) to afford 200 mg of the title product. 1H NMR (300 MHz, OMSO-d₆): 58.50-8.49 (d, J = 1.8 Hz, 1H), 8.37 (t, 1H), 8.00 (d, J = 1.5 Hz, 1H), 4.35-4.28 (m, 4H), 2.68 (s, 3H), 2.41 (m, 1H), 1.34-1.29 (t, = 7.2 Hz, 3H), 1.04-1.01 (d, J = 6.9 Hz, 6H); MS (m/z): 265 (M+H)⁺.

Step 5 : Preparation of 5-(isobutyramidomethyl)-2-methylnicotinic acid

The title compound was prepared following the procedure described in Intermediate- 5, step-5 using ethyl 5-(isobutyramidomethyl)-2-methylnicotinate (200 mg, 0.76 mmol) and LiOH (70 mg, 1.66 mmol) in 1,4-Dioxane (2 mL) and H₂0 (0.5 mL) to afford 150 mg of the title product. 1H NMR (300 MHz, OMSO-d₆): δ 8.45 (s, 1H), 8.36 (t, 1H), 8.01 (s, 1H), 4.28-4.26 (d, = 5.7 Hz, 2H), 2.68 (s, 3H), 2.38 (m, 1H), 1.03-1.01 (d, 7 = 6.6 Hz, 6H).

Intermediate-8

2-Chloro-5-(isobutyramidomethyl)benzoic acid

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

The title compound was prepared following the procedure described in step-5 of Intermediate-2 using methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (Intermediate-2, step-4 product, 2.50 g, 10.59 mmol), DIPEA (4.78 g, 37.07 mmol) and isobutyryl chloride (1.70 g, 15.89 mmol) in THF (20 mL) to afford 1.2 g of the title product. 1H NMR (300 MHz, OMSO-d₆): δ 8.35 (t, 1H), 7.66 (s, 1H), 7.55-7.52 (d, J = 8.1 Hz, 1H), 7.43-7.40 (d, J = 8.1 Hz, 1H), 4.26 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H), 2.44 (m, 1H), 1.02 (d, J = 6.9 Hz, 6H).

Step 6: Preparation of 2-chloro-5-(isobutyramidomethyl)benzoic acid

The title compound was prepared following the procedure described in step-6 of Intermediate-2 using methyl 2-chloro-5-(isobutyramidomethyl)benzoate (1.20 g, 4.45 mmol) and NaOH (534 mg, 13.35 mmol) in THF:MeOH:H₂0 (3 :2: 1 ; 12 mL) to afford 700 mg of the title product. 1H NMR (300 MHz, OMSO-d₆): δ 13.38 (br s, 1H), 8.34 (t, 1H), 7.64 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.39-7.36 (d, J = 8.4 Hz, 4.27-4.25 (d, = 6.3 Hz, 2H), 2.42-2.37 (m, 1H), 1.04-1.01 (d, = 6.9 Hz, 6H).

Intermediate-9

7-Amino-2-(ieri-butyl)-4,4-dimethyl-3,4-dihydroisoquinolin-l(2H)-one

Step 1 : Preparation of 2-bromo-N-(ieri-butyl)-5-nitrobenzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-1 using 2-bromo-5-nitrobenzoic acid (500 mg, 2.04 mmol), N- [(dimethylamino)-lH-l,2,3-triazolo-[4,5-^]pyridin-l-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (775 mg, 2.04 mmol), tert- butylamine (298 mg, 4.08 mmol) and DIPEA (1.05 g, 8.16 mmol) in C¾CN (5 mL) to afford 420 mg of the title product. 1H NMR (300 MHz, DMSO- ₆): δ 8.29 (s, 1H), 8.16-8.12 (dd, J = 2.4, 8.7 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.96-7.93 (d, J = 8.7 Hz, 1H), 1.37 (s, 9H).

Step 2: Preparation of 2-bromo-N-(ieri-butyl)-N-(2-methylallyl)-5-nitrobenzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-2 using 2-bromo-N-(ieri-butyl)-5-nitrobenzamide (420 mg, 1.40 mmol), NaH (1 12 mg, 2.80 mmol, 60% in mineral oil) and 3-bromo-2-methylpropene (378 mg, 2.80 mmol) in DMF (3 mL) to afford 220 mg of the title product. 1H NMR (300 MHz, DMSO- e): δ 8.12-8.09 (m, 1H), 8.04 (s, 1H), 7.96-7.93 (d, J = 8.7 Hz, 1H), 5.03- 4.96 (d, 7 = 20.4 Hz, 2H), 3.33 (s, 2H), 1.52 (s, 9H), 1.43 (s, 3H).

Step 3 : Preparation of 2-(ieri-butyl)-4,4-dimethyl-7-nitro-3,4-dihydroisoquinolin- l(2H)-one

The title compound was prepared following the procedure described in Intermediate- 1, step-3 using 2-bromo-N-(ieri-butyl)-N-(2-methylallyl)-5-nitrobenzamide (190 mg,

0.54 mmol), tetraethylammonium chloride (88 mg, 0.54 mmol), sodium formate (40 mg, 0.59 mmol), sodium acetate (95 mg, 1.16 mmol) and Pd(OAc)₂ (12 mg, 0.05 mmol) in DMF (2 mL) to afford 100 mg of the title product. 1H NMR (300 MHz, DMSO- e): δ 8.59 (s, 1H), 8.33-8.31 (d, = 7.8 Hz, 1H), 7.70-7.67 (d, = 8.7 Hz, 1H), 3.42 (s, 2H), 1.48 (s, 9H), 1.31 (s, 6H).

Step 4: Preparation of 7-amino-2-(ieri-butyl)-4,4-dimethyl-3,4-dihydroisoquinolin- l(2H)-one

The title compound was prepared following the procedure described in Intermediate-

1, step-4 using 2-(ieri-butyl)-4,4-dimethyl-7-nitro-3,4-dihydroisoquinolin-l(2H)-one (90 mg, 0.33 mmol), iron powder (185 mg, 3.30 mmol), and H₄Cl (143 mg, 2.64 mmol) in EtOH:H₂0 (2: 1, 6 mL) to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO- e): δ 7.09 (s, 1H), 6.99-6.97 (d, = 8.1 Hz, 1H), 6.67-6.64 (d, = 7.8 Hz, 1H), 5.06 (br s, 2H), 3.23 (s, 2H), 1.44 (s, 9H), 1.16 (s, 6H); MS (m/z): 247 (M+H)⁺.

Intermediate- 10

7-Amino-2-(4,4-dimethylcyclohexyl)isoquinolin-l(2H)-one

Step 1 : Preparation of 2-(2,4-dimethoxybenzyl)-7-nitroisoquinolin-l(2H)-one

To a solution of 2-methyl-5-nitrobenzoic acid (1.0 g, 5.52 mmol) in methanol (10 mL) was added cone. H₂S0₄ (0.5 mL) and the reaction mixture was heated at reflux for 16 h. Then the reaction mixture was concentrated and the residue was diluted with EtOAc. Then the mixture was washed with saturated aqueous NaHC0₃ solution, water and brine. The organic layer was separated, dried, filtered and concentrated to afford 1.0 g of methyl 2-methyl-5-nitrobenzoate which was used for the next step without further purification.

A mixture of methyl 2-methyl-5-nitrobenzoate (1.0 g, 5.12 mmol) and l-ie/t-butoxy- N,N,N',N'-tetramethylmethanediamine (2.23 g, 12.81 mmol) was heated at 1 15 °C for 2 h. Then the reaction mixtuer was concentrated and purified by column chromatography to afford 600 mg of (E)-methyl 2-(2-(dimethylamino)vinyl)-5- nitrobenzoate. To a solution of (E)-methyl 2-(2-(dimethylamino)vinyl)-5- nitrobenzoate (600 mg, 2.40 mmol) in toluene (5 mL) was added (2,4- dimethoxyphenyl)methanamine (602 mg, 3.60 mmol) and the reaction mixture was heated at 120 °C for 2 h. Then the reaction mixture was concentrated and the residue was triturated with EtOAc: Et₂0 (1 :9) and the solid precipitate was filtered and dried to afford 700 mg of the title product. 1H NMR (400 MHz, DMSO- ₆): δ 9.32-9.31 (d, = 2.4 Hz, 1H), 8.41-8.38 (dd, = 2.4, 8.8 Hz, 1H), 7.62-7.60 (d, = 9.6 Hz, 1H), 7.48-7.46 (d, J = 7.2 Hz, 1H), 7.44-7.42 (d, J = 8.0 Hz, 1H), 6.52-6.49 (m, 3H), 5.15 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H).

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

A solution of 2-(2,4-dimethoxybenzyl)-7-nitroisoquinolin-l(2H)-one (700 mg, 2.06 mmol) in trifluoroacetic acid (2 mL) was heated at 85 °C for 3 h. Then the reaction mixture was concentrated and triturated with EtOAc to afford 300 mg of the title product. 1H NMR (400 MHz, DMSO- ₆): δ 1 1.77 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.46-8.43 (dd, J = 2.0, 8.4 Hz, 1H), 7.93-7.90 (d, J = 8.8 Hz, 1H), 7.48-7.45 (t, J = 6.4 Hz, 1H), 6.74-6.73 (d, J = 7.2 Hz, 1H).

Step 3 : Preparation of 2-(4,4-dimethylcyclohexyl)-7-nitroisoquinolin-l(2H)-one

To a solution of 7-nitroisoquinolin-l(2H)-one (100 mg, 0.52 mmol) and 4,4- dimethylcyclohexanol (100 mg, 0.79 mmol) in THF (2 mL) were added PPh₃ (342 mg, 1.30 mmol) and diisopropylazodicarboxylate (263 mg, 1.30 mmol) and the reaction mixture was heated at reflux for 6 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 100 mg of the title product. MS (m/z): 301 (M+H)⁺.

Step 4: Preparation of 7-amino-2-(4,4-dimethylcyclohexyl)isoquinolin-l(2H)-one The title compound was prepared following the procedure described in Intermediate- 1, step-4 using 2-(4,4-dimethylcyclohexyl)-7-nitroisoquinolin-l(2H)-one (100 mg, 0.33 mmol), iron powder (185 mg, 3.30 mmol), and H₄CI (143 mg, 2.65 mmol) in EtOH:H₂0 (2: 1, 3 mL) to afford 30 mg of the title product. MS (m/z): 271 (M+H)⁺.

Intermediate- 1 1

7-Amino-2-isopropylisoquinoli -l(2H)-one

Step 1 : Preparation of 2-isoprop -7-nitroisoquinolin-l(2H)-one

To a solution of 7-nitroisoquinolin-l(2H)-one (Intermediate- 10, step-2 product, 100 mg, 0.53 mmol) in CH₃CN (1 mL) were added isopropyl bromide (86 mg, 1.05 mmol) and K₂C0₃ (219 mg, 1.59 mmol). The reaction mass was heated at reflux for 12 h and the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 60 mg of the title product. 1H MR (400 MHz, DMSO- e): δ 8.96 (d, = 2.4 Hz, 1H), 8.47-8.44 (dd, = 2.4, 8.8 Hz, 1H), 7.93-7.91 (d, = 8.8 Hz, 1H), 7.85-7.83 (d, = 7.6 Hz, 1H), 6.88-6.86 (d, = 7.2 Hz, 1H), 5.21- 5.14 (m, 1H), 1.37-1.35 (d, = 6.8 Hz, 6H); MS (m/z): 233 (M+H)⁺.

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

The title compound was prepared following the procedure described in Intermediate- 1, step-4 using 2-isopropyl-7-nitroisoquinolin-l(2H)-one (60 mg, 0.26 mmol), iron powder (145 mg, 2.58 mmol), and NH₄C1 (1 12 mg, 2.07 mmol) in EtOH: H₂0 (2: 1, 3 mL) to afford 50 mg of the title product. MS (m/z): 203 (M+H)⁺.

Intermediate- 12

7-Amino-2-(ie/ -butyl)isoquinolin-l(2H)-one

Step 1 : Preparation of 2-(ieri-butyl)-7-nitroisoquinolin-l(2H)-one

The title compound was prepared following the procedure described in Intermediate- 10, step-1 using methyl 2-methyl-5-nitrobenzoate (500 mg, 2.56 mmol), \-tert- butoxy-N,N,N',N'-tetramethylmethanediamine (1.03 g, 5.89 mmol), ie/ -butylamine (467 mg, 6.4 mmol) in toluene (5 mL) to afford 350 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 8.93 (s, 1H), 8.43-8.40 (d, = 9.3 Hz, 1H), 7.86-7.82 (t, = 7.8 Hz, 2H), 6.73-6.71 (d, = 7.8 Hz, 1H), 1.64 (s, 9H).

Step 2: Preparation of 7-amino-2-(ie/ -butyl)isoquinolin-l(2H)-one

The title compound was prepared following the procedure described in Intermediate- 1, step-4 using 2-(ieri-butyl)-7-nitroisoquinolin-l(2H)-one (300 mg, 1.22 mmol), iron powder (410 mg, 7.32 mmol), and H₄C1 (395 mg, 7.32 mmol) in EtOH: H₂0 (2: 1, 12 mL) to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO- ₆): δ 7.32- 7.31 (d, = 2.1 Hz, 1H), 7.28-7.25 (d, = 8.1 Hz, 1H), 7.20-7.17 (d, = 7.8 Hz, 1H), 6.90 (dd, 1H), 6.33-6.30 (d, J = 7.8 Hz, 1H), 5.46 (br s, 2H), 1.60 (s, 9H).

