MX2013003362A - Matrix metalloproteinase inhibitors. - Google Patents

Abstract

The present invention relates to methyl sulfonamides and N-formamides derivatives of formula (I) and to processes for their syntheses. The invention also relates to pharmacological compositions containing these derivatives and methods of treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatie arthritis, psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, neointimal proliferation which leads to restenosis and ischemic heart failure, stroke, renal disease, tumor metastasis, and other inflammatory disorders characterized by over expression and over activation of an matrix metalloproteinase using the compounds.

Description

MATRIX METALOPROTEINASE INHIBITORS Field of the Invention The present invention relates to derivatives of methyl sulfonamides and N-formamides and to processes for their synthesis. The invention also relates to pharmaceutical compositions containing the compounds of the present invention and methods for treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, lung inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, neointima proliferation leading to restenosis and ischemic heart failure, stroke, kidney disease, tumor metastasis and other inflammatory disorders characterized by over-expression and over-activation of a matrix metalloproteinase using the compounds Background of the Invention Metalloproteinases (MMPs) are a naturally occurring superfamily of proteinases (enzymes) found in most mammals. The superfamily is composed of at least 26 members of zinc-containing enzymes produced by many cell types and that share structural and functional characteristics. Based on structural and functional considerations, proteinases have been classified into different families and subfamilies (Vartak et al., J. Drug Targeting, 15, pages 1-20 (2007) and Hopper, FEBS, 354, pages 1-6 (1994)). , such as collagenases (MMP-1, -8 and -13), gelatinases (MP-2 and -9), metalloelastases (MMP-12), MT-MMPs (MMP-14, -15, -16, -17 , -24 and -25), matrilysins (MMP-7 and -26), stromelysins (MMP-3, -10 and -11) and shedasas such as enzymes that convert TNF (TACE and ACE).

Metalloproteinases are believed to be important in the processes of physiological disease involving remodeling, such as respiratory diseases, embryonic development, bone formation and uterine remodeling during menstruation. A major biological function of MMPs is to catalyze the decomposition of connective tissues or extra-cellular matrix by their ability to hydrolyze various tissue or matrix components. Apart from its role in degrading the connective tissue, MMPs are involved in the activation of (pro) forms of zymogen from other MMPs in order to induce the activation of MMP. They are also involved in the biosynthesis of TNF-alpha that is involved in many pathological conditions.

MMP-9, which belongs to the gelatinase family, plays a major role in chronic inflammatory disorders similar to COPD, asthma and rheumatoid arthritis. The concentration of MMP-9 has been reported to be increased in asthma-like diseases, interstitial pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS) and in chronic obstructive pulmonary disease (COPD). Because of its proteolytic ability, MMP-9 has been implicated in the remodeling of airway and lung tissue in chronic inflammatory diseases, such as severe asthma and COPD. MMP-9 is also likely to be physiologically important due to its ability to regulate the digestion of extracellular matrix components as well as the activity of other proteases and cytokines. MMP-9 is secreted in neutrophils, macrophages, osteoclasts, which are easily induced by cytokines and growth factors and play a role in various physiological and pathological processes.

MMP-12, also known as macrophage elastase or metalloelastase, is expressed in activated macrophages and has been shown to be secreted from alveolar macrophages of smokers as well as in foam cells in atherosclerotic lesions. The MMP-12 blocked mouse studies have shown the development of significant emphysema, thus supporting its function in COPD. MMP-9 (gelatinase B, type IV 92 kDa collagenase) is a member of the MMP family that is released as a proenzyme and is subsequently activated via a protease cascade in vivo.

Overexpression or over-activation of an MMP, or an imbalance between a MMP and a natural (ie, endogenous) tissue inhibitor of a matrix metalloproteinase (TIMP) has been linked to a pathogenesis of diseases characterized by decomposition of the connective tissue or extracellular matrix.

Inhibition of the activity of one or more MMPs may be of benefit in the treatment of various inflammatory, autoimmune and allergic diseases such as, joint inflammation, GI tract inflammation, skin inflammation, collagen remodeling, healing disorders. of wounds, etc.

The design and the therapeutic application of the MMP inhibitors have revealed that the requirement of a molecule that is an effective inhibitor of the MMP class of enzymes is a functional group (eg carboxylic acid, hydroxamic acid or sulfhydryl) capable of chelating the active site Zn2 + ion (Whittaker et al., Chem. Rev., 99; pages 2735-76 (1999).

Document O 95/35276 discloses the JV-substituted arylsulfonyl amino acid and its hydroxamic acid derivatives as matrix metalloproteinase inhibitors. WO 00/06561 discloses tricyclic sulfonamide compounds as matrix metalloproteinases. U.S. Patent No. 6,366,675 discloses N-sulfonyl diamine: carboxylic acid derivatives used as matrix metalloprotease inhibitors. Document O 2004/113279 discloses substituted glycine derivatives useful for treating inflammatory conditions or autoimmune disorders as matrix metalloproteinase inhibitors.

Research has been carried out on the identification of inhibitors that are selective, for example, for a few of the MMP subtypes. An MMP inhibitor of improved selectivity would avoid potential side effects associated with the inhibition of MMPs that are not involved in the pathogenesis of the disease being treated.

In addition, the use of more selective MMP inhibitors would require the administration of a lower amount of the inhibitor for the treatment of the disease than would otherwise be required and, after administration, divided in vivo between multiple MMPs. Still further, administration of a lower amount of the compound would improve the safety margin between the dose of the inhibitor required for the therapeutic activity and the dose of the inhibitor at which the toxicity is observed.

Many drugs exist as asymmetric three-dimensional molecules, that is, chiral and therefore will have several stereoisomers depending on the number of chiral centers present. The importance of evaluating new chemical entities that have chiral centers as individual isomers is to understand their effect in pharmacological and toxicological aspects. Frequently there are pharmacodynamic, pharmacokinetic and / or toxicological differences between the enantiomers / diastereomers. Even if the natural physiological mediators are achiral, based on their target environment, their receptors / enzymes may demonstrate a preference for only an optically pure enantiomer of agonists, antagonists or inhibitors. From a pharmacokinetic point of view, chirality can have an influence on drug absorption, distribution, metabolism and elimination. Pure individual isomers may also offer advantages in terms of these pharmacokinetic parameters thus allowing greater capacity for development of such molecules as drug candidates. It is also known that chirality has a significant effect of the physicochemical properties and crystallinity of a chiral molecule which in turn has profound effects on the pharmacokinetics and capacity for the development of the molecule. In addition to those mentioned in the foregoing, the regulatory principles guide the development of preferably individual isomers as drug candidates to avoid any pharmacological, pharmacokinetic and toxicological problems that may arise due to the interactions of an unwanted isomer with undesirable molecular targets.

In this context, synthetic strategies for producing pure individual isomers offers advantages over analytical techniques of isomer separation not only in terms of cost and efficiency but larger quantities of the compound can be prepared to make the pharmaceutical test. In this manner, the compounds of the present invention, which are individual chiral isomers, have improved potency, improved pharmacokinetic and / or physicochemical properties as compared to the racemic compounds.

The present invention is directed to overcome the problems encountered in the art.

Brief Description of the Invention The present invention provides the methyl sulfonamide derivatives and formamides as inhibitors of matrix metalloproteinase, corresponding processes for the synthesis of and pharmaceutical compositions containing the compounds of the present invention. The present invention relates to matrix metalloproteinase inhibitors useful as effective therapeutic or prophylactic agents in the treatment of various inflammatory, autoimmune and allergic diseases and other inflammatory disorders characterized by over-expression and over-activation of a matrix metalloproteinase using the compounds The present invention discloses a novel class of compounds that are double MMP9 / 12 inhibitors and have desirable activity profiles. The compounds of this invention have beneficial potency and / or selectivity.

Pharmaceutical compositions containing such compounds are provided together with pharmaceutically acceptable carriers or diluents, which can be used for the treatment or prevention of inflammatory and autoimmune diseases. These pharmaceutical compositions can be administered or co-administered by a wide variety of routes including, for example, oral, topical, rectal, intranasal or parenteral route. The composition can also be administered or co-administered in slow release dosage forms.

Algh, the specific enantiomers have been shown by way of example, racemates, diastereomers and pharmaceutically acceptable salts are also provided. Also included are pharmaceutical compositions comprising the compounds, their enantiomers, racemates, diastereomers and pharmaceutically acceptable salts.

The therapeutically effective amount of one or more compounds of the present invention can be used in combination with one or more other therapeutic agents, for example, other anti-inflammatory agents, antihypertensive agents and immunosuppressive agents.

Other objects will be set forth in the accompanying description and in part will be apparent from the description or may be by the practice of the invention.

Detailed description of the invention According to one aspect, compounds having the structure of Formula I are provided: Formula I which includes racemates, enantiomers, or diastereomers thereof; or a pharmaceutically acceptable salt thereof, wherein, L1 can be selected from the bond, 0, S, CH2, NR4, NHC0 (CH2) n, (CH2) nC0NH, NHCONH, S02NH, NHS02, NHCO (O), -0- (CH2) n, - (CH2) n -0-, -0C (0) NH-, C (S) NH, NHC (S), NHC (S) NH or -C00- where n can be zero or an integer between 1 and 2; R1 can be selected from hydrogen, C6-C6 alkyl, hydroxyl, Ci-C6 alkoxy, cyano, nitro, halogen, | halogen-Ci-C6 alkyl, C5-Ci2 aryl, C6-C12 heteroaryl, cycloalkyl C3-C6 wherein aryl, heteroaryl, cycloalkyl is optionally substituted by one or more substituents independently selected from R5; R2 can be CHO or S02-Ci-C6 alkyl; R3 can be unsubstituted or substituted heteroaryl or -OCONHR 'where R' is C6-Ci2 aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl each of which is optionally substituted by one or more independently selected substituents of R5; R 4 can be H or C 1 -C 6 alkyl; R5 can be selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogen-C1-C6 alkyl, halo-Ci-C6 alkoxy, azido, thiol, alkylthiol, - (CH2) n_ORf, -C (= 0 ) -Rf, -COORf, -NRfRq, - (CH2) nC (= 0) NRfRq, - (CH2) n -NHC (= 0) Rf, - (CH2) n-0-C (= 0) -NRfRq, (CH2) nNHC (= 0) NRfRq, - (CH2) n-0-C (= 0) -Rf, - (CH2) n-NH-C (= 0) -Rf or - (CH2) nS (= 0 ) m-NRfRq. { wherein R £ and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined above and m is an integer of 0-2} .

One aspect of the invention encompasses compounds that include, for example, 2- [Formyl (4'-methyl-biphenyl-4-yl) amino] -4- (6-methyl-4-oxo-1,2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. . 1); 4- (7-Chloro-4-oxo-1,2,3-benzotriazin-3 (4 #) -yl) -2- [formyl (4'-methyl-biphenyl-4-yl) -amino] -butanoic acid (Compound no. 2 ); 2- [(4'-Ethylbiphenyl-4-yl) (formyl) amino] -4- (5-methyl-4-oxo-l, 2,3-benzotriazin-3 (4)) -yl) butanoic acid (Compound no. . 3); O- [(4-Fluorophenyl) carbamoyl] -N-formyl- (4 '-methyl-bi-phenyl-4-yl) homoserine (Compound No. 4); W-Formyl-W- (4 '-methylbiphenyl-4-yl) -0- [(4-methylphenyl) -carbamoyl] homoserine (Compound No. 5); 0- [(3,4-Dichlorophenyl) carbamoyl] -W-formyl-N- (4 '-methylbiphenyl-4-yl) homoserine (Compound No. 6); AJ- (4'-Ethylbiphenyl-4-yl) -N-formyl-0-. { [4- (propan-2-yl) -phenyl] carbamoyl} homoserin (Compound No. 7); N- (4'-Ethylbiphenyl-4-yl) -0- [(3-fluorophenyl) carbamoyl] -N-formylhomoserin (Compound No. 8); 0- [(2,4-Difluorophenyl) carbamoyl] -N- (4'-ethylbifeni1-4-i1) -N-formylhomoserin (Compound No. 9); N- (4'-ethylbiphenyl-4-yl) -0- [(2-fluorophenyl) carbamoyl] -N-formylhomoserin (Compound 10); N- (4'-Ethylbiphenyl-4-yl) -N-formyl-O-. { [4- (trifluoromethyl) -phenyl] carbamoyl} Homoserine (Compound No. 11); 7- (4'-Ethylbiphenyl-4-yl) -W-formyl-O- [(2-methylphenyl) -carbamoyl] homoserine (Compound No. 12); N- (4'-Ethylbiphenyl-4-yl) -0- [(4-ethylphenyl) carbamoyl] -A7-formylhomoserine (Compound No. 13); N- (4'-Ethylbiphenyl-4-yl) -N-formyl-O- [(4-methoxyphenyl) -carbamoyl] homoserine (Compound No. 14); O- [(2,6-Dichlorophenyl) carbamoyl] -N- (4'-ethylbiphenyl-4-yl) -N-formylhomoserine (Compound No. 15); 2- [Biphenyl-4-yl (methylsulfonyl) amino] -4- (1,3-dioxo-1,3-dihydro-2f / -isoindol-2-yl) butanoic acid (Compound No. 16); 4- (1, 3-dioxo-l, 3-dihydro-2tf-isoindol-2-yl) -2- acid. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} -butanoic (Compound No. 17); 4- (1, 3-dioxo-l, 3-dihydro-2íí-isoindol-2-yl) -2- [(4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] butanoic acid (Compound No. 18); Acid 2-. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 19); 4- (7-Methoxy-4-oxo-l, 2,3-benzotriazin-3 (4J?) -yl) -2 acid. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} -butanoic (Compound No. 20); Acid 2-. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} -4- [4-oxo-7- (trifluoromethyl) -1,2,3-benzotriazin-3 (4H) -yl] butanoic (Compound No. 21); 4- (1, 3-dioxo-l, 3-dihydro-2tf-isoindol-2-yl) -2- acid. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} -butanoic (Compound No. 22); 4- (6-Methoxy-4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) -2. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} butanoic (Compound No. 23); 4- (7-Methyl-4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) -2- acid. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} butanoic (Compound No. 24); Acid 2-. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} -4- [-OXO-7- (trifluoromethyl) -1,2,3-benzotriazin-3 (4H) -yl] -butanoic acid (Compound No. 25); Acid 2-. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} -4- (-oxo-l, 2, 3-benzotriazin-3 (H) -yl) butanoic (Compound No. 26); 2- [(3 ', 4' -difluorobiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (H) -yl) butanoic acid (Compound no. 27); 2- [(4'-Ethylbiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 28); Acid 2-. { [4- (2-methoxypyrimidin-5-yl) phenyl] (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4 H) -yl) -butanoic acid (Compound No. 29); 2- [(3'-Fluoro-4 '-methylbiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic acid ( Compound No. 30); 2- [(2 ', 4'-dimethoxybiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2, 3-benzotriazin-3. {H) -yl) butanoic acid ( Compound No. 31); 2- [(4-Methoxyphenyl) (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 32); 4- (7-Methoxy-4-oxo-1,2,3-benzotriazin-3 (4 H) -yl) -2- [(4-methoxyphenyl) (methylsulfonyl) amino] butanoic acid (Compound No. 33); 4- (1, 3-Dioxo-1,3-dihydro-2-t-isoindol-2-yl) -2- [(4-methoxyphenyl) (methylsulfonyl) amino] butanoic acid (Compound No. 34); 2- [(4-Methoxyphenyl) (methylsulfonyl) amino] -4- (5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindo-2-yl) butanoic acid (Compound No. 35); 4- (7-Methoxy-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -2- acid. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} butanoic (Compound No. 36); 4- (5-Methyl-l, 3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) -2- acid. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} butanoic (Compound No. 37); 2- t (3'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4-yl) -yl) butanoic acid (Compound No. 38); 2- [(4'-Fluorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 39); Acid 2-. { (methylsulfonyl) [4 '- (propan-2-yl) ifenyl-4-yl] -amino} -4- (-oxo-l, 2, 3-benzotriazin-3 (AH) -yl) butanoic (Compound No. 40); 2- [Biphenyl-4-yl (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 41); Acid 2-. { [4- (6-methylpyridin-3-yl) phenyl] (methylsulfonyl) -amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 42); Acid 2-. { (methylsulfonyl) [4- (pyrimidin-5-yl) phenyl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4) -yl) butanoic (Compound No. 43); Acid 2-. { (Methylsulfonyl) [4- (pyridin-3-yl) phenyl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 44); Acid 2-. { (methylsulfonyl) [4 '- (trifluoromethyl) biphenyl-4-yl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4 f) -yl) butanoic (Compound No. 45); Acid 2-. { (methylsulfonyl) [4- (pyridin-4-yl) phenyl] amino} -4- (-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 46); 2- [(3 ', 4'-Dichlorobiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 47); 2- [(4'-tert-Butylbiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 48) ); 2- [(2 ', 3' -difluorobiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4 H) -yl) butanoic acid (Compound No. 49); 2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -butanoic acid ( Compound No. 50); 4- (1, 3-dioxo-l, 3-dihydro-2tf-isoindol-2-yl) -2- acid. { (methylsulfonyl) [4- (propan-2-yl) phenyl] amino} butanoic (Compound No. 51); 4- (6-Methoxy-oxo-l, 2,3-benzotriazin-3 (H) -yl) -2- acid. { (methylsulfonyl) [4- (propan-2-yl) phenyl] amino} butanoic (Compound No. 52); 4- (7-Methyl-4-oxo-l, 2, 3-benzotriazin-3 (H) -yl) -2- acid. { (methylsulfonyl) [4- (propan-2-yl) phenyl] amino} butanoic (Compound No. 53); 4- (1, 3-Dioxo-1,3-dihydro-2-fluoro-isoindol-2-yl) -2- [(4-ethylphenyl) (methylsulfonyl) amino] butanoic acid (Compound No. 54); 2- [(4-Ethylphenyl) (methylsulfonyl) amino] -4- (5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) butanoic acid (Compound No. 55); 2- [(4-Ethylphenyl) (methylsulfonyl) amino] -4- (7-methyl-4-oxo-1,2,3-benzotriazin-3 (4J7) -yl) butanoic acid (Compound No. 56); 2- [(4-Ethylphenyl) (methylsulfonyl) amino] -4- (6-methoxy-4-oxo-l, 2,3-benzotriazin-3 (H) -yl) butanoic acid (Compound No. 5); 2- [(Methylsulfonyl) (phenyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 58); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (5-methyl-1,3-dioxo-1,3-dihydro-2-yl-isoindol-2-yl) butanoic acid (Compound No. 59); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (5-chloro-4-oxo-l, 2,3-benzotriazin-3 (4 H) -yl) butanoic acid (Compound No. 60); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (7-chloro-4-oxo-l, 2,3-benzotriazin-3 (4tf) -i1) butanoic acid (Compound no. 61); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (7-methyl-4-oxo-l, 2,3-benzotriazin-3 (4H) -i1) butanoic acid (Compound no. 62); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- [4-γ-7- (trifluoromethyl) -1,2, 3-benzotriazin-3 (4H) -yl] - butanoic (Compound No. 63); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (5-methoxy-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 64); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (5-fluoro-4-oxo-l, 2,3-benzotriazin-3 (H) -yl) butanoic acid (Compound no. 65); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (1-methyl-2, -dioxo-1,4-dihydroquinazolin-3 (2H) -yl) -butanoic acid (Compound no. 66); 4- Acid. { (methylsulfonyl) [l-oxo-4- (4-oxo-l, 2, 3-benzo-triazin-3 (4H) -yl) -1- (prop-2-en-l-yloxy) butan-2- il] amino} -benzoic (Compound No. 67); 2- [. { 4- [(4-methylphenyl) carbamoyl] phenyl} (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4i) -yl) -butanoic acid (Compound No. 68); Acid ° 2- [. { 4- [(4-chlorophenyl) carbamoyl] phenyl} (methyl-sulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) -butanoic acid (Compound No. 69); Acid 2-. { (methylsulfonyl) [4- (phenylcarbamoyl) phenyl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 70); 2- [. { 4- [(3-fluorophenyl) carbamoyl] phenyl} (methyl-sulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4 f) -yl) -butanoic acid (Compound No. 71); 2- [(Methylsulfonyl) (4. {[[4- (propan-2-yl) phenyl] -carbamoyl}. Phenyl) amino] -4- (4-oxo-l, 2,3-benzotriazine) 3 (4H) -yl) butanoic (Compound No. 72); 2- [. { 4- [(4-methoxyphenyl) carbamoyl] phenyl} (methyl-sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4i /) -yl) -butanoic (Compound No. 73); 2- [. { 4- [(4-fluorophenyl) carbamoyl] phenyl} (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4 f) -yl) -butanoic acid (Compound No. 74); 2- [(Methylsulfonyl) (4- {[4- (trifluoromethyl) phenyl] carbamoyl] phenyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) | il) butanoic (Compound No. 75); (2R) -2- [(4'-Fluorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 76); Acid (2R) -2-. { (methylsulfonyl) [4- (pyrimidin-5-yl) phenyl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 77); Acid (2R) -2-. { (methylsulfonyl) ['- (propan-2-yl) biphenyl-4-yl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4 H) -yl) utanoic (Compound No. 78); [2R) -2- [(3 ',' -dichlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid ( Compound No. 79); Acid (2R) -2- [(3 ',' -difluorobiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) - butanoic (Compound No. 80); (2R) -2- [(3'-Fluoro-4 '-methylbiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) - il) -butanoic (Compound No. 81); (2R) -2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 82); (2R) -2- [(3'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) utanoic acid (Compound no. 83); (2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) - il) -butanoic (Compound No. 84); Acid { 2R) -2- [biphenyl-4-yl (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) -butanoic acid (Compound No. 85); Acid { 2R) -2-. { [4- (6-methoxypyridin-3-yl) phenyl] (methyl sulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4i?) -yl) -butanoic acid (Compound No. 86); (2S) -2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 87); (2S) -2- [(3 ',' -dichlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4 H) -yl) butanoic acid (Compound No. 88); (2S) -2- [(3'-Fluoro-4 '-methylbiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2, 3-benzotriazin-3 (4tf) - il) -butanoic (Compound No. 89); (2S) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methyl-sulphonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4? ) -yl) -butanoic (Compound No. 90); Acid { 2R) -2- [(3 ', 4'-dimethoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4tf) -yl) -butanoic ( Compound No. 91); Acid (2R) -2-. { [4- (2, 3-dihydro-l, 4-benzodioxin-6-yl) phenyl] (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 92); Acid { 2R) -2- [(4'-methoxy-3 '-methylbiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (H) -yl) -butanoic (Compound No. 93); (2R) -2- [(4'-Fluoro-3'-methylbiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (H) - il) -butanoic (Compound No. 94); Acid (2R) -2-. { (methylsulfonyl) [4 '- (trifluoromethoxy) biphenyl-4-yl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4i) -yl) butanoic (Compound No. 95); Acid (2R) -2-. { [4'-chloro-3 '- (trifluoromethyl) biphenyl-4-yl] (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (H) -yl) butanoic (Compound No. 96); Acid (2R) -2- [(3'-Fluoro-4 '-methoxybiphenyl-4-yl) (methyl sulfonyl) amino] -4- [4-oxo-7- (trifluoromethyl) -1,2,3-benzo -triazin-3 (4) -yl] butanoic (Compound No. 97); (2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methyl sulfonyl) amino] -4- (8-methyl-4-oxo-l, 2,3-benzotriazin-3) - (4H) -yl) butanoic (Compound No. 98); (2R) -4- (7-Chloro-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -2- [(3'-fluoro-4'-methoxybiphenyl-4-yl) ( methylsulfonyl) -amino] butanoic (Compound No. 99); Acid (2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (7-methoxy-4-oxo-l, 2,3-benzotriazin-3-) (4H) -yl) butanoic (Compound No. 100); Acid \ 2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methyl-sulfonyl) amino] -4- (6-methyl-4-oxo-l, 2,3-benzotriazin- 3- (4H) -yl) butanoic (Compound No. 101); Acid [2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methyl-sulfonyl) amino] -4- (8-methoxy-4-oxo-l, 2,3-benzotriazin- 3- (4H) -yl) butanoic (Compound No. 102); (2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (6-fluoro-4-oxo-l, 2,3-benzotriazin-3-) '(4H) -yl) butanoic (Compound No. 103); 4- (5-Chloro-4-oxo-l, 2, 3-benzotriazin-3 (4tf) -yl) -2- [(4-chlorophenyl) (methylsulfonyl) amino] butanoic acid (Compound No. 104); 2- [(4-Bromophenyl) (methylsulfonyl) amino] -4- (-oxo-1,2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 105); 2- [(4-Chlorophenyl) (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (fí) -yl) butanoic acid (Compound no. 106); 2- [(4-Chlorophenyl) (methylsulfonyl) amino] -4- (7-methyl-4-oxo-l, 2,3-benzotriazin-3 (H) -yl) butanoic acid (Compound No. 107); 2- [(4-Chlorophenyl) (methylsulfonyl) amino] -4- (6-methoxy-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 108).

