WO2011161615A1 - 5-lipoxygenase inhibitors - Google Patents

5-lipoxygenase inhibitors Download PDF

Info

Publication number
WO2011161615A1
WO2011161615A1 PCT/IB2011/052695 IB2011052695W WO2011161615A1 WO 2011161615 A1 WO2011161615 A1 WO 2011161615A1 IB 2011052695 W IB2011052695 W IB 2011052695W WO 2011161615 A1 WO2011161615 A1 WO 2011161615A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pyrazol
propanamide
fluorophenyl
methoxyphenyl
Prior art date
Application number
PCT/IB2011/052695
Other languages
French (fr)
Inventor
Ashwani Kumar Verma
Sanjay Malhotra
Srinivasa Marimganti
Abhijit Ray
Suman Gupta
Punit Srivastava
Sunanda Ghosh Dastidar
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2011161615A1 publication Critical patent/WO2011161615A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to pyrazole derivatives and to 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
  • 5 -Lipoxygenase is a key enzyme that oxidizes arachidonic acid into biologically active leukotrienes, namely cysteinyl leukotrienes and leukotriene B4 (Clin. Exp. Allergy Rev., 1, p. 196 (2001)).
  • Leukotrienes play an important role in the pathophysiology of inflammatory/allergic diseases including bronchial asthma (Clin. Exp. Allergy Rev., 1, p. 264 (2001)), allergic rhinitis (Clin. Exp. Allergy Rev. 1, p. 235 (2001)), urticaria, atopic dermatitis (Clin. Exp.Allergy Rev. 1, p. 305 (2001)), chronic obstructive pulmonary disease (Eur. Respir. J, 22, p. 926 (2003)), etc.
  • 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.
  • LTA4 is converted to either cysteinyl leukotrienes and/or leukotriene B4 (Clin. Exp. Allergy Rev. l, p. 196 (2001); Curr. Drug Targets - Inflammation & Allergy, !, p. 23, 2002; Drug Safety, 26, p. 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. Critic Care Med., 157, p.
  • 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., ⁇ , p. 220 (2001)). Inhalation of leukotrienes also increases influx of inflammatory cells in the airway of animals (Clin. Exp. Allergy Rev., ⁇ , p. 220 (2001)) and humans (Am. J. Respir Crit. Care Med., 151, S210,
  • 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.
  • they interact with other biological redox system, which lead to side effects like methaemoglobin formation (J. Med. Chem., 35, p. 1299-1318 (1992)).
  • Iron ligand inhibitors represent a class of drugs that inhibit leukotriene synthesis by chelating the iron at the catalytic center of 5-LO.
  • 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, p. 287-292 (1991)).
  • Non-redox type inhibitors compete with arachidonic acid or lipid hydroperoxide (LOOH) for binding to 5-LO without redox properties.
  • LOOH lipid hydroperoxide
  • ZLJ-6 potently inhibited 5-LO and cyclooxygenase, and blocked the production of LTB4, TXB2 and PGE2.
  • ZLJ-6 is an ideal substitute for classical nonsteroidal anti-inflammatory therapy (Eur. J. Pharm., 607(1-3), p. 244-250 (2009)).
  • 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.
  • 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 2008/071456 discloses 3H-pyrazolopyridines and salts thereof
  • compositions comprising same, methods of preparing same and same.
  • U.S. Publication No. 2006/0075376 discloses cycloalkyl heterocycles for treating hepatitis C virus.
  • WO 03/026649 discloses substituted pyrazole compounds to increase endogenous testosterone production.
  • WO 01/87287 discloses substituted pyrazole compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds.
  • the present invention relates topyrazole derivatives having anti-inflammatory activity and associated pathologies. Also provided, are processes for synthesizing such compounds.
  • 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
  • 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.
  • 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, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates having the same type of activity are also provided as well as pharmaceutical compositions comprising such compounds.
  • 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, p2-agonists, p38 MAP Kinase inhibitors, PDE-IV inhibitors or
  • the present invention relates to compounds having the structure of Formula 1
  • Ring A is selected from phenyl, pyridine, pyrazine, triazine, tetrazole, thiazole, imidazole and oxazole each of which is optionally substituted by one or more substituents independently selected from R 1 ;
  • Ring B is selected from phenyl, C 3-10 cycloalkyl and a 6-10 membered heteroaryl each of which is optionally substituted by one or more substituents independently selected from R 2 ;
  • R 2 is selected from the group consisting of hydrogen, hydroxy, d-C 5 alkyl, d- C 5 alkoxy, CN, halogen, CF 3 ,heteroaryl,d-C 5 alkylamino, NR f R q , d-C 5 alkyl- NHCO-d-C 5 alkyl and COOR f ;
  • R f and R q are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and R f and R q may together form a ring system together with the heteroatom to which they are attached;
  • R 3 is hydrogen or R 3 and R 4 together with the nitrogen atom to which they are attached forms a C 5-1 o ring system wherein 1-3 carbon atom in the ring are replaced by heteroatom selected from N, O or S and the ring system can optionally be substituted by one or more substituents independently selected from R 5 ;
  • R 4 is selected from the group consisting of -(CH 2 ) m -(0) s -phenyl,-(CH 2 ) m -(0) s - heterocyclyl or -(CH 2 ) m -(0) s -heteroaryl, wherein each of phenyl, heterocyclyl and heteroaryl is optionally substituted by one or more substituents selected from R 5 ;
  • R 5 is selected from the group consisting of hydrogen, halogen, CrC 5 alkyl,nitro,
  • n is an integer 1-2;
  • n is an integer 0-3;
  • s is an integer 0-1;
  • x is an integer 1-3.