Intermediate- 13

7-Amino-4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-l(2H)- one

Step 1 : Preparation of 2-bro -5-nitro-N-(3-(trifluoromethyl)phenyl)benzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-1 using 2-bromo-5-nitrobenzoic acid (500 mg, 2.04 mmol), N- [(dimethylamino)-lH-l,2,3-triazolo-[4,5-^]pyridin-l-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (775 mg, 2.04 mmol), 3- (trifluoromethyl)aniline (657 mg, 4.08 mmol) and DIPEA (1.05 g, 8.16 mmol) in CH₃CN (5 mL) to afford 395 mg of the title product. 1H NMR (300 MHz, DMSO- ₆): δ 1 1.04 (s, 1H), 8.50 (d, J = 3.0 Hz, 1H), 8.27-8.24 (dd, J = 3.0, 6.0 Hz, 1H), 8.20 (s, 1H), 8.08-8.05 (d, = 8.7 Hz, 1H), 7.89-7.86 (d, = 7.8 Hz, 1H), 7.66-7.61 (t, = 9.0 Hz, 1H), 7.53-7.51 (d, J = 7.8 Hz, 1H); MS (m/z): 388 (M-H)^".

Step 2: Preparation of 2-bromo-N-(2-methylallyl)-5-nitro- V-(3- (trifluoromethyl)phenyl)benzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-2 using 2-bromo-5-nitro-N-(3-(trifluoromethyl)phenyl)benzamide (395 mg, 1.02 mmol), NaH (82 mg, 2.04 mmol, 60% in mineral oil) and 3-bromo-2- methylpropene (275 mg, 2.04 mmol) in DMF (5 mL) to afford 204 mg of the title product. MS (m/z): 445 (M+H)⁺.

Step 3 : Preparation of 4,4-dimethyl-7-nitro-2-(3-(trifluoromethyl)phenyl)-3,4- dihydroisoquinolin-l(2H)-o

The title compound was prepared following the procedure described in Intermediate- step-3 using 2-bromo-N-(2-methylallyl)-5-nitro-N-(3- (trifluoromethyl)phenyl)benzamide (200 mg, 0.45 mmol), tetraethylammonium chloride (75 mg, 0.45 mmol), sodium formate (34 mg, 0.50 mmol), sodium acetate (78 mg, 0.95 mmol) and Pd(OAc)₂ (12 mg, 0.05 mmol) in DMF (3 mL) to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO- ₆): δ 8.66 (d, 1H), 8.45-8.43 (dd, 7 = 3.0, 6.0 Hz, 1H), 7.83-7.69 (m, 5H), 3.92 (s, 2H), 1.43 (s, 6H); MS (m/z): 365 (M+H)⁺.

Step 4: Preparation of 7-amino-4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one The title compound was prepared following the procedure described in Intermediate- 1, step-4 using 4,4-dimethyl-7-nitro-2-(3-(trifluoromethyl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one (120 mg, 0.33 mmol), iron powder (185 mg, 3.30 mmol), and H₄C1 (143 mg, 2.64 mmol) in EtOH: H₂0 (2: 1, 6 mL) to afford 90 mg of the title product. 1H NMR (300 MHz, DMSO- ₆): δ 7.76 (s, 1H), 7.69-7.62 (m, 3H), 7.19 (d, J = 3.0 Hz, 1H), 7.13-7.1 1 (d, 7 = 8.7 Hz, 1H), 6.79-6.76 (m, 1H), 5.25 (br s, 2H), 3.74 (s, 2H), 1.28 (s, 6H).

Intermediate- 14

2-(Isobutyramidomethyl)-4-(trifluoromethyl)thiazole-5-carboxylic acid

Step 1 : Preparation of ethyl 2-bromo-4,4,4-trifluoro-3-oxobutanoate

To a solution of ethyl 4,4,4-trifluoro-3-oxobutanoate (10 g, 54.3 mmol) in benzene (100 mL) were added N-bromosuccinimide (9.6 g, 54.3 mmol) and azobisisobutyronitrile (445 mg, 2.71 mmol) and the reaction mixture was heated at 70°C for 5 h. Then the reaction mixture was concentrated and the residue was treated with a mixture of diethyl ether and n-Pentane (1 : 1). The precipitated solid was filtered and the filtrate was concentrated. The residue was purified by column chromatography to afford 10 g of the title product. 1H NMR (300 MHz, CDC1₃): δ 5.21 (s, 1H), 4.37-4.30 (q, = 6.6 Hz, 2H), 1.34-1.1 (t, 7 = 7.2 Hz, 3H).

Step 2: Preparation of ethyl 2-amino-4-(trifluoromethyl)thiazole-5-carboxylate

To a solution of ethyl 2-bromo-4,4,4-trifluoro-3-oxobutanoate (2.1 g, 7.98 mmol) in ethanol (15 mL) was added thiourea (600 mg, 7.89 mmol) and the reaction mixture was heated at reflux for 3 h. Then the reaction mixture was concentrated and the residue was treated with aqueous NH₃. The resulting solid precipitate was filtered and washed with diethyl ether to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.24 (s, 2H), 4.24-4.17 (q, = 6.9 Hz, 2H), 1.25-1.21 (t, = 7.2 Hz, 3H).

Step 3 : Preparation of ethyl 2-bro -4-(trifluoromethyl)thiazole-5-carboxylate

To a suspension of ethyl 2-amino-4-(trifluoromethyl)thiazole-5-carboxylate (2.0 g, 8.33 mmol) in CH₃CN (10 mL) and copper(II) bromide (2.79 g, 12.49 mmol) was added ie/ -butyl nitrite (1.3 g, 12.49 mmol) at 0-5°C and the reaction mixture was stirred at the same temperature for 30 minutes, before it was warmed to rt and stirred for another 1-2 h. Then the reaction mixture was diluted with EtOAc and was treated with a saturated solution of NaHC0₃. The precipitated solid was filtered and the filtrate was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to provide 2.1 g of the title product. 1H MR (300 MHz, CDC1₃): δ 4.40-4.36 (q, = 6.3 Hz, 2H), 1.41-1.36 (t, = 6.9 Hz, 3H).

Step 4: Preparation of ethyl 2-carbamoyl-4-(trifluoromethyl)thiazole-5-carboxylate

A suspension of ethyl 2-bromo-4-(trifluoromethyl)thiazole-5-carboxylate (2.1 g, 6.90 mmol) and copper (I) cyanide (927 mg, 10.36 mmol) in DMF (10 mL) was heated at 130-140°C for 3-4 h. The reaction mass was quenched with water at rt and was extracted with ethyl acetate. The organic layer was separated, dried, filtered, and concentrated to afford 1.01 g of the title product. MS (m/z):269 (M+H)⁺.

Step 5 : Preparation of ethyl 2-cyan -4-(trifluoromethyl)thiazole-5-carboxylate

To a solution of ethyl 2-carbamoyl-4-(trifluoromethyl)thiazole-5-carboxylate (1.0 g,

3.73 mmol) in CH₂CI₂ were added Et₃N (1.7 g, 16.8 mmol) and trifluoroacetic anhydride (2.74 g, 13.05 mmol) at 0-5 °C. The reaction mass was stirred at rt for 12- 14 h before it was diluted with water and was extracted with CH₂CI₂. The organic layer was separated, dried, filtered, and concentrated to afford 700 mg of the title product. 1H NMR (300 MHz, OMSO-d₆): δ 4.50-4.43 (q, = 6.9 Hz, 2H), 1.44-1.40 (t, 7 = 7.2 Hz, 3H).

Step 6: Preparation of ethyl 2-(((ieri-butoxycarbonyl)amino)methyl)-4- (trifluoromethyl)thiazole-5-carboxylate

The title compound was prepared following the procedure described in Intermediate- 5, step-3 using ethyl 2-cyano-4-(trifluoromethyl)thiazole-5-carboxylate (100 mg, 0.40 mmol), Et₃N (404 mg, 4.0 mmol) and di-ie/t-butyl dicarbonate (872 mg, 4.0 mmol), 10% Pd/C (200 mg) in EtOAc (5 mL) to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 7.69 (t, 1H), 4.44-4.42 (d, J = 6.0 Hz, 2H), 4.36-4.23 (q, J = 7.2 Hz, 2H), 1.41 (s, 9H), 1.31-1.26 (t, J = 7.2 Hz, 3H); MS (m/z): 353 (M-H)^".

Step 7: Preparation of ethyl 2-(isobutyramidomethyl)-4-(trifluoromethyl)thiazole-5- carboxylate

A solution of ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-4- (trifluoromethyl)thiazole-5-carboxylate (531 mg, 1.50 mmol) in HC1 in EtOH (10 mL) was stirred at rt for 3 h. The reaction mixture was concentrated and the concentrate was dissolved in DMF (10 mL). The solution was treated with isobutyric acid (510 mg, 5.8 mmol), EDCI-HC1 (557 mg, 2.9 mmol) and Et₃N (439 mg, 4.35 mmol) at rt. Then the reaction mixture was stirred at rt for 12-14 h before it was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 400 mg of the title product. 1H NMR (300 MHz, DMSO- d₆): δ 8.85 (t, 1H), 4.56-4.54 (d, = 6.0 Hz, 2H), 4.35-4.28 (q, = 6.9 Hz, 2H), 2.47- 2.44 (m, 1H), 1.30-1.25 (t, J = 7.2 Hz, 3H), 1.06-1.04 (d, J = 6.9 Hz, 6H).

Step 8: Preparation of 2-(isobutyramidomethyl)-4-(trifluoromethyl)thiazole-5- carboxylic acid

The title compound was prepared following the procedure described in step-6 of Intermediate-2 using ethyl 2-(isobutyramidomethyl)-4-(trifluoromethyl)thiazole-5- carboxylate (100 mg, 0.31 mmol) and NaOH (50 mg, 1.23 mmol) in THF:MeOH:H₂0 (3 :2: 1 ; 12 mL) to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.83 (t, 1H), 4.54-4.52 (d, = 5.7 Hz, 2H), 2.46-2.44 (m, 1H), 1.06-1.04 (d, = 6.9 Hz, 6H).

Intermediate- 15

7-Amino-4,4-dimethyl-2-(2,4,4-trimethylpentan-2-yl)-3,4-dihydroisoquinolin-l(2H)- one

Step 1 : Preparation of 2-brom -5-nitro-N-(2,4,4-trimethylpentan-2-yl)benzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-1 using 2-bromo-5-nitrobenzoic acid (752 mg, 3.06 mmol), N- [(dimethylamino)-lH-l,2,3-triazolo-[4,5-^]pyridin-l-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (1.1 g, 3.06 mmol), 2,4,4- trimethylpentan-2-amine (528 mg, 4.08 mmol) and DIPEA (792 mg, 6.1 1 mmol) in C¾CN (10 mL) to afford 640 mg of the title product. 1H NMR (300 MHz, DMSO- d₆): δ 8.18-8.13 (m, 2H), 7.6-7.93 (m, 2H), 1.83 (s, 2H), 1.41 (s, 6H), 1.01 (s, 9H). Step 2: Preparation of 2-bromo-N-(2-methylallyl)-5-nitro-N-(2,4,4-trimethylpentan-2- yl)benzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-2 using 2-bromo-5-nitro-N-(2,4,4-trimethylpentan-2-yl)benzamide (590 mg, 1.65 mmol), NaH (132 mg, 3.33 mmol, 60% in mineral oil) and 3-bromo-2- methylpropene (445 mg, 3.33 mmol) in DMF (5 mL) to afford 245 mg of the title product. 1H NMR (300 MHz, CDC1₃): δ 8.10 (d, = 2.4 Hz, 1H), 8.03-7.99 (dd, = 3.0, 8.7 Hz, 1H), 7.71-7.68 (d, = 9.0 Hz, 1H), 5.08-5.02 (d, = 19.8 Hz, 2H), 3.89- 3.83 (d, = 20.1 Hz, 1H), 3.42-3.35 (d, = 19.2 Hz, 1H), 2.29-2.24 (m, 1H), 2.03- 1.99 (m, 1H), 1.73 (s, 3H), 1.44 (s, 6H), 1.07 (s, 9H). MS (m/z): 412 (M+H)⁺.

Step 3 : Preparation of 4,4-dimethyl-7-nitro-2-(2,4,4-trimethylpentan-2-yl)-3,4- dihydroisoquinolin-l(2H)-on

The title compound was prepared following the procedure described in Intermediate- 1, step-3 using 2-bromo-N-(2-methylallyl)-5-nitro-N-(2,4,4-trimethylpentan-2- yl)benzamide (245 mg, 0.59 mmol), tetraethylammonium chloride (99 mg, 0.59 mmol), sodium formate (44 mg, 0.65 mmol), sodium acetate (82 mg, 1.29 mmol) and Pd(OAc)₂ (13 mg, 0.05 mmol) in DMF (3 mL) to afford 150 mg of the title product. 1H NMR (300 MHz, CDC1₃): δ 8.90 (d, = 2.7 Hz, 1H), 8.27-8.25 (d, = 8.4 Hz, 1H), 7.43-7.41 (d, = 8.7 Hz, 1H), 3.42 (s, 2H), 2.14 (s, 2H), 1.59 (s, 6H), 1.37 (s, 6H), 0.98 (s, 9H).