In another aspect, there are provided herein pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds, described herein, together with one or more pharmaceutically acceptable carriers, excipients or diluents.

In another aspect, methods are provided herein for treating or prophylaxis of an animal or a human suffering from various inflammatory or allergic diseases, which comprises administering to a mammal in need thereof a therapeutically effective amount of one or more compounds of Formula 1, described herein.

In one embodiment, the diseases or conditions of inflammation and associated pathologies are selected from asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, lung inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis, gingivitis. , atherosclerosis, dry eye, neointima proliferation leading to restenosis and ischemic heart failure, stroke, kidney disease, tumor metastasis and other inflammatory disorders.

In yet another aspect, the present invention relates to the therapeutically effective amount of compounds of Formula I in combination with one or more other therapeutic agents used in treating various inflammatory and allergic diseases. Examples of such therapeutic agents include, but are not limited to, 1) anti-inflammatory, experimental or commercial agents (i) such as non-steroidal anti-inflammatory agents of piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, kinase / cathepsin inhibitors of MAP PDE-4 / p38, (ii) inhibitors LTC4 / LTD4 / LTE4 / LTB4 of leukotrienes, 5-lipoxygenase inhibitor and PAF receptor antagonists, (iii) Cox-2 inhibitors, (iv) MP inhibitors and (v) interleukin-I inhibitors; 2) antihypertensive agents, (i) ACE inhibitors, for example enalapril, lisinopril, valsartan, telmisartan and quinapril, (ii) angiotensin II receptor antagonists and agonists, for example losartan, candesartan, irbesartan, valsartan and eprosartan, (iii) ) ß-blockers and (iv) calcium channel blockers. 3) immunosuppressive agents such as cyclosporine, azathioprine and methotrexate and anti-inflammatory corticosteroids.

The following definitions apply to the terms, as used herein.

The term "alkyl" unless otherwise specified, refers to a branched or unbranched monorradical saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n -decyl, tetradecyl and the like.

The term "alkenyl" unless otherwise specified, refers to a monororadical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans or geminal geometry.

The term "alkynyl" unless otherwise specified, refers to a monororadical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms.

The term "cycloalkyl" unless otherwise specified, refers to cyclic alkyl groups of 3 to 20 carbon atoms having a single cyclic ring or multiple fused rings, which may optionally contain one or more olefinic bonds, unless they are otherwise limited by definition. Such cycloalkyl groups may include, for example, only ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl and the like or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane or cyclic alkyl groups at which fuses an aryl group, for example, indane and the like. Spiro and fused ring structures can also be included.

The term "aryl" unless otherwise specified, refers to the aromatic system having 6 to 14 carbon atoms, wherein the ring system may be mono-, bi- or tricyclic and are carbocyclic aromatic groups. For example, aryl groups include, but are not limited to, phenyl, biphenyl, anthryl or naphthyl ring and the like.

The term "aryloxy" represents the O-aryl group wherein aryl is the same as defined above.

The term "heteroaryl", unless otherwise specified, refers to an aromatic ring structure containing 5 or 6 ring atoms or a bicyclic or tricyclic aromatic group having from 8 to 10 ring atoms , with one or more heteroatom (s) independently selected from N, O or S and optionally benzofused or fused heteroaryl having 5-6 members in the ring.

The term "heterocyclyl", unless otherwise specified, refers to a monocyclic or bicyclic non-aromatic cycloalkyl group having from 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by selected heteroatoms of O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 members in the ring.

The terms "cycloalkylalkyl", "arylalkyl", "heteroarylalkyl", "heterocyclylalkyl" refer respectively to the cycloalkyl, aryl, heteroaryl or heterocyclyl group linked to the rest of the molecule via an alkyl group.

The term "amino" refers to -NH2.

The term "halogen" refers to fluorine, chlorine, bromine or iodine; The term "leaving group" refers to groups that exhibit or potentially exhibit the properties of being labile under synthetic conditions and also, of being easily separated from synthetic products under defined conditions. Examples of leaving groups include, but are not limited to, halogen (for example F, CI, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy or hydroxy radicals and the like.

The term "protecting groups" refers to portions that prevent the chemical reaction at a location of a molecule proposed to be left unaffected during chemical modification of such a molecule. Unless otherwise specified, the protecting groups can be used in groups, such as hydroxy, amino or carboxy. Examples of protecting groups are found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2- Edtion, John Wiley and Sons, New York, N.Y. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups used are not critical, since the portions / portion derived (s) are / are stable to subsequent reaction conditions and can be removed without interrupting the remainder of the molecule.

The compounds of this invention may contain an asymmetric carbon atom and thus may occur as racemic mixtures, enantiomers and diastereomers. These compounds can also exist as conformers / rotamers. All of these isomeric forms of these compounds are included in the present invention. Each stereogenic carbon atom can be of the RT S configuration. Although the specific compounds exemplified in this application can be represented in a particular stereochemical configuration, the compounds having either the opposite stereochemistry at any given chiral center or mixture thereof are contemplate as part of the invention.

The term "pharmaceutically acceptable salts" forming part of this invention includes the salts of the carboxylic acid moiety, which can be prepared by reacting the compound with the appropriate base to provide corresponding base addition salts. Examples of such base are alkali metal hydroxide including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide. Additionally, salts of organic bases such as lysine, arginine, guanidine, ethanolamine, choline and the like, inorganic bases, for example also include ammonium or substituted ammonium salts. If appropriate, compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrohalides, such as hydrochloride, hydrobromide, and hydroiodide; other mineral acids and their corresponding salts, such as sulfate, nitrate, phosphate etc. and alkyl and mono-arylsulfonates, such as ethane sulfonate, toluene sulfonate and benzene sulfonate; and other organic acids and their corresponding salts, such as acetate, tartrate, maleate, succinate, citrate, etc.

In another aspect, the compounds, disclosed herein, can be prepared by the following reaction sequences as depicted in the Schemes and I saw.

Scheme I Formula 2 or the 3 Formula 4 Formula 5 Formula Formula 10 Formula 1 2 Formula 13 Formula 1 when R3 is (Formula 1 when KJ «nitroaryl, I. 'CJ trilay« j OCONUK'. L 'ts link) The compound of Formula 10 (Route A) and Formula 13 (Route B) can be prepared according to Scheme I. In this manner, reacting 4-bromo-nitrobenzene with a compound of Formula 2 (wherein O is the aryl or heteroaryl ring and R6 is hydrogen, alkyl, halogen, alkoxy or halogen-Ci-C6 alkyl) gives a compound of Formula 3 which in reduction forms a compound of the Formula. The reaction of a compound of Formula 4 with alpha- bromolactone gives a compound of Formula 5 which in formylation forms a compound of Formula 6. The compound of Formula 6 in the ring opening forms a compound of Formula 7 (wherein Rp is the carboxy protecting group, such such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC-anhydride) which in the reaction with a compound of Formula 8 (wherein (^ is a heteroaryl ring, R5 is the same as defined in above) gives a compound of Formula 9 which finally in the deprotection gives a compound of Formula 10. The reaction of a compound of Formula 7 with a compound of Formula 11 (where R 'is the same as defined in the foregoing) gives a compound of Formula 12 which on deprotection gives a compound of Formula 13.

The coupling of 4-bromo-nitrobenzene with a compound of Formula 2 to give a compound of Formula 3 can be carried out in the presence of the inorganic base of, for example, potassium carbonate, sodium carbonate, sodium, potassium acetate in the presence of a solvent selected from, tetrahydrofuran, W / W-dimethylformamide, dimethyl sulfoxide, toluene or mixture (s) thereof.

The reduction of a compound of Formula 3 to give a compound of Formula 4 can be carried out using the reducing agent selected from, for example, Raney Nickel in hydrazine hydrate or ammonium formate, zinc, tin or iron in the presence of hydrochloric acid or lithium-aluminum hydride, Pd / C in H2 in the presence of a solvent, for example, tetrahydrofuran, methanol, ethanol, diethyl ether, dioxane or mixture (s) thereof.

The coupling of a compound of Formula 4 with alpha-bromolactone to give a compound of Formula 5 can be carried out using the inorganic base selected from, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate. sodium using the solvent selected from, for example, acetonitrile, water or mixture (s) thereof.

The formylation of a compound of Formula 5 for a compound of Formula 6 can be carried out using the formylating agent selected from, for example, formic acid, formic acetic anhydride, chloral, formic acid. activated using α, β'-dicyclohexylcarbodiimide (DCC) or l-ethyl-3- (3-dimethylamino-propyl) carbodiimide (EDCI), activated formyl ester, ammonium formate in the presence of a solvent selected from, for example, toluene , dimethoxymethane, xylene or mixture (s) thereof.

The ring opening of a compound of Formula 6 to give a compound of Formula 7 can be carried out with alkyl / aryl halide in the presence of 18-crown-6 using one or more inorganic bases selected from sodium bicarbonate , sodium hydroxide, potassium hydroxide, lithium hydroxide in the presence of a solvent, for example,?,? '- dimethylformamide, methanol, ethanol, propanol, butanol, tetrahydrofuran, acetonitrile, water or mixture (s) thereof .

The coupling of a compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9 can be carried out in the presence of redox coupling. The oxidizing part of the redox coupling is selected from, for example, 1, 1 '- (azodicarbonyl) piperidine (ADDP), 4,7-dimethyl-3,5,7-hexahydro-1,4,4,7-tetrazocin-3,8-dione (DHTD), N,?,? ' , W-tetramethylazodicarboxamide (TMAD),?,?,? ' ,? '- tetraisopropylazodicarboxamide (TIP A), diethyl azodi-carboxylate (DEAD), di-t-butylazodicarboxylate or diisopropylazodicarboxylate (DIAD). The reduction part of the redox coupling is selected from, for example, tributylphosphine, triphenylphosphine, p- (dimethylaminophenyl) or triscyclohexylphosphine in the presence of a solvent, for example, tetrahydrofuran, dimethyl sulfoxide,?, '-dimethylformamide, acetonitrile or mixture (s) of them.

Deprotection of a compound of Formula 9 to give a compound of Formula 10 can be carried out in the presence of mineral acid, for example, hydrochloric, hydrobromic, hydroiodic acid in a solvent selected from dichloromethane, chloroform, carbon tetrachloride , dichloroethane, methanol, ethanol, acetonitrile, tetrahydrofuran or mixture (s) thereof.

Or alternatively, deprotection of a compound of Formula 9 to give a compound of Formula 10 can be carried out in the presence of one or more organic acids (s), for example, trifluoroacetic acid / toluenesulfonic acid or sulfonic acid camphor, in a solvent selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, methanol, ethanol, acetonitrile, tetrahydrofuran or mixture (s) thereof.

Or alternatively, deprotection of a compound of Formula 9 to give a compound of Formula 10 can be carried out in the presence of the inorganic base, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, hydroxide of cesium, potassium carbonate in a solvent selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, methanol, ethanol, acetonitrile, tetrahydrofuran or mixture (s) thereof. .0 alternatively, deprotection of a compound of Formula 9 to give a compound of Formula 10 can be carried out in the presence of deprotection agents, for example, Pd / C in the presence of H2, Pd / C with ammonium formate, Pd / C in the presence of triethylsilane, ozone, boron trichloride dimethyl sulphide (BCI3, SMc2), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), tetrakis triphenylphosphine in the presence of morpholine using the solvent selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, methanol, ethanol, acetonitrile, tetrahydrofuran or mixture (s) thereof.

The reaction of a compound of Formula 7 with a compound of Formula 11 to give a compound of Formula 12 can be carried out in the presence of the base selected from, for example, triethylamine, W, N'-dimethylaminopyridine, 2, 6-lutidine, 1-methylpiperidine, W-ethyldiisoproylamine, N, W-diisopropylethylamine or W-methyl-morpholine in a solvent selected from, tetrahydrofuran, W, N'-dimethylformamide, dimethyl sulfoxide, acetonitrile or mixture (s) thereof.

Deprotection of a compound of Formula 12 to give a compound of Formula 13 can be carried out under similar conditions as described for the compound of Formula 9 to give a compound of Formula 10.

Scheme II Formula 20 Formula 19 Formula 1 8 (Formula 1 when it is heteroariio and L 'is in e) The compound of Formula 20 can be prepared according to Scheme II. In this manner, the alpha halogenation of a compound of Formula 14 (wherein it is a heteroaryl ring, R 5 is the same as defined above) to give a compound of Formula 15 (wherein Hal is F, CI, Br, I) which in the protection gives a compound of Formula 16 (wherein Rp is the same as defined in the above). The reaction of a compound of Formula 16 with a compound of Formula 17 (wherein Ak is alkyl of CT.-6 and Rx is alkyl, halogen, aryl, heteroaryl) can take place in two ways.

Route C (when Rk is halogen): The compound of Formula 16 reacts with a compound of Formula 17 to form a compound of Formula 18 which in coupling with a compound of Formula 2 (wherein O is the aryl or heteroaryl ring and R6 is the same as defined above) gives a compound of Formula 19. The compound of Formula 19 in deprotection gives a compound of Formula 20.

Route D (when Rk is aryl / heteroaryl substituted with R 6): The compound of Formula 16 in the reaction with a compound of Formula 17 gives a compound of Formula 19 in which deprotection gives a compound of Formula 20 .

The alpha halogenation of a compound of Formula 14 to form a compound of Formula 15 can be carried out in the presence of red phosphorus / Br2, in the presence of a solvent selected from, for example, carbon tetrachloride, chloroform, dichloromethane, dichloroethane or mixture (s) thereof.

The O-protection of a compound of Formula 15 to give a compound of Formula 16 can be carried out with the carboxy protecting group, for example, methyl, benzyl, allyl, t-butyl, silyl, BOC anhydride in the presence of the organic base selected from, for example, triethylamine, N, W-dimethylaminopyridine, 2,6-lutidine, 1-methylpiperidine, N-ethyldiisoproylamine, N, N'-diisopropyl-ethylamine or W-methylmorpholine using solvents selected from, tetrahydrofuran, N, W-dimethylformamide, dimethyl sulfoxide, acetonitrile or mixture (s) thereof.

Alternatively, the O-protection of a compound of Formula 15 to give a compound of Formula 16 can be carried out with the carboxy protecting group, for example, methyl, benzyl, allyl, t-butyl, silyl, anhydride BOC in the presence of the selected inorganic base of, sodium bicarbonate, lithium bicarbonate, potassium bicarbonate in one or more solvents selected from, for example, _V, W-dimethylformamide, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, methanol, ethanol , water or mixture (s) thereof.

The reaction of a compound of Formula 16 with a compound of Formula 17 (Route C) to give a compound of Formula 18 can be carried out in the presence of the inorganic base selected from, for example, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, barium carbonate using solvent, for example, acetonitrile, tetrahydrofuran, dioxane,?,? '- dimethylformamide, dimethyl sulfoxide or mixture (s) thereof.

The coupling of a compound of Formula 18 with a compound of Formula 2 to give a compound of Formula 19 can be carried out in the presence of the inorganic catalyst selected from, for example, bis- (diphenylphosphino) ferro-cencium palladium dichloride. II (Pd (dppf) Cl2), tetrakis (triphenylphosphine) palladium (0) [Pd (Ph3P) 4], palladium acetate or dichlorotriphenyl-phosphine palladium (II), with the appropriate base selected from, for example, potassium carbonate , sodium acetate, potassium acetate in the presence of the solvent selected from, tetrahydrofuran, N, N'-dimethylformamide, dimethyl sulfoxide, toluene or mixture (s) thereof.

Deprotection of a compound of Formula 19 to give a compound of Formula 20 can be carried out under similar conditions as described for the compound of Formula 9 to give a compound of Formula 10.

The reaction of a compound of Formula 16 with a compound of Formula 17 (Route D) to give a compound of Formula 19 can be carried out in the presence of the inorganic base selected from, for example, potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate in a solvent, for example, acetonitrile, tetrahydrofuran, N, W-dimethylformamide, dimethyl sulfoxide or mixture (s) thereof.

Scheme III . { Formula 1 when K; to htttroarilo, G.1"link and R1 arüo heteroarüo suitituido with OkS'l The compound of Formula 26b (Route E), Formula 29 (Route F), Formula 31 (Route G), Formula 36 (Route H) can be prepared according to the Scheme. III. In this manner, reacting a compound of Formula 17a (wherein Rk- is hydrogen, halogen, alkoxy, aryloxy, aryl, carboxy) with alpha-hydroxy lactone gives a compound of Formula 21 which in the ring opening gives a compound of Formula 22. The carboxy protection of the compound of Formula 22 gives a compound of Formula 23 (wherein Rp is the same as defined above).

Route E (when it is halogen): the compound of Formula 23 in the hydroxy protection gives a compound of Formula 24 (wherein Rp- is the hydroxy protecting group). Coupling a compound of Formula 24 with a compound of Formula 24a (wherein R6 is alkyl, aryl, heteroaryl) gives a compound of Formula 25 which upon deprotection gives a compound of Formula 26. The reaction of a compound of Formula 26 with a compound of Formula 27 gives a compound of Formula 26a. Deprotection of a compound of Formula 26a gives a compound of Formula 26b.

Route F (when it is alkoxy / aryloxy / halogen / hydrogen): the reaction of a compound of Formula 23 with a compound of Formula 27 gives a compound of Formula 28 which upon deprotection gives a compound of Formula 29 .

Route G: (when it is aryl substituted with halogen and Rp is allyl): the reaction of a compound of Formula 23 with a compound of Formula 27 gives a compound of Formula 30 which upon deprotection gives a compound of Formula 31 Route H: (when COORp): Coupling a compound of Formula 23 with a compound of Formula 27 gives a compound of Formula 32 which upon deprotection gives a compound of Formula 33. The coupling of a compound of Formula 33 with a compound of Formula 34 gives a compound of Formula 35 which ultimately in deprotection forms a compound of Formula 36.

