Field of the Invention

The present invention relates to pyrazole derivatives and to a process for their synthesis as 5 -lipoxygenase (5-LO) inhibitors. The present invention also relates to pharmacological compositions containing these pyrazole derivatives, as well as methods of treating bronchial asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis, Type I diabetes, psoriasis, allograft rejection, inflammatory bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis, allergic rhinitis and other

inflammatory and/or autoimmune disorders.

Background of the Invention

5 -Lipoxygenase (5-LO) is a key enzyme that oxidizes arachidonic acid into biologically active leukotrienes, namely cysteinyl leukotrienes and leukotriene B4 (Clin. Exp. Allergy Rev., 1, 196, 2001). Leukotrienes play an important role in the

pathophysiology of inflammatory/allergic diseases including bronchial asthma (Clin. Exp. Allergy Rev., 1, 264, 2001), allergic rhinitis (Clin. Exp. Allergy Rev., 1, 235, 2001), urticaria, atopic dermatitis (Clin. Exp. Allergy Rev., 1, 305, 2001), chronic obstructive pulmonary disease (Eur. Respir. J, 22, 926, 2003), etc. Incidence of

allergic/inflammatory diseases are on the rise globally (Emerging Therapeutic Targets, 3, 229, 1999; Expert Opin. Investigational Drugs, 10, 1361, 2000).

A variety of stimuli, namely antigen-antibody reaction, cold or hyperosmotic shock etc., that elevate intracellular calcium level, can evoke arachidonic acid release from cell membrane under the influence of cytosolic phospholipase A2. Arachidonic acid is transferred to nuclear membrane by 5-LO binding protein (FLAP) and acted upon by 5-LO enzyme to generate 5-hydroperoxyeicosatetraenoic acid (HPETE). HPETE is converted to LTA4 by 5-LO. Depending upon cell type, LTA4 is converted to either cysteinyl leukotrienes and/or leukotriene B4 (Clin. Exp. Allergy Rev., 1, 196, 2001 ; Curr. Drug Targets - Inflammation & Allergy, 1, 23, 2002; Drug Safety, 26, 484, 2003).

Leukotrienes are generated by a variety of inflammatory cell types. Neutrophils and monocytes generate LTB4, whereas mast cells, basophils, eosinophils and bronchial epithelial cells produce cysteinyl leukotrienes. LTB4 acts as a chemoattractant for neutrophils through specific cell surface receptors. Cysteinyl leukotrienes, which include LTC4, LTD4 and LTE4, act on CysLTl and CysLT2 receptors and increase bronchial smooth muscle contractility, promote mucosal secretion, increase vascular permeability and encourage eosinophil recruitment. (Am. J. Respir. Critical Care Med., 157, S210, 1998; Thorax, 55, S32, 2000; Clin. Exp. Allergy Rev., 1, 196, 2001 ; Clin. Exp. Allergy Rev., 1, 220, 2001 ; Drug Safety, 26, 484, 2003).

There is evidence suggesting that cysteinyl leukotrienes can increase airway smooth muscle contractility in preclinical (Am. J. Respir. Crit. Care Med., 157, S214, 1998) and clinical studies (Clin. Exp. Allergy Rev., 1 , 220, 2001). Inhalation of leukotrienes also increases influx of inflammatory cells in the airway of animals (Clin. Exp. Allergy Rev., 1, 220, 2001) and humans (Am. J. Respir. Crit. Care Med, 157, S210, 1998). Efficacy of leukotriene biosynthesis inhibitors and leukotriene receptor antagonists has been tested in numerous trials involving asthma patients (Clin. Exp. Aller. Rev., 1, 254, 2001; Drug Safety, 26, 483, 2003; NEJM, 340, 197, 1999; Am. J. Respir. Crit. Care Med, 157, S233, 1998). Similarly, evidence is emerging based on animal and human data that leukotriene pathway modulators can play a role in arthritis (J. Pharmacol. Exp. Ther., 285, 946, 1998), allergic rhinitis and urticaria (Clin. Exp. Allergy Rev., 1, 235, 2001) but this needs to be explored further.

5-LO inhibitors can be classified according to the mechanism of enzyme inhibition. Redox inhibitors like phenidone, AA-861 , L-656,224 or BW-755C reduce the active site iron of the enzyme into the ferrous form and keep the enzyme in its inactive state. However, they interact with other biological redox system, which lead to side effects like methaemoglobin formation (J. Med. Chem., 35, 1299-1318, 1992). Iron ligand inhibtors represent a class of drugs that inhibit leukotriene synthesis by chelating the iron at the catalytic center of 5-LO. Most of the compounds of this class are hydroxamic acid or N-hydroxyurea derivatives, such as the orally active compound zileuton and BWA4C (Br. J. Pharmacol., 94, 528-539, 1988). N-hydroxyurea and hydroxamates are weak redox active compounds and it is presumed that the 5-LO inhibitory action of these drugs might be related in part to these properties (Biochem J, 274, 287-292, 1991). In order to avoid the drawbacks associated with redox and iron chelators, efforts towards the non-redox inhibitor class is essential. Non-redox type inhibitors compete with arachidonic acid or lipid hydroperoxide (LOOH) for binding to 5-LO without redox properties. A sequence of methoxyalkylthiazoles and methoxytetrahydropyrans has been identified as potent 5-LO inhibitors acting in non-redox fashion {Expert Opin. Ther. Pat., 120, 355-75, 2010).

Several leukotriene receptor antagonists, montelukast, zafirlukast, and pranlukast, and one 5-LO inhibitor, zileuton, have already been launched in the market for bronchial asthma after both categories of molecules showed efficacy in clinical trials. Zileuton, a redox and iron chelator 5-LO inhibitor, and leukotriene receptor antagonists are presently used in the long term treatment of asthma. Recent data implicate 5-LO pathway in pain signaling. Recently, 5-LO expression in the central nervous system (CNS) and in pain efficacy of a new class of non-redox, non iron chelating 5-LO inhibitor is reported. CJ- 13610, 4-(3-(4-(2-methyl-lH-imidazol-l-yl)phenylthio)phenyl)-tetrah ydro-2H-pyran-4- carboxamide, demonstrated antihyperalgesic activity in inflammatory pain models including the acute carrageenan model and the chronic inflammatory model using complete Freund's adjuvant (J. Pharm., 617(1-3), 59-67, 2009). Recently, 2-amino-5- hydroxy- IH-indoles have been found to be efficient 5-LO inhibitors in cell-based and cell- free assays. Structural optimization led to novel benzo[g] indole- 3 -carboxylates exemplified by ethyl2-(3-chlorobenzyl)-5-hydroxy- lH-benzo[g]indole-3-carboxylate which inhibits 5-LO activity in human neutrophils and recombinant human 5-LO with IC ₅₀ values of 0.23 and 0.086 μΜ, respectively. It efficiently blocks 5-LO product formation in human whole blood assays (IC ₅₀ = 0.83-1.6 μΜ) and significantly prevents leukotriene B4 production in pleural exudates of carrageenan-treated rats, associated with reduced severity of pleurisy. Together, on the basis of their high potency against 5-LO and the marked efficacy in biological systems, these novel and straightforward benzo[g]indole-3- carboxylates may have potential as anti-inflammatory therapeutics (J. Med. Chem., 52(11), 3474, 2009). ZLJ-6 potently inhibited 5-LO and cyclooxygenase, and blocked the production of LTB4, TXB2 and PGE2. Thus, ZLJ-6 is an ideal substitute for classical non-steroidal anti-inflammatory therapy (Eur. J. Pharm., 607(1-3), 244-250, 2009). MK- 0633, setileuton is potent, orally bioavailable and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model (Med. Chem. Lett., 2010).