Step 4: Preparation of 7-amino-4,4-dimethyl-2-(2,4,4-trimethylpentan-2-yl)-3,4- dihydroisoquinolin-l(2H)-one

The title compound was prepared following the procedure described in Intermediate- 1, step-4 using 4,4-dimethyl-7-nitro-2-(2,4,4-trimethylpentan-2-yl)-3,4- dihydroisoquinolin-l(2H)-one (130 mg, 0.39 mmol), iron powder (218 mg, 3.91 mmol), and H₄C1 (168 mg, 3.12 mmol) in EtOH:H₂0 (2: 1, 6 mL) to afford 1 10 mg of the title product. 1H NMR (300 MHz, CDCI₃): δ 7.60 (s, 1H), 7.09-7.06 (m, 2H), 3.32 (s, 2H), 2.09 (s, 2H), 1.54 (s, 6H), 1.26 (s, 6H), 0.95 (s, 9H); MS (m/z): 303 (M+H)⁺.

Intermediate- 16

7-Amino-4,4-dimethyl-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)-3,4- dihydroisoquinolin-l(2H)-o

Step 1 : Preparation of 2-bromo-5-nitro-/V-((l5,45)-4- (trifluoromethyl)cyclohexyl)benzamide

To a solution of 2-bromo-5-nitrobenzoic acid (1.0 g, 4.07 mmol) in THF (5 mL) was added oxalyl chloride (1.04 g, 8.16 mmol) at 0 °C and the reaction mixture was stirred at rt for 2h before it was concentrated and the residue was dissolved in THF (5 mL). To the resulting solution were added (ls,4s)-4-(trifluoromethyl)cyclohexanamine (817 mg, 4.89 mmol) and DIPEA (2.0 g, 12.24 mmol) at 0 °C and the reaction mixture was stirred at rt for 2-3h. Then ice-water was added to the reaction mixture and the precipitated solid was filtered and dried to afford 1.5 g of the title product. 1H MR (300 MHz, DMSO-i¾): δ 8.65-8.62 (d, J = 6.6 Hz, 1H), 8.17-8.14 (m, 2H), 7.97-7.95 (d, J = 8.7 Hz, 1H), 3.71 (br s, 1H), 2.29 (br s, 1H), 2.03-1.89 (m, 4H), 1.45-1.22 (m, 4H).

Step 2: Preparation of 2-bromo-N-(2-methylallyl)-5-nitro-N-((ls,4s)-4- (trifluoromethyl)cyclohexyl)benzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-2 using 2-bromo-5-nitro-N-((l5,45)-4-(trifluoromethyl)cyclohexyl)benzamide (1.5 g, 3.79 mmol), NaH (182 mg, 7.59 mmol, 60% in mineral oil) and 3-bromo-2- methylpropene (1.02 g, 7.59 mmol) in DMF (10 mL) to afford 1.3 g of the title product.

Step 3 : Preparation of 4,4-dimethyl-7-nitro-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)- 3 ,4-dihydroisoquinolin- 1 (2 -one

The title compound was prepared following the procedure described in Intermediate- step-3 using 2-bromo-N-(2-methylallyl)-5-nitro-N-((ls,4s)-4-

(trifluoromethyl)cyclohexyl)benzamide (1.3 g, 2.90 mmol), tetraethyl ammonium chloride (478 mg, 2.90 mmol), sodium formate (217 mg, 3.19 mmol), sodium acetate (516 mg, 6.29 mmol) and Pd(OAc)₂ (65 mg, 0.29 mmol) in DMF (10 mL) to afford 490 mg of the title product. 1H NMR (300 MHz, CDC1₃): δ 8.92 (d, 7 = 2.4 Hz, 1H), 8.31-8.29 (d, 7 = 8.7 Hz, 1H), 7.49-7.46 (d, 7 = 8.1 Hz, 1H), 4.71 (m, 1H), 3.24 (s, 2H), 2.06 (m, 3H), 1.92-1.89 (m, 2H), 1.60- 1.50 (m, 2H), 1.37 (s, 6H), 1.25 (s, 2H). Step 4: Preparation of 7-amino-4,4-dimethyl-2-((l5,45)-4- (trifluoromethyl)cyclohexyl)-3,4-dihydroisoquinolin-l(2H)-one

The title compound was prepared following the procedure described in Intermediate- 1, step-4 using 4,4-dimethyl-7-nitro-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)-3,4- dihydroisoquinolin-l(2H)-one (100 mg, 0.27 mmol), iron powder (151 mg, 2.70 mmol), and H₄C1 (1 14 mg, 2.16 mmol) in EtOH:H₂0 (3 : 1, 6 mL) to afford 65 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): 5 7.12 (s, 1H), 7.03-7.00 (d, J = 8.1 Hz, 1H), 6.68-6.65 (d, 7 = 8.7 Hz, 1H), 5.13 (br s, 2H), 4.64 (m, 1H), 3.13 (s, 2H), 2.25 (m, 1H), 1.97-1.93 (m, 2H), 1.64 (m, 4H), 1.44 (m, 2H), 1.16 (s, 6H).

Intermediate- 17

7-Amino-4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-l(2H)- one

Step 1 : Preparation of 2-bro -5-nitro-N-(4-(trifluoromethyl)phenyl)benzamide

The title compound was prepared following the procedure described in Intermediate- 16, step-1 using 2-bromo-5-nitrobenzoic acid (5.0 g, 20.32 mmol), oxalyl chloride (5.16 g, 40.65 mmol), 4-(trifluoromethyl)aniline (4.90 g, 30.48 mmol) and DIPEA (3.93 g, 30.48 mmol) in THF (30 mL) to afford 5.60 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 1 1.15 (s, 1H), 8.47 (s, 1H), 8.27-8.23 (d, 7 = 10.5 Hz, 1H), 8.07-8.04 (d, 7 = 8.7 Hz, 1H), 7.95-7.92 (d, 7 = 7.5 Hz, 2H), 7.77-7.74 (d, 7 = 8.1 Hz, 2H); MS (m/z): 391 (M+H)⁺.

Step 2: Preparation of 2-bromo-N-(2-methylallyl)-5-nitro-N-(4- (trifluoromethyl)phenyl)benzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-2 using 2-bromo-5-nitro-N-(4-(trifluoromethyl)phenyl)benzamide (4.70 g, 12.08 mmol), NaH (866 mg, 21.7 mmol, 60% in mineral oil) and 3-bromo-2- methylpropene (3.26 g, 24.16 mmol) in DMF (25 mL) to afford 3.95 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.34 (s, 1H), 7.99-7.97 (d, = 7.2 Hz, 1H), 7.82-7.79 (d, J = 9.3 Hz, 2H), 7.64-7.61 (d, J = 8.7 Hz, 2H), 7.54-7.51 (d, J = 8.4 Hz, 2H), 4.87-4.84 (d, J = 7.8 Hz, 2H), 4.55 (br s, 2H), 1.79 (s, 3H).

Step 3 : Preparation of 4,4-dimethyl-7-nitro-2-(4-(trifluoromethyl)phenyl)-3,4- dihydroisoquinolin-l(2H)-o

The title compound was prepared following the procedure described in Intermediate- step-3 using 2-bromo-N-(2-methylallyl)-5-nitro-N-(4-

(trifluoromethyl)phenyl)benzamide (3.95 g, 8.91 mmol), tetraethyl ammonium chloride (1.47 g, 8.91 mmol), sodium formate (666 mg, 9.80 mmol), sodium acetate (1.58 g, 19.33 mmol) and Pd(OAc)₂ (199 mg, 0.89 mmol) in DMF (20 mL) to afford 2.90 g of the title product. 1H NMR (300 MHz, CDC1₃): δ 8.99 (s, 1H), 8.40-8.37 (d, = 8.4 Hz, 1H), 7.73-7.70 (d, = 8.4 Hz, 2H), 7.58-7.53 (d, = 9.0 Hz, 3H), 3.83 (s, 2H), 1.53 (s, 6H); MS (m/z): 365 (M+H)⁺.

Step 4: Preparation of 7-amino-4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one

The title compound was prepared following the procedure described in Intermediate- 1, step-4 using 4,4-dimethyl-7-nitro-2-(4-(trifluoromethyl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one (2.90 g, 7.97 mmol), iron powder (4.46 g, 79.67 mmol), and NH₄CI (3.41 g, 63.74 mmol) in EtOH:H₂0 (2: 1, 45 mL) to afford 2.19 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 7.79-7.67 (d, = 8.7 Hz, 2H), 7.65-7.62 (d, = 8.4 Hz, 2H), 7.21 (s, 1H), 7.14-7.1 1 (d, = 9.0 Hz, 1H), 6.97-6.76 (d, J = 10.5 Hz, 1H), 5.25 (br s, 2H), 3.74 (s, 2H), 1.28 (s, 6H); MS (m/z): 335 (M+H)⁺.

Intermediate- 18

4-(Difluoromethyl)-2-(isobutyramidomethyl)thiazole-5-carboxylic acid

Step 1 : Preparation of ethyl 2-bromo-4,4-difluoro-3-oxobutanoate

The title compound was prepared following the procedure described in Intermediate- 14, step-1 using ethyl 4,4-difluoro-3-oxobutanoate (6.69 g, 40.30 mmol), N- bromosuccinimide (8.6 g, 48.36 mmol) and azobisisobutyronitrile (330 mg, 2.01 mmol) in benzene (30 mL) to afford 6.0 g of the title product.

Step 2: Preparation of ethyl 2-amino-4-(difluoromethyl)thiazole-5-carboxylate

The title compound was prepared following the procedure described in Intermediate- 14, step-2 using ethyl 2-bromo-4,4-difluoro-3-oxobutanoate(9.9 g, 40.36 mmol) and thiourea (3.06 g, 40.36 mmol) in ethanol (50 mL) to afford 4 g of desired product. 1H NMR (300 MHz, DMSO-i¾): δ 8.14 (br s, 2H), 7.43-7.07 (t, = 54.3 Hz, 1H), 4.25- 4.18 (q, J = 6.9 Hz, 2H), 1.27-1.26 (t, J = 7.5 Hz, 3H).

Step 3 : Preparation of ethyl 2-bromo-4-(difluoromethyl)thiazole-5-carboxylate

The title compound was prepared following the procedure described in Intermediate- 14, step-3 using ethyl 2-amino-4-(difluoromethyl)thiazole-5-carboxylate (1.0 g, 4.50 mmol), copper (II) bromide (1.50 g, 6.7 mmol), ie/ -butyl nitrite (700 μΐ_^, 6.75 mmol) in CH₃CN (15 mL), to afford 1 g of the title product. 1H NMR (300 MHz, DMSO- ₆): δ 7.56-7.21 (t, 7 = 53.1 Hz, 1H), 4.37-4.30 (q, = 6.9 Hz, 2H), 1.32-1.27 (t, = 6.9 Hz , 3H).

Step 4: Preparation of ethyl 2-carbamoyl-4-(difluoromethyl)thiazole-5-carboxylate

The title compound was prepared following the procedure described in Intermediate- 14, step-4 using ethyl 2-bromo-4-(difluoromethyl)thiazole-5-carboxylate (6.3 g, 22.02 mmol), copper(I) cyanide (2.95 g, 33.04 mmol) in DMF (30 mL) to afford 2.6 g of the title product. 1H MR (300 MHz, CDC1₃): δ 8.1 1 (br s, 1H), 7.58-7.22 (t, J = 53.7 Hz, 1H), 7.28 (br s, 1H), 4.47-4.40 (q, J = 6.6 Hz, 2H), 1.44-1.39 (t, J = 6.9 Hz, 3H).

Step 5 : Preparation of ethyl 2-cyano-4-(difluoromethyl)thiazole-5-carboxylate

The title compound was prepared following the procedure described in Intermediate- 14, step-5 using ethyl 2-carbamoyl-4-(difluoromethyl)thiazole-5-carboxylate (2.6 g, 10.4 mmol), trifluoroacetic anhydride (9.82 g, 46.8 mmol), Et₃N (3.67 g, 36.4 mmol) in CH₂C1₂ (30 mL) to afford 1.8 g of the title product. 1H NMR (300 MHz, DMSO- d₆): δ 7.63-7.27 (t, 7 = 53.1 Hz, 1H), 4.43-4.35 (q, = 7.2 Hz, 2H), 1.35-1.30 (t, = 6.9 Hz, 3H); MS (m/z): 231 (M-H)^".