The reaction of a compound of Formula 17a with α-hydroxy lactone to give a compound of Formula 21 can be carried out under similar conditions as described for the reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.

The ring opening of a compound of Formula 21 to give a compound of Formula 22 can be carried out as described for the compound of Formula 6 to give a compound of Formula 7.

The carboxy protection of a compound of the Formula 22 to give a compound of Formula 23 can be carried out under similar conditions as described for the compound of Formula 15 to give a compound of Formula 16.

The hydroxy protection of a compound of the Formula 23 to give a compound of Formula 24 (Route E) can be carried out using the protecting group selected from, for example, tert-butyldimethylsilyl chloride (TBDMSC1), trimethylsilyl chloride (TMSC1), tert-butyldimethylsilyloxymethyl chloride ( TOMC1), triisopropyl silyl chloride (TIPSC1), benzoyl chloride in the presence of the base, for example, imidazole, A netilimidazole, triethylamine, pyridine, diisopropylethylamine, N, N'-dimethylaminopyridine in the presence of the solvent, for example ,?,? '- dimethylformamide, toluene, acetonitrile, dichloromethane or mixtures thereof.

Coupling of a compound of Formula 24 with a compound of Formula 24a to give a compound of Formula 25 can be carried out under similar conditions as for the reaction of a compound of Formula 18 with a compound of Formula 2 to give a compound of Formula 19.

Deprotection of a compound of Formula 25 to give a compound of Formula 26 can be carried out using the deprotection agent selected from, for example, boron trifluoride etherate (BF3.OEt2), HF-pyridine, trichloride boron, boron tribromide, cesium fluoride (CsF), potassium fluoride (KF), n-tetrabutylammonium fluoride, Pd / C in H2, potassium carbonate in the presence of the solvent, for example, dichloromethane, N, N ' dimethylformamide, acetonitrile, methanol, ethanol, acetone, tetrahydrofuran or mixtures thereof. / The reaction of a compound of Formula 26 with a compound of Formula 27 to give a compound of Formula 26a can be carried out under similar conditions as described for the reaction of a compound of Formula 7 with a compound of the formula Formula 8 to give a compound of Formula 9.

Deprotection of a compound of Formula 26a to give a compound of Formula 26b can be carried out under similar conditions as described for the deprotection of a compound of Formula 9 to give a compound of Formula 10.

The reaction of a compound of Formula 23 (Route F) with a compound of Formula 27 to give a compound of Formula 28 can be carried out under a similar condition as described for the reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.

Deprotection of a compound of Formula 28 to give a compound of Formula 29 can be carried out under similar conditions as described for the deprotection of a compound of Formula 9 to give a compound of Formula 10.

The reaction of a compound of Formula 23 (Route G) with a compound of Formula 27 to give a compound of Formula 30 can be carried out under similar conditions as described for the reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9 Deprotection of a compound of Formula 30 to give a compound of Formula 31 can be carried out under similar conditions as described for the deprotection of a compound of Formula 9 to give a compound of Formula 10.

The reaction of a compound of Formula 23 (Route H) with a compound of Formula 27 to give a compound of Formula 32 can be carried out under similar conditions as described for the compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9 .

Deprotection of a compound of Formula 32 to give a compound of Formula 33 can be carried out as described for the compound of Formula 9 to give a compound of Formula 10.

Coupling of a compound of Formula 33 with a compound of Formula 34 to give a compound of Formula 35 can be carried out using the selected base of triethylamine, N, W-dimethylaminopyridine, 2,6-lutidine, 1- methylpiperidine, N-ethyldiisoproylamine, N, N-diisopropylethylamine or W-methylmorpholine, in the presence of an additive for example hydroxybenzotriazole, 3-hydroxy-3,4-dihydro-4-oxo-l, 2,3-benzotriazine, 2- hydroxypyridine, N-hydroxysuccinimide or l-hydroxy-7-azabenzotriazole, with a suitable condensing agent, for example, dicyclohexyl-carbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, chlorotripyrrolidino-phosphonium hexafluorophosphate or hexafluorophosphate (benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium in the presence of a solvent selected from, for example, α, β-dimethylformamide, dimethyl sulfoxide, acetonitrile or mixture (s) thereof.

Deprotection of a compound of the Formula To give a compound of Formula 36 can be carried out under a similar condition as described for the compound of Formula 9 to give a compound of Formula 10.

Scheme IV Y The compound of Formula 43 can be prepared according to Scheme IV. Thus, protecting a compound of Formula 37 (wherein Rp is the same as defined above) gives a compound of Formula 38 (wherein Rp < is the same as defined above) which in the reaction with a compound of Formula 39 (wherein R6 is' alkyl and Ak is the same as defined above) gives a compound of Formula 40. The compound of Formula 40 in the deprotection gives a compound of Formula 41 which in the reaction with a compound of Formula 27 (wherein R 5 is the same as defined above) forms a compound of Formula 42. Deprotection of a compound of Formula 42 gives a compound of Formula 43 The protection of a compound of Formula 37 to give a compound of Formula 38 can be carried out under similar conditions as described for the compound of Formula 23 to give a compound of Formula 24.

The reaction of a compound of Formula 38 with a compound of Formula 39 to give a compound of Formula 40 can be carried out under similar conditions as described for the reaction of a compound of Formula 7 with a compound of the formula Formula 8 to give a compound of Formula 9.

Deprotection of a compound of Formula 40 to give a compound of Formula 41 can be carried out under similar conditions as described for the compound of Formula 25 to give a compound of Formula 26.

The reaction of a compound of Formula 41 with a compound of Formula 27 to give a compound of Formula 42 can be carried out under similar conditions as described for the reaction of a compound of Formula 7 with a compound of the formula Formula 8 to give a compound of Formula 9.

Deprotection of a compound of Formula 42 to give a compound of Formula 43 can be carried as described for the compound of Formula 9 to give a compound of Formula 10.

Scheme V Formula 52 Formula 51 Formula 50 Formula I [when R3 is heteroaryl, L1 is bond and neither is aril / hcrocroaryl) The compound of Formula 52 can be prepared according to Scheme V. In this way, reacting 4- (2-hydroxyethyl) -2,2-dimethyl-1,3-dioxolane with a compound of Formula 44 gives a compound of Formula 45 which in the ring opening gives a compound of Formula 46. The compound of Formula 46 in O-protection gives a compound of Formula 47 (wherein Rp »is the same in the above) in the which reaction with a compound of Formula 48 (wherein Hal and Ak are the same as defined above) gives a compound of Formula 49. Coupling a compound of Formula 49 with a compound of Formula 2 gives a compound of Formula 50. The compound of Formula 50 in the deprotection forms a compound of Formula 51 which finally on oxidation gives a compound of Formula 52.

The reaction of 4- (2-hydroxyethyl) -2,2-dimethyl-1,3-dioxolane with a compound of Formula 44 forms a compound of Formula 45 can be carried out under similar condition as for the compound of the Formula 7 with a compound of Formula 8 to give a compound of Formula 9.

The ring opening of a compound of Formula 45 to give a compound of Formula 46 can be carried out in the presence of mineral acids selected from, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid or in the presence of the catalytic amount of cerium (IV) ammonium nitrate (CAN), cerium (III) trifluoromethane sulfonate using solvent, for example, acetone, nitromethane, acetonitrile, water or mixtures thereof.

The protection of a compound of Formula 46 to give a compound of Formula 47 can be carried out under similar conditions as described for the compound of Formula 23 to give a compound of Formula 24.

The reaction of a compound of Formula 47 with a compound of Formula 48 to give a compound of Formula 49 can be carried out under similar conditions as described for the reaction of a compound of Formula 7 with a compound of the formula Formula 8 to give a compound of Formula 9.

The coupling of a compound of Formula 49 with a compound of Formula 2 to give a compound of Formula 50 can be carried out under similar conditions as described for coupling a compound of Formula 18 with a compound of the formula Formula 2 to give a compound of Formula 19.

Deprotection of a compound of Formula 50 to give a compound of Formula 51 can be carried out under a similar condition as described for the deprotection of a compound of Formula 25 to give a compound of Formula 26.

Oxidation of a compound of Formula 51 to give a compound of Formula 52 can be carried out using the oxidizing agent, for example, sodium chlorite and sodium hypochlorite in the presence of 2, 2, 6, 6-tetramethyl- piperidine-N-oxyl) (TEMPO), sodium periodate in the presence of ruthenium trichloride, potassium dichromate, potassium permanganate, using a solvent selected from, acetonitrile, carbon tetrachloride, water or mixture (s) thereof .

Scheme VI (Formula I when s3 is heteroaryl LI is bond, if it is aryl heteroaryl] The compound of Formula 61 can be prepared according to Scheme VI. In this way, protecting 4- (2-hydroxyethyl) -2,2-dimethyl-1,3-dioxolane gives a compound of Formula 53 (wherein Rp is the same as defined above) which in the ring opening forms a compound of Formula 54. The compound of Formula 54 in the additional protection gives a compound of Formula 55 (wherein Rp 'is the same as defined above) which in the reaction with a compound of Formula 48 (wherein Hal is the same as defined above) gives a compound of Formula 56. Coupling a compound of Formula 56 with a compound of Formula 2 gives a compound of Formula 57 which on deprotection form a compound of Formula 58. The reaction of a compound of Formula 58 with a compound of Formula 27 (wherein R 5 is the same as defined above) gives a compound of Formula 59. The compound of Formula 59 in the deprotection gives a compound of Formula 60 which in oxidation forms a A compound of Formula 61.

The protection of 4- (2-hydroxyethyl) -2,2-dimethyl-1,3-dioxolane to give a compound of Formula 53 can be carried out using alkyl / aryl halides using the inorganic base selected from lithium hydride, Sodium hydride or organic base selected from pyridine, triethylamine, trimethylamine, tributylamine, W-ethyldiiso-propylamine, 4-N, iV-dimethylaminopyridine, N-methylmorpholine or 2,6-lutidine in the presence of a solvent, for example, N , N '-dimethylformamide, dimethyl sulfoxide, acetonitrile or mixture (s) thereof.

The ring opening of a compound of Formula 53 to give a compound of Formula 55 can be carried out under similar conditions as described for the compound of Formula 45 to give a compound of Formula 46.

The protection of a compound 54 to give a compound of Formula 55 can be carried out under similar conditions as described for the protection of the compound of Formula 23 to give a compound of Formula 24.

The reaction of a compound of Formula 55 with a compound of Formula 48 to give a compound of Formula 56 can be carried out under similar conditions as described for the compound of Formula 7 with a compound of Formula 8 for give a compound of Formula 9.

The coupling of a compound of Formula 56 with a compound of Formula 2 to give a compound of Formula 57 can be carried out under similar conditions as described for coupling a compound of Formula 18 with a compound of the formula Formula 2 to give a compound of Formula 19.

Deprotection of a compound of Formula 57 to give a compound of Formula 58 can be carried out as described for the deprotection of a compound of Formula 9 to give a compound of Formula 10.

Coupling of a compound of Formula 58 with a compound of Formula 27 to give a compound 59 can be carried out under similar conditions as described for the compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.

Deprotection of a compound of Formula 59 to give a compound of Formula 60 can be carried out under similar conditions as described for the compound of Formula 25 to give a compound of Formula 26.

Oxidation of a compound of Formula 60 to give a compound of Formula 61 can be carried out under a similar condition as described for the compound of Formula 51 to give a compound of Formula 52.

In the above schemes, where specific reagents, for example, bases, acids, solvents, condensing agents, reducing agent, deprotection agents, hydrolyzing agents, catalysts, etc., as mentioned, it is to be understood that other reagents , for example, other acids, bases, solvents, condensing agents, reducing agent, deprotection agent, hydrolyzing agents, catalysts, etc., known to one of ordinary skill in the art can be used. Similarly, the reaction temperatures and durations can be adjusted according to the desired needs without undue experimentation and well within the skills of the ordinary person in the art.

The compounds described herein may be administered to an animal for treatment orally, topically, rectally, intrasely or by parenteral route. The pharmaceutical compositions disclosed herein comprise pharmaceutically effective amounts of the compounds described in the present formulation together with one or more pharmaceutically acceptable carriers, excipients or diluents.

Solid form preparations for oral administration include capsules, tablets, pills, powder, granules, lozenges, troches, wafers and suppositories. For solid form preparations, the active compounds can be mixed with one or more pharmaceutically acceptable, inert excipients or carriers. Tablets and capsules for oral administration may contain conventional excipients, such as binding agents and / or dissolution enhancers, for example, polyvinyl pyrrolidine, cellulose, starch mucilage, gelatin, sorbitol, syrup, acacia or tragacanth.; fillers or thickening agents, for example, microcrystalline cellulose, sugar, corn starch, calcium phosphate, sorbitol or lactose; lubricants, for example, talc, silica, polyethylene glycol, magnesium stearate or stearic acid; disintegrating agents and binder, for example, croscarmellose sodium, pregelatinized starch, sodium starch glycolate or potato starch; slip agents, for example, colloidal silicon dioxide or talc; non-stick, for example, magnesium stearate or sodium luaryl sulfate; and coating materials.

The capsules, tablets or pills may also comprise regulatory agents.

The tablets, capsule, pills or granules can be prepared using one or more coatings or coatings to modulate the release of the active ingredients, for example, enteric coatings or other coatings known to one of ordinary skill in the art.

General Example A formulation of a tablet could typically contain from 0.01 mg to 500 mg of the active compound while the weight of the tablet filling can vary from 50 mg to 1000 mg. An example is illustrated below: Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In such liquid form preparations, the active compounds can be mixed with water or one or more non-toxic solvents, solubilizing or emulsifying agents, for example, water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, for example, cottonseed, peanut, corn, germ, olive, castor oil and sesame, glycerol, sorbitan fatty acid esters or mixtures thereof . The oral compositions may also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or mixtures thereof.

Injectable preparations, for example, sterile injections and aqueous suspensions may be formulated according to methods known to one of ordinary skill in the art, and in particular, using one or more suitable dispersing or wetting and suspending agents. Suitable vehicles and solvents that may be employed include one or more of water, Ringer's solution, isotonic sodium chloride, or mixtures thereof.

Suppositories for rectal administration of the compound of this invention can be prepared by mixing the drug with suitable non-irritating excipients, such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at body temperature and which therefore melt at the rectum and release the drug.

Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compounds can be mixed under sterile condition with one or more pharmaceutically acceptable carriers and optionally any of the preservatives or buffer solutions as may be required. Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.

The pharmaceutical preparations can be in unit dosage form. In the unit dosage form, the preparations can be subdivided into unit doses containing appropriate amounts of active components. The unit dosage forms can be packaged preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, sachets, tablets, gels, creams or any combination and number of such packaged forms.

Table I Formula I 5 fifteen 25 The following examples are set forth to demonstrate general synthetic procedures for the preparation of representative compounds of the present invention. The plugs are provided to illustrate the particular aspect of the description and not to limit the scope of the present invention.

Experimental Various solvents, for example, dimethylformamide, benzene, tetrahydrofuran, etc., were dried using various drying reagents according to the procedure as described in the literature.

Broker synthesis Synthesis of 6-methyl-l, 2, 3-benzotriazin-4 (3ff) -one The title compound was prepared following the procedure outlined in J. Med. Chem., 35 (14), pages 2626-2630 (1992).

The following benzotriazine- (3H) -one analogs were prepared analogously: 7-Methoxy-1, 2, 3-benzotriazin-4 (3H) -one; 7- (Trifluoromethyl) -1,2, 3-benzotriazin- (3H) -one; 7-Methyl-l, 2, 3-benzotriazin-4 (3H) -one; 6-Methoxy-1, 2, 3-benzotriazin-4 (3H) -one; 5-Chloro-l, 2,3-benzotriazin-4 (3H) -one; 7-Chloro-l, 2,3-benzotriazin-4 (3H) -one; 5-Methoxy-1,2,3-benzotriazin-4 (3tf) -one; 5- Fluoro-l, 2, 3-benzotriazin-4. { 3H) -one; 8-Methoxy-1, 2, 3-benzotriazin-4 (3H) -one; 6-Fluoro-l, 2, 3-benzotriazin-4 (3H) -one.

Synthesis of 5-methyl-l, l-isoindol-l, 3 (2H) -dione The title compound was prepared following the procedure outlined in Chem. Ber. 1877, 10, 1163.

Synthesis of 4- (1, 3-dioxo-l, 3-dihydro-2fí-isoindol-2-yl) -butanoic acid To a solution of α-aminobutyric acid (20.68 g, 0.199 mol) and phthalic anhydride (29.6 g, 0.199 mol) in toluene (300 mL) was added triethylamine (3 mL, 0.0215 mol) and heated at 110 ° C for approximately 8 hours. After completion, the reaction mixture was allowed to cool to room temperature. The reaction mixture was washed with 1N HC1 solution (20 mL) at 40 ° C and the solid was crystallized from the organic layer. The residue was filtered, washed with water and dried under vacuum overnight to obtain the desired product.

Yield: 31.64 g LCMS: 234.2 (M + l) Synthesis of N- (4-bromophenyl) methane sulfonamide To a solution of 4-bromoaniline (100 g, 581 mmol) in dichloromethane (75 mL) and pyridine (75 mL) was added slowly methanesulfonyl chloride (99 g, 872 mmol). The reaction mixture was allowed to stir for about one hour at the same temperature. After one hour, dilute hydrochloric acid was added to the reaction mixture to remove the pyridine. The organic layer was collected, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using 60% ethyl acetate: hexane as eluent to provide a desired compound.

Yield: 110 g LCMS: 267.03, 268.97 (+ Na) Synthesis of N- [4- (4-methylphenoxy) phenyl] methane sulfonamide To a solution of 4- (4-methylphenoxy) aniline (3.5 g, 17.6 mmol) in pyridine (20 mL) and dichloromethane (20 mL) at 0 ° C was added methanesulfonyl chloride (2.2 mL, 26.4 mmol). The reaction mixture was allowed to stir at room temperature for about 2 hours. After completion of the reaction, pyridine was evaporated and the reaction mixture was extracted with ethyl acetate. The organic layer was collected, washed with water, dried over anhydrous sodium sulfate and evaporated to obtain a crude product. The crude product obtained was purified on a silica gel column using 25% ethyl acetate: hexane as eluent to obtain the desired compound.

Yield: 3.1 g The following compound can therefore be prepared: N- (4-methoxyphenyl) methanesulfonamide.

Synthesis of benzyl 2,4-dihydroxybutanoate To a solution of α-hydroxylactone (10 g, 0.098 mol) in methanol (50 mL) was added sodium hydroxide (5.88 g, 0.147 mol) in water (10 mL) and allowed to stir at room temperature for about one hour. The reaction mixture was concentrated and taken in?,? ' dimethylformamide (40 mL) and benzyl bromide (14 mL, 0.17 moles) was added dropwise. The reaction mixture was allowed to stir again overnight at room temperature. After completion of the reaction, the solvent was evaporated under vacuum and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate and evaporated under vacuum to obtain a crude product. The crude product was purified on a silica gel column using 80% ethyl acetate: hexane as eluent to give the title compound.

Yield: 10.4 g LCMS: 211.47 (M + l), 233.5 (M + Na) Synthesis of N- (biphenyl-4-yl) methanesulfonamide To the solution of 4-biphenyl amine (1 g, 0.0059 mol) in dimethylformamide (10 mL) was added potassium carbonate (1.63 g, 0.01 18 mol) and stirred for approximately 10 minutes and then methanesulfonyl chloride (3.64) was added. mL, 0.0472 moles) slowly. The reaction mixture was allowed to stir at room temperature for about 30 minutes. After completion, the reaction mixture was extracted with ethyl acetate while washing with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product which was purified on a column of silica gel to obtain the desired product.

Yield: 0.75 g Synthesis of 4-. { [4-hydroxy-l-oxo-l- (prop-2-en-l-yloxy) butan-2-yl] (methyl] sulfonyl) amino} tert-butyl benzoate Step a: Preparation of tert-butyl 4-nitrobenzoate To a solution of p-nitrophenol (10 g, 59.88 mmol) in tert-butanol (100 mL) and tetrahydrofuran (100 mL) were added?,? ' -dimethylaminopyridine (1.4 g, 11.97 mmoles) and Boc anhydride (38.4 mL, 179.64 mmoles) at room temperature. The reaction mixture was allowed to stir for about 10 hours at room temperature. The temperature was slowly increased to 35 ° C and the reaction mixture was stirred for about 6 hours. After completion, the solvent was evaporated under reduced pressure and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and evaporated under vacuum to obtain a crude product. The crude product was purified on a silica gel column using 20% ethyl acetate: hexane as eluent to obtain the desired compound.

Yield: 12 g Step b: Preparation of tert-butyl 4-aminobenzoate To a solution of the compound obtained from Step a (11 g) in tetrahydrofuran (50 mL) and methanol (50 mL) was added 10% Pd / C (3 g) and H2 was supplied at 60 psi in a Parr apparatus during approximately 2 hours. After completion, the reaction mixture was filtered through a pad of celite and the residue was washed with ethyl acetate. The obtained filtrate was concentrated under vacuum to obtain the desired compound.

Yield: 10 g.