In case of COPD, the leukotriene antagonists have exhibited only symptomatic relief. Inhibitors of 5-LO are expected to have a greater potential to exhibit efficacy in COPD because of their inhibitory effect on LTB4 mediated processes along with inhibition of cysteinyl leukotriene release. However, zileuton, the commercially available 5-LO inhibitor is associated with poor pharmacokinetic properties and adverse events, like elevation of hepatic transaminase levels. This has prompted the search for novel inhibitors of 5-LO with improved pharmacokinetic profiles and reduced adverse effects.

WO 2009/055917 discloses compounds and methods for inhibition of HDAC enzymatic activity. WO 2005/123703 relates to novel compounds for the treatment of central nervous system disorders, as well as, other disorders mediated by mGluRi receptors.

WO 00/39083 discloses pyrazole compounds for inhibiting prenylation in an organism.

WO 03/026649 discloses compounds which are used to increase endog

testosterone production.

In view of the above, there remains a need for novel derivatives as 5-LO inhibitors having anti-inflammatory activity.

Summary of the Invention

The present invention relates to pyrazole derivatives having anti-inflammatory activity and associated pathologies. Also provided are processes for synthesizing such compounds.

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

The pyrazole derivatives of the present invention and the pharmaceutical compositions containing these derivatives can be useful for inhibition and prevention of inflammation and associated pathologies, including inflammatory and autoimmune diseases, for example, bronchial asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, Type I diabetes, multiple sclerosis, allograft rejection, psoriasis, inflammatory bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis, allergic rhinitis and other inflammatory and/or autoimmune disorders.

Racemates, diastereomers, polymorphs, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates having the same type of activity are also provided as well as pharmaceutical compositions comprising such compounds in combination with suitable pharmaceutically acceptable excipients.

Therapeutically effective amounts of one or more compounds of the present invention can be used in combination with one or more other therapeutic agents, for example, COX inhibitors, BLTR antagonists, FLAP inhibitors, muscarinic receptor antagonists, 2-agonists, p38 MAP Kinase inhibitors, PDE-IV inhibitors or

corticosteroids.

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

Detailed Description of the Invention

In accordance with one aspect, there are provided compounds as 5-LO inhibitors having the structure of Formula I

Formula 1 stereoisomers, pharmaceutically acceptable salts or solvates thereof,

wherein

Ring A is selected from phenyl, pyridine, pyrazine, triazine, tetrazole, thiazole, imidazole or oxazole, each of which is optionally substituted by one or more substitutents independently selected from R ¹ ;

Ring B is selected from phenyl, C _3-10 membered cycloalkyl or 6-10 membered heteroaryl, each of which is optionally substituted by one or more substitutents independently selected from R ² ;

Ring C is selected from phenyl, cycloalkyl, heteroaryl or heterocyclyl;

R ^l is selected from the group consisting of hydrogen, Q-Csalkoxy, Ci-Csalkyl, cyano, halogen, nitro, oxo, hydroxyl, amino, alkylamino, COR _f , heteroaryl, NR _f R _q , COOR _f , CONR _f R _q , -OR _d wherein R _d is Q-Csalkyl, Q- alkyl-COOR _f and d- C ₃ alkyl-OH;

R is selected from the group consisting of hydrogen, Q-Csalkoxy, Ci-Csalkyl, cyano, halogen, carboxy, hydroxyl, NR _f R _q and heteroaryl;

R ³ is COOH, COOR _b , CH ₂ OR _a , alkyl, CONHR _b , CONR _a R _b wherein R _a can be selected from hydrogen or alkyl and R _b can be selected from alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl or R _a and R _b together with nitrogen to which they are attached form a ring which optionally may contain heteroatom selected from N, O and S;

R ⁴ is selected from hydrogen, halogen, alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, (CH ₂ ) _x -OR _d , -CO-alkyl, - CO-heteroaryl, -CO-aryl, -CO-heterocyclyl, -CO-cycloalkyl, aralkyloxy, heteroarylalkyloxy, heterocyclylalkyloxy, cycloalkylalkyloxy, -CONR _f R _q , alkylcarbonyl, COOR _d , (CH ₂ ) _s C(=0)OR _d , -CF ₃ or -OCF ₃ ;

Rd can be hydrogen or alkyl;

Rf and Rq are independently selected from hydrogen, alkyl, alkoxy, cycylalkyl, aryl, heteroaryl or heterocyclyl; s can be 0-2;

n is an integer from 1-2;

m is an integer from 1-4;

x is an integer from 1-3.

In another embodiment, the current invention provides a compound of Formula la,

Formula la

pharmaceutically acceptable salts or solvates thereof,

wherein

R ³ ' is COOH, COO-d-C ₅ alkyl, CH ₂ OH,CH ₂ 0 d-C ₅ alkyl, d-C ₅ alkyl, CONH ₂ , CONH(d-C ₅ alkyl) or CON(CH3)(d-C ₅ alkyl);

R^. R^x and m are same as defined earlier.

The following definitions apply to terms as used herein:

The term "alkyl" refers to a straight or branched fully saturated hydrocarbon chain which is optionally substituted by one or more halo atom, and which has 1 to 20 carbon atoms unless otherwise specified. This term is exemplified by groups such as methyl, ethyl, ^-propyl, wo-propyl, «-butyl, wo-butyl, t-butyl, «-hexyl, «-decyl, «-tetradecyl, trifluoromethyl, chloroethyl, and the like.

The term "cycloalkyl" refers to a non aromatic cyclic group having 3 to 20 ring carbon atoms and forms one to three rings and may optionally contain one or more olefinic bonds. Polycyclic ring systems may be a spiro, fused or bridged arrangement. Cycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, adamantlyl, bicyclo[2.2J]heptanyl, bicyclo[2.2.2]octane, tricycle[5.5JJ]decane, and the like. The term cycloalkylalkyloxy" denotes the group O-cycloalkyl wherein cycloalkyl is as defined above.