  • the current invention provides a compound of Formula la:
  • R 4' can be phenyl, heterocyclyl, heteroaryl optionally substituted with one or more substituents selected from R 5 ;
  • Ring A, ring B,R R 2 , R 5 and x are same as defined earlier.
  • R 4' ,Ring A, Ring B.R 1 R 2 and x are same as defined earlier.
  • the current invention provides a compound of Formula lc:
  • R 4' ,Ring A, Ring B ⁇ R 2 and x are same as defined earlier.
  • the current invention provides a compound of Formula
  • Ring A, Ring B,R 5 , and x are same as defined earlier.
  • 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.
  • alkenyl refers to a branched or unbranched unsaturated hydrocarbon group containing at least one double bond with cis or trans geometry, and preferably, having 2 to 20 carbon atoms.
  • alkenyl group include ethenyl, 2-propenyl and isopropenyl.
  • cycloalkyl refers to a non aromatic cyclic group having 3 to 20 ring carbon atoms and form 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[2.2.7]heptanyl, bicyclo[2.2.2]octane, tricycle [3.3.1.7]decane, and the like.
  • aryl 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 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
  • 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,0 and S.
  • 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.
  • heterocyclyl refers to a non-aromatic monocyclic or polycyclicring 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.
  • heterocyclyl ring system examples 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, 1,4-dioxane, and the like.
  • cycloalk lalkyF, arylalkyl, heteroarylalkyF , heterocyclylalkyF refers, respectively, to cycloalkyl, aryl, heteroaryl or heterocyclyl group linked the remainder of the molecule via an alkyl group.
  • amino refers to -NH 2
  • halogen refers to -F, -CI, -Br, and -I
  • 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 or 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.
  • 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 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,
  • the salts derived from inorganic bases include, but 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 not limited to, salts of natural or synthetic amino acids, betaine, caffeine, 2- diethylaminoethanol, N-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.
  • solvates refers to solvates with water (i.e., hydrates) or pharmaceutically acceptable solvents, for example, solvates with ethanol, and the like.
  • 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.
  • R'substitutedring A include phenyl, pyridyl, methoxyphenyl, methylphenyl, methylpropoxyphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, cyanophenyl, fluorophenyl, methoxy-methylphenyl ethylbenzoate, benzoic acid, phenoxyacetic acid, hydroxyphenyl, hydroxyethoxyphenyl, hydroxymethylphenyl or benzamide.
  • R 2 substituted ring B include cyclopropyl, pyridinyl, pyrazinyl, fluorophenyl, difluorophenyl, methoxyphenyl, ethylbenzoate, cyanophenyl, aminophenyl, (aminomethyl)phenyl, (acetylamino)methylphenyl or (lH)-tetrazolylphenyl.
  • the present invention relates to compound of Formula 1 wherein R 4 include benzyl, fluorobenzyl, difluorobenzyl, dichlorobenzyl, chlorobenzyl, phenoxyethyl, trifluoromethylbenzyl, methylbenzyl, dimethylbenzyl, thiophenylmethyl, thiophenylethyl, (methylpiperazinyl)ethyl, (methylpiperazinyl)benzyl, (oxoimidazolidinyl)ethyl, phenylethyl, (tetrahydrofuranyl)methyl,
  • the present invention relates to compound of Formula 1 wherein R 3 and R 4 together forms a ring system include pyrrolidinyl, piperidinyl or morpholinyl.
  • the invention encompasses compounds of present invention which may include but are not limited to the following, for example:
  • the compound of general Formula 1 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 together with one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • kits for treating or preventing conditions caused by inflammation and associated pathologies comprising administering to a mammal in need thereof therapeutically effective amount of one or more compounds of Formula 1 and their pharmaceutical compositions.
  • 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.
  • compositions comprising one or more compound having the structure of Formula 1 , 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, ⁇ 2- agonists, p38 MAP Kinase inhibitors, PDE-IV inhibitors or corticosteroids.
  • the compound of Formula 1 can be prepared according to Scheme I.
  • reacting a compound of Formula 2 (wherein Ring B and R 2 are same as defined earlier) with succinic anhydride gives a compound of Formula 3 which is then cyclised with compound of Formula 4 (wherein R 1 is same as defined earlier) to give a compound of Formula 5.
  • 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
  • LiHMDS hexamethyldisilazide
  • LDA lithium diisopropylamide
  • tetramethylpiperidine 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-ethyldiisoproylamine, 4-N,N- dimethylaminopyridine, N-methylmorpholine or 2,6-lutidine in the presence of polar solvents selected from methanol, ethanol, propanol, /so-propanol or butanol.
  • bases for example, trimethylamine, triethylamine, tributylamine, pyridine, N-ethyldiisoproylamine, 4-N,N- dimethylaminopyridine, N-methylmorpholine or 2,6-lutidine in the presence of polar solvents selected from methanol, ethanol, propanol, /so-propanol or butanol.