LCMS: 194.47 (+ l) Step c: Preparation of tert-butyl 4- [(methylsulfonyl) aznino] -benzoate of tert-butyl To a cooled solution with ice of the compound obtained from Step b (10 g, 51.81 mmol) in pyridine (50 mL) and dichloromethane (50 mL) was added methanesulfonyl chloride (8.86 g, 77.72 mmol). The reaction mixture was allowed to stir for about one hour at the same temperature. After one hour, HC1 (11N) solution was added to conduct the pH of the reaction mixture to our counterpart and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum to obtain the crude product. The obtained crude product was purified on a column of silica gel using 50% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 10 g LC S: 293.76 (+ Na) Step d: Preparation of f-butyl 4- [(methylsulfonyl) (2-oxotetrahydro-furan-3-yl) amino] benzoate To an ice-cooled solution of alpha-hydroxy lactone (1 g, 9.80 mmol) in tetrahydrofuran (30 mL) were added the compound obtained from Step c (2.6 g, 9.80 mmol) and triphenylphosphine (13.6 g, 14.70 mmol). The reaction mixture was stirred for about 15 minutes and diisopropylazodicarboxylate (DIAD) (2.9 g, 14.70 mmol) was added at the same temperature. The reaction mixture was allowed to stir for about 2 hours at room temperature. After complete conversion of the starting material, the solvent was evaporated under vacuum to obtain a crude compound. The crude compound was purified on a silica gel column using 30% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 6 g LCMS: 35 .82 (M).

Step e: Preparation of N- [4- (fcer-butoxycarbonyl) phenyl] -N- (methylsulfonyl) homoserine To an ice-cooled solution of the compound obtained from Step d (4 g, 11.26 mmol) in ethanol (30 mL) and methanol (10 mL) was added sodium hydroxide (0.495 g, 12.39 mmol) in water (5 mL). . The reaction mixture was allowed to stir at the same temperature for about 30 minutes. After 30 minutes, the solvent was evaporated and the reaction mixture was extracted with ethyl acetate while washing with water. The aqueous layer was acidified with aqueous sodium bisulfate solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated to obtain the desired compound. Performance: 3g Stage f: Preparation of 4-. { [4-hydroxy-l-oxo-l- (prop-2-en-l-yloxy) butan-2-yl] (methylsulfonyl) amino} tert-butyl benzoate To a solution of the compound obtained from step e (3 g, 8.04 mmole) in?,? ' dimethylformamide (25 mL) were added sodium bicarbonate (1 g, 12.06 mmol) and allyl bromide (1.07 g, 8.84 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for about 12 hours. After completion of the reaction, the solvent was evaporated and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to obtain the crude product. The crude product was purified on a silica gel column using 40% ethyl acetate: hexane to obtain the desired compound.

Yield: 1.4 g.

LC S: 413.87 (M + l).

Synthesis of N- (4'-chlorobiphenyl-4-yl) -N- (methylsulfonyl) homo-serinate of prop-2-en-l-yl Step a: Preparation of N- (4'-chlorobiphenyl-4-yl) methanesulfonamide To a solution of N- (4-bromophenyl) methanesulfonamide (2 g, 0.008 mol) in N, N'-dimethylformamide (15 mL) and water (15 mL) were added 4-chlorophenylboronic acid (2.49 g, 0.016 mol), potassium carbonate (3.3 g, 0.024 mol) and tetrakis. triphenylphosphine (277 mg, 0.002 mol). The reaction mixture was heated to 100 ° C for about 14 hours. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using 25% ethyl acetate: hexane as eluent to obtain the title compound.

Yield: 1.8 g Step b: Preparation of N- (4'-chlorobiphenyl-4-yl) -N- (2-oxotetrahydrofuran-3-yl) methane sulfonamide To a compound obtained from step a (10 g, 0.035 mol) in tetrahydrofuran (70 mL) were added a-hydroxy lactone (8.8 g, 0.05 mol) and triphenylphosphine (13.9 g, 0.05 mol) at 0 ° C. The reaction mixture was allowed to stir about 10 minutes and DIAD diisopropyl-azodicarboxylate (10.7 mL, 0.05 moles) was added thereto at 0 ° C. The reaction mixture was stirred again for about 2 hours at room temperature. After completion, the solvent was evaporated to obtain a crude product which was purified on a column of silica gel using 20% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 10 g LCMS: 365.71 (M + l) Step c: Preparation of N- (4'-chlorobiphenyl-4-yl) -N- (methyl-sulfonyl) homoserine To a solution of the compound obtained from step b (10 g, 0.0273 mol) in ethanol: water (10: 1) mixture (100 ml.-10 ml) a. 0 ° C was added sodium hydroxide (1.2 g, 0.037 mol) in water (2 mL). The reaction mixture was allowed to stir for about 2 hours at 0 ° C. After 2 hours, the solvent was evaporated under reduced pressure and the obtained residues were taken up in water and extracted with ethyl acetate. The aqueous layer obtained was acidified by aqueous sodium bisulfite solution and then extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound.

Performance: 10g Step d: Preparation of N- (4'-chlorobiphenyl-4-yl) -N- (methyl-sulfonyl) homoserinate of prop-2-en-1-yl To a compound obtained from step c (10 g, 0.026 mol) in a mixture of ethanol: water: DMF (60 mL: 6 mL: 60 mL) at room temperature was added sodium bicarbonate (2.1 g, 0.026 mol). The reaction mixture was allowed to stir at room temperature for about 30 minutes. After 30 minutes, the reaction mixture was concentrated under reduced pressure and treated with toluene. The toluene was evaporated and the residue thus obtained was taken in?,? ' -dimethylformamide dry (20 mL) at room temperature. To this reaction mixture, allyl bromide (3.4 g, 0.028 mol) was slowly added and stirred overnight at room temperature. After completion, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was collected, washed with water, brine, dried over anhydrous sodium sulfate solution and evaporated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using 30% ethyl acetate: hexane as eluent to obtain the title compound.

Yield: 5.2 g Example 1: Synthesis of 2- [formyl (4'-methyl-biphenyl-4-yl) -amino] -4- (6-methyl-4-oxo-l, 2,3-benzotriazin-3 (4)) -yl) butañoico (Compound No. 1) (Scheme I, Route A) Stage a: Preparation of 4-methyl-4 '-ni-robiphenyl To a solution of 4-bromo-nitrobenzene (5 g, 0.0247 moles) in N, N'-dimethylformamide (25 mL) were added potassium carbonate (10.2 g, 0.0741 moles) and 4-methylboronic acid (4 g, 0.0297 moles). ) under argon atmosphere and heated at 100 ° C for about 3 hours. After completion, the reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product which was purified on a column of silica gel using 15% ethyl acetate: hexane as eluent to obtain the desired compound.

Yield: 5.3 g LCMS: 236.07 (M + 23) Step b: Preparation of 4 '-methylbiphenyl-4-amine To a solution of the compound obtained from Step a (5.2 g, 0.0244 mol) in tetrahydrofuran (25 mL) and methanol (25 mL) was added 10% Pd / C (5.2 g) under vacuum and then hydrogen gas was supplied by balloon. The reaction mixture was allowed to stir for about 2 hours at room temperature. After completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under vacuum to obtain the title compound. Yield: 5 g LCMS: 184.01 (M + l) Step c: Preparation of 3- [(4'-methylbiphenyl-4-yl) axnino] -dihydrofuran-2 (3ff) -one To alpha-bromo lactone (3 g, 0.018 mol) was added the compound obtained from Step b (4.9 g, 0.027 mol) and heated at 100 ° C for about 3 hours. After completion of the starting material, the reaction mixture was evaporated under reduced pressure and purified on a silica gel column using 20% ethyl acetate: hexane as eluent to obtain the desired compound.

Performance: 4 g LCMS: 268.11 (M + l) Step d: Preparation of N- (4 '-methylbiphenyl-4-yl) -N- (2-oxo-tetrahydrofuran-3-yl) formamide To a solution of the compound obtained from Step c (2 g, 0.00749 mol) in toluene (30 mL) was added formic acid (0.4 g, 0.0089 mol) and heated to reflux for about 9 hours. After completion, the reaction mixture was evaporated under reduced pressure to obtain a crude product which was purified on a column of silica gel using 15% ethyl acetate: hexane as eluent for the title compound.

Yield: 1.9 g LCMS: 295.94 (M + l) Step e: Preparation of methyl N-formyl-N '- (4'-methylbiphenyl-4-yl) -homoserinate To a solution of the compound obtained from Step d (1.9 g, 0.0064 moles) in?,? ' Dimethylformamide (4 mL) and water (1 mL) were added with sodium hydroxide (0.309 g, 0.0077 mol) and stirred for about 30 minutes at room temperature. After 30 minutes the sodium bicarbonate (0.624 g, 0.0074 mole), 18-crown-6 (0.168 g, 0.00064 mole) and methyl iodide (1.3 g, 0.0914 mole) was added to the reaction mixture and stirred again overnight at room temperature. After completion, the reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product which was purified on a column of silica gel using 8% ethyl acetate: hexane as eluent.

Yield: 2.1 g Step f: Preparation of 2- [fonnyl (4 '-methylbiphenyl-4-yl) -amino] -4- (6-methyl-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoate of methyl ? a compound obtained from step e (0.3 g, 0.0009 mol) in tetrahydrofuran (5 mL) were added 6-methylbenzotriazinone (0.177 g, 0.001 1 mol) and triphenyl phosphine (0.353 g, 0.0013 mol) under an argon atmosphere. The The reaction mixture was allowed to dry at 0 ° C and diisopropylazodicarboxylate (0.272 g, 0.0013 mol) was added thereto and stirred for about 30 minutes at room temperature. After completion, the reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound which was purified on a silica gel column using 7% ethyl acetate: hexane as eluent to obtain the desired product. .

Yield: 0. 15 g LCMS: 470 (M + l) Step g: Preparation of 2- [formyl (4'-methyl-biphenyl-4-yl) amino] -4- (6-methyl-4-oxo-l, 2,3-benzotriazin-3 (42?) -yl) acid -butanoic To a compound obtained from Step f (0.15 g, 0.0003 mol) in tetrahydrofuran (5 mL) and methanol, (5 mL) was added lithium hydroxide solution (0.018 g, 0.0004 mol) in water (1 mL). The reaction mixture was allowed to stir for about one hour at room temperature. After completion, the reaction mixture was acidified with sodium bisulfate solution (pH ~ 2) and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude compound which was purified by preparative TLC using 10% methanol: dichloromethane as a mobile phase. Yield: 0.030 g LCMS-455.35 (M-l) 1 H NMR (400 MHz) d 8.40 (1H, s), 8.03-8.05 (1H, m), 7.87 (2H, m), 7.61 -7.63 (2H, m), 7.52-7.54 (2H, m), 7.40- 7.42 (2H, m), 7.24-7.26 (2H, m), 4.84 (1H, m), 4.39 (2H, m), 2.51 (2H, m), 2.28-2.33 (6H, m).

The following compounds can be prepared by following the above synthetic route. 4- (7-Chloro-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -2- [formyl (4'-methyl-biphenyl-4-yl) -amino] -butanoic acid (Compound No. 2) ); LCMS-447.23 (M-28) 2- [(4'-Ethylbiphenyl-4-yl) (formyl) amino] -4- (5-methyl-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. . 3) .

LCMS-469.34 (M-l) Example 2: Synthesis of O- [(-fluorophenyl) carbamoyl] - - formyl - N - (4 '-methylbiphenyl-4-yl) hornoserine (Compound No. 4) (Scheme I, Route B) Step a: Preparation of O- [(4-fluorophenyl) carbamoyl] -N-fonnyl-l- (4 '-methyl biphenyl-4-yl) methyl homoserinate To a solution of methyl N-formyl-N- (4'-methylbiphenyl-4-yl) homoserinate (0.3 g, 0.0009 mol) in tetrahydrofuran (5 mL) was added triethylamine (0.272 g, 0. 0027 moles) and 1-fluoro-4-isocyanatobenzene (0.147 g, 0.0010 moles) under an argon atmosphere at room temperature. The reaction mixture was allowed to stir for about 2 hours at room temperature. After completion, the reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified on a silica gel column using 15% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 0.15 g LCMS: 464.93 (M + l) Step b: Preparation of O- [(4-fluorophenyl) carbamoyl] -N-formyl-N- (4 '-methylbiphenyl-4-yl) homoserine To a compound obtained from Step a (0.15 g, 0.0003 mole) in tetrahydrofuran (5 mL) and methanol (5 mL) was added lithium hydroxide solution (0.018 g, 0.0004 mole) in water and stirred for about one hour. at room temperature. After completion, the reaction mixture was acidified with sodium bisulfite (pH ~ 2) and extracted with ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude compound which was purified by preparative TLC using 10% methanol: dichloromethane as a mobile phase to obtain a desired product.

Yield: 0.03 g LCMS-449.28 (M-l) XH NMR (400 MHz) d 9.63 (1H, s), 8.45 (1H, s), 7.67-7.69 (2H, m), 7.53-7.55 (4H, m), 7.26-7.28 (2H, m), 7.12- 7.14 (4H, m), 4.89-4.93 (1H, m), 4.06-4.10 (2H, s), 2.45 (2H, m), 2.41-2.43 (3H, m).

The following compounds can be prepared by following the above synthetic route.

W-Formyl-N- (4 '-methylbiphenyl-4-yl) -O- [(4-methylphenyl) -carbamoyl] homoserine (Compound No. 5); LCMS-417.27 (M-28) 0- [(3,4-Dichlorophenyl) carbamoyl] -W-formyl-N- (4 '-methylbiphenyl-4-yl) homoserine (Compound No. 6); LC S-501.15 (M) N- (4'-Ethylbiphenyl-4-yl) -W-formyl-O-. { [4- (propan-2-yl) -phenyl] carbamoyl} homoserin (Compound No. 7); LCMS-487.35 (M-l) N- (4'-Ethylbiphenyl-4-yl) -O- [(3-fluorophenyl) carbamoyl] -N-formylhomoserine (Compound No. 8); LCMS-463.33 (M-l) O- [(2,4-Difluorophenyl) carbamoyl] -? 7- (4'-ethylbiphenyl-4-yl) - N -omethylhomoserine (Compound No. 9); LCMS-481.32 (M-l) A7- (4'-Ethylbiphenyl-4-yl) -0- [(2-fluorophenyl) carbamoyl] -N-formylhomoserine (Compound 10); LCMS-463.33 (M-l) N- (4'-Ethylbiphenyl-4-yl) -N-formyl-O-. { [4- (trifluoromethyl) -phenyl] carbamoyl} Homoserine (Compound No. 11); LCMS-513.32 (M-l) N- (4'-Ethylbiphenyl-4-yl) -N-formyl-O- [(2-methylphenyl) -carbamoyl] homoserine (Compound No. 12); LCMS-459.33 (M-l) N- (4'-Ethylbiphenyl-4-yl) -O- [(4-ethylphenyl) carbamoyl] -N-formylhomoserine (Compound No. 13); LCMS-473.30 (M-l) N-. { 4'-Ethylbiphenyl-4-yl) -W-formyl-O- [(4-methoxyphenyl) -carbamoyl] homoserine (Compound No. 14); LCMS-475.35 (M-l) O- [(2,6-Dichlorophenyl) carbamoyl] -N- (4'-ethylbiphenyl-4-yl) -N-formylhomoserine (Compound No. 15); LCMS-515.29 (M-l) Example 3: Synthesis of 4- (1,3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) -2- [(4'-methoxybiphenyl-4-yl) (methyl) amino] -butanoic acid (Compound No. 18); (Scheme II, Route C) Step a: Preparation of 2-bromo-4- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) butanoic acid ? a solution of - (1,3-dioxo-1,3-dihydro-2-fluoro-isoindol-2-yl) butanoic acid (11.7 g, 0.050 mol) in carbon tetrachloride (60 mL) was added with red phosphorus (5.2 g, 0.167 mole) and heated to about 60 ° C. To this reaction mixture, bromine (40 mL, 0.792 mole) was added slowly over a period of about one hour and it was again heated to 60 ° C for about 8 hours then cooled to 0 ° C. After that, water (50 mL) was added to the reaction mixture. The reaction mixture was solidified and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution. The obtained aqueous layer was acidified (pH ~ 2) using aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to obtain the desired product.

Yield: 10.8 g LCMS: 313.4 (M + l) Step b: Preparation of tert-butyl 2-bromo-4- (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) butanoate To a solution of the compound obtained from Step a (180 mg, 0.576 mmol) in tetrahydrofuran (5 mL) was added Boc anhydride (1 mL, 0.461 mmol) and?,? '-dimethylaminopyridine (7 mg, 0.057 mmol). The reaction mixture was allowed to stir at room temperature for about 18 hours. After completion of the reaction, the solvent was distilled azeotropically using toluene and ethyl acetate to obtain a crude product. The crude product was purified on a silica gel column using 20% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 180 mg Step c: Preparation of 2- [(4-bromophenyl) (methylsulfonyl) -amino] -4- (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) tert-butyl butanoate To a solution of N- (4-bromophenyl) methanesulfonamide (1 g, 0.04 mol) in acetonitrile (20 mL) was added potassium carbonate (0.276 g)., 0.002 moles) at room temperature. The reaction mixture was allowed to stir for about 15 minutes and then the compound obtained from Step b (1472 g, 0.004 mole) was added. The reaction mixture was heated to about 80 ° C for about 56 hours. After completion, the reaction mixture was concentrated and the residue obtained was taken up in ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC using 30: hexane ethyl acetate as a mobile phase to obtain the desired product.

Yield: 1.7 g LCMS: 555.9 (M + NH4 +) Step d: Preparation of 4- (1,3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) -2- [(4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -butanoate of tert-butyl To a solution of a compound obtained from Step c (0.205 g, 0.381 mole) in dry iV, N '-dimethylformamide (5 mL) were added tetrakistriphenylphosphine (8 mg, 0.007 mole), potassium carbonate (0.21 g, 1.527 mole). ) and 4-methoxyphenylboronic acid (0.191 g, 1.259 mol) at room temperature. The reaction mixture was heated at 105 ° C for about 4.5 hours. After 4.5 hours, it was allowed to cool to room temperature and N, N'-dimethylformamide was evaporated and the residues obtained were taken in ethyl acetate. The organic layer was washed with water, brine and evaporated under vacuum to obtain the crude product which was purified by preparative TLC using 30% ethyl acetate: hexane as a mobile phase to obtain the desired product.

Yield: 0.161 g LCMS: 587.1 (+ Na) Step e: Preparation of 4- (1,3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) -2- [(4'-methoxybiphenyl-4-yl) (methylsulfonyl) -amino] b acid anoic To a solution of the compound obtained from step d (0.144 g, 0.00025 mol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.2 mL) at 0 ° C. The reaction mixture was allowed to stir for about 3 hours at 0 ° C and then at room temperature for about 4 hours.

After completion, the reaction mixture was extracted with dichloromethane, washed with water and brine. The organic layer was evaporated under reduced pressure to obtain a crude product which was purified on a silica gel column using 50% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 0.113 g LC S: 509.1 (M + l) XH NMR (CDC13, 400 Hz) d: 7.84 (2H, m), 7.71 (2H, m), 7.62. (4H, m), 7.51 (2H, d, J = 8 Hz), 6.97 (2H, d, J = 8 Hz), 5.04 (1H, m), 4.12 (2H, m), 3.85 (3H, s), 3.13 (3H, s), 2.36 (1H, m), 1.95 (1H, m).

Example 4: Synthesis of 2- [biphenyl-4-yl (methylsulfonyl) -aminol-4- (1,3-dioxo-1,3-dihydro-2-fluoro-isoindol-2-yl) butanoic acid (Compound No. 16) (Scheme II, Route D) Step a: Preparation of f-butyl 2- [biphenyl-4-yl (methylsulfonyl) amino] -4- (1,3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) butanoate To a solution of tert-butyl 2-bromo-4- (l, 3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) butanoate (300 mg, 0.815 mmol) in N, N'-dimethylformamide (5 mL) were added N- (biphenyl-4-yl) methanesulfonamide (161 mg, 0.652 mmol) and potassium carbonate (12 mg, 0.815 mmol). The reaction mixture was heated at 80 ° C for about 7.5 hours.

After completion, the reaction mixture was allowed to cool to room temperature and water was added thereto. The reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using 40% ethyl acetate: hexane as eluent to obtain the desired product. Yield: 152 mg LCMS: 552.1 (M + NH4 +) Step b: Preparation of 2- [biphenyl-4-yl (methylsulfonyl) -amino] -4- (1,3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) butanoic acid To an ice-cooled solution of the compound obtained from Step a (152 mg, 0.0002 mole) in dichloromethane (10 mL) was added trifluoroacetic acid (0.7 mL) and stirred for about 2.5 hrs at room temperature. After completion of the reaction, the solvent was evaporated and the reaction mixture was taken up in dichloromethane and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified on a silica gel column using 40% ethyl acetate: hexane as eluent to obtain the desired product. Yield: 41.6 mg ' LCMS: 479.0 (M + l) X H NMR (MeOH-d 6, 400 MHz): d 7.85 (4H, m), 7.78 (4H, m), 7.63 (2H, m), 7.45 (2H, m), 7.36 (1H, m), 4.88 (1H , m), 3.86 (2H, m), 3.15 (3H, s), 2.36 (1H, m), 1.89 (1H, m).