The term "aryF refers to an aromatic system having from 6 to 14 carbon atoms and up to three rings which may be fused or directly joined. Representative examples of such aryl group include, but are not limited to, phenyl, biphenyl, naphthyl, phenanthrene, anthracenyl, azulenyl, and indanyl. Aryl group may also comprise one or more rings which are not fully aromatic, and examples of such system are indane, indene, 2, 3 dihydrobenzofuran and 1 ,2,3,4-tetrahydronaphthalene

The term "aryloxy" denotes the group O-aryl, wherein aryl is as defined above. The term "heteroaryl" refers to an aromatic system having from 5 to 14 membered carbon atoms and up to three rings, which may be fused or directly joined, and containing from one to eight heteroatoms selected from N, O and S. Examples of heteroaryl groups are pyridinyl, quinolinyl, oxazolyl, imidazolyl, pyrrolyl, thiophenyl, 1,2,3-triazolyl, 1,2,4- triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like.

The term "heteroaryloxy" denotes the group O-heteroaryl wherein heteroaryl is as defined above.

The term "heterocyclyl" refers to a non-aromatic monocyclic or polycyclic ring system, which may be fused, spiro or bridged having 3 to 12 ring atoms and up to eight heteroatoms selected from N, O and S. Examples of heterocyclyl ring system include piperidine, morpholine, piperazine, isoquinoline, oxazolidine, tetrahydrofuran,

dihydrofuran, dihydropyridine, dihydroisoxazole, dihydrobenzofuran, azabicyclohexane, dihydroindole, tetrahydroquinoline, pyrrolidine, azepine, azetidine, aziridine,

tetrahydropyridine, benzthiazine, benzoxazinyl, isoindoline, azabicycle[3.7.0]hexyl, phenoxazine, tetrahydropyran, dioxane, and the like.

The term "heterocycloalkyloxy" denotes the group O-heteroaryl wherein heteroaryl is as defined above. The terms "cycloalkylalkyF, "arylalkyl", "heteroarylalkyl" , and "heterocyclylalkyF refer respectively to cycloalkyl, aryl, heteroaryl or heterocyclyl group linked the remainder of the molecule via an alkyl group.

The term "amino " refers to -NH ₂ . The term "halogen" refers to -F, -CI, -Br, and -I.

The term "protecting group" is used herein to refer to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Also the term "protecting group", unless otherwise specified, may be used with groups such as hydroxy, amino, and carboxy. The examples of such groups are found in T.W. Greene and P.G.M. Wuts, "Protective groups in organic synthesis", 3 ^rd edition, John Wiley and Sons Inc., New York, 1999.

The term "pharmaceutically acceptable salts" refers to the inorganic and organic base or acid addition salts of compounds of present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free form with a suitable organic or inorganic base or acid and isolating the salt thus obtained. Representative salts include, but are not limited to, trifluoroacetate, hydrochloride, acetate, fumarate, phosphate, tosylate, hydrobromide, sulfate, bisulfate, nitrate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, citrate, maleate, succinate, tartrate, naphthylate, mesylate,

glucoheptonate, lactobionate, laurylsulfonate, and the like. Where the compounds carry acidic moiety, the salts derived from inorganic bases include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, zinc, aluminium, as well as non-toxic ammonium, quaternary ammonium and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, triethylamine, ethylamine, diethylamine, and the like. The salts derived from organic bases include, but are not limited to, salts of natural or synthetic amino acids, betaine, caffeine, 2- diethylaminoethanol, V-ethylmorpholine, glucosamine, dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, piperazine, procaine, purine, tromethamine, and the like. The free base form may be regenerated by contacting the salt form with a base. While the free base form may differ from the salt form in terms of physical properties, such as solubility, the salts are equivalent to their respective free bases for the purposes of the present invention.

The term "pharmaceutically acceptable solvates" refers to solvates with water (i.e., hydrates) or pharmaceutically acceptable solvents, for example solvates with ethanol, and the like.

As used herein, the term "prodrugs" refers to the compounds that are rapidly transformed in vivo to yield the parent compound of general Formula (I), for example, by hydrolysis in the blood.

The disclosed compounds may be metabolized in vivo and these metabolites are also encompassed within the scope of the invention.

The term "polymorphs" includes all crystalline forms as well as amorphous forms for compounds described herein and as such are included in the scope of the present invention.

In another embodiment, the invention encompasses compounds of the present invention represented by, among others,

Ethyl(2J?)-( { 3 - [5-(2-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)(phenyl)ethanoate (Compound No. 10);

N- [2- Amino- 1 -(3 -fluoro-5-methylphenyl)-2-oxoethyl] -3 - [5-(3 -fluorophenyl)- 1 -(4- methoxy phenyl)- 1 H-pyrazol-3 -yl]propanamide (Compound No. 11);

N-[(lS)-l-(4-Chlorophenyl)ethyl]-3-[5-(3-fluorophenyl)-l- (4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 12);

Methyl( { 3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)(4-methoxy-3-methylphenyl)acetate (Compound No. 13);

N- { 2- [Ethyl(methyl)amino]- 1 -(3 -fluoro-5 -methylphenyl)-2-oxoethyl} -3 - [5-(3 - fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]propanamide (Compound

No. 14);

N- [ 1 -(4-Fluorophenyl)ethyl]-3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1H- pyrazol-3-yl]propanamide (Compound No. 15);

N- { 1 -(3-Chlorophenyl)-2-[ethyl(methyl)amino]-2-oxoethyl} -3-[5-(3- fluorophenyl)- l-(4-methoxy phenyl)-lH-pyrazol-3-yl]propanamide (Compound

No. 16);

Methyl(3 -chloro-4-methoxyphenyl)( { 3 - [5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]propanoyl}amino)acetate (Compound No. 17);

N- [( 1 R)-2- Amino-2-oxo- 1 -phenylethyl] -3-[5-(3 -fluorophenyl)- 1 -(4- methoxyphenyl)-lH-pyrazol-3-yl]propanamide (Compound No. 18);

N-[(lR)-l-(3-Chlorophenyl)ethyl]-3-[5-(3-fluorophenyl)-l-(4- methoxyphenyl)- 1 H-pyrazol-3 -yl]propanamide (Compound No. 19);

Ethyl(2i?)-( { 3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3-yl]

propanoyl}amino)(phenyl)ethanoate (Compound No. 20);

3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3-yl] -N- [( 1 i?)-2-methoxy-

1 -phenyl ethyljpropanamide (Compound No. 21);

3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N -[(li?)-l-(4- methyl phenyl)ethyl]propanamide (Compound No. 22);

N- [ 1 -(3-Fluoro-5 -methylphenyl)-2-(methylamino)-2-oxoethyl] -3 -[5-(3 - fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]propanamide (Compound