  • the coupling of a compound of Formula 5 with a compound of Formula 6 to form a compound of Formula 1 can be carried out using amine selected from triethylamine, N,N-dimethylaminopyridine,2,6-lutidine, 1 -methylpiperidine, N-ethyldiisoproylamine, N,N-diisopropylethylamine or N-methylmorpholine, in the presence of a 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, dicyclohexyl carbodiimide, 1 -(3 -dimethylaminopropyl)-3 - ethylcarbodiimide hydrochloride,chlorotripyrrolidino
  • the compound of Formula 9 (Path A), Formula 12 (Path B) and Formula 15 (Path C) can be prepared according to Scheme II.
  • the deprotection of a compound of Formula 7 gives a compound of Formula 8 which on coupling with compound of Formula 6 gives a compound of Formula 9.
  • the reaction with a compound of Formula 9 with a compound of Formula 10 gives a compound of Formula 1 1 which finally on hydrolysis gives a compound of Formula 12.
  • the reaction of compound of Formula 9 with a compound of Formula 13 gives a compound of Formula 14 which finally on deprotection gives a compound of Formula 15.
  • deprotection of a compound of Formula 7 to form a compound of Formula 8 can be carried out in the presence of deprotecting agents, for example, Pd/C with ammonium formate, Pd/C with triethylsilane, Pd/C in the presence of hydrogen in one or more polar solvent, selected from methanol, ethanol, propanol, isopropanol, and the like.
  • deprotecting agents for example, Pd/C with ammonium formate, Pd/C with triethylsilane, Pd/C in the presence of hydrogen in one or more polar solvent, selected from methanol, ethanol, propanol, isopropanol, and the like.
  • reaction of a compound of Formula 8 with a compound of Formula 6 to form a compound of Formula 9 can be carried out under similar conditions as for compound of Formula 5 with a compound of Formula 6 to form a compound of Formula 1 (Scheme I).
  • the reaction of a compound of Formula 9 with a compound of Formula 10 to form a compound of Formula 1 1 can be carried out using base such as sodium hydride, lithium hydride or potassium hydride in the presence of solvent, for example, NJf- dimethylformamide, dimethylsulfoxide, acetonitrile or tetrahydrofuran.
  • base such as sodium hydride, lithium hydride or potassium hydride
  • solvent for example, NJf- dimethylformamide, dimethylsulfoxide, acetonitrile or tetrahydrofuran.
  • the hydrolysis of a compound of Formula 11 to form a compound of Formula 12 can be carried out in a solvent selected from methanol, ethanol, tetrahydrofuran, 1 ,4-dioxane, water or mixture(s) thereof in the presence of a base, for example, lithium hydroxide, potassium hydroxide, sodium hydroxideor cesium hydroxide.
  • reaction of a compound of Formula 9 with a compound of Formula 13 to form a compound of Formula 14 can be carried in solvents selected from, NJf'- dimethylformamide, dimethylsulfoxide, acetonitrile or tetrahydrofuran in the presence of base, for example, lithium hydride, sodium hydride or potassium hydride.
  • the deprotection of a compound of Formula 14 to form a compound of Formula 15 can be carried out in the presence of one or more organic solvents selected from
  • tetrahydrofuran diethyl ether, 1,4-dioxane, dichloromethane and chloroform or a mixture thereof using base, for example, tetraw-butyl ammonium fluoride, hydrochloric acid or sodium fluoride.
  • R 2 is N0 2 ⁇
  • the compound of Formula 18 can be prepared according to Scheme III. The reduction of a compound of Formula 16 gives a compound of Formula 17 which upon coupling with a compound of Formula 6 gives a compound of Formula 18.
  • the reduction of a compound of Formula 16 to form a compound of Formula 17 can be carried out in the presence of one or more solvents selected from methanol, ethanol, propanol, isopropanol, using reducing agent, for example, Pd/C in the presence of hydrogen, lithium aluminium hydride, Raney Nickel in hydrazine hydrate or zinc, tin or iron in the presence of hydrochloric acid.
  • reducing agent for example, Pd/C in the presence of hydrogen, lithium aluminium hydride, Raney Nickel in hydrazine hydrate or zinc, tin or iron in the presence of hydrochloric acid.
  • the compound of Formula 20 (Path D), Formula 21 (Path E) and Formula 22 (Path F) can be prepared according to Scheme IV.
  • the reduction of a compound of Formula 19 gives a compound of Formula 20 (Path D) which upon acylation with a compound of Formula 20a (wherein R 7 is alkyl or aryl and U is leaving group for example, halide, acyloxy or aryloxy) gives a compound of Formula 22 (Path F).
  • the reaction of a compound of Formula 19 with sodium azide gives a compound of Formula 21 (Path E).
  • the reduction of a compound of Formula 19 to give a compound of Formula 20 can be carried out in presence of one or more reducing agents, for example, potassium borohydride in the presence of Raney Nickel, Nickel (II) chloride in combination with sodium borohydride, lithium aluminum hydride, Pd/C in the presence of hydrogen, Boron reagent using solvent selected from ethanol, methanol, propanol, wo-propanol.