The following compounds can be prepared by following the above synthetic route. 4- (1, 3-dioxo-l, 3-dihydro-2tf-isoindol-2-yl) -2- acid. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} - Butanoic (Compound No. 17); LCMS: 510.1 (M + l) Example 5: Synthesis of acid 2-. { [4- (6-methoxypyridin-3-yl) -phenyl] (methylsulfonyl) amino} -4- (4-0X0-1,2, 3-benzotriazin-3- (4ff) -yl) butanoic (Compound No. 19) (when Rk is halogen) (Esguema III, Ruta E) Step a: Preparation of N- (4-bromophenyl) -N- (2-oxotetra- ^ hydrofuran-3-yl) me anosulfonamide To a solution of -hydroxy lactone (673 mg, 0.0072 mol) at 0 ° C were added N- (4-bromophenyl) methanesulfonamide (1.5 g, 0.006 mol) and triphenylphosphine (2.35 g, 0.009 mol). The reaction mixture was allowed to stir for about 15 minutes at 0 ° C and diisopropylazodicarboxylate (1.8 g, 0.0009 mole) was added. The reaction mixture was stirred again for about 30 minutes at 0 ° C. After completion, the reaction mixture was concentrated to obtain a crude product which was purified on a column of silica gel using 40% ethyl acetate: hexane as eluent to obtain the desired compound.

Yield: 920 mg LCMS: 351.18 and 353.12 (M + NH4 +) Step b: Preparation of 2- [(4-bromophenyl) (methylsulfonyl) -amino] sodium 4-hydroxybutanoate To a solution of the compound obtained from Step a (1.5g, 0.0044 mole) in methanol (10 mL) was added sodium hydroxide (79 mg, 0.0044 mole) and stirred for about one hour at room temperature. After completion, the reaction mixture was concentrated and ethyl acetate was added and decanted to obtain the desired product.

Yield: 850 mg.

Step c: Preparation of benzyl N- (4-bromophenyl) -N- (methylsulfonyl) -homoserinate To a solution of the compound obtained from Step b (800 mg, 0.0022 mol) in N, N '-dimethylformamide (5 mL) at 0 ° C was added benzyl bromide (388 mg, 0.0022 mol). The reaction mixture was allowed to stir overnight at room temperature. After completion, reaction mixture was extracted with ethyl acetate while washing with water. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product thus obtained was purified on a silica gel column using 70% ethyl acetate: hexane to obtain the desired product.

Yield: 850 mg.

Step d: Preparation of N- (4-bromophenyl) -O- [tert-butyl- (dimethyl) silyl] -N- (methylsulfonyl) benzyl homoserinate To a solution of the compound obtained from Step c (800 mg, 0.0018 mol) in N, W-dimethylformamide (8 mL) were added tert-butyldimethylsilyl chloride (325 mg, 0.0021 mol) and imidazole (369 mg, 0.0054 mol). The reaction mixture was allowed to stir for about one hour at room temperature. After completion, the reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide the desired product.

Yield: 1.2 g LCMS: 556.77 and 558.78 (M + l) Step e: Preparation of O- [fcer-butyl (dimethyl) silyl] -N- [4- (6-methoxypyridin-3-yl) phenyl] -N-methylsulfonyl) benzyl homoserinate To a solution of the compound obtained from Step d (1.7 g, 0.0045 mol) in N, N'-dimethylformamide (20 mL) were added 5-methoxypyridineboronic acid (929 mg, 0.0061 mol), tetraqui triphenylphosphine palladium (O) (176 mg, 0.0008 mol) and potassium carbonate ( 1.26 g, 0.0091 moles). After the completion of the addition, the reaction mixture is heated to 110 ° C for about 3 hours. After 3 hours, the solvent was evaporated and the reaction mixture was extracted with ethyl acetate while washing with water. The combined organic layer was collected, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product obtained was purified on a silica gel column using 40% ethyl acetate to obtain the desired product.

Yield: 1.3 g Step f: Preparation of N- [4- (6-methoxypyridin-3-yl) phenyl] -N- (methylsulfonyl) benzyl omoserinate To a solution of the compound obtained from Step e (1.1 g, 0.0019 mol) in dichloromethane (20 mL) was added boron trifluoride etherate BF3.OEt (1.1 g, 0.0095 mol) slowly at room temperature. The reaction mixture was allowed to stir at room temperature for about one hour. After completion, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified on a silica gel column using 40% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 750 mg LCMS: 471.30 (M + l) Stage g: Preparation of 2-. { [4- (6-methoxypyridin-3-yl) phenyl] - (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) -butanoate benzyl To a solution of the compound obtained from Step f (250 mg, 0.531 mmol) in tetrahydrofuran (15 mL) at 0 ° C were added benzotriazinone (78 mg, 0.531 mmol) and triphenylphosphine (278 mg, 1.063 mmol). The reaction mixture was allowed to stir for about 15 minutes at 0 ° C and diisopropylazodicarboxylate (161 mg, 0.797 mmol) was added at the same temperature. The reaction mixture was stirred again for about one hour at the same temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using 40% ethyl acetate: hexane to obtain the desired product.

Yield: 200 mg.

LCMS: 600.88 (M + l) E-lid h: Preparation of acid 2-. { [4- (6-methoxypyridin-3-yl) -phenyl] (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3- (4H) -yl) butanoic To a solution of the compound obtained from Step g (200 mg) in tetrahydrofuran (10 mL) was added 10% Pd / C (200 mg) and hydrogen was supplied at 55 psi in an apparatus Parr for about 8 hours at room temperature. After completion, the reaction mixture was filtered through a pad of celite and the residue was washed with 20% methanol: dichloromethane. The filtrate was concentrated to obtain the solid material which was treated with ethyl acetate. The ethyl acetate layer was decanted to obtain the desired product.

Yield: 18 mg LCMS: 510.70 (M + l) * H NMR (DMSO-de, 400 MHz) d: 8.52 (1H, s), 8.25 (1H, d, J = 8 Hz), 8.18 (1H, d, J = 8 Hz), 8.05 (2H, m) , 7.92 (1H, m), 7.76 (2H, d, J = 8 Hz), 7.66 (2H, d, J = 8Hz), 6.92 (1H, d, J = 8 Hz), 4.48 (3H, m), 3.90 (3H, s), 3.29 (3H, s), 2.3 (1H, m), 1.90 (1H, m).

The following compounds can be prepared by following the above synthetic route. 4- (7-Methoxy-4-oxo-l, 2, 3-benzotriazin-3 (4i /) -yl) -2- acid. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} - butanoic (Compound No. 20); - LCMS: 540.71 (M + l) Acid 2-. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) -amino} -4- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazin-3 (4H) -yl] butanoic (Compound No. 21); LCMS: 578.74 (M + l) Example 6: Synthesis of 2- [(-methoxyphenyl) - (methylsulfonyl) aminol-4- (4-oxo-l .2.3-ben-otriazin-3 (4-yl) -yl) -butanoic acid (Compound No. 32) (Scheme III, Route F) Step a: Preparation of benzyl 2- [(4-methoxyphenyl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoate To a solution of N- (4-methoxyphenyl) -N- (methylsulfonyl) benzyl homoserinate (200 mg, 0.508 mol) in tetrahydrofuran (15 mL) were added triphenylphosphine (200 mg, 0.763 mol) and benzotriazinone (82 mg, 0.550). moles) at 0 ° C. The reaction mixture was stirred for approximately 15 minutes and diisopropylazodicarboxylate (154 mg, 0.763 mole) was added thereto at 0 ° C. The reaction mixture was stirred again for about 2 hours at room temperature. After completion, the solvent was evaporated to obtain a crude product which was purified on a silica gel column using 30% ethyl acetate: hexane as eluent to obtain the desired compound.

Yield: 180 mg Step b: Preparation of 2- [(4-methoxyphenyl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -butanoic acid To a compound obtained from Step a (180 mg) in tetrahydrofuran (10 mL) and methanol (10 mL) was added 10% Pd / C (60 mg) and hydrogen gas was supplied in a Parr apparatus at 50 psi during approximately one hour at temperature ambient. After one hour, the reaction mixture was filtered through a celite pad and the obtained residue was washed with 10% methanol: dichloromethane. The filtrate was concentrated under reduced pressure to obtain the desired compound.

Yield: 24 mg LCMS: 433. 69 (M + l) X H NMR (MeOD, 400 MHz): d 8.31 (1 H, d, J = 8 Hz), 8.14 (1 H, d, J = 8 Hz), 8.03 (1 H, m), 7.88 (1 H, m), 7.58 ( 2H, d, J = 8 Hz), 6.92 (2H, d, J = 8 Hz), 4.92 (1H, m), 4.57-4.67 (2H, m), 3.79 (3H, s), 3.14 (3H, s ), 2.48 (1H, m), 2.02 (1H, m).

The following compounds can be prepared by following the above synthetic route. 4- (6-Methoxy-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -2- acid. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} butanoic (Compound No. 23); LCMS: 539.84 (M + l) 4- (7-Methyl-4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) -2- acid. { [A- (4-methylphenoxy) phenyl] (methylsulfonyl) aminojbutanoic (Compound No. 24); LCMS: 523.78 (M + l) Acid 2-. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} -4- [4-OXO-7- (trifluoromethyl) -1,2,3-benzotriazin-3 (4H) -yl] -butanoic (Compound No. 25); LCMS: 572.86 (M + l) Acid 2-. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4iY) -yl) butanoic (Compound No. 26); LCMS: 509.74 (+ l) 4- (7-Methoxy-4-oxo-1,2,3-benzotriazin-3 (4H) -yl) -2- [(4-methoxyphenyl) (methylsulfonyl) amino] butanoic acid (Compound No. 33); LCMS: 463.79 (M + l) 4- (1, 3-Dioxo-1,3-dihydro-2-t-isoindol-2-yl) -2- [(4-methoxyphenyl) (methylsulfonyl) amino] butanoic acid (Compound No. 34); LCMS: 433.63 (M + l) 2- [(-methoxyphenyl) (methylsulfonyl) amino] -4- (5-methyl-1,3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) butanoic acid (Compound No. 35); LCMS: 469.70 (M + l) 4- (7-Methoxy-4-oxo-l, 2, 3-benzotriazin-3 (4'-yl) -2- { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} butanoic acid (Compound No. 36); LCMS: 539.84 (M + l) 4- (5-Methyl-l, 3-dioxo-l, 3-dihydro-2tf-isoindol-2-yl) -2- acid. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) aminojbutanoic (Compound No. 37); LCMS: 523.85 (M + l) 2- [(Methylsulfonyl) (phenyl) amino] -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 58); LCMS: 402.85 (M + l) 4- (5-Chloro-4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) -2- [(4-chlorophenyl) (ethylsulfonyl) amino] butanoic acid (Compound No. 104); LCMS: 473.67 (M + l) 2- [(-broraphenyl) (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (y) -yl) butanoic acid (Compound no. 105); LCMS: 481.54 and 483.51 (M + l) 2- [(4-Chlorophenyl) (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzothiazin-3 (4H) -yl) butanoic acid (Compound no. 106); LCMS: 437.33 (M + l) 2- [(4-Chlorophenyl) (methylsulfonyl) amino] -4- (7-methyl-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 107); LCMS: 451.70 (M + l) 2- [(4-Chlorophenyl) (methylsulfonyl) amino] -4- (6-methoxy-4-oxo-l, 2,3-benzotriazin-3 (H) -yl) butanoic acid (Compound No. 108); LCMS: 467.75 (M + l) Example 7: Synthesis of 2- [(4'-chlorobiphenyl-4-yl) (methyl-sulfonyl) amino] -4- (5-methyl-l, 3-dioxo-l, 3-dihydro-2-tf-isoindole -2-yl) butanoic (Compound No. 59) (Scheme III, Route G) Step a: Preparation of 2- [(4'-chlorobiphenyl-4-yl) (methyl-sulfonyl) amino] -4- (5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2) -yl) prop-2-en-l-yl butanoate To a solution of the hydroxyl derivative (0.250 g, 0.591 mol) in tetrahydrofuran (10 mL) were added triphenylphosphine (0.232 g)., 0.88 moles) and 4-methyl phthalimide (0.104 g, 0.65 moles) at 0 ° C. The reaction mixture was stirred for about 15 minutes and diisopropylazodicarboxylate (0.179 g, 0.088 mols) was added thereto at 0 ° C. The reaction mixture was stirred again for about 2 hours at room temperature. After completion, the solvent was evaporated to obtain a crude product which was purified on a silica gel column using 30% ethyl acetate: hexane as eluent to obtain the desired compound.

Yield: 0.25 g.

Step b: Preparation of 2- [(4'-chlorobiphenyl-4-yl) - (methylsulfonyl) amino] -4- (5-methyl-l, 3-dioxo-l, 3-dihydro-2ff-isoindol-2) acid -il) butañoico To a compound obtained from Step a (250 mg, 0. 441 mol) in acetonitrile (10 mL) at 0 ° C was added tetraqui triphenylphosphine (51 mg, 0.044 mol) and morpholine (384 mg, 4.4 mol). The reaction mixture was allowed to stir for about 3 hours at 0 ° C. After 3 hours, the reaction mixture was diluted by addition of water and extracted with ethyl acetate. The aqueous layer obtained was acidified with sodium bisulfite and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on preparative TLC using 10% methanol: dichloromethane as a mobile phase to obtain the desired product.

Yield: 35 mg LCMS: 526.84 (M + l) XH NR (MeOH-d6, 400 MHz): d 7.78 (2H, d, J = 8 Hz), 7.70 (1H, d, J = 4Hz), 7.61 (6H, m), 7.43 (2H, m), 4.73. (1H, m), 3.72-3.90 (2H, m), 3.20 (3H, s), 2.48 (3H, s), 2.31 (1H, m), 1.77 (1H, m).

The following compounds can be prepared by following the above synthetic route. 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (5-chloro-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 60); LCMS: 546.66 (M) 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (7-chloro-4-oxo-l, 2,3-benzotriazin-3 (H) -yl) butanoic acid (Compound no. 61); LCMS: 546.73 and 548.68 (M + l) 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (7-methyl-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 62); LCMS: 526.70 and 528.72 (M + l) 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- [4-OXO-7- (trifluoromethyl) -1,2,3-benzotriazin-3 (4tf) -yl] -butanoic acid (Compound No. 63); LCMS: 580.74 (M + l) 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (5-methoxy-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 64); LCMS: 542.76 (M + l) 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (5-fluoro-4-oxo-l, 2,3-benzotriazin-3 (47 /) -yl) butanoic acid (Compound No. 65); LCMS: 530.73 (M + l) 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl) -butanoic acid (Compound No. 66); LCMS: 543.6 (M + l) Example 8: Synthesis of 2- [. { 4- [(4-methylphenyl) -carbamoyl] phenyl} (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzo-triazin-3 (H) -yl) butanoic (Compound No. 68) Scheme III, Route H) Stage a: Preparation of 4-. { (methylsulfonyl) [l-oxo-4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) -1- (prop-2-en-l-yloxy) bu an-2- il ] Not me} tert-butyl benzoate To a solution of the hydroxyl derivative (1.4 g, 3.389 mmol) in tetrahydrofuran (20 mL) at 0 ° C were added triphenylphosphine (1.77 g, 6.779 mmol) and 1,2,3-benzotriazin-4 (3 H) -one ( 0.498 g, 3.389 mmol) after 5 minutes at the same temperature, diisopropyl azodicarboxylate (1027 g, 5084 mmol) was added. Then, the reaction mixture was stirred for 30 minutes at the same temperature. The solvent was evaporated and the purification was performed on a 60-120 mesh column of silica gel using 40% EtOAc: Hexane as eluent to obtain 3 gm of the product.

LCMS: 542.83 (M + l) Step b: Preparation of acid 4-. { (methylsulfonyl) [l-oxo-4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) -1- (prop-2-en-l-yloxy) butan-2-yl] Not me} benzoic To a solution of the compound obtained from Step a (3 g, 5.535 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (6 mL, 28782 mmol) at room temperature. The reaction mixture was allowed to stir for about 2 hours at the same temperature. After 2 hours, the solvent was evaporated and the reaction mixture was neutralized by aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated under vacuum to obtain the desired product.

Performance: 1 g LCMS: 486.78 (M + l) The following compounds can be prepared by following the above synthetic route. 4- Acid. { (methylsulfonyl) [l-oxo-4- (4-oxo-l, 2, 3-benztriazin-3 (4H) -yl) -l- (prop-2-en-1-yloxy) utan-2 - il] amino} - benzoic (Compound No. 67); LCMS: 486.78 (M + l) Stage c: Preparation of 2- [. { 4- [(4-methylphenyl) carbamoyl] -phenyl} (Methylsulfonyl) amino] -4- (4-oxo-l, 2, 3-benzotriazin-3 (4fl) -yl) butanoate of prop-2-en-1-yl To an ice-cooled solution of the compound obtained from Step b (400 mg, 0.823 mmol) in?,? '-dimethylformamide (20 mL) were added p-toludine (88 mg, 0.823 mmol), hydrochloride of 1- (3 -dimethylaminopropyl) -3-ethylcarbodiimide (236 mg, 1.234 mmol),?,? '-dimethylaminopyridine (20 mg, 0.164 mmol) and hydroxybenzotriazole (111 mg, 0.823 mmol). The reaction mixture was allowed to stir at room temperature for 12 hours. After completion, the solvent was evaporated and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum to obtain the crude product. The crude product obtained was purified on a silica gel column using 80% ethyl acetate: hexane as eluent to obtain the desired compound.

Yield: 520 mg Step d: Preparation of acid 2- [. { 4- [(4-methylphenyl) -carbamoyl] phenyl} methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzo-triazin-3 (4H) -yl) butanoic To an ice-cooled solution of the compound obtained from Step c (520 mg, 0.904 mmol) in acetonitrile (25 mL) were added tetrakiss triphenylphosphine palladium (O) (208 mg, 0.180 mmol) and morpholine (786 mg, 9.043 mmol). . The reaction mixture was allowed to stir at the same temperature for about 30 minutes. After 30 minutes, the solvent was evaporated and the reaction mixture was acidified using aqueous sodium bisulfate solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to obtain the crude product. The crude product was purified on preparative TLC using 10% methanol: dichloromethane as a mobile phase to obtain the desired compound.

Yield: 250 mg.

LC S: 535.84 (M + l), 557.82 (M + Na) XH NMR (DMS0-d6, 400 MHz) d: 10.3 (1H, s), 8.25 (2H, m), 8.20 (1H, m), 8.06-8.10 (3H, m), 7.96 (4H, m), 7.15 (2H, d, J = 8 Hz), 4.78 (1H, m). 4.51 (2H, m), 3.16 (3H, s), 2.42 (1H, m), 2.20 (3H, s), 1.95 (1H, m).

The following compounds can be prepared by following the above synthetic route. 2- [. { 4- [(-chlorophenyl) carbamoyl] phenyl} (Methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) -butanoic acid (Compound No. 69); LCMS: 555.74 and 557.72 (M + l) Acid 2-. { (methylsulfonyl) [4- (phenylcarbamoyl) phenyl] amino} 4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 70); LCMS: 521.80 (M + l) Acid 2 - [. { 4 - [(3-fluorophenyl) carbamoyl] phenyl} (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) -butanoic acid (Compound No. 71); LCMS: 539.74 (M + l) 2- [(Methylsulfonyl) (4-. {[[4- (propan-2-yl) phenyl] -carbamoyl}. Phenyl) amino] -4- (4-oxo-1,2,3-benzotriazine) 3 (H) -yl) butanoic (Compound No. 72); LCMS: 563.80 (M + l) 2- [. { - [(4-methoxyphenyl) carbamoyl] phenyl} (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4 H) -yl) -butanoic acid (Compound No. 73); LCMS: 551.77 (M + l) 2- [. { 4- [(4-fluorophenyl) carbamoyl] phenyl} (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) -butanoic acid (Compound No. 74); LCMS: 539.74 (M + l) 2- [(Methylsulfonyl) (4- {[4- (trifluoromethyl) phenyl] -carbamoyl} phenyl) amino] -4- (-oxo-l, 2,3-benzotriazin-3 (4H) - il) butanoic (Compound No. 75).

LCMS: 589.75 (M + l) Example 9: Synthesis of 4- (1,3-dioxo-1,3-dihydro-2-fluoro-isoindol-2-yl) -2- acid. { (methylsulfonyl) [4-propan-2-yl) phenyl] -amino} Utanoic (Compound No. 51) (Scheme IV) Stage a: Preparation of 4-. { [tert-butyl (dimethyl) silyl] oxy} Benzyl-2-hydroxybutanoate To an ice-cooled solution of benzyl 2,4-dihydroxybutanoate (10.4 g, 49.52 mmol) in dichloromethane (100 mL) were added triethylamine (8.3 mL, '59.42 mmol) followed by tert-butyldimethylsilyl chloride (8.20 g, 54.47 g). mmoles) and N, IV'-dimethylaminopyridine (241 mg, 1.98 mmol). The reaction mixture was allowed to stir at room temperature for about one hour. After completion, the reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to provide the crude compound. The crude compound obtained was purified on column chromatography using silica gel and eluting with 10% ethyl acetate: hexane as eluent to obtain the desired compound.