Step 6: Preparation of ethyl 2-(((ieri-butoxycarbonyl)amino)methyl)-4- (difluoromethy l)thi azol e- 5 -carb oxy 1 ate

The title compound was prepared following the procedure described in Intermediate- 5, step-3 using ethyl 2-cyano-4-(difluoromethyl)thiazole-5-carboxylate (600 mg, 2.5 mmol), di-feri-butyl dicarbonate (1.12 g, 4.13 mmol), 10% Pd/C (300 mg) and Et₃N (417 mg, 4.13 mmol) in THF (6 mL) to afford 500 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 7.94 (t, 1H), 7.57-7.21 (t, J = 53.4 Hz, 1H), 4.44-4.42 (q, J = 7.2 Hz, 2H), 1.41(s, 9H), 1.32-1.27 (t, 7 = 6.6 Hz, 3H).

Step 7: Preparation of ethyl 2-(isobutyramidomethyl)-4-(difluoromethyl)thiazole-5- carb oxy late

The title compound was prepared following the procedure described in Intermediate- 14, step-7 using ethyl 2-(((ieri-butoxycarbonyl)amino)methyl)-4- (difluoromethyl)thiazole-5-carboxylate (500 mg, 1.49 mmol), HC1 in EtOH (3 mL), EDCI-HC1 (517 mg, 2.7 mmol), Isobutyric acid (237 mg, 2.7 mmol), Et₃N (545 mg, 5.40 mmol) in DMF (2 mL) to afford 350 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.84 (t, 1H), 7.57-7.27 (t, = 53.7 Hz, 1H), 4.57-4.55 (d, = 5.7 Hz, 2H), 4.36-4.29 (q, = 6.9 Hz, 2H), 2.45 (m, 1H), 1.32-1.27 (t, = 7.2 Hz, 3H), 1.07- 1.05 (d, = 6.9 Hz, 6H); MS (m/z): 307 (M-H)^".

Step 8: Preparation of 2-(isobutyramidomethyl)-4-(difluoromethyl)thiazole-5- carboxylic acid

The title compound was prepared following the procedure described in step-6 of Intermediate-2 using ethyl 2-(isobutyramidomethyl)-4-(difluoromethyl)thiazole-5- carboxylate (350 mg, 1.14 mmol) and NaOH (91 mg, 2.23 mmol) in THF:MeOH:H₂0 (3 :2: 1; 6 mL) to afford 140 mg of the title product. 1H NMR (300 MHz, OMSO-d₆): δ 8.82 (t, 1H), 7.59-7.23 (t, = 53.7 Hz, 1H), 4.55-4.53 (d, = 6.3 Hz, 2H), 2.09 (m, 1H), 1.06-1.04 (d, = 6.6 Hz, 6H); MS (m/z): 279 (M+H)⁺.

Intermediate- 19

( ?)-7-Amino-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-l(2H)- one

Step 1 : Preparation of ( ?)-2-bromo-/V-(3,3-dimethylbutan-2-yl)-5-nitrobenzamide

The title compound was prepared following the procedure described in Intermediate- 16, step-1 using 2-bromo-5-nitrobenzoic acid (500 mg, 2.04 mmol), oxalyl chloride (362 mg, 2.85 mmol), (7?)-3,3-dimethylbutan-2-amine (206 mg, 2.04 mmol) and DIPEA (256 mg, 4.08 mmol) in THF (5 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, OMSO-d₆): δ 8.39-8.36 (d, = 9.3 Hz, 1H), 8.18-8.14 (dd, = 3.0 Hz, 1H), 8.07-8.00 (d, = 3.0 Hz, 1H), 7.98-7.95 (d, = 8.7 Hz, 1H), 3.89-3.44 (m, 1H), 1.10-1.07 (d, = 6.9 Hz, 3H), 0.92 (s, 9H).

Step 2: Preparation of ( ?)-2-bromo-N-(3,3-dimethylbutan-2-yl)-N-(2-methylallyl)-5- nitrobenzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-2 using ( ?)-2-bromo-N-(3,3-dimethylbutan-2-yl)-5-nitrobenzamide (3 10 mg, 0.95 mmol), NaH (45 mg, 1.89 mmol, 60% in mineral oil) and 3-bromo-2- methylpropene (255 mg, 1.89 mmol) in DMF (2 mL) to afford 50 mg of the title product.

Step 3 : Preparation of ( ?)-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-7-nitro-3,4- dihydroisoquinolin-l(2H)-one

The title compound was prepared following the procedure described in Intermediate- 1, step-3 using ( ?)-2-bromo-N-(3,3-dimethylbutan-2-yl)-N-(2-methylallyl)-5- nitrobenzamide (180 mg, 0.47 mmol), tetraethylammonium chloride (77 mg, 0.47 mmol), sodium formate (35 mg, 0.50 mmol), sodium acetate (83 mg, 1.01 mmol) and Pd(OAc)₂ (10 mg, 0.04 mmol) in DMF (3 mL) to afford 120 mg of the title product. 1H NMR (300 MHz, CDC1₃): δ 8.94-8.93(d, = 2.7 Hz, 1H), 8.30-8.28 (d, = 8.4 Hz, 1H), 7.47-7.44 (d, = 9.0 Hz, 1H), 4.92-4.87 (m, 1H), 3.39-3.23 (q, = 12.9 Hz, 2H), 1.45 (s, 3H), 1.30 (s, 3H), 1.23-1.20 (d, = 6.9 Hz, 3H), 1.00 (s, 9H).

Step 4: Preparation of ( ?)-7-amino-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-3,4- dihydroisoquinolin-l(2H)-one

The title compound was prepared following the procedure described in Intermediate- 1, step-4 using ( ?)-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-7-nitro-3,4- dihydroisoquinolin-l(2H)-one (60 mg, 0.20 mmol), iron powder (1 10 mg, 1.97 mmol), and NH₄C1 (84 mg, 1.57 mmol) in EtOH:H₂0 (5 :2, 7 mL) to afford 45 mg of the title product. 1H MR (300 MHz, CDCI₃): δ 8.1 1 (s, 1H), 7.66 (d, 1H), 7.31 -7.15 (d, 1H), 4.87-4.79 (m, 1H), 3.33-3.15 (m, 2H), 1.37-1.35 (d, J = 6.3 Hz, 3H), 1.24- 1.16 (m, 6H), 0.98 (s, 9H); MS (m/z): 275 (M+H)⁺.

Intermediate-20

7-Amino-4,4-dimethyl-2-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin- l(2H)-one

Step 1 : Preparation of 2-bro -5-nitro-N-(6-(trifluoromethyl)pyridin-3-yl)benzamide

The title compound was prepared following the procedure described in Intermediate- 16, step-1 using 2-bromo-5-nitrobenzoic acid (1.00 g, 4.08 mmol), oxalyl chloride (777 mg, 6.12 mmol), 6-(trifluoromethyl)pyridin-3 -amine (661 mg, 4.08 mmol) and DIPEA (1.05 g, 8.16 mmol) in THF (10 mL) to afford 1.20 g of the title product. 1H MR (300 MHz, DMSO-i¾): δ 1 1.34 (s, 1H), 8.97 (s, 1H), 8..55 (s, 1H), 8.46-8.43 (d, = 8.7 Hz, 1H), 8.30-8.27 (d, = 8.4 Hz, 1H), 8.10-8.07 (d, = 8.7 Hz, 1H), 7.99- 7.96 (d, 7 = 8.4 Hz, 1H).

Step 2: Preparation of 2-bromo-N-(2-methylallyl)-5-nitro-N-(6- (trifluoromethyl)pyridin-3-yl)benzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-2 using 2-bromo-5-nitro-N-(6-(trifluoromethyl)pyridin-3-yl)benzamide (700 mg, 1.79 mmol), NaH (143 mg, 3.58 mmol, 60% in mineral oil) and 3-bromo-2- methylpropene (483 mg, 3.58 mmol) in DMF (8 mL) to afford 410 mg of the title product. 1H MR (300 MHz, DMSO-i¾): δ 8.50 (s, 1H), 8.02 (m, 2H), 7.67-7.59 (m, 3H), 4.97-4.87 (d, = 28.5 Hz, 2H), 4.58 (br s, 2H), 1.89 (s, 3H); MS (m/z): 444 (M+H)⁺. Step 3 : Preparation of 4,4-dimethyl-7-nitro-2-(6-(trifluoromethyl)pyridin-3-yl)-3,4- dihydroisoquinolin-l(2H)-o

The title compound was prepared following the procedure described in Intermediate- 1, step-3 using 2-bromo-N-(2-methylallyl)-5-nitro-N-(6-(trifluoromethyl)pyridin-3- yl)benzamide (410 mg, 0.92 mmol), tetraethylammonium chloride (153 mg, 0.92 mmol), sodium formate (69 mg, 1.01 mmol), sodium acetate (162 mg, 2.00 mmol) and Pd(OAc)₂ (20 mg, 0.09 mmol) in DMF (3 mL) to afford 250 mg of the title product. 1H MR (300 MHz, CDC1₃): δ 9.00 (s, 1H), 8.99 (s, 1H), 8.42-8.39 (d, J = 7.5 Hz, 1H), 8.03-8.01 (d, J = 6.3 Hz, 1H), 7.80-7.77 (d, J = 8.4 Hz, 1H), 7.61-7.58 (d, J = 8.7 Hz, 1H), 3.88 (s, 2H), 1.51 (s, 6H); MS (m/z): 366 (M+H)⁺.

Step 4: Preparation of 7-amino-4,4-dimethyl-2-(6-(trifluoromethyl)pyridin-3-yl)-3,4- dihydroisoquinolin-l(2H)-one

The title compound was prepared following the procedure described in Intermediate- 1, step-4 using 4,4-dimethyl-7-nitro-2-(6-(trifluoromethyl)pyridin-3-yl)-3,4- dihydroisoquinolin-l(2H)-one (250 mg, 0.68 mmol), iron powder (382 mg, 6.84 mmol), and H₄C1 (294 mg, 5.47 mmol) in EtOH:H₂0 (5:2, 7 mL) to afford 180 mg of the title product. MS (m/z): 336 (M+H)⁺.

Intermediate-21

(S)-7-Amino-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-l(2H)- one

Step 1 : Preparation of (S)-2-bromo-/V-(3,3-dimethylbutan-2-yl)-5-nitrobenzamide

The title compound was prepared following the procedure described in Intermediate- 16, step-1 using 2-bromo-5-nitrobenzoic acid (1.00 g, 4.08 mmol), thionyl chloride (2 mL), (S)-3,3-dimethylbutan-2-amine (619 mg, 6.12 mmol) and DIPEA (1.58 g, 12.25 mmol) in THF (5 mL) to afford 1.30 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.39-8.36 (d, J = 9.0 Hz, 1H), 8.17-8.14 (dd, J = 8.7 Hz, 1H), 8.07-8.06 (d, J = 3.0 Hz, 1H), 7.98-7.95 (d, J = 9.0 Hz, 1H), 3.89-3.84 (m, 1H), 1.10-1.07 (d, = 7.2 Hz, 3H), 0.92 (s, 9H); MS (m/z): 329 (M)⁺.

Step 2: Preparation of (S)-2-bromo-N-(3,3-dimethylbutan-2-yl)-N-(2-methylallyl)-5- nitrobenzamide

The title compound was prepared following the procedure described in Intermediate- 1, step-2 using (S)-2-bromo-N-(3,3-dimethylbutan-2-yl)-5-nitrobenzamide (1.3 g, 3.95 mmol), NaH (316 mg, 7.90 mmol, 60% in mineral oil) and 3-bromo-2-methylpropene (1.60 g, 7.92 mmol) in DMF (5 mL) to afford 295 mg of the title product. MS (m/z): 383 (M)⁺.

Step 3 : Preparation of (S)-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-7-nitro-3,4- dihydroisoquinolin-l(2H)-one

The title compound was prepared following the procedure described in Intermediate- 1, step-3 using (S)-2-bromo-N-(3,3-dimethylbutan-2-yl)-N-(2-methylallyl)-5- nitrobenzamide (290 mg, 0.76 mmol), tetraethyl ammonium chloride (125 mg, 0.76 mmol), sodium formate (56 mg, 0.83 mmol), sodium acetate (134 mg, 1.64 mmol) and Pd(OAc)₂ (34 mg, 0.15 mmol) in DMF (5 mL) to afford 163 mg of the title product. 1H NMR (300 MHz, CDC1₃): δ): δ 8.94 (s, 1H), 8.30-8.28 (d, = 8.1 Hz, 1H), 7.47-7.44 (d, J = 9.0 Hz, 1H), 4.90-4.85 (m, 1H), 3.40-3.24 (q, J = 13.2 Hz, 2H), 1.45 (s, 3H), 1.31 (s, 3H), 1.23-1.20 (d, 7 = 7.5 Hz, 3H), 1.0 (s, 9H).

Step 4: Preparation of (S)-7-amino-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-3,4- dihydroisoquinolin-l(2H)-one

The title compound was prepared following the procedure described in Intermediate- 1, step-4 using (S)-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-7-nitro-3,4- dihydroisoquinolin-l(2H)-one (160 mg, 0.53 mmol), iron powder (293 mg, 5.26 mmol), and NH₄C1 (226 mg, 4.20 mmol) in EtOH:H₂0 (5:2, 7 mL) to afford 140 mg of the title product. 1H NMR (300 MHz, OMSO-d₆): δ 7.12 (s, 1H), 7.02-7.00 (d, = 7.8 Hz, 1H), 6.69-6.66 (d, = 8.4 Hz, 1H), 5.12 (br s, 2H), 4.70-4.68 (m, 1H), 3.18 (s, 2H), 1.26-1.23 (d, J = 8.1 Hz, 3H), 1.13 (s, 6H), 0.91 (s, 9H).