No. 23);

3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [2 -hydroxy- 1 -(4- methoxy-3-methylphenyl)ethyl]propanamide (Compound No. 24);

N- [2- Amino- 1 -(4-methoxy-3 -methylphenyl)-2-oxoethyl] -3- [5 -(3 -fluorophenyl)- 1 - (4-methoxy phenyl)- 1 H-pyrazol-3 -yl]propanamide (Compound No. 25);

N-[(li?)-2-(Ethylamino)-2-oxo-l-phenylethyl]-3-[5-(3-fluorop henyl)-l-(4- methoxyphenyl)-l H-pyrazol-3 -yl]propanamide (Compound No. 26);

(3-Chlorophenyl)({3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)- lH-pyrazol-3-yl] propanoyl}amino)acetic acid (Compound No. 27); 3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N-[( 15)-2-hydroxy- 1 -phenyl ethyl]propanamide (Compound No. 28);

(3 -Fluoro-5-methylphenyl)( { 3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanoyl}amino)acetic acid (Compound No. 29);

(3 -Chloro-4-methoxyphenyl)( { 3 -[5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanoyl}amino)acetic acid (Compound No. 30);

( { 3 -[5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)(4-methoxy-3-methylphenyl)acetic acid (Compound No. 31);

(2R)-( { 3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)(phenyl)ethanoic acid (Compound No. 32);

Ethyl(2R)-({3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyr azol-3- yl]propanoyl} amino) (phenyl)ethanoate (Compound No. 33);

Ethyl(2#)-( { [5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3- yl]carbonylamino)(phenyl)ethanoate (Compound No. 34);

Ethyl(2 ?)-({3-[l-(4-cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3- yl]propanoyl}amino)(phenyl)ethanoate (Compound No. 35); and

Ethyl(2 ?)-({3-[l-(4-methoxyphenyl)-5-(3-methylphenyl)-lH-pyrazol-3- yl]propanoyl}amino(phenyl)ethanoate (Compound No. 36).

and pharmaceutically acceptable salts, or solvates, thereof.

The compound of general Formula 1 and Formula 1 a will usually be provided as a pharmaceutical composition and therefore, in a further embodiment of the invention there is provided a pharmaceutical composition comprising therapeutically effective amounts of one or more compounds of general Formula 1 and Formula la together with one or more pharmaceutically acceptable carriers, excipients, or diluents.

In another embodiment, provided herein are methods for treating or preventing conditions caused by inflammation and associated pathologies, comprising administering to a mammal in need thereof a therapeutically effective amount of one or more compounds of Formula 1 and Formula la and their pharmaceutical compositions.

In one embodiment, the diseases or conditions of inflammation and associated pathologies are selected from bronchial asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, Type I diabetes, multiple sclerosis, allograft rejection, psoriasis, inflammatory bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis, allergic rhinitis and other inflammatory and/or autoimmune disorders. In yet another embodiment, provided herein, are pharmaceutical compositions comprising one or more compound having the structure of Formula 1 and Formula la as defined above in combination with at least one or more other therapeutic agent selected from COX inhibitors, BLTR antagonists, FLAP inhibitors, muscarinic receptor antagonists, p2-agonists, p38 MAP Kinase inhibitors, PDE-IV inhibitors or

corticosteroids.

Compounds disclosed herein may be prepared, for example, by techniques well known in the organic synthesis and familiar to a practitioner ordinarily skilled in art of this invention. In addition, the processes described herein may enable the synthesis of compounds of the present invention. However, these may not be the only means by which the compounds described in the invention may be synthesized. Further, the various synthetic steps, described herein, may be prepared in alternated sequences in order to furnish the desired compounds.

Scheme I

Formula 1 when ring A, B and C are

phenyl .

The compound of Formula 7 can be prepared according to Scheme I. Thus, reacting a compound of Formula 2 (wherein R ² is same as defined earlier) with succinic anhydride gives a compound of Formula 3. The reaction of a compound of Formula 3 with a compound of Formula 4 (wherein R ¹ is same as defined earlier) gives a compound of Formula 5 which upon reaction with a compound of Formula 6 (R ³ and R ⁴ are same as defined earlier), gives a compound of Formula 7.

The reaction of a compound of Formula 2 with succinic anhydride to form a compound of Formula 3 can be carried out using base, for example, lithium

hexamethyldisilazide (LiHMDS), lithium diisopropylamide (LDA), lithium

tetramethylpiperidine (LiTMP) in the presence of one or more solvents selected from tetrahydrofuran, dimethylformamide, 1 ,4-dioxane or diethyl ether.

The reaction of a compound of Formula 3 with a compound of Formula 4 to form a compound of Formula 5 can be carried out in the presence of bases, for example, trimethylamine, triethylamine, tributylamine, pyridine, N-ethyldiisopropylamine, 4-N,N- dimethylaminopyridine, N-methylmorpholine or 2,6-lutidine in the presence of polar solvents selected from ethanol, propanol, /so-propanol.

The reaction of a compound of Formula 5 with a compound of Formula 6 to form a compound of Formula 7 can be carried using base selected from triethylamine, NJV- dimethylaminopyridine,2,6-lutidine, 1-methylpiperidine, N-ethyldiisopropylamine, N,N- diisopropylethylamine or N-methylmorpholine, in the presence of additives, 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, dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, chlorotripyrrolidinophosphonium hexafluorophosphate or (benzotriazol- 1 -yloxy)tm-(dimemylamino)phosphonium hexafluorophosphate.

Scheme II

Formula 12

The compound of Formula 9 (Path A), Formula 10 (Path B), Formula 11 (Path C) and Formula 12 (Path D) can be prepared according to Scheme II. The hydrolysis of a compound of Formula 8 (R is C1-C4 alkyl, R ¹ , R ² and R ⁴ are same as defined earlier) gives a compound of Formula 9 which upon amidation gives a compound of Formula 10 (wherein R _x and R _y are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl or R _x and R _y together with nitrogen to which they are attached form a ring which optionally may contain heteroatom selected from N, O and S). The reduction of a compound of Formula 8 gives a compound of Formula 11 which upon alkylation gives a compound of Formula 12 (wherein R' is alkyl). The hydrolysis of a compound of Formula 8 to form a compound of Formula 9 can be carried out in a solvent selected from, for example, methanol, ethanol, tetrahydrofuran, dioxane, water or mixture(s) thereof in the presence of a base, for example, lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide or barium hydroxide.