Yield: 9.6 g LCMS: 325.67 (M + l), 347.64 (M + Na) Step b: Preparation of O- [tert-butyl (dimethyl) silyl] -N- (methyl-sulfonyl) -N- [4- (propan-2-yl) phenyl] benzyl homoserinate To an ice-cooled solution of the compound obtained from Step a (1 g, 3.08 mmol) in tetrahydrofuran (5 mL) were added N- [4- (propan-2-yl) phenyl] methanesulfonamide (722 mg, 3.39 g. mmoles) and triphenylphosphine (1.21 g, 4.62 mmol) under an argon atmosphere. Diisopropylazodicarboxylate (0.67 mL, 3.39 mmol) was added dropwise and the reaction mixture was allowed to stir at the same temperature for about 30 minutes. After completion, the solvent was evaporated under vacuum and the crude compound obtained was purified on silica gel using 20% ethyl acetate: hexane as eluent to obtain the desired compound.

Yield: 1.7 g.

Step c: Preparation of N- (methylsulfonyl) -N- [4- (propan-2-yl) -phenyl] benzyl homoserinate ? a solution of the compound obtained from Step b (1.7 g, 3.27 mmol) in dichloromethane (10 mL) was added borate trifluoride etherate BF3.OEt2 (2 mL, 16.35 mmol) slowly at room temperature. The reaction mixture was allowed to stir at room temperature for about one hour. After completion, the reaction mixture was rapidly cooled with saturated sodium bicarbonate solution. sodium and extracted with dichloromethane. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude compound. The crude compound obtained was purified on a column of silica gel and eluted with 40% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 510 mg Step d: Preparation of 4- (1,3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) -2-. { (methylsulfonyl) [4- (propan-2-yl) phenyl] amino} benzyl butanoate To an ice-cooled solution of the compound obtained from Step c (170 mg, 0.41 mmol) in tetrahydrofuran (10 mL) were added phthalimide (67 mg, 0.46 mmol) and triphenylphosphine (161 mg, 0.61 mmol). Diisopropylazodicarboxylate (0.09 mL, 0.46 mmol) was added to the reaction mixture and stirred for about 30 minutes at the same temperature. After completion, the solvent was evaporated and the obtained crude product was purified on silica gel column chromatography using 50% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 150 mg Step e: Preparation of 4- (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) -2- acid. { (methylsulfonyl) [4- (propan-2-yl) phenyl] -amino} butañoico To a solution of the compound obtained from Step d (150 mg, 0.280 mmol) in tetrahydrofuran (10 mL) at room temperature was added 10% Pd / C (100 mg) and hydrogen gas was supplied by balloon. The reaction mixture was allowed to stir for about 30 minutes at the same temperature. After completion, the reaction mixture was filtered using a pad of celite and the residue obtained was washed with 10% methanol solution: dichloromethane. The filtrate was concentrated and the purification was carried out in preparative TLC using 10% methanol: dichloromethane as a mobile phase to provide the desired product.

Yield: 30 mg.

LC S: 445.79 (M + l), 467.75 (M + Na) XH NMR (McOD-d6, 400 MHz) 5: 7.78-7.85 (2H, m), 7.52 (1H, d, J = 8 Hz), 7.29 (1H, d, J = 8 Hz), 4.90 (1H, m ), 3.74-3.91 (2H, m), 3.29 (3H, s), 2.93 (1H, m), 2.20 (1H, m), 1.79 (1H, m), 1.25 (6H, dd, J = 8 Hz) .

The following compounds can be prepared by following the above synthetic route. 4- (6-Methoxy-4-oxo-l, 2,3-benzotriazin-3 (Oi) -yl) -2- acid. { (methylsulfonyl) [4- (propan-2-yl) phenyl] amino} butanoic (Compound No. 52); LCMS: 475.82 (M + l) 4- (7-Methyl-4-oxo-l, 2,3-benzotriazin-3 (4 H) -yl) -2- acid. { (methylsulfonyl) [4- (propan-2-yl) phenyl] amino} butanoic (Compound No. 53); LCMS: 459.83 (M + l) 4- (1, 3-Dioxo-1,3-dihydro-2i-isoindol-2-yl) -2- [(4-ethylphenyl) (methylsulfonyl) amino] butanoic acid (Compound No. 54); LCMS: 431.75 (M + l) 2- [(4-Ethylphenyl) (methylsulfonyl) amino] -4- (5-methyl-1,3-dioxo-l, 3-dihydro-2'T-isoindol-2-yl) butanoic acid (Compound No. 55); LCMS: 445.79 (M + l) 2- [(4-Ethylphenyl) (methylsulfonyl) amino] -4- (7-methyl-4-oxo-1,2,3-benzotriazin-3 (4) -yl) butanoic acid (Compound No. 56); LCMS: 445.79 (M + l) 2- [(4-Ethylphenyl) (methylsulfonyl) amino] -4- (6-methoxy-4-oxo-l, 2,3-benzotriazin-3 (AH) -yl) butanoic acid (Compound No. 57); LCMS: 461.79 (M + l) Example 10: Synthesis of 2- [(3 ', 4' -difluorobiphenyl-4-yl) (methylsulfonyl) aminol-4- (4-oxo-l, 2,3-benzotriazin-3 (4ff) -yl) butanoic acid (Compound No. 27) (Scheme V) Step a: Preparation of 3- [2- (2,2-dimethyl-1,3-dioxolan-4-yl) -ethyl] -1,2,3-benzotriazin-4 (3H) -one To a solution cooled with ice of 4- (2- hydroxyethyl) -2,2-dimethyl-1,3-dioxolane (3.8 g, 0.025 mol) in tetrahydrofuran (50 mL) were added benzotriazinone (4.2 g, 0.028 mol) and triphenylphosphine (13.6 g, 0.051 mol). The reaction mixture was allowed to stir for about 15 minutes at 0 ° C and diisopropylazodicarboxylate (7.3 mL, 0.038 moles) was added thereto. The reaction mixture was stirred again for about 2 hours at room temperature. After the completion of the reaction, the solvent was evaporated under vacuum to obtain the crude product which was purified on a column of silica gel using 30% ethyl acetate: hexane as eluent to obtain the desired product.

Performance: llg LC S: 294.99 (M + Na) Step b: Preparation of 3- (3,4-dihydroxybutyl) -1, 2, 3-benzo-triazin-4 (3H) -one To a solution of the compound obtained from Step a (11 g, 39.954 mmol) in acetone (60 mL) was added concentrated HC1 (12 mL) and the reaction mixture was allowed to stir at room temperature for about one hour. After one hour, the solvent was evaporated under reduced pressure and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum to obtain the crude compound. The crude compound obtained was purified on a column of silica gel using 70% ethyl acetate: exano as eluent to obtain the desired product. Yield: 4.5 g LCMS: 236.49 (M + l) Step c: Preparation of benzoate of 2-hydroxy-4- (4-oxo-l, 2,3-benzo-triazin-3 (4.H) -il) utilo To an ice-cooled solution of the compound obtained from Step b (1 g, 0.0042 mole) in dichloromethane (150 mL) were added triethylamine (1.1 mL, 0.0085 mole) and benzoyl chloride (0.5 mL, 0.0042 mole) and stirred at the same temperature for about 2 hours and will temper the environment for about 3 hours. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was collected, dried over anhydrous sodium sulfate and evaporated under vacuum to obtain the crude product. The crude product was purified on a silica gel column using 70% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 1.8 g LCMS: 340.59 (M + l) Step d: Preparation of 2- [(4-bromophenyl) - (ethethylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4fT) -yl) -butyl benzoate To an ice-cooled solution of the compound obtained from Step c (1.8 g, 0.0053 mol) in tetrahydrofuran (20 mL) were added triphenylphosphine (2.78 g, 0.0161 mol) and N- (4-bromophenyl) methanesulfonamide (1.46 g, 0.00584 mol). The reaction mixture was allowed to stir for about 15 minutes and then diisopropylazodicarboxylate (1.5 mL, 0.00796 moles) was added at the same temperature. The reaction mixture was stirred again at room temperature for about one hour. After one hour, the solvent was evaporated under reduced pressure to obtain a crude product. The obtained crude product was purified on a silica gel column using 30% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 1.3 g.

Step e: Preparation of 2- [(3 ', 4'-difluoro-biphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzo-triazin-3 benzoate 4ff) -yl) butyl To a solution of the compound obtained from Step d (400 mg, 0.0007 mol) in N, N'-dimethylformamide (15 mL) were added tetrakis triphenylphosphine palladium (O) (40 mg, 0.000035 mol), potassium carbonate (290 mg). , 0.0021 moles) and. 3, 4-difluorobenzene boronic acid (221 mg, 0.0014 mol). The reaction was heated to 110 ° C for about 3 hours. After 3 hours, the solvent was evaporated and the reaction mixture was taken up in ethyl acetate and washed with water.

The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using 50% ethyl acetate: hexane to obtain the desired product.

Yield: 300 mg LCMS: 606.27 (M + 2).

Step f: Preparation of N- (3 ', 4'-difluorobiphenyl-4-yl) -N- [1-hydroxy-4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) bu an-2-yl] -methanesulfonamide To a solution of the compound obtained from Step e (300 mg, 0.496 moles) in methanol (10 mL) and tetrahydrofuran (10 mL) was added potassium carbonate (102 mg, 0.745 moles) and stirred for about one hour at room temperature. ambient. After one hour, the solvent was evaporated and the reaction mixture was taken in ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product obtained was purified on a silica gel column using 60% ethyl acetate: hexane as eluent to obtain the desired product. Yield: 200 mg LCMS: 501.81 (M + l) Step g: Preparation of 2- [(3 ', 4'-difluorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) acid butanoic To a solution of the compound obtained from Step f (200 mg, 0.4 moles) in acetonitrile (10 mL) were added 2, 2, 6, 6-tetramethylpiperidine-N-oxyl (6 mg, 0.04 moles), sodium chlorite ( 72 mg, 0.8 mol) and 5% aqueous solution of sodium hypochlorite (59 mg, 0.8 mol). The reaction was heated to 35 ° C for about 6 hours. After 6 hrs, the solvent was evaporated and the reaction mixture was taken in ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on preparative TLC using 10% methanol: dichloromethane as a mobile phase to obtain the desired product.

Yield: 30 mg.

LCMS: 515.72 (M + l) XH NMR (DMSO-d6, 400 ??) d: 8.28 (2H, d, J = 4 Hz), 8.22 (1H, d, J = 8 Hz), 8.12 (1H, dd, J = 8 and 4 Hz ), 7.96 (1H, m), 7.85 (4H, m), 7.58 (2H, m), 4.74 (1H, d, J = 8 HZ), 4.56 (2H, m, -NCH2), 3.21 (3H, s) ), 2.48 (2H, m).

The following compounds can be prepared by following the above synthetic route. 4- (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) -2- acid. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} - Butanoic (Compound No. 22); LCMS: 510.69 (M + l) 2- [(4'-Ethylbiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (H) -yl) butanoic acid (Compound No. 28); LCMS: 507.79 (M + l) Acid 2-. { [4- (2-methoxypyrimidin-5-yl) phenyl] (methyl-sulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) -butanoic acid (Compound No. 29); LCMS: 51 1.76 (M + 1) 2- [(3'-Fluoro-4 '-methylbiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic acid ( Compound No. 30); LCMS: 51 1.76 (M + l) 2- [(2 ', 4'-dimethoxybiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 31); LCMS: 539.84 (M + l) 2- [(3'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4 - (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 38); LCMS: 509.81 (M + l) 2- [(4'-Fluorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 39); LCMS: 497.78 (M + l) Acid 2-. { (methylsulfonyl) [4 '- (propan-2-yl) biphenyl-4-yl] -amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 40); LCMS: 521.82 (M + l) 2- [Biphenyl-4-yl (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4 f) -yl) butanoic acid (Compound No. 41); LCMS: 479.78 (M + l) Acid 2-. { [4- (6-methylpyridin-3-yl) phenyl] (methylsulfonyl) -amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (H) -yl) butanoic (Compound No. 42); LCMS: 494.83 (M + l) Acid 2-. { (methylsulfonyl) [4- (pyrimidin-5-yl) phenyl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -i1) butanoic (Compound No. 43); LCMS: 481.79 (M + l) Acid 2-. { (methylsulfonyl) [4- (pyridin-3-yl) phenyl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4K) -yl) butanoic (Compound No. 44); LCMS: 480.79 (M + l) Acid 2-. { (methylsulfonyl) [4 '- (trifluoromethyl) biphenyl-4-yl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 45); LCMS: 547.83 (M + l) Acid 2-. { (methylsulfonyl) [4- (pyridin-4-yl) phenyl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4 H) -yl) butanoic (Compound No. 46); LC S: 480.7969 (M + l) 2- [(3 ', 4'-Dichlorobiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 47); LCMS: 547.76 and 549.71 (M + l) 2- [(4'-tert-Butylbiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 48) ); LCMS: 535.87 (M + l) 2- [(2 ', 3' -difluorobiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4tf) -yl) butanoic acid (Compound no. 49); LCMS: 515.79 (M + l) 2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -butanoic acid ( Compound No. 50).

LCMS: 527.81 (M + l) Example 11: Synthesis of acid. { 2R) -2- [(3 ',' -dichlorobiphenyl-4-yl) (methylsulfonyl) aminol-4- (4-oxo-l, 2,3-benzotriazin-3 (4ff) -yl) butanoic (Compound no. 79): Scheme V Step a: Preparation of 3- [2- (2, 2-dimethyl-1,3-dioxolan-4-yl) -ethyl] -1,2, 3-benzotriazin- (3H) -one To an ice-cooled solution of 4- (2-hydroxyethyl) -2,2-dimethyl-1,3-dioxolane (20 g, 0.136 mole) in tetrahydrofuran (200 mL) were added benzotriazinone (22 g, 0.150 mole) and triphenylphosphine (71 g, 0.273 mole). The reaction mixture was allowed to stir for about 15 minutes at 0 ° C and diisopropylazodicarboxylate (41.5 g, 0.205 mole) was added thereto. The reaction mixture was stirred again for 2 hours at room temperature. After the completion of the reaction, the solvent was evaporated under vacuum to obtain a crude product which was purified on a column of silica gel using 30% ethyl acetate: hexane as eluent to obtain the desired product. Yield: 69 g Step b: Preparation of 3- (3,4-dihydroxyethyl) -1,2,3-benzo-triazine-4 (3H) -one To a solution of the compound obtained from Step a (69 g, 0.250 moles) in acetone (200 mL) was added concentrated HC1 (70 mL) and the reaction mixture was allowed to stir at room temperature for about one hour. After one hour, the solvent was evaporated under reduced pressure and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum to obtain the crude compound. The crude compound obtained was purified on a silica gel column using 70% ethyl acetate: hexane as eluent to obtain the desired product. Yield: 21 g Step c: Preparation of 2-hydroxy-4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -11) butyl benzoate To an ice-cooled solution of the compound obtained from Step b (21 g, 0.089 mole) in dichloromethane (100 mL) were added triethylamine (27 g, 0.268 mole) and benzoyl chloride (15.5 mL, 0.134 mole) and stirred at the same temperature for about 3 hours. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was collected, dried over anhydrous sodium sulfate and evaporated under vacuum to obtain the crude product. The crude product was purified on a silica gel column using 70% ethyl acetate: hexane as eluent to obtain the desired product. Performance: 16 g Step d: Preparation of 2- [(4-bromophenyl) - (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -butyl benzoate To an ice-cooled solution of the compound obtained from Step c (11 g, 0.032 mole) in tetrahydrofuran (100 mL) were added triphenylphosphine (17 g, 0.064 mole) and N- (4-bromophenyl) methane sulfonamide (8.95 g, 0.035 mole). The reaction mixture was allowed to stir for about 15 minutes and then diisopropylazodicarboxylate (9.8 g, 0.048 mole) was added at the same temperature. The reaction mixture was stirred again at room temperature during about one hour. After one hour, the solvent was evaporated under reduced pressure to obtain a crude product. The obtained crude product was purified on a silica gel column using 30% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 1.3 g.

Step e: Preparation of 2- [(3 ', 4'-dichlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl benzoate butyl To a solution of the compound obtained from Step d (0.8g, 0.0014 mole) in N, W'-dimethylformamide (20 mL) were added tetrakis triphenylphosphine palladium (0) (0.08 g, 0.00007 mole), potassium carbonate (.58 g, 0.0042 mole) and acid 3, 4 -Boroonic chlorobenzene (0.535 g, 0.0028 mole). The reaction was heated to 110 ° C for about 3 hours. After 3 hours, the solvent was evaporated and the reaction mixture was taken up in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using 50% ethyl acetate: hexane to obtain the desired product.

Yield: 850 mg Step f: Preparation of N- (3 ', 4'-dichlorobiphenyl-4-yl) -N- [1-hydroxy-4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butan-2-yl] -methanesulfonamide To a solution of the compound obtained from Step e (0.85 g, 0.00133 mole) in methanol (15 mL) was added potassium carbonate (0.276 g, 0.0020 mole) and stirred for about one hour at room temperature. After one hour, the solvent was evaporated and the reaction mixture was taken in ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product obtained was purified on a silica gel column using 60% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 0.430 g.

LCMS: 533.13 (+) Step g: Preparation of 2- [(3 ', 4'-dichlorobiphenyl-4-yl) - (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4ff) -il) acid ) -bu anoic To a solution of the compound obtained from Step f (0.43 g 0.0008 mole) in acetonitrile (15 mL) were added 2, 2, 6, 6-tetramethylpiperidine-N-oxyl (0.012 g, 0.000007 mole), sodium chlorite (0.145). g, 0.0016 mole) and 5% aqueous solution of sodium hypochlorite (0.12 g, 0.0016 mole). The reaction was heated to 35 ° C for about 6 hours. After 6 hours, the solvent was evaporated and the reaction mixture was taken up in ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on preparative TLC using 10% methanol: dichloromethane as a mobile phase to obtain the desired product.

Yield: 0.15 g. lH NMR (DMSO-d6, 400 MHz): 8.22 (2H, m), 8.16 (1H, m), 8.03-8.05 (2H, m), 7.67-7.71 (6H, m), 4.63 (1H, m), 4.55 (2H, m), 3.15 (3H, s), 2.14 (1H, m), 1.99 (1H, m) LCMS: 547.11 (M + l) The following compounds can be prepared by following the above synthetic route.

Acid (22?) -2- [(4'-Fluorobiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4 H) -yl) butanoic acid (Compound No. 76); LCMS: 497.19 (M + l) Acid { 2R) -2-. { (methylsulfonyl) [4- (pyrimidin-5-yl) phenyl] -amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 77); LCMS: 481.21 (M + l) Acid { 2R) -2-. { (methylsulfonyl) [4 '- (propan-2-yl) biphenyl-4-yl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (tf) -i1) butanoic (Compound No. 78); LCMS: 521.29 (M + l) Acid (2R) -2- [(3 ', 4'-difluorobiphenyl-4-yl) (methyl-sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -il ) -butanoic (Compound No. 80); LCMS: 515.22 (M + l) Acid (21?) -2- f (3 '-fluoro-4' -methylbiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4tf) -yl) -butanoic (Compound No. 81); LCMS: 51 1.32 (M + l) Acid (21?) -2- [(4'-chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4 //) -yl) butanoic acid (Compound No. 82); LCMS: 513.71 (M + l) Acid (21?) -2- [(3'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 83); LCMS: 509.25 (M + l) Acid (21?) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (411) -yl) -butanoic (Compound No. 84); LCMS: 527.22 (M + l) (2R) -2- [biphenyl-4-yl (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4 #) -yl) butanoic acid (Compound No. 85); LCMS: 479.25 (M + l) Acid (21?) -2-. { [4- (6-methoxypyridin-3-yl) phenyl] (methyl-sulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) -butanoic acid (Compound No. 86); LCMS: 510.169 (M + l) (2S) -2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4 #) -yl) butanoic acid (Compound No. 87); LCMS: 513.23 (M + l) (2S) -2- [(3 ', 4'-Dichlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4 / l) -il) ) butanoic (Compound No. 88); LCMS: 547.22 and 549.11 (M + l) (2S) -2- [(3'-Fluoro-4 '-methylbiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) - il) -butanoic (Compound No. 89); LCMS: 511.27 (M + l) (2S) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) - il) -butanoic (Compound No. 90); LCMS: 527.28 (M + l) (2R) -2- [(3 ', 4'-dimethoxybiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -butanoic (Compound No. 91); LCMS: 537.5 (M-l) Acid (2R) -2-. { [4- (2, 3-dihydro-l, 4-benzodioxin-6-yl) phenyl] (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 92); LCMS: 537.30 (M + l) (2R) -2- [(4'-Methoxy-3 '-methylbiphenyl-4-yl) (pethylsulphonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (H)) -yl) -butanoic (Compound No. 93); LCMS: 545.22 (M + l) (2R) -2- [(4'-Fluoro-3'-methylbiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (AH) -il) ) - butanoic (Compound No. 94); LCMS: 533.27 (M + l) Acid (2R) -2-. { (methylsulfonyl) [4 '- (trifluoromethoxy) -biphenyl-4-yl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (H) -yl) butanoic (Compound No. 95); LCMS: 563.16 (M + l) Acid (2R) -2-. { [4'-chloro-3 '- (trifluoromethyl) biphenyl-4-yl] - (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (H) -yl) butanoic (Compound No. 96); LCMS: 581.9 (M + l) Example 12: Synthesis of. { 2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -A- [4-oxo-7- (trifluoromethyl) -1,2,3-benzotriazin-3 ( H) -yl] butanoic (Compound No. 97) (Scheme VI) Step a: Preparation of (4S) -4- [2- (benzyloxy) ethyl] -2,2-dimethyl-1,3-dioxolane To an ice-cooled solution of 2 - [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanol (5 g, 34.24 mmol) in?,? '- dimethylformamide (50 mL) was added sodium hydride (1.06 g, 44.52 mmoles) and stirred for approximately 15 minutes. After 15 minutes, benzyl bromide (7.02 g, 41.09 mmol) was added and stirred again for about one hour at the same temperature. After completion of the reaction, the aqueous ammonium chloride solution was added and the solvent evaporated under vacuum. The reaction mixture was taken in ethyl acetate and washed with water. The organic layer was collected, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using 20% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 8 g LCMS: 237.30 (M + l) Step b: Preparation of (25) -4- (benzyloxy) butane-1,2-diol To a solution of the compound obtained from Step a (8 g) in acetone (50 mL) was added hydrochloric acid (12 mL, 11 N) at room temperature and stirred for about 3 hours at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure and the pH was adjusted to neutral by the addition of aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate while washing with water. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using 20% ethyl acetate: hexane as eluent to obtain the desired compound.