Intermediate-22

4,4-Dimethyl-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)-l,2,3,4-tetrahydroisoquinolin- 7-amine

Step 1 : Preparation of ethyl 2-bromo-5-nitrobenzoate

To a solution of 2-bromo-5-nitrobenzoic acid (1.50 g, 6.12 mmol) in CH₂CI₂ (10 mL) was added oxalyl chloride (1.10 g, 12.24 mmol) and the resulting solution was stirred at rt for 30 minutes. Then the reaction mixture was concentrated and the residue was dissolved in EtOH and the resulting solution was stirred at rt for 2h before it was concentrated and the residue was dissolved in EtOAc. Then water was added to the resulting solution and the organic layer was washed with brine, separated, dried, filtered and concentrated to afford 1.0 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.50 (d, J = 3.0 Hz, 1H), 8.27-8.23 (dd, J = 3.0, 8.7 Hz, 1H), 8.06-8.03 (d, J = 8.7 Hz, 1H), 4.41-4.34 (q, J = 6.9 Hz, 2H), 1.37-1.32 (t, J = 7.2 Hz, 3H).

Step 2: Preparation of (2-bromo-5-nitrophenyl)methanol

To a solution of ethyl 2-bromo-5-nitrobenzoate (1.0 g, 3.86 mmol) in ethanol (20 mL) was added NaBH₄ (1.47 g, 38.6 mmol) at 0-5°C. The reaction mass was stirred at rt for 3-4 h. Then the reaction mixture was quenched with a saturated aq. solution of NH₄C1 and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated to afford 750 mg of the title product. 1H NMR (300 MHz, OMSO-d₆): δ 8.29 (s, 1H), 8.05-8.02 (d, J = 8.4 Hz, 1H), 7.89-7.86 (d, J = 8.4 Hz, 1H), 5.84 (br s, 1H), 4.57 (s, 2H).

Step 3 : Preparation of 2-bromo-5-nitrobenzyl methanesulfonate

To a solution of (2-bromo-5-nitrophenyl)methanol (750 mg, 3.24 mmol) in CH₂C1₂ (10 mL) were added DIPEA (3.0 mL) and CH₃S0₂C1 (444 mg, 3.89 mmol). The reaction mass was stirred at rt for 3-4 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 to afford 1.0 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.36 (s, 1H), 8.13-8.10 (dd, = 2.4, 8.7 Hz, 1H), 7.82-7.80 (d, J = 8.7 Hz, 1H), 5.37 (s, 2H), 3.16 (s, 3H).

Step 4: Preparation of (ls,4s)-N-(2-bromo-5-nitrobenzyl)-4- (trifluoromethyl)cyclohexanamine

To a solution of 2-bromo-5-nitrobenzyl methanesulfonate (1.0 g, 3.23 mmol) in DMF (15 mL), K₂C0₃ and (ls,4s)-4-(trifluoromethyl)cyclohexanamine (540 mg, 3.23 mmol) were added. The reaction mixture was heated at 80 °C 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 1.5 g of the title product. 1H

NMR (300 MHz, DMSO-i¾): δ 8.40 (s, 1H), 8.00-7.97 (d, J = 8.1 Hz, 1H), 7.73-7.70 (d, J = 8.7 Hz, 1H), 4.12-4.08 (m, 1H), 3.98 (s, 2H), 2.53 (t, 1H), 2.14-1.98 (m, 4H), 1.44-1.13 (m, 4H).

Step 5 : Preparation of (l5,45)-N-(2-bromo-5-nitrobenzyl)-N-(2-methylallyl)-4- (trifluoromethyl)cyclohexanamine

The title compound was prepared following the procedure described in Intermediate- step-2 using (ls,4s)-N-(2-bromo-5-nitrobenzyl)-4-

(trifluoromethyl)cyclohexanamine (1.5 g, 3.94 mmol), K₂C0₃ (1.08 g, 7.89 mmol) and 3-bromo-2-methylpropene (1.06 g, 7.89 mmol) in DMF (5 mL) to afford 900 mg of the title product. 1H NMR (300 MHz, CDCI₃): δ 8.52 (s, 1H), Ί .95-1.92 (d, = 7.8 Hz, 1H), 7.69-7.66 (d, = 8.7 Hz, 1H), 4.93 (s, 1H), 4.84 (s, 1H), 3.72 (s, 2H), 3.08 (s, 2H), 2.53 (m, 1H), 2.03-2.00 (m, 4H), 1.76 (s, 3H), 1.33-1.22 (m, 4H), 0.87-0.85 (m, 1H); MS (m/z): 436 (M+H)⁺.

Step 6: Preparation of 4,4-dimethyl-7-nitro-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)- 1,2,3,4-tetrahydroisoquinoli

The title compound was prepared following the procedure described in Intermediate- step-3 using (l5,45)-N-(2-bromo-5-nitrobenzyl)-N-(2-methylallyl)-4- (trifluoromethyl)cyclohexanamine (900 mg, 2.06 mmol), tetraethylammonium chloride (721 mg, 4.34 mmol), sodium formate (154 mg, 2.27 mmol), sodium acetate (341 mg, 2.06 mmol) and Pd(OAc)₂ (40 mg, 0.21 mmol) in DMF (5 mL) to afford 600 mg of the title product. 1H NMR (300 MHz, CDC1₃): 8.01-7.98 (d, = 7.8 Hz, 1H), 7.88 (s, 1H), 7.44-7.41 (d, J = 8.4 Hz, 1H), 3.84 (br s, 2H), 2.54 (br s, 3H), 2.04 (m, 4H), 1.38-1.36 (m, 4H), 1.24 (s, 6H), 0.87-0.85 (m, 1H); MS (m/z): 357 (M+H)⁺. Step 7: Preparation of 4,4-dimethyl-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)-l,2,3,4- tetrahydroisoquinolin-7-amine

The title compound was prepared following the procedure described in Intermediate- 1, step-4 using 4,4-dimethyl-7-nitro-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)-l,2,3,4- tetrahydroisoquinoline (600 mg, 1.68 mmol), iron powder (267 mg, 5.05 mmol), and NH₄CI (910 mg, 16.85 mmol) in EtOH:H₂0 (2: 1, 10 mL) to afford 400 mg of the title product. 1H NMR (300 MHz, CDC1₃): δ 7.09-7.06 (d, = 8.1 Hz, 1H), 6.57-6.54 (d, = 8.4 Hz, 1H), 6.34 (s, 1H), 3.75 (br s, 2H), 2.56-2.49 (br s, 3H), 2.06 (m, 4H), 1.93 (m, 4H), 1.27 (s, 6H), 0.87-0.85 (m, 1H); MS (m/z): 327 (M+H)⁺.

Examples

Example- 1

2-Chloro-N-(2-cyclohexyl-4,4-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinolin-7-yl)-5- (pi val ami domethy l)b enzami de

A solution of 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-2, 73 mg, 0.27 mmol) in thionyl chloride (2 mL) was stirred at rt for 1 h and the reaction mixture was concentrated. The concentrate was dissolved in THF (1 mL) and was added to a solution of 7-amino-2-cyclohexyl-4,4-dimethyl-3,4-dihydroisoquinolin- l(2H)-one (Intermediate- 1, 50 mg, 0.18 mmol) in THF (1 mL) and DIPEA (93 mg, 0.72 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 22 mg of the title product. 1H MR (300 MHz, DMSO- ₆): δ 10.61 (s, 1H), 8.18 (m, 2H), 7.83 (d, = 8.7 Hz, 1H), 7.50 (d, = 8.4 Hz, 1H), 7.39-7.32 (m ,3H), 4.48 (m, 1H), 4.28 (d, = 5.7 Hz, 2H), 3.23 (s, 2H), 1.81-1.77 (m, 2H), 1.56-1.33 (m, 8H), 1.24 (s, 6H), 1.12 (s, 9H); MS (m/z): 524 (M+H)⁺.

Example-2

2-Chloro-N-(2-(4,4-dimethylcyclohexyl)-4,4-dimethyl- 1 -oxo- 1,2,3,4- tetrahydroisoquinol -7-yl)-5-(pivalamidomethyl)benzamide

The title compound was prepared following the procedure described in Example- 1 using 7-amino-2-(4,4-dimethylcyclohexyl)-4,4-dimethyl-3,4-dihydroisoquinolin- l(2H)-one (Intermediate-3, 50 mg, 0.17 mmol), 2-chloro-5- (pivalamidomethyl)benzoic acid (Intermediate-2, 67 mg, 0.25 mmol), DIPEA (88 mg, 0.68 mmol), thionyl chloride (1 mL) and THF (3 mL) to afford 35 mg of the title product. 1H MR (300 MHz, DMSO- ₆): δ 10.60 (s, 1H), 8.20-8.17 (m, 2H), 7.81 (d, 1H), 7.51-7.49 (d, = 8.4 Hz, 1H), 7.39 (s, 1H), 7.35-7.34 (m, 2H), 4.21 (m, 1H), 4.29-4.27 (d, = 5.7 Hz, 2H), 3.13 (s, 2H), 1.80-1.60 (m, 2H), 1.42-1.37 (m, 6H), 1.26 (s, 6H), 1.12 (s, 9H), 0.97 (s, 3H), 0.94 (s, 3H); MS (m/z): 552 (M+H)⁺.

Example-3 6-Chloro-N-(2-(4,4-dimethylcyclohexyl)-4,4-dimethyl- 1 -oxo- 1,2,3,4- tetrahydroisoquinol -7-yl)-2-fluoro-3-(isobutyramidomethyl)benzamide

The title compound was prepared following the procedure described in Example- 1 using 7-amino-2-(4,4-dimethylcyclohexyl)-4,4-dimethyl-3,4-dihydroisoquinolin- l(2H)-one (Intermediate-3, 50 mg, 0.17 mmol), 6-chloro-2-fluoro-3- (isobutyramidomethyl)benzoic acid (Intermediate-4, 67 mg, 0.24 mmol), DIPEA (88 mg, 0.68 mmol), thionyl chloride (1 mL) and THF (3 mL) to afford 16 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 10.86 (s, lH), 8.37 (t, 1H), 8.16 (s, 1H), 7.67 (d, 1H), 7.38 (m, 3H), 4.31 (m, 1H), 4.29 (d, 2H), 3.25 (s, 2H), 2.48 (m, 1H), 1.72 (m, 2H), 1.41 (m, 6H), 1.25 (s, 6H), 1.03-1.01 (d, J = 7.5 Hz, 6H), 0.96 (s, 3H), 0.92 (s, 3H); MS (m/z): 556 (M+H)⁺.

Example-4

2-(pifluoromethyl)-N-(2-(4,4-dimethylcyclohexyl)-4,4-dimethyl- 1-oxo- 1,2,3, 4- tetrahydroisoquinolin-7-y -5-(isobutyramidomethyl)nicotinamide

To a solution of 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-5, 56 mg, 0.21 mmol) in DMF (2 mL) were added (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1 1 1 mg, 0.25 mmol), 7-amino-2-(4,4-dimethylcyclohexyl)-4,4-dimethyl-3,4-dihydroisoquinolin-l(2H)-one (Intermediate-3, 50 mg, 0.17 mmol) and DIPEA (44 mg, 0.34 mmol). Then the reaction mixture was stirred at rt for 3 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 27 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.78 (s, 1H), 8.66 (s, 1H), 8.44 (t, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.83 (d, 1H), 7.41-7.38 (d, J = 8.4 Hz, 1H), 7.14 (t, = 55.2 Hz, 1H), 4.42 (m, 3H), 3.27 (s, 2H), 2.49 (m, 1H), 1.69 (m, 2H), 1.42-1.37 (m, 6H), 1.26 (s, 6H), 1.05-1.03 (d, J = 6.6 Hz, 6H), 0.97 (s, 3H), 0.93 (s, 3H); MS (m/z): 555 (M+H)⁺.

Example-5

6-Chloro-N-(2-(4,4-dimethylcyclohexyl)-4,4-dimethyl- 1 -oxo- 1,2,3,4- tetrahydroisoquinolin-7-yl)-2-fluoro-3-((3-fluoro-2,2- dimethylpropanamido)methyl)benzamide

To a solution of 6-chloro-2-fluoro-3-((3-fluoro-2,2- dimethylpropanamido)methyl)benzoic acid (Intermediate-6, 76 mg, 0.25 mmol) in CH₂CI₂ (2 mL) was added oxalyl chloride (63 mg, 0.50 mmol) was stirred at rt for 1 h before it was concentrated. The concentrate was dissolved in THF (1 mL) and the resulting solution was added to a solution of 7-amino-2-(4,4-dimethylcyclohexyl)-4,4- dimethyl-3,4-dihydroisoquinolin-l(2H)-one (Intermediate-3, 50 mg, 0.17 mmol) in THF (1 mL) and DIPEA (44 mg, 0.72 mmol) at -10 °C. The reaction mass was slowly warmed to rt over 45 minutes. Then the reaction mixture 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 13 mg of the title product. 1H MR (300 MHz, DMSO- ): δ 10.89 (s, 1H), 8.35 (t, 1H), 8.18 (s, 1H), 7.78 (d, 1H), 7.40-7.32 (m, 3H), 4.48-4.32 (m, 5H), 3.27 (s, 2H), 1.69 (m, 2H), 1.42 (m, 6H), 1.26 (s, 6H), 1.15 (s, 6H), 0.97 (s, 3H), 0.93 (s, 3H); MS (m/z): 588 (M+H)⁺.