Amidation of a compound of Formula 9 to form a compound of Formula 10 can be carried out in a solvent, for example, N,N-dimethylformamide, tetrahydrofuran, 1,4- dioxane or diethyl ether and a base, for example, triethylamine, N,N- dimethylaminopyridine,2,6-lutidine, 1-methylpiperidine, N,N-diisopropylethylamine or N- methylmorpholine, in the presence of additives, for example, hydroxybenzotriazole

(HOBt), 3-hydroxy-3,4-dihydro-4-oxo-l,2,3-benzotriazine (DHBT),2-hydroxypyridine, N- hydroxysuccinimide (NHS) or l-hydroxy-7-azabenzotriazole (HO At), with a suitable condensing agent, for example, dicyclohexylcarbodiimide (DCC), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),

chlorotripyrrolidinophosphonium hexafluorophosphate (PyClOP) or (benzotriazol- 1 - yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate (BOP).

The reduction of a compound of Formula 8 to give a compound of Formula 1 1 can be carried in the presence of polar aprotic solvents, for example, tetrahydrofuran, ether, N,jV-dimethylformamide, acetonitrile or mixture(s) thereof with suitable reducing agent, for example, sodium borohydride, lithium aluminium hydride or diisobutylaluminum hydride.

The alkylation of a compound of Formula 11 to form a compound of Formula 12 can be carried out in the presence of base, for example, cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate in the solvents selected from N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran or 1,4-dioxane.

In the above scheme, where specific reagents, for example, bases, solvents, coupling agents, activating agents, etc., are disclosed, it is to be understood that other reagents, e.g., bases, solvents, coupling agents, activating agents, etc., known to one of ordinary skill in the art may be used. Similarly, reaction temperatures and durations may be adjusted according to the desired needs without undue experimentation and well within the abilities of one of ordinary skill in the art. All the epimers, unless otherwise specified in the above scheme, are also encompassed within the scope of the invention.

The compounds described herein may be administered to an animal for treatment orally, topically, rectally, internasally, or by parenteral route. Pharmaceutical

compositions disclosed herein comprise pharmaceutically effective amounts of compounds, described herein, formulated together with one or more pharmaceutically acceptable carriers, excipients or diluents.

Solid form preparations for oral administration include capsules, tablet, pills, powder, granules, lozenges, troches, cachets and suppositories. For solid form preparations, active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carrier, for example, sodium citrate, dicalcium phosphate and/or fillers or extenders (for example, starches, lactose, sucrose, glucose, mannitol, silicic acid, or mixtures thereof); binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, acacia or mixtures thereof; disintegrating agents, for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates, sodium carbonate, or mixtures thereof; absorption acceletors, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol mono stearate, or mixtures thereof; adsorbants, for example, Kaolin; lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauaryl sulfate, or mixtures thereof.

Capsules, tablets or pills may also comprise buffering agents. Tablets, capsules, pills or granules can be prepared using one or more coatings or shells to modulate the release of active ingredients, for example, enteric coatings or other coatings known to one of ordinary skill in the art.

Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In such liquid form preparations, active compounds can be mixed with water or one or more non-toxic solvents, solubilizing agents or emulsifiers, 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, groundnut, corn, germ, olive, castor and sesame oil, glycerol, fatty acid esters of sorbitan, or mixtures thereof. Oral compositions can 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.

Acceptable 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 nonirritating excipients such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at body temperature and which therefore melt in 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. Active compounds can be admixed under sterile condition with one or more pharmaceutically acceptable carriers and optionally any preservatives or buffers as may be required. Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.

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

Table 1

Formula 1 wherein n is one

Experimental

Various solvents used were dried using drying reagents according to procedures described in the literature. Wherever room temperature or ambient temperature is used, it is 25°C to 30°C.

Synthesis of Intermediates

Synthesis of Methyl Amino(3-Fluoro-5-Methylphenyl)Acetate

To a solution of ±-amino(3-fluoro-5-methylphenyl)acetic acid (0.09 g, 0.491 mmol) in dry ethanol (5 ml) was added thionyl chloride (0.106 ml, 1.473 mmol) drop-wise at 0°C. The reaction mixture was stirred at room temperature overnight. After completion, reaction mixture was concentrated under vacuum, basified with saturated sodium bicarbonate solution (pH~9) and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated off under vacuum to afford the title compound as light brown oil. Yield: 0.08 g. Synthesis of Methyl Amino(4-Methoxy-3-MethylphenvDAcetate

To a solution of ±amino(4-methoxy-3-methylphenyl)acetic acid (1 g, 5.12 mmol) in dry methanol (50 ml) was added thionyl chloride (1.1 ml, 5.12 mmol) drop-wise at 0°C. The reaction mixture was stirred overnight at room temperature. After completion, reaction mixture was concentrated under vacuum, basified with saturated solution of sodium bicarbonate (pH~9) and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated off under vacuum to afford the tittle compound as light brown oil. This compound was used as such for the next step without further purification. Yield: lg.

Synthesis of Methyl (2R)-Amino(4-Hydroxyphenyl)Ethanoate

To a solution of (2J?)-amino(4-hydroxyphenyl)ethanoic acid (1 g, 5.98 mmol) in dry methanol (50 ml) was added thionyl chloride (1.05 ml, 154.97 mmol) drop- wise at 0°C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum, basified with a saturated solution of sodium bicarbonate (pH~9) and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated off under vacuum to afford the title compound as light brown oil. This compound was used as such for the next step without purification. Yield: 1 g.

Example 1 : Synthesis of Ethyl (2i?Vr(3-r5-(3-Fluorophenvn-l-(4-Methoxyphenvn-lH- Pyrazol-3-YllPropanoyl|Amino (PhenvnEthanoate (Compound No. 2) (Scheme I)

Step A: Preparation of 6-(3-Fluorophenyl)-4, 6-Dioxohexanoic Acid

In a three-neck round bottom flask was taken 3-fluoroacetophenone (3 Og, 217.17 mmol) in freshly distilled dry THF (100 ml) under an argon atmosphere and cooled to -78°C. To this solution was added LiHMDS (20%, 1M solution in THF, 434.32 ml, 434.32 mmol) drop-wise at -78°C and stirred at the same temperature for one hour.

Succinic anhydride (43.43 g, 434.32 mmol) dissolved in dry THF (200 ml) was added drop-wise into the reaction mixture at same temperature under an argon atmosphere. The reaction mixture was stirred at -78 °C for one hour and then at room temperature for 2 hours. After completion, the reaction mixture was diluted by the addition of water and concentrated hydrochloric acid was added until pH became acidic (pH~4) and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated off under vacuum to afford a crude product which was purified through column chromatography over silica gel (100- 200) eluting with ethyl acetate:hexane (2:3) to afford the title compound as white solid. Yield: 24 g.