Performance: 5g LCMS: 197.24 (M + l) Step c: Preparation of (25) -4- (benzyloxy) -2-hydroxybutyl benzoate To an ice-cooled solution of the compound obtained from Step b (5 g, 31.05 mmoles) in dichloromethane (100 mL) were added triethylamine (9.4 g, 93.16 mmole) and benzoyl chloride (3.9 g, 27.95 mmole). The reaction mixture was allowed to stir for about 45 minutes at the same temperature. After 45 minutes, the reaction mixture was extracted with dichloromethane while washing with water. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using 60: hexane ethyl acetate as eluent to obtain the desired compound.

Performance: 5g LCMS: 301.25 (M + l) Step d: Preparation of (2R) -4- (benzyloxy) -2- [(4-bromophenyl) (methylsulfonyl) amino] butyl benzoate To a solution of the compound obtained from Step c (5 g, 16.66 mmol) in tetrahydrofuran (100 mL) at 0 ° C was added. add triphenyl phosphine (8.7 g, 33.33 mol), IV (4-bromophenyl) methanesulfonamide (4.58 g, 18.33 mmol) and diisopropylazodicarboxylate (5 g, 25 mmol). The reaction mixture was allowed to stir for about one hour at the same temperature. After that the reaction mixture was concentrated to obtain a crude product which was purified on silica gel column catography using 60% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 14 g LC S: 534.04 (M + 2) Step e: Preparation of (2R) -4- (benzyloxy) -2- [(3'-fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] butyl benzoate To a solution of the compound obtained from Step d (5 g, 9,398 mmol) in N, W-dimethylformamide (50 mL) were added 3-fluoro-4-methoxyphenylboronic acid (3.19 g, 18,796 mmole), potassium carbonate (3.89). g, 28,195 mmoles) and tetrakistriphenyl phosphine palladium (O) (542 mg, 0.469 mmoles). The reaction mixture was heated to 110 ° C for about 3 hours. After 3 hours, the solvent was evaporated and the reaction mixture was extracted with ethyl acetate while washing with water. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using 30% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 4.3 g Step f: Preparation of (2J¾) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4-hydroxybutyl benzoate To a solution of the compound obtained from Step e (4.39 g, 0.008 mol) in tetrahydrofuran (60 mL) and methanol (40 mL) was added Pd / C (2.5 g) in the presence of hydrogen gas supplied using a balloon. The reaction mixture was allowed to stir overnight at room temperature. After completion, the reaction mixture was filtered through celite and the residue thus obtained was washed with 10% methanol: dichloromethane (200 mL). The filtrate was collected and dried to obtain the desired compound.

Performance: 2.5 g LCMS: 488.16 Step g: Preparation of (2R) -2- [(3'-Fluoro-4'-methoxybiphenyl) -yl) (methylsul onyl) amino] -4- [4-oxo- (trifluorornethyl) -1 benzoate , 2, 3-benzotriazin-3 (4H) -yl] butyl To a solution of the compound obtained from Step f (2.5 g, 0.0051 mole) in tetrahydrofuran (30 mL) were added 7-trifluoromethoxy benzotriazinone (1.21 g, 0.00564 mole) and triphenyl phosphine (2.68 g, 0.010 mole) at room temperature under nitrogen atmosphere. After 5 minutes, diisopropylazodicarboxylate (1.55 g, 0. 0077 moles) under nitrogen atmosphere and the reaction mixture was stirred at the same temperature for about one hour. After completion, the reaction mixture was extracted with ethyl acetate and washed with water. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using 30% ethyl acetate: hexane as eluent to obtain the desired product.

Yield: 4.2 g LCMS: 685.15 (M + l) Step h: Preparation of N- (3 '-fluoro-4' -methoxybiphenyl-4-yl) -N-. { (2R) -l-hydroxy-4- [4-oxo-7- (trifluoromethyl) -1,2, 3-benzo-triazin-3 (4H) -yl] butan-2-yl} methanesulfonamide To a solution of the compound obtained from Step g (4.2 g, 0.00614 mol) in methanol (40 mL) at room temperature was added potassium carbonate (1.27 g, 0.00921 mol) under an argon atmosphere. The reaction mixture was allowed to stir for about one hour at the same temperature. After completion, the solvent was evaporated and the reaction mixture was extracted with ethyl acetate while washing with water. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using 40% ethyl acetate: hexane as eluent to obtain a desired compound.

Yield: 3.1 g LCMS: 581.04 Step i: Preparation of (2R) -2- [(3'-Fluoro-4'-methoxy-biphenyl-4-yl) (methylsulfonyl) amino] -4- [4-oxo-7- (trifluoro-me ) -1,2, 3-benzotriazin-3 (4H) -yl] bu anoic acid To a solution of the compound obtained from Step h (900 mg, 1552 mmol) in acetonitrile: carbon tetrachloride (12ml: 12ml: 16ml) at room temperature were added ruthenium trichloride (13 mg, 0.062 mmol) and sodium periodate. (996 mg, 4.66 mmol). The reaction mixture was allowed to stir for about 30 minutes at the same temperature. After completion, the solvent was evaporated and the reaction mixture was extracted with ethyl acetate while washing with water. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on preparative TLC using 10% methanol: dichloromethane as a mobile phase to obtain the desired product.

Yield: 107 mg.

LCMS: 595 (M + l) 1H NMR (DMSO-d6, 400 ??): d 8.59 (1H, s), 8.44 (1H, d, J = 8 Hz), 8.22 (1H, d, J = 8 Hz), 7.71 (2H, d, J = 8 Hz), 7.59 (3H, m), 7.50 (1H, d, J = 8 Hz), 7.25 (1H, t, J = 8 Hz), 4.82 (1H, m), 4.55 (2H, m), 3.88 (3H, s, -OCH3), 3.17 (3H, s, S-CH3), 2.4 (1H, m), 1.90 (1H, m).

The following compounds can be prepared by following the above synthetic route. (2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (8-methyl-4-oxo-l, 2,3-benzotriazin-3) (4H) -yl) butanoic (Compound No. 98); LCMS: 541.11 (M + l) (2R) -4- (7-Chloro-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -2- [(3'-fluoro-4'-methoxybiphenyl-4-yl) acid (methylsulfonyl) -amino] butanoic (Compound No. 99); LCMS: 561.00 (M + l) Acid (2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (7-methoxy-4-oxo-l, 2,3-benzotriazin- 3- (4 Ji) -yl) butanoic (Compound No. 100); LCMS: 557.10 (M + l) Acid { 2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (6-methyl-4-oxo-l, 2,3-benzotriazin-3- (4H ) -il) utanoic (Compound No. 101); LCMS: 541.05 (M + l) Acid (21?) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (8-methoxy-4-oxo-l, 2,3-benzotriazin -3- (4H) -yl) butanoic (Compound No. 102); LCMS: 557.10 (M + l) Acid (2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (6-fluoro-4-oxo-l, 2,3-benzotriazin- 3- (4H) -yl) butanoic (Compound No. 103).

Assay for Metallo Matrix Proteinases (MMPs) New chemical entities (NCEs) of the present invention and corresponding standards used in the present invention were prepared (10 mM extract) in 100% DMSO and subsequent dilutions were made in 50% DMSO-50% TCNB (50 mM Tris , 10 mM CaCl 2, 150 mM NaCl, 0.05% Brij-35, pH 7.5). 1 μ? of the compound and 88 μ? of TCNB was added to the cavities of the 96-well plate to achieve the desired final concentration of NCE (the final DMSO concentration should not exceed 0.5%). 1 μ? of recombinant, activated MMPs was added to each well (20-100 ng / 100 μl of reaction mixture) except the "negative cavity". (MMP-1, 9 &14 enzymes required before activation.) For this, the enzyme supplied was incubated with either APMA, 1 mM final concentration, for a period of 1 hour at 37 ° C). The incubation was done at room temperature (~ 25 ° C) for 4 minutes to 5 minutes. The reaction was started with 10 μ? of substrate 100 μ? (ES001: Aliquots were freshly diluted in TCNB, extract: 2 mM) and the increase in fluorescence was monitored at excitation wavelength 320 nm followed by emission at 405 nm for 25-30 cycles. The increase in fluorescence (RFU) was calculated for positive, negative and NCE / standard cavities. The percent inhibition compared to the controls was calculated and the IC50 values were determined using the Graph-prism software.

Activities for MMP-9 gave IC50 values below 10 micromolar. The activities for MMP12 gave IC 50 values from 35 nanomolar to 10 micromolar.

Claims (4)