  • one or more reducing agents for example, potassium borohydride in the presence of Raney Nickel, Nickel (II) chloride in combination with sodium borohydride, lithium aluminum hydride, Pd/C in the presence of hydrogen, Boron reagent using solvent selected from ethanol, methanol, propanol, wo-propanol.
  • reaction of compound of Formula 19 with sodium azide to give a compound of Formula 21 which can be carried out in the presence of organic base, for example, triethylamine, N,7V-dimethylaminopyridine,2,6-lutidine, 1-methylpiperidine, N,N- diisopropylethylamine or N-methylmorpholine, in one or more solvent selected from toluene, dimethoxymethane, xylene, or mixture thereof.
  • organic base for example, triethylamine, N,7V-dimethylaminopyridine,2,6-lutidine, 1-methylpiperidine, N,N- diisopropylethylamine or N-methylmorpholine, in one or more solvent selected from toluene, dimethoxymethane, xylene, or mixture thereof.
  • the 7V-acylation of a compound of Formula 20 with a compound of Formula 20a to form a compound of Formula 22 can be carried in the presence of a base, for example, triethylamine, pyridine, N-ethyldiisopropylamine, N-methylmorpholine, 4- dimethylaminopyridine, 1-methylimidazole, 1,2,4-triazole using relatively polar including polar aprotic solvent, for example, dimethylformamide, dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethylsulphoxide, N,7V-dimethyl acetamide, trifluoroethanol, l-methyl-2- pyrrolidinone, 1,1, 1,3,3,3, -hexafluoro-2-propanol,or mixture thereof.
  • a base for example, triethylamine, pyridine, N-ethyldiisopropylamine, N-methylmorpholine, 4- dimethyla
  • the compound of Formula 24 (Path G), 25 (Path H) and 26 (Path I) can be prepared according to Scheme V.
  • the hydrolysis of compound of Formula 23 gives a compound of Formula 24 which on amidation gives a compound of Formula 25.
  • the reduction of a compound of Formula 23 gives a compound of Formula 26.
  • the hydrolysis of compound of Formula 23 (Path G) to form a compound of Formula 24 can be carried out in a solvent selected from, for example, methanol, ethanol, tetrahydrofuran, 1 ,4-dioxane, water or mixture(s) thereof in the presence of a base, for example, lithium hydroxide, potassium hydroxide or sodium hydroxide.
  • a solvent selected from, for example, methanol, ethanol, tetrahydrofuran, 1 ,4-dioxane, water or mixture(s) thereof in the presence of a base, for example, lithium hydroxide, potassium hydroxide or sodium hydroxide.
  • the compound of Formula 24 can be coupled with ammonium carbonate to form a compound of Formula 25 using base, for example, triethylamine, N- ethyldiisopropylamine, N,N-dimethylaminopyridine,2,6-lutidine, 1-methylpiperidine, N,N- diisopropylethylamine or N-methylmorpholine, in the presence of a 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, dicyclohexyl carbodimide, l-(3-dimethylaminopropyl)-3- ethylcarbodimide hydrochloride,chlorotripyrrolidinophosphoniumhexafluorophosphate or (
  • the reduction of a compound of Formula 23 to form a compound of Formula 26 can be carried out using reducing agents, for example, sodium borohydride, potassium borohydride, lithium aluminium hydride, diisobutylaluminium hydride or B3 ⁇ 4 (Borane) in the presence of polar aprotic solvents, for example, tetrahydrofuran, diethylether, 1,4- dioxane, dimethylformamide, acetonitrile or mixture(s) thereof or in the presence of protic solvents, for example, methanol, ethanol, isopropanol, water or mixture(s) thereof.
  • reducing agents for example, sodium borohydride, potassium borohydride, lithium aluminium hydride, diisobutylaluminium hydride or B3 ⁇ 4 (Borane) in the presence of polar aprotic solvents, for example, tetrahydrofuran, diethylether, 1,4- dioxane, di
  • the coupling of a compound of Formula 9 with a compound of Formula 27 to give a compound of Formula 28 can be carried out in the presence of a redox couple.
  • the oxidizing part of the redox couple is selected from the group 1,1 '-(azodicarbonyl) piperidine (ADDP), 4,7-dimethyl-3,5,7-hexahydro-l,2,4,7-tetrazocin-3,8-dione (DHTD), N,N,A ⁇ N'-tetramethylazodicarboxamide (TMAD), ⁇ , ⁇ , ⁇ ', ⁇ '- tetraisopropylazodicarboxamide (TIP A), diethyl azodicarboxylate (DEAD), di-t- butylazodicarboxylate or diisopropylazodicarboxylate (DIAD).
  • the reduction part of the redox couple is phosphine, such as, for example, trialkylphosphine (such as
  • tributylphosphine tributylphosphine
  • triarylphosphine such as, triphenylphosphine, p- (dimethylaminophenyl)diphenylphosphine
  • tricycloalkylphosphine such as,
  • triscyclohexylphosphine or tetraheteroarylphosphine.
  • the phosphine reagents with a combination of aryl, alkyl, or heteroaryl substituents may also be used (such as, diphenylpyridylphosphine) in solvent selected from toluene, xylene, diethyl ether, tetrahydrofuran or N,N'-dimethylformamide.