Mass spectrum (m/z +ve ion mode): 239 [M ⁺ +l]

Step B: Preparation of 3-[5-(3-Fluorophenyl)-l-(4-Methoxyphenyl)-lH-Pyrazole-3- Yl] Propanoic Acid

To a solution of compound obtained from step A (1 1 g, 46.21 mmol) in dry ethanol (10 ml) was added 4-methoxyphenyl hydrazine (8 g, 46.21 mmol) and triethylamine (12.8 ml, 92.43 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 4 hours to 5 hours. After completion of reaction, the solvent was evaporated off under vacuum, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated off to afford a brown residue which was purified through column chromatography over silica gel (100-200) eluting with ethyl acetate :hexane (1 :5) to afford the title compound as light brown solid. Yield: 8 g.

Mass spectrum (m/z +ve ion mode): 341 [M ⁺ +l].

Step C: Preparationof Ethy](2R)-({3-[5-(3-Fluorophenyl)-l-(4-Methoxyphenyl)-lH- Pyrazol-3-Yl]Propanoyl}Amino)(Phenyl)Ethanoate

To the solution of the compound obtained from step B (0.5 g, 1.47 mmol) in N, Λ - dimethylforaiamide (5 ml) was added 1 -hydroxybenzotriazole (HOBT, 0.198 g, 1.47 mmol), N-ethyldiisopropylamine (Huing's base, 0.75 ml, 4.41 mmol) and ethyl (2R)- amino(phenyl)ethanoate (0.316 g, 1.76 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then l-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl, 0.42 g, 2.20 mmol) was added. The reaction mixture was again stirred at room temperature for 12 hours. After completion, the solvent was evaporated off under vacuum, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated off under vacuum to afford an oily residue. The crude product was purified through flash column chromatography eluting with ethyl acetate :hexane (1 :1) to afford the title compound as white solid. Yield: 0.32 g.

1H NMR (400 MHz, DMSO- ₆ ): δ 8.77 (d, J= 7.33 Hz, 1H, -NH), 7.32 - 7.40 (m, 7H, Ar- H), 7.13 - 7.19 (m, 3H, Ar-H), 6.93 - 7.03 (m, 3H, Ar-H), 6.50 (s, 1H, -CH), 5.44 (d, J= 7.07 Hz, 1H, -CH), 4.01 - 4.07 (m, 2H, -OCH ₂ ), 2.87 (t, J= 7 AO Hz, 2H, -CH ₂ ), 2.62 (t, J = 7.45 Hz, 2H, -CH ₂ ) and 1.11 (t, J = 3.50 Hz, 3H, -CH ₃ )

Mass spectrum (m/z, +ve ion mode): 502 [M^+l].

The compounds mentioned below were prepared by following the same route of synthesis as above.

Methyl(3 -fluoro-5 -methylphenyl)( { 3 - [5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- lH-pyrazol-3-yl]propanoyl}amino)acetate (Compound No. 1);

Mass spectrum (m/z +ve ion mode): 520 pvT+l]

Ethyl(3 -chlorophenyl)( { 3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)acetate (Compound No. 3);

Mass spectrum (m/z +ve ion mode): 536 [M ⁺ +l]

3 - [5-(3-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3-yl] -N- [( 1 S)- 1 -(4-methyl phenyl)ethyl]propanamide (Compound No. 6);

Mass spectrum (m/z +ve ion mode): 458 [M ⁺ +l]

3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N -[(15)-l- phenylpropyl]propanamide (Compound No. 7);

Mass spectrum (m/z +ve ion mode): 458 [M ⁺ +l]

3- [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -TV- [( 1 S)- 1 -phenyl ethyl] propanamide (Compound No. 8);

Mass spectrum (m/z +ve ion mode): 444 [M ⁺ +l]

Ethyl(2i?)-({3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH-py razol-3- yl]propanoyl}amino)(phenyl)ethanoate (Compound No. 10);

Mass spectrum (m/z +ve ion mode): 502 [M ⁺ +l]

N-[(15)-l-(4-Chlorophenyl)ethyl]-3-[5-(3-fluorophenyl)-l-(4- methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 12);

Mass spectrum (m/z +ve ion mode): 478 [M^+l]

Methyl ( { 3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)(4-methoxy-3-methylphenyl)acetate (Compound No. 13); Mass spectrum (m/z +ve ion mode): 532 [M ⁺ +l]

TV- [ 1 -(4-Fluorophenyl)ethyl] -3 - [5 -(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 15);

Mass spectrum (m/z +ve ion mode): 462 [M ⁺ +l]

Methyl (3 -chloro-4-methoxyphenyl)( { 3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]propanoyl}amino)acetate (Compound No. 17); Mass spectrum (m/z +ve ion mode): 552 [M ⁺ +l]

N-[(IR)- 1 -(3-Chlorophenyl)ethyl]-3-[5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1H- pyrazol-3-yl]propanamide (Compound No. 19);

Mass spectrum (m/z +ve ion mode): 478 [Μ* ^" +1]

Ethyl (2i?)-({3-[l-(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3- yl]propanoyl}amino)(phenyl)ethanoate (Compound No. 20);

Mass spectrum (m/z +ve ion mode): 484 [M ⁺ +l]

3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N -[(li?)-l-(4- methyl phenyl)ethyl]propanamide (Compound No. 22);

Mass spectrum (m z +ve ion mode): 458 [M ⁺ +l]

Ethyl(2i?)-( { 3 - [5 -(4-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)(phenyl)ethanoate (Compound No. 33);

Mass spectrum (m/z +ve ion mode): 502 [M ⁺ +l]

Ethyl(2i?)-( { [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]carbonylamino)(phenyl)ethanoate (Compound No. 34);

Mass spectrum (m/z +ve ion mode): 474 [M ⁺ +l]

Ethyl(2i?)-({3-[l-(4-cyanophenyl)-5-(3-fluorophenyl)-lH-pyra zol-3- yl]propanoyl} amino) (phenyl)ethanoate (Compound No. 35);

Mass spectrum (m/z +ve ion mode): 487 [M ⁺ +l]

Ethyl (2i?)-({3-[l-(4-methoxyphenyl)-5-(3-methylphenyl)-lH-pyrazol -3- yl]propanoyl} amino (phenyl)ethanoate (Compound No. 36).

Mass spectrum (m/z +ve ion mode): 498 [M ⁺ +l]

Example 2: Synthesis of ((S- S-fS-FluorophenvD-l-^-MethoxyphenvD-lH-Pyrazol-S

-Y11Propanoyl}Aminoy4-Memoxy-3-MethylphenvD Acetic Acid (Compound No. 31) (Scheme II, Path A

To a solution of methyl({3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol - 3-yl]propanoyl}amino)(4-methoxy-3-methylphenyl)acetate (0.1 g, 0.188 mmol) in tetrahydrofuran (3 ml) was added lithium hydroxide (IN, 0.4 ml, 0.40 mmol) and stirred at room temperature for 2 hours. After completion of reaction, solvent was the solvent evaporated off under vacuum and IN HC1 solution was added until pH became acidic (pH~3). The reaction mixture was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulphate. The organic layer was filtered and the solvent evaporated off under vacuum to afford the title compound as white solid. Yield: 0.075 g.