CLAIMS compound of the Formula Formula I which includes racemates, enantiomers, or diastereomers thereof; or a pharmaceutically acceptable salt thereof, characterized in that, L1 is selected from the bond, 0, S, CH2, NR4, NHC0 (CH2) n, (CH2) nC0NH, NHCONH, S02NH, NHS02, NHCO (O), -0- (CH2) n, - (CH2) n-0-, -0C (0) NH-, C (S) NH, NHC (S), NHC (S) NH or -C0O- where n is zero or an integer between 1 and 2; R1 is selected from hydrogen, Ci-C6 alkyl, hydroxyl, C1-C6 alkoxy, cyano, nitro, halogen, halogen-C1-C6 alkyl / Cs-Ci2 aryl, C6-Ci2 heteroaryl, C3 cycloalkyl C6 wherein aryl, heteroaryl, cycloalkyl is optionally substituted by one or more substituents independently selected from R5; R2 is CHO or S02-Ci-C6 alkyl; R3 is unsubstituted or substituted heteroaryl or -0C0NHR 'where R' is C6-Ci2 aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl each of which is optionally substituted by one or more substituents independently selected from R5; R4 is H or Ci-C6 alkyl; R5 is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogen-Ci-C6 alkyl, halo-Ci-C6 alkoxy, azido, thiol, alkylthiol, - (CH2) n-ORf, -C (= 0) -Rf, -COORf, -NRfRq, - (CH2) n ~ C (= 0) NRfRq, - (CH2) n-NHC (= 0) Rf, - (CH2) n-0-C (= 0) -NRfRq, (CH2) nNHC (= 0) - NRfRq, - (CH2) n-0-C ( = 0) -Rf, - (CH2) n-NH-C (= 0) -Rf or - (CH2) nS (= 0) m-NRfRq. { wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined above and m is an integer of 0-2} .
1. 2. A compound of Formula I, characterized in that it is: 2- [Formyl (4'-methylbiphenyl-4-yl) amino] -4- (6-methyl-4-oxo-1,2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 1) ); 4- (7-Chloro-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -2- [formyl (4'-methyl-biphenyl-4-yl) -amino] -butanoic acid (Compound No. 2) ); 2- [(4'-Ethylbiphenyl-4-yl) (formyl) amino] -4- (5-methyl-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. . 3); O- [(4-Fluorophenyl) carbamoyl] -N-formyl-N- (4 '-methyl-biphenyl-4-yl) homoserine (Compound No. 4); N-Formyl-N- (4 '-methylbiphenyl-4-yl) -0- [(4-methylphenyl) -carbamoyl] homoserine (Compound No. 5); 0- [(3,4-Dichlorophenyl) carbamoyl] -W-formyl-N- (4 '-methylbiphenyl-4-yl) homoserine (Compound No. 6); N- (4'-Ethylbiphenyl-4-yl) -N-formyl-O- ([4- (propan-2-yl) -phenyl] carbamoyl.} Homoserine (Compound No. 7); N- (4'-Ethylbiphenyl- -yl) -O- [(3-fluorophenyl) carbamoyl] -N-formylhomoserine (Compound No. 8); 0- [(2,4-Di fluorophenyl) carbamoyl] -N- (4'-ethylbiphenyl -yl) -N-formylhomoserine (Compound No. 9); N- (4'-ethylbiphenyl-4-yl) -0- [(2-fluorophenyl) carbamoyl] -N-formylhomoserin (Compound 10); N- ('-ethyl-phenyl-4-yl) -N-formyl-O-. { [4- (trifluoromethyl) -phenyl] carbamoyl} Homoserine (Compound No. 11); N- (4'-Ethylbiphenyl-4-yl) -N-formyl-O- [(2-methylphenyl) -carbamoyl] homoserine (Compound No. 12); N- (4'-Ethylbiphenyl-4-yl) -0- [(4-ethylphenyl) carbamoyl] -N-formylhomoserine (Compound No. 13); N- (4'-Ethylbiphenyl-4-yl) -N-formyl- - [(-methoxyphenyl) -carbamoyl] homoserine (Compound No. 14); 0- [(2,6-Dichlorophenyl) carbamoyl] -N- (4'-ethylbiphenyl-4-yl) -N-formylhomoserin (Compound No. 15); 2- [Biphenyl-4-yl (methylsulfonyl) amino] -4- (1, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl) butanoic acid (Compound No. 16); 4- (1, 3-Dioxo-l, 3-dihydro-2i-isoindol-2-yl) -2- acid. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} -butanoic (Compound No. 17); 4- (1, 3-dioxo-l, 3-dihydro-2íí-isoindol-2-yl) -2- [(4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] butanoic acid (Compound No. 18); Acid 2-. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (i?) - il) butanoic (Compound No. 19); 4- (7-Methoxy-4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) -2. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} -butanoic (Compound No. 20); Acid 2-. { [- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} -4- [4-oxo-7- (trifluoromethyl) -1,2,3-benzotriazin-3 (4H) -yl] butanoic (Compound No. 21); 4- (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) -2- acid. { [4- (6-methoxypyridin-3-yl) phenyl] (methylsulfonyl) amino} -butanoic (Compound No. 22); 4- (6-Methoxy-oxo-l, 2,3-benzotriazin-3 (4f) -yl) -2 acid. { [- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} butanoic (Compound No. 23); 4- (7-Methyl-4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) -2. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} butanoic (Compound No. 24); Acid 2-. { [- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} -4- [4-OXO-7- (trifluoromethyl) -1,2,3-benzotriazin-3 (4J1) -yl] -butanoic (Compound No. 25); Acid 2-. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 26); 2- [(3 ', 4' -difluorobiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 27); 2- [(4'-Ethylbiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 28); Acid 2-. { [4- (2-methoxypyrimidin-5-yl) phenyl] (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) -butanoic acid (Compound No. 29); 2- [(3'-Fluoro-4 '-methylbiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic acid ( Compound No. 30); 2- [(2 ', 4'-dimethoxybiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4if) -yl) butanoic acid (Compound no. 31); 2- [(4-Methoxyphenyl) (methylsulfonyl) amino] -4- (-oxo-1,2,3-benzotriazin-3 (H) -yl) butanoic acid (Compound No. 32); 4- (7-Methoxy-4-oxo-l, 2, 3-benzotriazin-3 (H) -yl) -2- [(4-methoxyphenyl) (methylsulfonyl) amino] butanoic acid (Compound No. 33); 4- (1, 3-Dioxo-1,3-dihydro-2-t-isoindol-2-yl) -2- [(4-methoxyphenyl) (methylsulfonyl) amino] butanoic acid (Compound No. 34); 2- [(4-Methoxyphenyl) (methylsulfonyl) amino] -4- (5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindo-2-yl) butanoic acid (Compound No. 35); 4- (7-Methoxy-oxo-1,2,3-benzotriazin-3 (4H) -yl) -2- acid. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) amino} butanoic (Compound No. 36); 4- (5-Methyl-l, 3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) -2- acid. { [4- (4-methylphenoxy) phenyl] (methylsulfonyl) aminofbutanoic (Compound No. 37); 2- [(3'-Methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) utanoic acid (Compound No. 38); 2- [(4'-Fluorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 39); Acid 2-. { (methylsulfonyl) [4 '- (propan-2-yl) biphenyl-4-yl] -amino} -4- (4 -oxo-1, 2, 3-benzotriazin-3 (4i7) -yl) butanoic (Compound No. 40); 2- [Biphenyl-4-yl (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 41); Acid 2-. { [4- (6-methylpyridin-3-yl) phenyl] (methylsulfonyl) -amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 42); Acid 2-. { (methylsulfonyl) [4- (pyrimidin-5-yl) phenyl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4 Ji) -yl) butanoic (Compound No. 43); Acid 2-. { (Methylsulfonyl) [- (pyridin-3-yl) phenyl] amino} -4 - (4-oxo-l, 2, 3-benzotriazin-3 (4 H) -yl) butanoic (Compound No. 44); Acid 2-. { (methylsulfonyl) [4 '- (trifluoromethyl) biphenyl] 4-yl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 45); Acid 2-. { (methylsulfonyl) [4- (pyridin-4-yl) phenyl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 46); 2- [(3 ', 4'-Dichlorobiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 47); 2- [('- er-Butylbiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 48); 2- [(2 ', 3' -difluorobiphenyl-4-yl) (methylsulfonyl) -amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (fí) -yl) butanoic acid (Compound no. 49); 2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) - butanoic (Compound No. 50); 4- (1, 3-dioxo-l, 3-dihydro-2 # -isoindol-2-yl) -2- acid. { (methylsulfonyl) [4- (propan-2-yl) phenyl] amino} butanoic (Compound No. 51); 4- (6-Methoxy-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -2- acid. { (methylsulfonyl) [4- (propan-2-yl) phenyl] amino} butanoic (Compound No. 52); 4- (7-Methyl-4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) -2- acid. { (methylsulfonyl) [4- (propan-2-yl) phenyl] amino} butanoic (Compound No. 53); 4- (1, 3-Dioxo-1,3-dihydro-2-t-isoindol-2-yl) -2- [(4-ethylphenyl) (methylsulfonyl) amino] butanoic acid (Compound No. 54); 2- [(4-Ethylphenyl) (methylsulfonyl) amino] -4- (5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) butanoic acid (Compound No. 55); 2- [(4-Ethylphenyl) (methylsulfonyl) amino] -4- (7-methyl-4-oxo-1,2,3-benzotriazin-3 (H) -yl) butanoic acid (Compound No. 56); 2- [(4-Ethylphenyl) (methylsulfonyl) amino] -4- (6-methoxy-4-oxo-l, 2,3-benzotriazin-3 (42) -yl) butanoic acid (Compound No. 57); 2- [(Methylsulfonyl) (phenyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4i) -yl) butanoic acid (Compound No. 58); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) butanoic acid (Compound No. 59); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (5-chloro-4-oxo-l, 2,3-benzotriazin-3 (4 Ji) -yl) butanoic acid (Compound No. 60); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (7-chloro-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 61); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (7-methyl-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 62); 2- [('-chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- [4-OXO-7- (trifluoromethyl) -1,2,3-benzotriazin-3 (4 #) -yl] -butanoic acid (Compound No. 63); 2- [('-chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (5-methoxy-4-oxo-l, 2,3-benzotriazin-3 (yl) -yl) butanoic acid (Compound no. 64); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (5-fluoro-4-oxo-l, 2,3-benzotriazin-3 (H) -yl) butanoic acid (Compound no. 65); 2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl) -butanoic acid (Compound No. 66); 4- Acid. { (methylsulfonyl) [l-oxo-4- (4-oxo-l, 2, 3-benzo-triazin-3 (4tf) -yl) -1- (prop-2-en-l-yloxy) butan-2- il] amino} -benzoic (Compound No. 67); 2- [. { 4- [(4-methylphenyl) carbamoyl] phenyl} (methyl-sulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) -butanoic acid (Compound No. 68); 2- [. { 4- [(4-chlorophenyl) carbamoyl] phenyl} (methyl-sulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) -butanoic acid (Compound No. 69); Acid 2-. { (methylsulfonyl) [4- (phenylcarbamoyl) phenyl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4ff) -yl) butanoic (Compound No. 70); 2- [. { - [(3-fluorophenyl) carbamoyl] phenyl} (methyl-sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4tf) -yl) -butanoic acid (Compound No. 71); 2- [(Methylsulfonyl) (4. {[[4- (propan-2-yl) phenyl] -carbamoyl}. Phenyl) amino] -4- (4-oxo-l, 2,3-benzotriazine) 3 (4H) -yl) butanoic (Compound No. 72); 2- [. { 4- [(-methoxyphenyl) carbamoyl] phenyl} (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3. {4H) -yl) -butanoic acid (Compound No. 73); 2- [. { 4- [(4-fluorophenyl) carbamoyl] phenyl} (methyl-sulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4tf) -yl) -butanoic acid (Compound No. 74); 2- [(Methylsulfonyl) (4- {[4- (trifluoromethyl) phenyl] -carbamoyl] phenyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl} ) butanoic (Compound No. 75); (2R) -2- [(4'-Fluorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 76); Acid (2R) -2-. { (methylsulfonyl) [4- (pyrimidin-5-yl) phenyl] amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 77); Acid (2R) -2-. { (methylsulfonyl) [4 '- (propan-2-yl) biphenyl-4-yl] amino} -4- . { 4 -oxo-1,2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound No. 78); Acid { 2R) -2- [(3 ', 4'-dichlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4 #) -yl) butanoic ( Compound No. 79); Acid { 2R) -2- [(3 ', 4'-difluorobiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -butanoic (Compound No. 80); (2R) -2- [(3'-Fluoro-4 '-methylbiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4)) - il) -butanoic (Compound No. 81); (2R) -2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 82); (2R) -2- [(3'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 83); (2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (4H) - il) -butanoic (Compound No. 84); (2R) -2- [Biphenyl-4-yl (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) -butanoic acid (Compound No. 85); Acid (2.R) -2-. { [4- (6-methoxypyridin-3-yl) phenyl] (methyl sulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (AH) -yl) -butanoic (Compound No. 86); (2S) -2- [(4'-Chlorobiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (AH) -yl) butanoic acid (Compound no. 87); (2S) -2- [(3 ', 4'-Dichlorobiphenyl-4-yl) (methylsulfonyl) amino] -A- (4-oxo-l, 2,3-benzotriazin-3 (AH) -yl) butanoic acid (Compound No. 88); (2S) -2- [(3'-Fluoro-4 '-methylbiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (AH) - il) -butanoic (Compound No. 89); (2S) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2, 3-benzotriazin-3 (AH) - il) -butanoic (Compound No. 90); (2R) -2- [(3 ', 4'-dimethoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazin-3 (AH) -yl) - butanoic (Compound No. 91); Acid (2R) -2-. { [4- (2, 3-dihydro-l, 4-benzodioxin-6-yl) phenyl] (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (H) -yl) butanoic (Compound No. 92); (2R) -2- [(4'-Methoxy-3 '-methylbiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2,3-benzotriazine-3 (4H) - il) -butanoic (Compound No. 93); (2R) -2- [(4'-Fluoro-3 '-methylbiphenyl-4-yl) (methyl sulfonyl) amino] -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) - il) -butanoic (Compound No. 94); Acid { 2R) -2-. { (methylsulfonyl) [4 '- (trifluoromethoxy) biphenyl-4-yl] amino} -4- (-oxo-l, 2, 3-benzotriazin-3 (4tf) -yl) butanoic (Compound No. 95); Acid (2R) -2-. { [4'-chloro-3 '- (trifluoromethyl) biphenyl-4-yl] (methylsulfonyl) amino} -4- (4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) butanoic (Compound No. 96); [2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methyl sulfonyl) amino] -4- [4-oxo-7- (trifluoromethyl) -1,2, 3-benzoic acid -triazin-3 (4H) -yl] butanoic (Compound No. 97); [2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methyl sulfonyl) amino] -4- (8-methyl-4-oxo-l, 2,3-benzotriazin-3) acid - (4H) -yl) butanoic (Compound No. 98); (2R) -4- (7-Chloro-4-oxo-l, 2,3-benzotriazin-3 (4H) -yl) -2- [(3'-fluoro-4'-methoxybiphenyl-4-yl) ( methylsulfonyl) -amino] butanoic (Compound No. 99); Acid { 2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methyl sulfonyl) amino] -4- (7-methoxy-4-oxo-l, 2,3-benzotriazin-3- ( 4f1) -yl) butanoic (Compound No. 100); (2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (6-methyl-4-oxo-l, 2,3-benzotriazin-3) (4H) -yl) butanoic (Compound No. 101); (2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (8-methoxy-4-oxo-l, 2,3-benzotriazin-3) (4H) -yl) butanoic (Compound No. 102); (2R) -2- [(3'-Fluoro-4'-methoxybiphenyl-4-yl) (methylsulfonyl) amino] -4- (6-fluoro-4-oxo-1,2,3-benzotriazin-3) (4H) -yl) butanoic (Compound No. 103); 4- (5-Chloro-4-oxo-l, 2, 3-benzotriazin-3 (4H) -yl) -2- [(4-chlorophenyl) (methylsulfonyl) amino] butanoic acid (Compound No. 104); 2- [(4-Bromophenyl) (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4H) -yl) butanoic acid (Compound no. 105); 2- [(4-Chlorophenyl) (methylsulfonyl) amino] -4- (4-oxo-1,2,3-benzotriazin-3 (4 yl) -yl) butanoic acid (Compound no. 106); 2- [(Chlorophenyl) (methylsulfonyl) amino] -4- (7-methyl--oxo-1,2,3-benzotriazin-3 (4 H) -yl) butanoic acid (Compound No. 107);
2. 2- [(4-Chlorophenyl) (methylsulfonyl) amino] -4- (6-methoxy-4-oxo-l, 2,
3. 3-benzotriazin-3 (4 H) -yl) butanoic acid (Compound No. 108). includes racemates or diastereomers thereof; or one pharmaceutically acceptable salt thereof. 3. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound according to claims 1 and 2, together with one or more pharmaceutically acceptable carriers, excipients or diluents. 4. A compound according to claims 1 and 2, characterized in that it is for use in the treatment or prophylaxis of an animal or a human suffering from an inflammatory or allergic disease. 5. A compound according to claim 4, characterized in that the inflammatory or allergic disease is asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, lung inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, neointimal proliferation associated with restenosis and ischemic heart failure, apoplectic attack, kidney disease, tumor metastasis. 6. A pharmaceutical composition according to claim 3, characterized in that it also comprises one or more additional active ingredients selected from: a) anti-inflammatory agents, selected from (i) the nonsteroidal anti-inflammatory agents of piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, PDE-4 inhibitors, MAP kinase inhibitors / cathepsin p38, (ii) ) inhibitors LTC4 / LTD4 / LTE4 / LTB4 of leukotrienes, 5-lipoxygenase inhibitor and PAF receptor antagonists, (iii) Cox-2 inhibitors, (iv) other MP inhibitors and (v) interleukin-I inhibitors; b) antihypertensive agents, selected from (i) ACE inhibitors, for example enalapril, lisinopril, valsartan, telmisartan and quinapril, (ii) angiotensin II receptor antagonists and agonists, losartan, candesartan, irbesartan, valsartan and eprosartan, (iii) β-blockers and (iv) calcium channel blockers. 3) immunosuppressive agents selected from cyclosporine, azathioprine and methotrexate and anti-inflammatory corticosteroids. 7. A process for preparing a compound of Formula 10 (Formula 1 when R 3 is heteroaryl, L 1 is bond, R 2 is CHO and R 1 is aryl or substituted heteroaryl) and Formula 13 (Formula 1 when R 3 is -OCONHR ', L 1 is link R2 is CHO and R1 is aryl or substituted heteroaryl) characterized in that it comprises: reacting
4. 4-bromo-4-nitrobenzene with a compound of Formula 2 Formula 2 to give a compound of Formula 3; Formula 3 reducing a compound of Formula 3 to give a compound of Formula 4 Formula 4 reacting a compound of Formula 4 with alpha-bromolactone, to give a compound of Formula 5 Formula 5 formylating a compound of Formula 5 to give a compound of Formula 6 Formula 6 ring opening of a compound of Formula 6 to give a compound of Formula 7 Formula 7 f) reacting a compound of Formula 7 with a compound of Formula 8 Formula 8 to give a compound of Formula 9 g) deprotecting a compound of Formula 9 to give a compound of Formula 10 Formula 10 h) reacting a compound of Formula 7 with a compound of Formula 11 Formula 7 Formula 1 1 to give a compound of Formula 12 Formula 12 i) deprotecting a compound of Formula 12 to give a compound of Formula 13 Formula 13 where, Or is an aryl or heteroaryl ring; R6 is hydrogen, alkyl, halogen, alkoxy or halogen-Ci-C6 alkyl; R p is a carboxy protecting group, such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC anhydride; (^) 1 It is a heteroaryl ring; R 'is aryl of ^ -C ^ heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl each of which is optionally substituted by one or more substituents independently selected from R5; R5 is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogen-alkyl of i-Ce, halogen-alkoxy of Ci-C6, azido, thiol, alkylthiol, - (CH2) n-ORf, -C (= 0) -Rf, -COORf, -NRfRq, - (CH2) nC (= 0) NRfRq, - (CH2) n -NHC (= 0) Rf, - (CH2) "- 0-C (= 0) -NRfRq, ( CH2) nNHC- (= 0) NRfRq, - (CH2) n-0-C (= 0) -Rf, - (CH2) n "NH-C (= 0) -R £ o - (CH2) nS (= 0) m-NRfRq., Wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer between 1 and 2 and m is an integer of 0-2.}. 8. A process for preparing a compound of Formula 20 (Formula 1 when R 3 is heteroaryl, L 1 is bond, R 2 is SC> 2-C 1-6 alkyl and R 1 is aryl or substituted heteroaryl) characterized in that it comprises: a) halogenating a compound of Formula 14 in the alpha position Formula 14 to give a compound of Formula 15 Formula 15 protecting a compound of Formula 15 to give a compound of Formula 16 Formula 1 reacting a compound of the Formula with a compound of Formula 17 (where it is halogen) to give a compound of Formula 18 Formula 17 Formula 18 coupling a compound of Formula 18 with a compound of Formula 2 to give a compound of Formula 19 Formula 2 Formula 1 deprotecting a compound of Formula 19 to give a compound of Formula 20 Formula 20 f) reacting a compound of Formula 16, with a compound of Formula 17 (where R is aryl / heteroaryl substituted with R6) Formula 16 Formula 17 to give a compound of the Formula Formula 19 g) deprotecting a compound of Formula 19 to give a compound of Formula 20 Formula 20 where, it is a heteroaryl ring; R p is a carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC anhydride; R5 is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogen-C1-C6 alkyl, halo-Ci-C6 alkoxy, azido, thiol, alkylthiol, - (CH2) n-0Rf, -C (= 0) -Rf, -COORf, -NRfRq, - (CH2) nC (= 0) NRfRq, - (CH2) n-NHC (= 0) Rf, - (CH2) n-0-C (= 0) -NRfRq, (CH2) nNHC- (= 0) -NRfRq, - (CH2) n-0-C (= 0) -Rf, - (CH2) n "NH-C (= 0) -Rf O - (CH2) nS (= 0) m-NRfRq. { wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n can be zero or an integer between 1 and 2 and m is an integer of 0-2}; Hal is F, CI, Br, I; Ak is Ci-6 alkyl; is an aryl or heteroaryl ring; R6 is hydrogen, alkyl, halogen, alkoxy or halogen-alkyl of 1-6. A process for preparing a compound of Formula 26b (Formula 1 when R3 is heteroaryl, L1 is bond, R2 is S02-C1- alkyl- 6 and R1 is aryl / heteroaryl substituted with OR6 ') and Formula 29 (Formula 1 when R3 is heteroaryl, L1 is bond, R2 is S02 ~ Ci ~ 6 alkyl and R1 is halogen / hydrogen, alkoxy / aryloxy), characterized because it includes: a) reacting a compound of Formula 17a with alpha hydroxy lactone, to give a compound of Formula 21 Formula 17a Formula 2 1 b) ring opening of a compound of Formula 21 to give a compound of Formula 22 Formula 22 c) protecting a compound of Formula 22 in the carboxyl group to give a compound of Formula 23 Formula 23 d) protecting a compound of Formula 23 (when Rk 'is halogen) in the hydroxyl group to give a compound of Formula 24 Formula 24 coupling a compound of Formula 24 with a compound of Formula 24a, to give a compound of Formula 25 Formula 24a Formula 25 deprotecting a compound of Formula 25 to give a compound of Formula 26 reacting a compound of Formula 26 with a compound of Formula 27, to give a compound of Formula 26a deprotecting a compound Formula 26a to give a compound Formula 26b Formula 26b i) reacting, a compound of Formula 23 (when Rk 'is alkoxy / aryloxy / halogen / hydrogen) with a compound of Formula 27 to give a compound of Formula 2í Formula 28 j) deprotecting a compound of Formula 28 to give a compound of Formula 29; Formula 29 where, Ak is Ci-6 alkyl: R p is a carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC anhydride; RP 'is a hydroxyl protecting group such as benzoyl, tert-butyldimethylsilyl, trimethylsilyl, tert-butyldimethylsilyloxymethyl, triisopropylsilyl groups; it is a heteroaryl ring; Rk 'is hydrogen, halogen, alkoxy, aryloxy, aryl, carboxy; R5 is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, Ci-6-haloalkyl, Ci-6-haloxy-alkoxy, azido, thiol, alkylthiol, - (CH2) n-0Rf, -C (= 0) -Rf, -COORf, -NRfRq, - (CH2) n "C (= 0) NRfRq, - (CH2) n -NHC (= 0) Rf, - (CH2) n-0-C (= 0) -NRfRq , (CH2) nNHC - (= 0) NRfRq, - (CH2) n-0-C (= 0) -Rf, - (CH2) n-NH-C (= 0) -Rf or - (CH2) nS ( = 0) m-NRfRq { Where Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and. alkylheterocyclyl; n can be zero or an integer between 1 and 2 and m is an integer of 0-2} , Or is an aryl or heteroaryl ring; OR6 wherein R6 'is hydrogen, alkyl, halogen, alkoxy or halogen-Ci ~ 6 alkyl. 10. A process for preparing a compound of the Formula 31 (Formula 1 when R3 is heteroaryl, L1 is bond, R2 is S02-Ci-6 alkyl and R1 is aryl / heteroaryl substituted with halogen) and Formula 36 (Formula 1 when R3 is heteroaryl, L1 is -CONH- , R2 is S02-Ak and R1 is aryl / heteroaryl), characterized in that it comprises: a) reacting a compound of Formula 23 (when Rk- is aryl / heteroaryl substituted with halogen and Rp is allyl) with a compound of Formula 27 Formula 23 Formula 27 to give a compound of Formula 30 b) deprotecting a compound of Formula 30 to give a compound of Formula 31; Formula 31 reacting a compound of the Formula (when it is -COORp) with a compound of Formula 27 Formula 23 Formula 27 20 to give a compound of Formula 32; Formula 32 25 d) deprotecting a compound of Formula 32 to give a compound of Formula 33 / Ak Formula 33 e) coupling a compound of Formula 33 with a compound of Formula 34 Formula 34 to give a compound of Formula 35 Ak Formula 3 f) deprotecting a compound of Formula 35 to give a compound of Formula 36; Ak Formula 36 where, Ak is Ci-6 alkyl; Hal is F, CI, Br, I; R p is a carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC anhydride; is an aryl or heteroaryl ring; (4) is a heteroaryl ring; R5 is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, Ci-6-haloalkyl, Ci-6-haloxy-alkoxy, azido, thiol, alkylthiol, - (CH2) n-ORf, -C (= 0) -Rf, -COORf, -NRfRq, - (CH2) n ~ C (= 0) NRfRq, - (CH2) n -NHC (= 0) Rf, - (CH2) n-0-C (= 0) -NRfRq , (CH2) nNHC- (= 0) NRfRq, - (CH2) n-0-C (= 0) -Rf, - (CH2) n-NH-C (= 0) -Rf or - (CH2) nS ( = 0) m-NRfRq (wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkyl-heteroaryl and alkylheterocyclyl; n may be zero or an integer between 1 and 2 and m is an integer of 0-2.}; R6 is hydrogen, alkyl, halogen, alkoxy or halo-C1-6 alkyl. 11. A process for preparing a compound of Formula 43 (Formula 1 when R3 is heteroaryl, L1 is bond, R2 is S02-Ci-6 alkyl and R1 is aryl / heteroaryl), characterized in that it comprises: a) protecting a compound of Formula 37, to give a compound of Formula 38 Formula 37 Formula 38 b) reacting a compound of Formula 38 with a compound of Formula 39 to give a compound of Formula 40 NlISO.Ak Formula 39 Formula 40 Check out a compound of the give a compound of the Formula Formula 41 d) reacting a compound of Formula 41 with a compound of Formula 27 to give a compound of Formula 42 Formula 27 Formula 42 Check out a compound of the give a compound of the Formula Formula 43 where, Ak is Ci-6 alkyl: is an aryl or heteroaryl ring; R p is a carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC anhydride; RP 'is a hydroxyl protecting group such as benzoyl, tert-butyldimethylsilyl, trimethylsilyl, tert-butyldimethylsilyloxymethyl, triisopropylsilyl groups; it is a heteroaryl ring; R5 is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogen-Ci-6alkyl, halogen-Ci-6alkoxy, azido, thiol, alkylthiol, - (CH2) n-ORf, -C (= 0) -Rf, -COORf, -NRfRq, - (CH2) nC (= 0) NRfRq, - (CH2) n -NHC (= 0) Rf, - (CH2) n-0-C (= 0) -NRf q, (CH2) nNHC- (= 0) NRfRq, - (CH2) n-0-C (= 0) -Rf - (CH2) n -NH-C (= 0) -Rf or - (CH2) nS (= 0 ) m-NRfRq. { wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer between 1 and 2 and m is an integer of 0-2}; R6 is hydrogen, alkyl, halogen, alkoxy or halogen-alkyl of 0? -6 · 12. A process for preparing a compound of Formula 52 (Formula 1 when R3 is heteroaryl, L1 is bond, R2 is S02-Ci-6 alkyl and R1 is aryl / substituted heteroaryl), characterized in that it comprises: a) reacting a compound of the Formula 44 with 4- (2-hydroxyethyl) -2,2-dimethyl 1,3-dioxolane to give a compound of Formula 45 Formula 44 Formula 45 b) ring opening of a compound of Formula 45 to give a compound of Formula 46 Formula 46 c) protecting a compound of Formula 46 to give a compound of Formula 47 Formula 47 d) reacting a compound of Formula 47 with a compound of Formula 48 to give a compound of Formula 49 Formula 48 Formula 49 e) coupling a compound of Formula 49 with a compound of Formula 2 to give a compound of Formula 50 Formula 2 Formula 50 f) deprotecting a compound of Formula 50 to give a compound of Formula 51 Formula 5 1 g) oxidizing a compound of Formula 51 to give a compound of Formula 52 Formula 52 eenn ddoonnddee ,, Akus eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee oo-- eess uunn aanniilllloo aarriilloo oo hheetteerrooaarriilloo;; Rpp R '' eess uunn ggrruuppoo pprrootteeccttoorr hhiiddrrooxxiilloo ttaall bbeennzzooiilloo ccoommoo ,, ssiilliilloo ttoo iinncclluuyyee tteerr-- bbuuttiillddiimmeettiill-- ssiilliilloo ttrriimmeettiillssiilliilloo ,, ,, tteerr - bbuuttiillddiimmeettiillssiilliill-- ooxxiimmeettiilloo ttrriiiissoopprrooppiillssiilliilloo ,,;; eess uunn aanniilllloo hheetteerrooaarriilloo;; Hal is F, CI, Br, I; Y R6 is hydrogen, alkyl, halogen, alkoxy halogen-alkyl of i.e. 13. A process for preparing a compound of Formula 61 (Formula 1 when R3 is heteroaryl, L1 is bond, R2 is S02-Ci-6 alkyl and R1 is aryl / substituted heteroaryl), characterized in that it comprises: protect 4- (2-hydroxyethyl) -2, 2-dimethyl dioxolane to give a compound of Formula 53; Formula 3 ring opening of a compound of Formula 53 to give a compound of Formula 54; Formula 54 protecting a compound of Formula 54 to give a compound of Formula 55; Formula 55 reacting a compound of Formula 55 with a compound of Formula 48 to give a compound of Formula 56; Formula 48 Formula 56 E) coupling a compound of Formula 56 with a compound of Formula 2 to give a compound of Formula 57 Formula 2 Formula 57 Check out a compound of the give a compound of the Formula reacting a compound of Formula 58 with a compound of Formula 27 to give a compound of Formula 59 Formula 27 Formula 59 h) deprotecting a compound of Formula 59 to give a compound of Formula 60 Formula 60 25 i) oxidizing a compound of Formula 60 to give a compound of Formula 61 Formula 61 where, Ak is Ci-e alkyl: Or is an aryl or heteroaryl ring; RP 'and RP "is a hydroxyl protecting group such as benzoyl, tert-butyldimethylsilyl, trimethylsilyl, tert-butyldimethylsilyloxymethyl, triisopropylsilyl groups; it is a heteroaryl ring; R5 is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogen-Ci-6alkyl, halogen-Ci-6alkoxy, azido, thiol, alkylthiol, - (CH2) n-ORf, -C (= 0) -Rf, -COORf, -NRfRq, - (CH2) nC (= 0) NRfRq, - (CH2) n -NHC (= 0) Rf, - (CH2) n-0-C (= 0) -NRfRq, ( CH2) nNHC - (= 0) NRfRq, - (CH2) n-0-C (= 0) -Rf, - (CH2) n-NH-C (= 0) -Rf or - (CH2) nS (= 0 ) m-NRfRq (wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkyl- heteroaryl and alkylheterocyclyl; n can be zero or an integer between 1 and 2 and m is an integer of 0-2}; Hal is F, CI, Br, I; Y R6 is hydrogen, alkyl, halogen, alkoxy or halo-Ci-6 alkyl.