  • the compounds, described herein, may be administered to an animal for treatment orally, topically, rectally, internasally, or by parenteral route.
  • 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.
  • 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 accelerators, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol mono stearate or mixtures thereof; adsorbents, for example, Kaolin; lubricants, for example, talc, calcium stearate, magnesium stearate, solid
  • polyethyleneglycol sodium lauryl 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.
  • 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 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 coca 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.
  • compositions may be in unit dosage form.
  • the preparations can be subdivided into unit doses containing appropriate quantities of active components.
  • 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 1
  • R3 is hydrogen and n is one
  • Step A Preparation of 6-(3-fluorophenyl)-4, 6-dioxohexanoic acid
  • 3-fluoroacetophenone (30g, 217.17 mmol) in freshly distilled dry THF (100 ml) under an argon atmosphere and cooled to -78°C.
  • LiHMDS (20%, 1M solution in THF, 434.32 ml, 434.32 mmoles) dropwise at -78°C and allowed to stir at the same temperature for one hour.
  • Step B Preparation of 3-[5-(3-Fluorophenyl)-l-(4-Methoxyphenyl)-lH-Pyrazol-3- Yll Propanoic Acid
  • step a To a solution of compound obtained from step a (11 g, 46.21 mmoles) in dry ethanol (110 ml) was added 4-methoxyphenyl hydrazine (8 g, 46.21 mmoles) and triethylamine (12.8 ml, 92.43 mmoles) at room temperature. The reaction mixture was allowed to stir at room temperature for 4 hours to 5 hours. After the completion of reaction, solvent was evaporated under vacuum, diluted with water and extracted with ethyl acetate.
  • Step C Preparation of 3-[5-(3-Fluorophenyl)-l-(4-Methoxyphenyl)-lH-Pyrazol-3- Yil-N-(3-Methylbenzyl)Propanamide
  • Step 2 Synthesis of 3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-l//-pyrazol-3-yl] propanoic acid
  • Step 3 Synthesis of iV-(3-Chlorobenzyl)-3-[5-(3-Fluorophenyl)-l-(4-Methoxyphenyl)- liT-Pyrazol-S-YlJPropanamide
  • Mass spectrum (m/z, +ve ion mode): 466 [M + +l+2] and 464 [M + +l].
  • Mass spectrum (m/z, +ve ion mode): 540[M + +1+2+2], 538[M + +1+2] and 536[M + +1]
  • Mass spectrum (m/z, +ve ion mode): 486[M + +1+2+2], 484[M + +1+2] and 482[M +
  • Step A Preparation of 3-[5-(3-Fluorophenyl)-l-(4-Hydroxyphenyl)-l J i- r -Pyrazol-3- Yl] Propanoic Acid
  • Step B Preparation of N-(3-Fluorobenzyl)-3-[5-(3-Fluorophenyl)-l-(4

Abstract

The present invention relates to pyrazole derivatives of formula 1 and to process as 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.

Description

5-LIPOXYGENASE INHIBITORS
Field of the Invention
The present invention relates to pyrazole derivatives and to 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, p. 196 (2001)). Leukotrienes play an important role in the pathophysiology of inflammatory/allergic diseases including bronchial asthma (Clin. Exp. Allergy Rev., 1, p. 264 (2001)), allergic rhinitis (Clin. Exp. Allergy Rev. 1, p. 235 (2001)), urticaria, atopic dermatitis (Clin. Exp.Allergy Rev. 1, p. 305 (2001)), chronic obstructive pulmonary disease (Eur. Respir. J, 22, p. 926 (2003)), etc. Incidence of
allergic/inflammatory diseases are on the rise globally (Emerging Therapeutic Targets,3, p. 229 (1999); Expert Opin. Investigational Drugs, 10, p. 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. l, p. 196 (2001); Curr. Drug Targets - Inflammation & Allergy, !, p. 23, 2002; Drug Safety, 26, p. 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. Critic Care Med., 157, p. S210 (1998); Thorax, 55, p. S32, (2000); Clin. Exp. Allergy Rev., 1, p. 196 (2001); Clin. Exp. Allergy Rev., 1, p. 220 (2001); Drug Safety, 26, p. 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., \, p. 220 (2001)). Inhalation of leukotrienes also increases influx of inflammatory cells in the airway of animals (Clin. Exp. Allergy Rev., \, p. 220 (2001)) and humans (Am. J. Respir Crit. Care Med., 151, S210,
(1998)). Efficacy of leukotriene biosynthesis inhibitors and leukotriene receptor antagonists has been tested in numerous trials involving asthma patients (Clin. Exp. Aller. Reviewl, p. 254 (2001); Drug Safety, 26, p. 483 (2003); NEJM, 340, p. 197 (1999); Am. J. Respir. Crit. Care Med, 157, p. S233 (1998)). Similarly, evidence is emerging based on animal and human data that leukotriene pathway modulators can play role in arthritis (J. Pharmacol. Exp. Ther., 285, p. 946 (1998)) allergic rhinitis and urticaria (Clin. Exp. Aller. Review, l, p. 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, p. 1299-1318 (1992)). Iron ligand inhibitors 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, p. 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, p. 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, p. 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- 1 -yl)phenylthio)phenyl)-tetrahydro-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), p. 59-67 (2009)). Recently, 2-amino-5- hydroxy-lH-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 IC50 values of 0.23 and 0.086 μΜ, respectively. It efficiently blocks 5-LO product formation in human whole blood assays (IC50 = 0.83-1.6μΜ) and significantly prevented 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(1 1), p. 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 nonsteroidal anti-inflammatory therapy (Eur. J. Pharm., 607(1-3), p. 244-250 (2009)).