1H NMR (400 MHz, DMSO-<¾: 612.68 (br. s, 1H, -C0 ₂ H), 8.55 (d, J - 7.07 Hz, 1H, - NH), 7.36 (q, J = 7.49 Hz, 1H, Ar-H), 7.07 - 7.26 (m, 6H, Ar-H), 6.79 - 7.03 (m, 5H, Ar- H), 6.51 (s, 1H, -CH), 5.24 (d, J = 7.07 Hz, 1H, -CH), 3.76 (s, 3H, -OMe), 3.75 (s, 3H, - OMe), 2.85 (t, J= 7.45 Hz, 2H, -CH ₂ ), 2.58 (t, J= 7.33 Hz, 2H, -CH ₂ ) and 2.10 (s, 3H, Ar-CH ₃ )

Mass spectrum (m/z +ve ion mode): 518 [M ⁺ +l]

The compounds mentioned below were prepared by following the same route of synthesis as above.

(3 -Chlorophenyl)( { 3 -[5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)acetic acid (Compound No. 27);

Mass spectrum (m/z +ve ion mode): 508 [M ⁺ +l]

(3 -Fluoro-5-methylphenyl)({ 3 -[5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanoyl}amino)acetic acid (Compound No. 29);

Mass spectrum (m/z +ve ion mode): 506 [M ⁺ +l]

(3 -Chloro-4-methoxyphenyl)( { 3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanoyl}amino)acetic acid (Compound No. 30);

Mass spectrum (m/z +ve ion mode): 538 [M ⁺ +l]

(2i?)-({3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol -3- yl]propanoyl}amino)(phenyl)ethanoic acid (Compound No. 32);

Mass spectrum (m/z +ve ion mode): 474 [M ⁺ +l]

Example 3 Synthesis of iV-r2-Amino-l-(4-Methoxy-3-Methylphenyl)-2-Oxoethyll-3-[5-

(3 -Fluorophenyl)- 1 -(4-Methoxyphenyl)- lH-Pyrazol-3 - YllPropanamide (Compound No. 25) (Scheme II, Path B)

To a solution of ({3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanoyl}amino)(4-methoxy-3-methylphenyl)acetic acid (0.09 g, 0.17 mmol) in N, iV- dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (HOBT, 0.034 g, 0.25 mmol), N-ethyldiisopropyl amine (Hunig's base, 0.072 ml, 0.41 mmol) and ammonium carbonate (0.082 g, 0.835 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes and then l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl, 0.05 g, 0.25 mmol) was added. The reaction mixture was again stirred at room temperature for about 12 hours. After completion of reaction, the solvent was evaporated off under vacuum, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated off under vacuum to afford an oily residue which was purified through flash column chromatography eluting with ethyl acetate:hexane (19:1) to afford the title compound as light yellow solid. Yield: 0.025 g. 1H NMR (400 MHz, DMSO-t¼): δ 8.35 (d, J= 8.03 Hz, 1H, -NH), 7.55 (s, 1H, Ar-H), 7.31 - 7.40 (m, 1H, Ar-H), 7.10 - 7.20 (m, 6H, Ar-H), 6.87 - 7.06 (m, 2H, Ar-H), 6.79 (d, J = 9.03 Hz, 1H, Ar-H), 6.49 (s, 1H, -CH), 5.30 (d, J= 8.03 Hz, 1H, -CH), 3.76 (s, 3H, - OMe), 3.72 (s, 3H, -OMe), 2.83 (t, J= 7.50 Hz, 2H, -CH ₂ ), 2.59 (t, J= 7.50 Hz, 2H, -CH ₂ ) and 2.07 (s, 3H, Ar-CH ₃ )

Mass spectrum (m/z, +ve ion mode): 517 [M ⁺ +l].

The compounds mentioned below were prepared by following the same route of synthesis as above.

N- [2- Amino- 1 -(3-fluoro-5-methylphenyl)-2-oxoethyl] -3 - [5-(3 -fluorophenyl)- 1 -(4-

Example 4: Synthesis of 3- 5-(3-Fluorophenyl)-l-(4-Methoxyphenyl -lH-Pyrazol-3-Yll-

N-r(lSV2-Hvdroxy-l -Phenyl Ethyl! Propanamide (Compound No. 28 ; (Scheme II, Path

To an ice-cold solution of ethyl(2i?)-({3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)- lH-pyrazol-3-yl]propanoyl}amino)(phenyl)ethanoate (0.3 g, 0.59 mmol) in dry distilled tetrahydrofuran (3 ml) was added lithium aluminum hydride (1 M, solution in THF, 0.89 ml, 0.89 mmol) drop-wise with constant stirring. The reaction mixture was stirred at 0°C for 30 minutes. After completion of reaction, a saturated solution of Na ₂ S0 ₄ was added drop-wise with constant stirring at 0°C until a white gelatinous precipitate was obtained. The reaction was filtered through pre- washed celite pad and washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated off under vacuum to afford an oily residue which was purified through column chromatography eluting with ethyl acetate :hexane (4: 1) to afford the title compound as colorless oil. Yield: 0.2 g.

1H NMR (400 MHz, DMSO-<¾): 57.47 (d, J= 8.34 Hz, 1H, -NH), 6.29 - 6.57 (m, 11H, Ar-H), 6.09 - 6.17 (m, 2H, Ar-H), 5.64 (s, 1H, -CH), 4.03 (t, J= 6.90 Hz, 1H, -CH), 2.93 (s, 3H, -OMe), 2.65 - 2.76 (m, 2H, -OCH ₂ ), 2.02 (t, J= 6.90 Hz, 2H, -CH ₂ ) and 1.74 (t, J= 7.33 Hz, 2H, -CH ₂ )

Mass spectrum (m/z +ve ion mode): 460 [M ⁺ +l]

The compounds mentioned below were prepared by following the same route of synthesis as above.