Example-6

N-(2-(4,4-dimethylcyclohexyl)-4,4-dimethyl- 1 -oxo- 1 ,2,3 ,4-tetrahydroisoquinolin-7- yl)-5-(isobutyramidomethy -2-methylnicotinamide

The title compound was prepared following the procedure described in Example-5 using 7-amino-2-(4,4-dimethylcyclohexyl)-4,4-dimethyl-3,4-dihydroisoquinolin- l(2H)-one (Intermediate-3, 50 mg, 0.17 mmol), 5-(isobutyramidomethyl)-2- methylnicotinic acid (Intermediate-7, 47 mg, 0.20 mmol), oxalyl chloride (63 mg, 0.50 mmol), and DIPEA (43 mg, 0.33 mmol) in DMF (1 mL) to afford 38 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 10.56 (s, 1H), 8.43 (s, 1H), 8.36 (t, 1H), 8.19 (s, 1H), 7.84 (d, 1H), 7.69 (s, 1H), 7.39-7.36 (d, J = 9.0 Hz, 1H), 4.42 (m, 1H), 4.29 (d, 2H), 3.27 (s, 2H), 2.50 (s, 3H), 2.49 (m, 1H), 1.73-1.69 (m, 2H), 1.42- 1.37 (m, 6H), 1.26 (s, 6H), 1.03-1.01 (d, J = 7.2 Hz, 6H), 0.97 (s, 3H), 0.93 (s, 3H); MS (m/z): 519 (M+H)⁺.

Example-7

2-Chloro-N-(2-(4,4-dimethylcyclohexyl)-4,4-dimethyl- 1 -oxo- 1,2,3,4- tetrahydroisoquinolin-7-yl -5-(isobutyramidomethyl)benzamide

The title compound was prepared following the procedure described in Example-4 using 7-amino-2-(4,4-dimethylcyclohexyl)-4,4-dimethyl-3,4-dihydroisoquinolin- l(2H)-one (Intermediate-3, 60 mg, 0.20 mmol), 2-chloro-5- (isobutyramidomethyl)benzoic acid (Intermediate-8, 72 mg, 0.28 mmol), (benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate) (156 mg, 0.30 mmol), and DIPEA (77 mg, 0.60 mmol) in DMF (3 mL) to afford 38 mg of the title product. 1H NMR (300 MHz, DMSO- ₆): δ 10.61 (s, 1H), 8.37 (t, 1H), 8.19 (s, 1H), 7.84-7.82 (d, J = 6.0 Hz, 1H), 7.52-7.49 (d, J = 8.4 Hz, 1H), 7.41-7.33 (m, 3H), 4.43 (m, 1H), 4.30-4.28 (d, J = 6.0 Hz, 2H), 3.27 (s, 2H), 2.43 (m, 1H), 1.73-1.69 (m, 2H), 1.42-1.38 (m, 6H), 1.26 (s, 6H), 1.04-1.02 (d, J = 6.9 Hz, 6H), 0.97 (s, 3H), 0.93 (s, 3H); MS (m/z): 538 (M+H)⁺.

Example-8

N-(2-(tert-butyl)-4,4-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinolin-7-yl)-2-chloro-5- (i sobuty rami domethy l)b enzami de

The title compound was prepared following the procedure described in Example-4 using 7-amino-2-(ieri-butyl)-4,4-dimethyl-3,4-dihydroisoquinolin-l(2H)-one (Intermediate-9, 90 mg, 0.37 mmol), 2-chloro-5-(isobutyramidomethyl)benzoic acid (Intermediate-8, 143 mg, 0.56 mmol), (benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate) (291 mg, 0.56 mmol), and DIPEA (6 mg, 0.74 mmol) in DMF (3 mL) to afford 88 mg of the title product. 1H NMR (300 MHz, DMSO- ₆): δ 10.57 (s, 1H), 8.37 (t, 1H), 8.21 (s, 1H), 7.78-7.75 (d, J = 93 Hz, 1H), 7.52-7.50 (d, J = 8.1 Hz, 1H), 7.40 (s, 1H), 7.35-7.32 (d, J = 8.7 Hz, 2H), 4.29 (d, J = 5.4 Hz, 2H), 3.30 (s, 2H), 2.42 (m, 1H), 1.47 (s, 9H), 1.25 (s, 6H), 1.04-1.02 (d, J = 6.9 Hz, 6H); MS (m/z): 484 (M+H)⁺.

Example-9

2-Chl oro-N-(2-(4,4-dimethylcyclohexyl)-l -oxo-1, 2-dihydroisoquinolin-7-yl)-5- (pi val ami domethy l)b enzami de

The title compound was prepared following the procedure described in Example- 1 using 7-amino-2-(4,4-dimethylcyclohexyl)isoquinolin-l(2H)-one (Intermediate- 10, 30 mg, 0.1 1 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-2, 45 mg, 0.16 mmol), DIPEA (43 mg, 0.33 mmol), thionyl chloride (0.5 mL) and THF (1 mL) to afford 15 mg of the title product. 1H NMR (400 MHz, DMSO-i¾) : δ 10.78 (s, 1H), 8.66 (s, 1H), 8.18 (t, J = 5.8 Hz, 1H), 7.98-7.96 (d, J = 7.6 Hz, 1H), 7.66-7.64 (d, J = 8.8 Hz, 1H), 7.57-7.55 (d, J = 7.6 Hz, 1H), 7.53-7.51 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.36-7.34 (d, J = 8.8 Hz, 1H), 6.64-6.62 (d, J = 7.2 Hz, 1H), 4.77-4.71 (m, 1H), 4.30- 4.29 (d, J = 6.0 Hz, 2H), 1.93-1.84 (m, 2H), 1.58-1.38 (m, 6H), 1.13 (s, 9H), 0.97 (s, 3H), 0.89 (s, 3H); MS (m/z): 522 (M+H)⁺.

Example- 10 2-Chloro-N-(2-isopropyl-l-oxo-l,2-dihydroisoquinolin-7-yl)-5- (pi val ami domethy l)b enzami de

The title compound was prepared following the procedure described in Example- 1 using 7-amino-2-isopropylisoquinolin-l(2H)-one (Intermediate- 1 1, 50 mg, 0.25 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-2, 99 mg, 0.37 mmol), DIPEA (94 mg, 0.73 mmol), thionyl chloride (1 mL) and THF (2 mL) to afford 38 mg of the title product. 1H NMR (400 MHz, DMSO- ₆): δ 10.77 (s, 1H), 8.66 (d, 7 = 2.4 Hz, 1H), 8.17-8.15 (t, 7 = 5.6 Hz, 1H), 7.95-7.93 (dd, 7 = 2.0, 8.4 Hz, 1H), 7.64-7.62 (d, 7 = 8.8 Hz, 1H), 7.52-7.50 (d, 7 = 8.4 Hz, 1H), 7.47-7.45 (d, 7 = 7.6 Hz, 1H), 7.44-7.43 (d, 7 = 2.0 Hz, 1H), 7.35-7.32 (dd, 7 = 2.0, 8.4 Hz, 1H), 6.65-6.63 (d, 7 = 7.6 Hz, 1H), 5.22-5.15 (m, 1H), 4.29-4.28 (d, 7 = 6.0 Hz, 2H), 1.33-1.31 (d, 7 = 6.8 Hz, 6H), 1.12 (s, 9H); MS (m/z): 454 (M+H)⁺.

Example- 1 1

N-(2-(tert-butyl)- 1-oxo-l, 2-dihydroisoquinolin-7-yl)-2-chl oro-5- (pi val ami domethy l)b enzami de

The title compound was prepared following the procedure described in Example-5 using 7-amino-2-(tert-butyl)isoquinolin-l(2H)-one (Intermediate- 12, 250 mg, 1.16 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-2, 400 mg, 1.48 mmol), DIPEA (449 mg, 3.48 mmol), oxalyl chloride (224 mg, 1.78 mmol) and THF (5 mL) to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO- ₆): δ 10.76 (s, 1H), 8.67 (s, 1H), 8.18 (t, 1H), 7.93-7.90 (d, 7 = 9.3 Hz, 1H), 7.62-7.59 (d, 7 = 8.7 Hz, 1H), 7.52-7.50 (m, 2H), 7.44 (s, 1H), 7.36 (d, 1H), 6.54-6.52 (d, 7 = 7.2 Hz, 1H), 4.30-4.29 (d, 7 = 5.1 Hz, 2H), 1.66 (s, 9H), 1.13 (s, 9H); MS (m/z): 468 (M+H)⁺.

Example- 12

2-(Difluoromethyl)-N-(4,4-dimethyl- 1 -oxo-2-(3 -(trifluoromethyl)phenyl)- 1,2,3,4- tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)nicotinamide

The title compound was prepared following the procedure described in Example-4 using 7-amino-4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin- l(2H)-one (Intermediate-13, 60 mg, 0.18 mmol), 2-(difluoromethyl)-5- (isobutyramidomethyl)nicotinic acid (Intermediate-5, 74 mg, 0.27 mmol), (benzotriazol-l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (141 mg, 0.27 mmol), and DIPEA (46 mg, 0.36 mmol) in DMF (2 mL) to afford 27 mg of the title product. 1H NMR (300 MHz, DMSO- ₆): δ 10.86 (s, 1H), 8.68 (s, 1H), 8.47 (t, 1H), 8.29 (d, 7 = 2.5 Hz, 1H), 7.98 (s, 1H), 7.96-7.93 (d, 7 = 9.0 Hz, 1H), 7.81 (s, 1H), 7.74-7.66 (m, 3H), 7.52-7.50 (d, 7 = 8.4 Hz, 1H), 7.16 (t, 7 = 54.0 Hz, 1H), 4.424.40 (d, 7 = 6.0 Hz, 1H), 3.85 (s, 2H), 1.37 (s, 6H), 1.05-1.03 (d, 7 = 6.6 Hz, 6H); MS (m/z): 589 (M+H)⁺.

Example- 13

N-(4,4-dimethyl-l-oxo-2-(3-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydroisoquinolin-7- yl)-2-(isobutyramidomethyl)-4-(trifluoromethyl)thiazole-5-carboxamide

The title compound was prepared following the procedure described in Example-4 using 7-amino-4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin- l(2H)-one (Intermediate-13, 60 mg, 0.18 mmol), 2-(isobutyramidomethyl)-4- (trifluoromethyl)thiazole-5-carboxylic acid (Intermediate- 14, 80 mg, 0.27 mmol), (benzotriazol-l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (141 mg, 0.27 mmol), and DIPEA (46 mg, 0.36 mmol) in DMF (2 mL) to afford 24 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 1 1.08 (s, 1H), 8.88 (t, 1H), 8.22 (s, 1H), 7.85-7.65 (m, 5H), 7.51-7.49 (d, = 8.7 Hz, 1H), 4.59-4.57 (d, = 6.3 Hz, 2H), 3.83 (s, 2H), 1.36 (s, 6H), 1.07-1.05 (d, J = 6.6 Hz, 6H); MS (m/z): 613 (M+H)⁺.

Example- 14

2-(Difluoromethyl)-N-(4,4-dimethyl-l-oxo-2-(2,4,4-trimethylpentan-2-yl)-l,2,3,4- tetrahydroisoquinolin-7- -5-(isobutyramidomethyl)nicotinamide

The title compound was prepared following the procedure described in Example-4 using 7-amino-4,4-dimethyl-2-(2,4,4-trimethylpentan-2-yl)-3,4-dihydroisoquinolin- l(2H)-one (Intermediate- 15, 1 10 mg, 0.37 mmol), 2-(difluoromethyl)-5- (isobutyramidomethyl)nicotinic acid (Intermediate-5, 1 18 mg, 0.44 mmol), (benzotriazol-l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (284 mg, 0.55 mmol), and DIPEA (140 mg, 1.09 mmol) in DMF (2 mL) to afford 55 mg of the title product. 1H MR (300 MHz, CDC1₃): δ 8.95 (br s, 1H), 8.59 (s, 1H), 7.98-7.91 (m, 3H), 7.03 (s, 1H), 6.72 (m, 2H), 4.45 (d, 2H), 3.36 (s, 2H), 3.18 (m, 1H), 2.46 (m, 1H), 2.10-1.85 (m, 6H), 1.31 (s, 6H), 1.17-1.14 (d, J = 6.9 Hz, 6H), 0.96 (s, 9H); MS (m/z): 557 (M+H)⁺.