Recently, it was reported by Merck, a series of novel 5-LO inhibitors that are potent, selective and orally bioavailable. Their major focus was to preserve the 5-LO potency while reducing the affinity for the hERG potassium channel. This work culminated in the identification of 4-(4-fluorophenyl)-7-[({5-[(25 -l ,1 ,l-trifluoro-2-hydroxybutan-2-yl]- l ,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one MK-0633 (setileuton) was selected for clinical development for the treatment of respiratory diseases (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 2009/069044 nhibitors.
Figure imgf000006_0001
WO 2008/071456 discloses 3H-pyrazolopyridines and salts thereof,
pharmaceutical compositions comprising same, methods of preparing same and same.
Figure imgf000006_0002
U.S. Publication No. 2006/0075376 discloses cycloalkyl heterocycles for treating hepatitis C virus. WO 03/026649 discloses substituted pyrazole compounds to increase endogenous testosterone production. WO 01/87287 discloses substituted pyrazole compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds.
Figure imgf000006_0003
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 topyrazole 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, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates having the same type of activity are also provided as well as pharmaceutical compositions comprising such compounds.
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, p2-agonists, p38 MAP Kinase inhibitors, PDE-IV inhibitors or
corticosteroids.
Other objects will be set forth in 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
The present invention relates to compounds having the structure of Formula 1
Figure imgf000008_0001
Formula 1
pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, wherein
Ring A is selected from phenyl, pyridine, pyrazine, triazine, tetrazole, thiazole, imidazole and oxazole each of which is optionally substituted by one or more substituents independently selected from R1;
Ring B is selected from phenyl, C3-10 cycloalkyl and a 6-10 membered heteroaryl each of which is optionally substituted by one or more substituents independently selected from R2;
R^s selected from the group consisting of hydrogen, hydroxy, d-C5alkyl, d- C5alkoxy, CN, halogen, CF3, nitro, -C=0, d-C5alkylamino, d-C3alkyl-OH, CORf, heteroaryl, NRfRq, COORf, CONRfRq and -ORa wherein R<j is C C5alkyl, d-C3alkyl-COORf or d-C3alkyl-OH.
R2is selected from the group consisting of hydrogen, hydroxy, d-C5alkyl, d- C5alkoxy, CN, halogen, CF3,heteroaryl,d-C5alkylamino, NRfRq, d-C5alkyl- NHCO-d-C5alkyl and COORf;
Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and Rf and Rq may together form a ring system together with the heteroatom to which they are attached;
R3 is hydrogen or R3 and R4 together with the nitrogen atom to which they are attached forms a C5-1o ring system wherein 1-3 carbon atom in the ring are replaced by heteroatom selected from N, O or S and the ring system can optionally be substituted by one or more substituents independently selected from R5;
R4 is selected from the group consisting of -(CH2)m-(0)s-phenyl,-(CH2)m-(0)s- heterocyclyl or -(CH2)m-(0)s-heteroaryl, wherein each of phenyl, heterocyclyl and heteroaryl is optionally substituted by one or more substituents selected from R5; R5 is selected from the group consisting of hydrogen, halogen, CrC5alkyl,nitro,
CF3, -CO, COORf, hydroxyalkyl, piperazine, Ci-C3alkyl-COORf, C C3alkyl-
CONRfRq, C!-C5alkyl-piperazine and phenyl;
n is an integer 1-2;
m is an integer 0-3;
s is an integer 0-1;
x is an integer 1-3.
In another emb diment, the current invention provides a compound of Formula la:
Figure imgf000009_0001
Formula la
pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, wherein
R4' can be phenyl, heterocyclyl, heteroaryl optionally substituted with one or more substituents selected from R5;
Ring A, ring B,R R2 , R5 and x are same as defined earlier.
In another embodiment the current invention provides a compound of Formula lb:
Figure imgf000009_0002
Formula lb
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, and stereoisomers thereof,
wherein R4',Ring A, Ring B.R1 R2 and x are same as defined earlier.
In yet another embodiment, the current invention provides a compound of Formula lc:
Figure imgf000010_0001
Formula lc
pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, wherein
R4',Ring A, Ring B^R2 and x are same as defined earlier.
In yet another embodiment, the current invention provides a compound of Formula
Id:
Figure imgf000010_0002
Formula Id
pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, wherein
N
is selected from pyrrolidine, piperidine and morpholine
Figure imgf000010_0003
Ring A, Ring B,R5, and x 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 "alkenyl", unless and otherwise specified, refers to a branched or unbranched unsaturated hydrocarbon group containing at least one double bond with cis or trans geometry, and preferably, having 2 to 20 carbon atoms. Examples of alkenyl group include ethenyl, 2-propenyl and isopropenyl.