N-[\ -(3-Chlorophenyl)-2-hydroxyethyl]-3-[5-(3-fluorophenyl)- 1 -(4- methoxyphenyl)-lH-pyrazol-3-yl]propanamide (Compound No. 4);

Mass spectrum (m/z +ve ion mode): 494 [M ⁺ +l]

N-[l-(3-Fluoro-5-methylphenyl)-2-hydroxyethyl]-3-[5-(3-fluor ophenyl)-l-(4- methoxyphenyl)-lH-pyrazol-3-yl]propanamide (Compound No. 5);

Mass spectrum (m/z +ve ion mode): 492 [M ⁺ +l]

3 - [5-(3-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [( 1 #)-2-hydroxy- 1 -phenyl ethyljpropanamide (Compound No. 9);

Mass spectrum (m/z +ve ion mode): 460 [M ⁺ +l]

3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-i V-[2-hydroxy-l-(4- methoxy-3-methylphenyl)ethyl]propanamide (Compound No. 24);

Mass spectrum (m/z +ve ion mode): 504 [M ⁺ +l]

Example 5: Synthesis of 3- 5-(3-Fluorophenyl -l-(4-Methoxyphenyl -lH-Pyrazol-3-Y11- iV-r(lff)-2-Methoxy-l -Phenyl Ethyl! Propanamide (Compound No.2n (Scheme II. Path Ό)

To a solution of 3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N - [(l ?)-2-hydroxy-l-phenylethyl]propanamide (0.1 g, 0.21 mmol) in N,iV- dimethylformamide (1.5 ml) was added cesium carbonate (0.14 g, 0.43 mmol) at room temperature and stirred for 10 minutes. To this reaction mixture was added methyl iodide (0.0136 ml, 0.21 mmol) at same temperature under an argon atmosphere. The reaction mixture was allowed to heat at 70°C for 2 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated off under vacuum to obtain a crude product which was purified through column

chromatography over silica gel (100-200) eluting with ethyl acetate:hexane (1 : 1) to afford the title compound as white solid. Yield: 0.05g.

1H NMR (400 MHz, DMSO-i¾: δ 8.56 (d, J= 8.53 Hz, 1H, -NH), 7.22 - 7.43 (m, 6H, Ar- H), 7.11 - 7.21 (m, 3H, Ar-H), 6.93 - 7.00 (m, 4H, Ar-H), 6.46 (s, 1H, -CH), 5.13 - 5.23 (m, 1H, -CH), 4.15 - 4.28 (m, 2H, -CH ₂ OMe), 3.77 (s, 3H, -OMe), 3.66 (s, 3H, -OMe), 2.86 (t, J= 6.90 Hz, 2H, -CH ₂ ) and 2.58 (t, J= 7.40 Hz, 2H, -CH ₂ )

Mass spectrum (m/z +ve ion mode): 474 [M ⁺ +l]

Pharmacological activity

5-LO Enzyme Assay

The NCEs/standard compounds diluted in DMSO (20 μΐ), TEC buffer (50 mMTris; pH 7.5, 2 mM EDTA, 2 raM CaCl ₂ ) was added in black assay plate along with 1 μΐ of the serially diluted NCEs/standard compound. 5-LO enzyme (recombinant enzyme/neutrophil lysate) appropriately diluted in TEC buffer and added in the assay plate except the negative well (for reducing condition, glutathione peroxidase (25 mU/well) and reduced glutathione (100 μΜ/well) or 100 μΜ DTT were also added). The reaction mixture was incubated for about 30 minutes at room temperature. 10 mM stock solution of 2 ', 7'-

Dichlorodihydrofluorecein diacetate (H ₂ DCFDA) (1 :100 in TEC Buffer) was prepared and 10 μΐ per well was added in all wells including the "positive" and "negative" wells. The mixture was incubated for 10 minutes to 15 minutes. A mixture of arachidonic acid (2.5 μΜ/well) and ATP (5 μΜ/well) was added in all the wells. The volume was made up to 100 μΐ with TEC buffer and incubated for 1 hour. The fluorescence was read at 480 ran excitation/520 ran emission. The % inhibition and IC ₅₀ were calculated.

The IC ₅₀ values of compounds (Compound No. 1-7) ranged from 10 nM to 500 nM. Some compounds showed ICso in the range of 0.5 μΜ to 5 μΜ. LTB4 Release Inhibition Assay (with and without HpODE)

Human blood was collected by venipuncture from healthy volunteers and neutrophils were isolated using Ficoll Hypaque gradient (density 1.077 g/ml). Cells were suspended in PBSG (pH 7.2) at a concentration of 0.2 10 ⁶ cells/ml (PBSG = PBS containing lmg/ml glucose). 200 μΐ of cell suspension was added along with 1 μΐ of suitably diluted NCE/vehicle per well in a 24 well plate and incubated for 47 minutes at 37°C with or without 13-HpODE (final cone 3 μΜ). 20 μΐ of PBSG having Mg ²⁺ & Ca ²⁺ (5 μΐ of 1M MgCl ₂ + 5 μΐ of 1M CaCl ₂ + 990 μΐ of PBSG; total 1ml; final concentration = 250 μΜ each) was added and incubated further for 3 minutes. 20 μΐ of Ca ionophore A23187 (3 μg/ml) was added per well and incubated further for 10 minutes at 37°C (final concentration 0.3 μg/ml). The reaction was stopped by adding 80 μΐ of chilled methanol. Plate was centrifuged at 3600 rpm for 10 minutes at 4°C and supernatant was collected. 100 μΐ was used for LTB ₄ release assay using ELISA kit as described by the manufacturer (Assay Designs Inc). Selectivity Assays: a. 12-LOX and 15-LOX Assay

12-LOX and 15-LOX assays were performed using in-house enzymes. Both the enzyme assays were based on the oxidation of the substrate H ₂ DCFDA to the highly fluorescent 2', 7'-dichloro-fluorescein (DCF) product. Briefly, 20 μΐ of buffer was added in the assay plate along with 1 μΐ of varying concentrations of compound. The recombinant 12-LOX/15-LOX enzymes were appropriately diluted in reaction buffer and added in the plate. The reaction mixture was incubated for 30 minutes. Subsequently, 10μΜ of H ₂ DCFDA dye was added per well and incubated for 15 minutes. Arachidonic acid (0.5 μΜ/well) and ATP (5 μΜ/well) were added and the fluorescence was read at 480 nm excitation/520 nm emission after an incubation of 1 hour at room temperature.

b. FLAP Assay

8-10 ml of fresh blood sample was collected and leukocytes were isolated. Cells were centrifuged at 1 ^x 10 ⁵ g for 60 minutes at 4°C to prepare the membranes. Protein was estimated using Bradford estimation and stored at -80°C until use. Radioligand binding assay was performed using [ ³ H] MK886. Protein concentration per well was 30-60 μg. The reaction mixture was incubated for 30 minutes at room temperature with continuous shaking followed by harvesting using GF/B filter mats. Counting was performed using microbeta scintillation counter and % inhibition was calculated.

c. COX-l/COX-2 Assay

COX-1 and COX-2 enzyme assays were performed by using commercially available enzymes (Cayman) and using a commercially available enzyme assay kit (Cayman Chemicals Cat No: 700100). NCEs or standards were incubated with COX enzymes for 15 minutes and reaction was started with addition of substrate (10 μΐ of 10- acetyl-3,7-dihydroxyphenoxazine), as per the manufacturer's instructions. Increase in fluorescenece was monitored at Exc 535 nm and Em 590 nm, respectively. All assays were run in duplicate. % inhibition was calculated using control wells.