Example- 15

2-(Difluoromethyl)-/V-(4,4-dimethyl-l-oxo-2-((l 5,45)-4-(trifluoromethyl)cyclohexyl)- l,2,3,4-tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)nicotinamide

The title compound was prepared following the procedure described in Example-4 using 7-amino-4,4-dimethyl-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)-3,4- dihydroisoquinolin-l(2H)-one (Intermediate- 16, 65 mg, 0.19 mmol), 2- (difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-5, 65 mg, 0.23 mmol), (benzotriazol-l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (155 mg, 0.29 mmol), and DIPEA (67 mg, 0.52 mmol) in DMF (1 mL) to afford 18 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.81 (br s, 1H), 8.66 (s, 1H), 8.46 (t, 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.85 (m, 1H), 7.42-7.39 (d, J = 8.4 Hz, 1H), 7.14 (t, 1H), 4.52 (m, 1H), 4.40 (d, 2H), 3.24 (m, 2H), 2.26 (m, 1H), 1.95 (m, 2H), 1.78-1.68 (m, 4H), 1.44 (m, 3H), 1.25 (s, 6H), 1.05-1.03 (d, = 6.6 Hz, 6H); MS (m/z): 595 (M+H)⁺.

Example- 16

2-(Difluoromethyl)-N-(4,4-dimethyl-l-oxo-2-(4-(trifluoromethyl)phenyl)-l,2,3,4- tetrahydroisoquinolin-7- -5-(isobutyramidomethyl)nicotinamide

The title compound was prepared following the procedure described in Example-4 using 7-amino-4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin- l(2H)-one (Intermediate- 17, 2.19 g, 6.55 mmol), 2-(difluoromethyl)-5- (isobutyramidomethyl)nicotinic acid (Intermediate-5, 2.45 g, 9.04 mmol), (benzotriazol-l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (3.73 g, 9.83 mmol), and DIPEA (2.5 g, 19.6 mmol) in DMF (15 mL) to afford 3.65 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.85 (s, 1H), 8.67 (s, 1H), 8.45 (t, 1H), 8.29 (s, 1H), 7.98-7.92 (m, 2H), 7.82-7.80 (d, J = 8.7 Hz, 2H), Ί .69-1.66 (d, J = 7.8 Hz, 2H), 7.52-7.49 (d, J = 8.7 Hz, 1H), 7.34-6.97 (t, J = 54.6 Hz, 1H), 4.42 (d, J = 5.4 Hz, 2H), 3.84 (s, 2H), 2.50 (m, 1H), 1.37 (s, 6H), 1.05-1.03 (d, J = 6.9 Hz, 6H); MS (m/z): 589 (M+H)⁺.

Example- 17

4-(Difluoromethyl)-N-(4,4-dimethyl-l-oxo-2-(4-(trifluoromethyl)phenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)-2-(isobutyramidomethyl)thiazole-5-carboxamide

The title compound was prepared following the procedure described in Example-4 using 7-amino-4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin- l(2H)-one (Intermediate- 17, 50 mg, 0.15 mmol), 4-(difluoromethyl)-2- (isobutyramidomethyl)thiazole-5-carboxylic acid (Intermediate- 18, 50 mg, 0.18 mmol), (benzotriazol-l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (1 16 mg, 0.22 mmol), and DIPEA (57 mg, 0.44 mmol) in DMF (1 mL) to afford 26 mg of the title product. 1H NMR (300 MHz, OMSO-d₆): δ 10.76 (s, 1H), 8.87 (t, 1H), 8.26 (br s, 1H), 7.92 (m, 1H), 7.82-7.79 (d, = 8.1 Hz, 2H), 7.68-7.65 (d, = 8.7 Hz, 2H), 7.51-7.49 (m, 1H), 7.34 (t, 1H), 4.49-4.57 (d, J = 6.3 Hz, 2H), 3.84 (s, 2H), 2.50 (m, 1H), 1.36 (s, 6H), 1.09-1.07 (d, J = 6.6 Hz, 6H); MS (m/z): 595 (M+H)⁺.

Example- 18

( ?)-2-(difluoromethyl)-N-(2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-l-oxo-l,2,3,4- tetrahydroisoquinolin-7-yl -5-(isobutyramidomethyl)nicotinamide

The title compound was prepared following the procedure described in Example-4 using ( ?)-7-amino-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-3,4-dihydroisoquinolin- l(2H)-one (Intermediate- 19, 60 mg, 0.22 mmol), 2-(difluoromethyl)-5- (isobutyramidomethyl)nicotinic acid (Intermediate-5, 89 mg, 0.33 mmol), (benzotriazol-l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (170 mg, 0.33 mmol), and DIPEA (84 mg, 0.65 mmol) in DMF (2 mL) to afford 14 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.78 (s, 1H), 8.64 (s, 1H), 8.45 (t, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.81-7.78 (d, J = 7.8 Hz, 1H), 7.39-7.36 (d, 7 = 8.4 Hz, 1H), 7.31-6.94 (t, 7 = 54.9 Hz, 1H), 4.70-4.68 (m, 1H), 4.39-4.38 (d, 7 = 5.7 Hz, 2H), 3.27 (s, 2H), 2.43-2.41 (m, 1H), 1.33 (s, 3H), 1.17-1.13 (m, 6H), 1.09-1.06 (d, 7 = 7.2 Hz, 6H), 0.91 (s, 9H); MS (m/z): 529 (M+H)⁺.

Example- 19

2-(Difluoromethyl)-N-(4,4-dimethyl-l-oxo-2-(6-(trifluoromethyl)pyridin-3-yl)- l,2,3,4-tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)nicotinamide

The title compound was prepared following the procedure described in Example-4 using

7-amino-4,4-dimethyl-2-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin- l(2H)-one (Intermediate-20, 80 mg, 0.24 mmol), 2-(difluoromethyl)-5- (isobutyramidomethyl)nicotinic acid (Intermediate-5, 97 mg, 0.36 mmol), (benzotriazol-l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (185 mg, 0.36 mmol), and DIPEA (92 mg, 0.71 mmol) in DMF (2 mL) to afford 20 mg of the title product. 1H MR (300 MHz, DMSO-i¾): δ 10.91 (s, 1H), 8.92 (s, 1H), 8.67 (s, 1H), 8.48 (t, 1H), 8.33 (s, 1H), 8.18-8.15 (d, 7 = 9.3 Hz, 1H), 8.02-7.94 (m, 2H), 7.54- 7.51 (d, 7 = 8.1 Hz, 1H), 7.34-6.98 (t, 7 = 53.7 Hz, 1H), 4.42-4.40 (d, 7 = 5.7 Hz, 2H), 3.91 (s, 2H), 2.45 (m, 1H), 1.38 (s, 6H), 1.05-1.03 (d, 7 = 6.6 Hz, 6H); MS (m/z): 590 (M+H)⁺.

Example-20

(S)-2-(difluoromethyl)-N-(2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-l-oxo-l,2,3,4- tetrahydroisoquinolin-7-yl -5-(isobutyramidomethyl)nicotinamide

The title compound was prepared following the procedure described in Example-4 using (S)-7-amino-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-3,4-dihydroisoquinolin- l(2H)-one (Intermediate-21, 100 mg, 0.36 mmol), 2-(difluoromethyl)-5- (isobutyramidomethyl)nicotinic acid (Intermediate-5, 148 mg, 0.55 mmol), (benzotriazol-l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (284 mg, 0.55 mmol), and DIPEA (140 mg, 1.09 mmol) in DMF (2 mL) to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.77 (s, 1H), 8.66 (s, 1H), 8.45 (t, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.82-7.80 (d, 7 = 6.3 Hz, 1H), 7.41-7.38 (d, 7 = 8.1 Hz, 1H), 7.32-6.97 (t, 7 = 53.7 Hz, 2H), 4.73-4.70 (m, 1H), 4.42-4.40 (d, 7 = 5.7 Hz, 2H), 2.45 (m, 1H), 1.36 (s, 3H), 1.19-1.16 (d, 7 = 12.0 Hz, 3H), 1.18 (s, 3H), 1.09-1.06 (d, 7 = 6.9 Hz, 6H), 0.94 (s, 9H); MS (m/z): 529 (M+H)⁺.

Example-21

2-(Difluoromethyl)-N-(4,4-dimethyl-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)- l,2,3,4-tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)nicotinamide

The title compound was prepared following the procedure described in Example-4 using 4,4-dimethyl-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)-l, 2,3,4- tetrahydroisoquinolin-7-amine (Intermediate-22, 40 mg, 0.12 mmol), 2- (difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-5, 36 mg, 0.12 mmol), (dimethylamino)-N,N-dimethyl(3H-[l,2,3]triazolo[4,5-^]pyridin-3- yloxy)methaniminium hexafluorophosphate (69 mg, 0.18 mmol), and DIPEA (47 mg, 0.37 mmol) in DMF (2 mL) to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.56 (s, 1H), 8.65 (s, 1H), 8.44 (t, 1H), 7.91(s, 1H), 7.38 (m, 2H), 7.30 (m, 1H), 7.30-6.93 (t, J = 53.7 Hz, 1H), 4.1 1 (d, 2H), 3.68 (s, 2H), 2.46 (s, 2H), 2.24 (m, 2H), 1.95-1.92 (d, 7 = 8.1 Hz, 4H), 1.36-1.33 (m, 4H), 1.21 (s, 6H), 1.05-1.03 (d, 7 = 6.6 Hz, 6H), 0.87-0.85 (m, 1H); MS (m/z): 581 (M+H)⁺.

Example-22 2-Chloro-N-(4,4-dimethyl-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)-l,2,3,4- tetrahydroisoquinolin-7-y -5-(isobutyramidomethyl)benzamide

The title compound was prepared following the procedure described in Example-4 using 4,4-dimethyl-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)-l,2,3,4- tetrahydroisoquinolin-7-amine (Intermediate-22, 100 mg, 0.31 mmol), 2-chloro-5- (isobutyramidomethyl)benzoic acid (Intermediate-8, 78 mg, 0.31 mmol), (dimethylamino)-N,N-dimethyl(3H-[l,2,3]triazolo[4,5-^]pyridin-3- yloxy)methaniminium hexafluorophosphate (174 mg, 0.46 mmol), and DIPEA (1 18 mg, 0.92 mmol) in DMF (5 mL) to afford 65 mg of the title product. 1H MR (300 MHz, OMSO-d₆): δ 10.37 (s, 1H), 8.35 (t, 1H), 7.50-7.47(d, = 7.8 Hz, 1H), 7.38- 7.34 (m, 3H), 7.31-7.25 (m, 2H), 4.28-4.26 (d, = 6.0 Hz, 2H), 3.67 (s, 2H), 2.45- 2.39 (m, 2H), 2.22 (m, 2H), 1.98-1.97 (m, 4H), 1.36-1.32 (m, 4H), 1.20 (s, 6H), 1.03- 1.01 (d, = 6.9 Hz, 6H), 0.87-0.85 (m, 1H); MS (m/z): 564 (M+H)⁺.

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 PGH₂ (prostaglandin H₂) to product PGE₂ (prostaglandin E₂) by isomerization in the presence of reduced glutathione (GSH). mPGES-1 inhibitors were screened by assessing their ability to inhibit formation of PGE₂ from PGH₂ in the presence of mPGES-1 using an anti-PGE₂ antibody based detection method. Recombinant human mPGES-1 was generated in-house by expression in CHO cells (Ouellet M et al. (2002), Protein Expression and Purification 26: 489 - 495). The 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. The final concentration of DMSO in the reaction was 0.5 % (v/v). Negative controls were comprised of all assay reagents except the enzyme. Positive controls were comprised of the 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 PGH₂ at a concentration of 15 μΜ for 1 minute. The reaction was stopped by addition of Stannous chloride (l lmg/ml) and PGE₂ 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 the percent of reaction occurring in the positive control. Concentration response curves were plotted using percent inhibition of maximum enzyme reaction. The IC₅₀ value was calculated from the 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 IC₅₀ (nM) details for selected examples. The compounds prepared were tested using the above assay procedure and were found to have IC₅₀ less than 200nM, preferably less than ΙΟΟηΜ, more preferably less than 50nM or most preferably less than 20nM.

The IC₅₀ (nM) values of some of the compounds are set forth in Table 1 wherein "A" refers to an IC₅₀ value of less than 50 nM, "B" refers to IC₅₀ value in range of 50.01 to 100.0 nM and "C" refers to IC₅₀ values more than 100 nM.

Table 1 :

Sr. Example No. Percentage inhibition at ICso (nM) No. 1 μΜ 10 μΜ

8 Example- 8 95.26 99.81 B

9 Example-9 96.39 97.12 A

10 Example- 10 84.37 91.84 C

11 Example- 11 79.88 98.17 C

12 Example- 12 97.28 97.21 A

13 Example- 13 70.69 97.04 -

14 Example- 14 96.99 98.63 A

15 Example- 15 96.94 98.49 A

16 Example- 16 96.72 99.43 A

17 Example- 17 2.39 44.94 -

18 Example- 18 96.91 98.12 A

19 Example- 19 95.62 100.00 A

20 Example-20 92.03 99.95 B

21 Example-21 92.68 98.08 B

22 Example-22 95.85 94.69 A

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

The inhibition of mPGES-1 enzyme in the A549 cell line was monitored as inhibition of IL-Ιβ induced PGE₂ release. A549 cells were maintained in DMEM medium with 10% FBS and 1% Penicillin-Streptomycin Solution in 5% C0₂ 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. The assay was carried out in a total volume of 200 μΕ. Test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare 2 mM stock solution and then diluted using plain DMEM. The 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 and analyzed by the addition of PGE₂-D2 and anti-PGE₂ cryptate conjugate supplied by the CisBio HTRF kit in a 96 well half area blackwell EIA/RIA plate. The assay plate was incubated overnight at 4-5° C before being read in an Artemis (K-101) (Japan) HTRF plate reader and levels of PGE₂ calculated by extrapolation from the standard curve.