The term "cycloalkyl" refers to a non aromatic cyclic group having 3 to 20 ring carbon atoms and form 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[2.2.7]heptanyl, bicyclo[2.2.2]octane, tricycle [3.3.1.7]decane, and the like.
The term "aryl" 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 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 "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,0 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 "heterocyclyl" refers to a non-aromatic monocyclic or polycyclicring 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, 1,4-dioxane, and the like.
The terms "cycloalk lalkyF, "arylalkyl", "heteroarylalkyF , "heterocyclylalkyF refers, respectively, to cycloalkyl, aryl, heteroaryl or heterocyclyl group linked the remainder of the molecule via an alkyl group.
The term "amino " refers to -NH2
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 or 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", 3rdEdition, 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 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 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 not limited to, salts of natural or synthetic amino acids, betaine, caffeine, 2- diethylaminoethanol, N-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.
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.
One embodiment of the present invention relates to compound of Formula 1 wherein R'substitutedring A include phenyl, pyridyl, methoxyphenyl, methylphenyl, methylpropoxyphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, cyanophenyl, fluorophenyl, methoxy-methylphenyl ethylbenzoate, benzoic acid, phenoxyacetic acid, hydroxyphenyl, hydroxyethoxyphenyl, hydroxymethylphenyl or benzamide.
According to another embodiment the present invention relates to compound of
Formula 1 wherein R2 substituted ring B include cyclopropyl, pyridinyl, pyrazinyl, fluorophenyl, difluorophenyl, methoxyphenyl, ethylbenzoate, cyanophenyl, aminophenyl, (aminomethyl)phenyl, (acetylamino)methylphenyl or (lH)-tetrazolylphenyl.
According to another embodiment the present invention relates to compound of Formula 1 wherein R4 include benzyl, fluorobenzyl, difluorobenzyl, dichlorobenzyl, chlorobenzyl, phenoxyethyl, trifluoromethylbenzyl, methylbenzyl, dimethylbenzyl, thiophenylmethyl, thiophenylethyl, (methylpiperazinyl)ethyl, (methylpiperazinyl)benzyl, (oxoimidazolidinyl)ethyl, phenylethyl, (tetrahydrofuranyl)methyl,
(dihydrobenzofuranyl)methyl, pyridinylmethyl, chloropyridinylmethyl,
(methylpyridinyl)methyl, morpholinylpropyl, (ethylpyrrolidinyl)methyl,
(oxopyrrolidinyl)propyl, methylbenzoate, benzoic acid, (methylpiperazinyl- pyridinyl)methyl,(methylpiperazinyl)(methyl)benzyl,
(fluoro)methylbenzyl,(fluoro)(methylpiperazinyl)benzyl,
(chloro)(methylpiperazinyl)benzyl, hydroxymethylbenzyl, (chloro)fluorobenzyl, (chloro)- difluorobenzyl, (chloro)(fluoro)methylbenzyl or (methyl)(phenyl)oxazolylmethyl. According to another embodiment the present invention relates to compound of Formula 1 wherein R3 and R4 together forms a ring system include pyrrolidinyl, piperidinyl or morpholinyl.
In another embodiment, the invention encompasses compounds of present invention which may include but are not limited to the following, for example:
3 - [5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(4- fluorobenzyl)propanamide (Compound No. 1);
3-[5-Cyclopropyl- 1 -(4-methoxyphenyl)- lH-pyrazol-3-yl]-N-(2,3-dichlorobenzyl) propanamide (Compound No. 2 );
3 - [5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2,4-dichlorobenzyl) propanamide (Compound No. 3);
N-(2-Chlorobenzyl)-3 - [5-cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 4);
3 - [5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2- fluorobenzyl)propanamide (Compound No. 5);
3-[5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N-(2-phenoxyethyl) propanamide (Compound No. 6);
3 - [5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [2- (trifluoromethyl)benzyl]propanamide (Compound No. 7);
3 - [5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3-yl] -N-(3 ,4-dichlorobenzyl) propanamide (Compound No. 8);
N-(3 -Chlorobenzyl)-3 - [5-cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 9);
3 - [5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -methylbenzyl) propanamide (Compound No. 10);
N-Benzyl-3-[5-cyclopropyl-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]propanamide (Compound No. 11);
3 - [5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(thiophen-2- ylmethyl)propanamide (Compound No. 12);
N-(3 -Fluorobenzyl)-3 - [5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 13);
jV-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-iH-pyrazol-3-yl] propanamide (Compound No. 14);
3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(thiophen-2- ylmethyl)propanamide (Compound No. 15);
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N- [2-(thiophen-2- yl)ethyl]propanamide (Compound No. 16); 3 -[5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2- phenoxyethyl)propanamide (Compound No. 17);
N-Benzyl-3 -[5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 18);
N-(2-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 19);
N-(3-Chlorobenzyl)-3-[5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 20);
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2 -methylbenzyl) propanamide (Compound No. 21);
3 -[5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N-(3 -methylbenzyl) propanamide (Compound No. 22);