The concentration response curves were plotted as a percentage (%) of maximal response obtained in the absence of test antagonist. The IC₅₀ value was calculated from the concentration response curve by nonlinear regression analysis using GraphPad PRISM software.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I)

(I)

or a pharmaceutically acceptable salt thereof,

wherein,

W is selected from Ci_-8alkyl, Ci_-8alkoxyCi_-8alkyl, haloCi_-8alkyl, hydroxyCi. 8alkyl, carboxylCi_-8alkyl, C3-i₂cycloalkyl and 3 to 15 membered heterocyclyl;

each occurrence of R^x and R^y, which may be the same or different, are independently selected from hydrogen, Ci_-8alkyl and C6-i₄arylCi_-8alkyl;

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

2. The compound according to claim 1, wherein Q¹ is CH or CR⁴, Q² is CH, Q³ is N or CH, and Q⁴ is CR⁴.

3. The compound according to claim 1 or 2, wherein each occurrence of R⁴ is independently selected from CH₃, CF₃, CHF₂, CI and F.

4. The compound according to any one of claims 1 to 3, wherein R¹ is isopropyl, tert-butyl, 2,4,4-trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, K)-3,3-dimethylbutan- 2-yl, (S)-3,3-dimethylbutan-2-yl, cyclohexyl, 4,4-dimethylcyclohexyl, 4- (trifluoromethyl)cyclohexyl, (ls,4s)-4-(trifluoromethyl)cyclohexyl, 4- (trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl or 6-(trifluoromethyl)pyridin-3-yl.

5. The compound according to any one of claims 1 to 4, wherein R² is hydrogen or methyl.

6. The compound according to any one of claims 1 to 5, wherein R³ is methyl or absent.

7. The compound according to any one of claims 1 to 6, wherein n is 1.

8. The compound according to any one of claims 1 to 7, wherein R^x and R^y are hydrogen.

9. The compound according to any one of claims 1 to 8, wherein W is isopropyl, ie/ -butyl or l-fluoro-2-methylpropan-2-yl.

10. The compound according to claim 1, wherein

Q¹ is CH or CR⁴;

Q² is CH;

Q³ is N or CH;

Q⁴ is CR⁴;

R¹ is isopropyl, ie/t-butyl, 2,4,4-trimethylpentan-2-yl, 3,3-dimethylbutan-2- yl, (R)-3,3-dimethylbutan-2-yl, (S)-3,3-dimethylbutan-2-yl, cyclohexyl, 4,4- dimethylcyclohexyl, 4-(trifluoromethyl)cyclohexyl, (ls,4s)-4- (trifluoromethyl)cyclohexyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl or 6-(trifluoromethyl)pyridin-3-yl;

R² is hydrogen or methyl;

R³ is methyl or absent;

each occurrence of R⁴ is independently CH₃, CF₃, CHF₂, CI or F;

n is 1 ;

R^x is hydrogen;

R^y is hydrogen; and

W is isopropyl, ie/t-butyl or l-fluoro-2-methylpropan-2-yl.

1 1. A compound of the formula (II)

or a pharmaceutically acceptable salt thereof,

wherein,

W is selected from Ci-salkyl, Ci-salkoxyCi-salkyl, haloCi-salkyl, hydroxyCi. salkyl, carboxylCi-salkyl, C₃-i₂cycloalkyl and 3 to 15 membered heterocyclyl;

R¹ is selected from Ci-salkyl, Ci-salkoxyCi-salkyl, haloCi-salkyl, hydroxyCi. salkyl, carboxylCi-salkyl, C₃-i₂cycloalkyl, C6-i₄ ryl,

3-15 membered heterocyclyl, 3-15 membered heterocyclylCi-salkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi-salkyl;

R² is selected from hydrogen, and Ci-salkyl;

R³ is selected from hydrogen and Ci-salkyl; and

each occurrence of R⁴ is independently selected from halogen, nitro, cyano, hydroxyl, Ci-salkyl, Ci-salkoxy, Ci-salkoxyCi-salkyl, haloCi-salkyl, hydroxyCi-salkyl, C₃-i₂cycloalkyl and

12. The compound according to claim 1 1, wherein Q¹ is CH or CR⁴, Q² is CH, Q³ is N or CH, and Q⁴ is CR⁴.

13. The compound according to claim 1 1 or 12, wherein each occurrence of R⁴ is independently selected from CH₃, CF₃, CHF₂, CI and F.

14. The compound according to any one of claims 1 1 to 13, wherein R¹ is isopropyl, ie/ -butyl, 2,4,4-trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (R)-3,3- dimethylbutan-2-yl, (S)-3,3-dimethylbutan-2-yl, cyclohexyl, 4,4-dimethylcyclohexyl, 4-(trifluoromethyl)cyclohexyl, (l5,45)-4-(trifluoromethyl)cyclohexyl, 4-

(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl or 6-(trifluoromethyl)pyridin-3-yl.

15. The compound according to any one of laims 1 1 to 13 wherein R¹ is

16. The compound according to any one of claims 1 1 to 15, wherein R² and R³ are methyl.

17. The compound according to any one of claims 1 1 to 16, wherein W is isopropyl, ie/t-butyl or l-fluoro-2-methylpropan-2-yl.

18. The compound according to claim 1 1, wherein

Q¹ is CH or CR⁴;

Q² is CH;

Q³ is N or CH;

Q⁴ is CR⁴;

(trifluoromethyl)cyclohexyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl or

6- (trifluoromethyl)pyridin-3-yl;

R² is methyl;

R³ is methyl;

each occurrence of R⁴ is independently CH₃, CF₃, CHF₂, CI or F; and

W is isopropyl, ie/ -butyl or l-fluoro-2-methylpropan-2-yl.

19. A compound selected from

2-Chloro-N-(2-cyclohexyl-4,4-dimethyl- 1 -oxo- 1 ,2,3 ,4-tetrahydroisoquinolin-

7- yl)-5-(pivalamidomethyl)benzamide;

2-Chloro-N-(2-(4,4-dimethylcyclohexyl)-4,4-dimethyl- 1 -oxo- 1 ,2,3,4- tetrahydroisoquinolin-7-yl)-5-(pivalamidomethyl)benzamide;

6-Chloro-N-(2-(4,4-dimethylcyclohexyl)-4,4-dimethyl- 1 -oxo- 1 ,2,3,4- tetrahydroisoquinolin-7-yl)-2-fluoro-3-(isobutyramidomethyl)benzamide;

2-(Difluoromethyl)-N-(2-(4,4-dimethylcyclohexyl)-4,4-dimethyl-l-oxo- l,2,3,4-tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)nicotinamide; 6-Chloro-N-(2-(4,4-dimethylcyclohexyl)-4,4-dimethyl- 1 -oxo- 1 ,2,3 ,4- tetrahydroisoquinolin-7-yl)-2-fluoro-3-((3-fluoro-2,2- dimethylpropanamido)methyl)benzamide;

N-(2-(4,4-dimethylcyclohexyl)-4,4-dimethyl- 1 -oxo- 1 ,2,3 ,4- tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)-2-methylnicotinamide;

2-Chloro-N-(2-(4,4-dimethylcyclohexyl)-4,4-dimethyl- 1 -oxo- 1 ,2,3 ,4- tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)benzamide;

N-(2-(tert-butyl)-4,4-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinolin-7-yl)-2- chloro-5-(isobutyramidomethyl)benzamide;

2-Chloro-N-(2-(4,4-dimethylcyclohexyl)-l -oxo-1, 2-dihydroisoquinolin-7-yl)- 5-(pivalamidomethyl)benzamide;

2-Chloro- V-(2-isopropyl- 1 -oxo- 1 ,2-dihydroisoquinolin-7-yl)-5- (pi val ami domethy l)b enzami de;

N-(2-(tert-butyl)-l-oxo-l,2-dihydroisoquinolin-7-yl)-2-chloro-5- (pi val ami domethy l)b enzami de;

2-(Difluoromethyl)-N-(4,4-dimethyl-l-oxo-2-(3-(trifluoromethyl)phenyl)- l,2,3,4-tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)nicotinamide;

2-(Difluoromethyl)-N-(4,4-dimethyl-l-oxo-2-(2,4,4-trimethylpentan-2-yl)- l,2,3,4-tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)nicotinamide;

2-(Difluoromethyl)-iV-(4,4-dimethyl-l-oxo-2-((ls,4s)-4- (trifluoromethyl)cyclohexyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)-5- (isobutyramidomethyl)nicotinamide;

2-(Difluoromethyl)-N-(4,4-dimethyl-l-oxo-2-(4-(trifluoromethyl)phenyl)- l,2,3,4-tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)nicotinamide;

( ?)-2-(difluoromethyl)-N-(2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-l-oxo- l,2,3,4-tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)nicotinamide;

2-(Difluoromethyl)-N-(4,4-dimethyl-l-oxo-2-(6-(trifluoromethyl)pyridin-3- yl)-l,2,3,4-tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)nicotinamide;

(S)-2-(difluoromethyl)-N-(2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-l-oxo- l,2,3,4-tetrahydroisoquinolin-7-yl)-5-(isobutyramidomethyl)nicotinamide;

and pharmaceutically acceptable salts thereof.

20. A compound of the formula

or a pharmaceutically acceptable salt thereof.

21. A compound selected from

7-amino-4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin- l(2H)-one;

4,4-dimethyl-7-nitro-2-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin- l(2H)-one;

and pharmaceutically acceptable salts thereof.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable excipient.

23. The pharmaceutical composition according to claim 22, wherein the pharmaceutically acceptable excipient is a carrier or diluent.

24. A method of treating a mPGES-1 mediated disease, disorder or syndrome in a subject comprising administering an effective amount of a compound according to any one of claims 1 to 20.

25. A method of treatment of disease, disorder, syndrome or condition selected from the group consisting of inflammation, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, pain, inflammatory pain, chronic pain, acute pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections, influenza, common cold, herpes zoster, hepatitis C, AIDS, bacterial infections, fungal infections, dysmenorrhea, burns, pain associated with surgical or dental procedures, dental pain, malignancies hyperprostaglandin E syndrome, classic Bartter syndrome, synovitis, 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, cancer, neurodegenerative disorders, autoimmune diseases, multiple sclerosis, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary heart disease, and sarcoidosis comprising administering a compound according to any one of claims 1 to 20.

26. The method according to claim 25, wherein the disease, disorder, syndrome or condition is pain.

27. The method according to claim 25, wherein the disease, disorder, syndrome or condition is chronic or acute pain.

28. The method according to claim 25, wherein the disease, disorder, syndrome or condition is rheumatoid arthritic pain, osteoarthritic pain or dental pain

29. The method according to claim 25, wherein the disease, disorder, syndrome or condition is inflammation, asthma or chronic obstructive pulmonary disease.

30. The method according to claim 25, wherein the disease, disorder, syndrome or condition is a neurodegenerative disorder selected from Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis.

31. A method of treating, preventing or managing cancer comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 20.

32. A process for preparing a compound of formula (II)

(II)

or a pharmaceutically acceptable salt thereof, which comprises: reacting a compound o formula (3) with a compound of formula (4) to form a compound of formula (II):

wherein, Q¹, Q², Q³ and Q⁴, which may be same or different, are independently selected from N, CH and CR⁴; with a proviso that Q², Q³ and Q⁴ are not N simultaneously;

R² is selected from hydrogen, and Ci_-8alkyl;

R³ is selected from hydrogen and Ci_-8alkyl;

each occurrence of R⁴ is independently selected from halogen, nitro, cyano, hydroxyl, Ci_-8alkyl, Ci_-8alkoxy, Ci_-8alkoxyCi_-8alkyl, haloCi_-8alkyl, hydroxyCi_-8alkyl, C_3-i₂cycloalkyl and C_3-8cycloalkylCi_-8alkyl and

LG represent OH or CI or Br or O-alkyl or O-aiyl or 0(C=0)-alkyl)

33. The process according to claim 32, wherein LG is OH.

34. The process according to claim 33, wherein a compound of formula (3) is reacted with a compound of formula (4) using a coupling reagent in DCM, dimethylformamide (DMF) or tetrahydrofuran (THF) and optionally in the presence of a base.

35. The process according to claim 34, wherein coupling reagent is PyBOP (benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate) and base is N,N-diisopo ylethylamine (DIPEA).

36. The process according to claim 33, wherein a compound of formula (3) is reacted with a compound of formula (4) using isobutyl chloroformate, oxalyl chloride or thionyl chloride in DMF, DCM or THF, in the presence of DIPEA or Et₃N.

37. The process according to claim 33, wherein a compound of formula (3) is reacted with a compound of formula (4) using PyBOP (benzotriazol-l-yl- oxy)tripyrrolidinophosphonium hexafluorophosphate and DIPEA in DMF.