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -y ] ] -N- [2-(4- methylpiperazin-l-yl)ethyl]propanamide (Compound No. 23);
3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[2-(2- oxoimidazolidin-l-yl)ethyl]propanamide (Compound No. 24);
N-Benzyl-3 - [5-(3 -fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl]propanamide
(Compound No. 25);
N-(2-Chlorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl]propanamide (Compound No. 26);
N-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-phenyl-lH-pyrazol-3-yl]propanamide (Compound No. 27);
3-[5-(3-Fluorophenyl)-l-phenyl-lH-pyrazol-3-yl]-7V-[2-(trifluoromethyl) benzyl]propanamide (Compound No. 28);
N-(3 -Fluorobenzy 1) -3 - [5 -(3 -fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -y l]propanamide (Compound No. 29);
3 -[5-(3-Fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl] -7V-(3 - methylbenzyl)propanamide (Compound No. 30);
3 - [5 -(3 -Fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl]-7V- [2-(4-methylpiperazin- 1 - yl)ethyl]propanamide (Compound No. 31);
3-[5-(3-Fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl]- 1 -(pyrrolidin- 1 -yl)propan- 1 -one (Compound No. 32);
3 -[5 -(3 -Fluorophenyl)- 1 -phenyl-lH-pyrazol-3-yl]- 1 -(piperidin- 1 -yl)propan- 1 -one (Compound No. 33);
3 - [5 -(3 -Fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl] - 1 -(morpholin-4-y l)propan- 1 -one (Compound No. 34);
N-(3-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l-phenyl-lH-pyrazol-3-yl]propanamide (Compound No. 35); 3- [5 -Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3- fluorobenzyl)propanamide (Compound No. 36);
3- [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]- 1 -(morpholin-4- yl)propan-l-one (Compound No. 37);
3- [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]- 1 -(piperidin- 1 - yl)propan-l-one (Compound No. 38);
3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(4-methylbenzyl) propanamide (Compound No. 39);
N-(4-Chlorobenzyl)-3 - [5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 40);
N-(3,4-Dichlorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 41);
N-Benzyl-3 - [ 1 -(4-methoxyphenyl)-5-phenyl- 1 H-pyrazol-3 -yl]propanamide (Compound No. 42);
N-(2-Fluorobenzyl)-3-[l-(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3- yl]propanamide (Compound No. 43);
N-(2-Chlorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5-phenyl- 1 H-pyrazol-3 - yl]propanamide (Compound No. 44);
3-[l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-(2- methylbenzyl)propanamide (Compound No. 45);
3 - [ 1 -(4-Methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 -yl] -N-(2- phenoxyethyl)propanamide (Compound No. 46);
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2-phenylethyl) propanamide (Compound No. 47);
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(tetrahydrofuran-
2- ylmethyl)propanamide (Compound No. 48);
N-(2,3 -Dihydro- 1 -benzofuran-5 -ylmethyl)-3 -[5 -(3 -fluorophenyl)- 1 -(4- methoxyphenyl)-lH-pyrazol-3-yl]propanamide (Compound No. 49);
N-(2,3-Dichlorobenzyl)-3-[5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 50);
N-(4-Chlorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5-phenyl- 1 H-pyrazol-3 - yl]propanamide (Compound No. 51);
N-(4-Fluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 - yl]propanamide (Compound No. 52);
3- [l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-(4- methylbenzyl)propanamide (Compound No. 53);
3-[l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-(thiophen-3- ylmethyl)propanamide (Compound No. 54); 3 - [ 1 -(4-Methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 -yl] -N-[2-(thiophen-2-yl)ethyl] propanamide (Compound No. 55);
3 - [ 1 -(4-Methoxyphenyl)- 5 -phenyl- 1 H-pyrazol-3 -yl] -N- [2-(2-oxoimidazolidin- 1 - yl)ethyl]propanamide (Compound No. 56);
N-Benzyl-3 - [ 1 -(4-cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl]propanamide
(Compound No. 57);
3 - [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(2-fluorobenzyl) propanamide (Compound No. 58);
N-(2-Chlorobenzyl)-3 -[ 1 -(4-cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 59);
3 - [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl]-N-(2-methylbenzyl) propanamide (Compound No. 60);
3 - [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(2-phenoxyethyl) propanamide (Compound No . 61 ) ;
N-(4-Chlorobenzyl)-3-[l -(4-cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 62);
3 - [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(4-fluorobenzyl) propanamide (Compound No. 63);
3 - [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(4-methylbenzyl) propanamide (Compound No.64);
3 - [ 1 -(4-Cyanophenyl)-5 -(3-fluorophenyl)- 1 H-pyrazol-3-yl] -N-(thiophen-2- ylmethyl)propanamide (Compound No. 65);
3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-[2-(thiophen-2- yl)ethyl]propanamide (Compound No. 66);
3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-[2-(2- oxoimidazolidin-l-yl)ethyl]propanamide (Compound No. 67);
3 - [ 1 -(4-Cyanophenyl)-5 -(3-fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(3-methylbenzyl) propanamide (Compound No. 68);
N-(3 -Chlorobenzyl)-3 -[ 1 -(4-cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] propanamide(Compound No. 69);
N-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxy-2-methylphenyl)-lH- pyrazol-3-yl]propanamide(Compound No. 70);
3-[5-(3-Fluorophenyl)-l-(pyridin-2-yl)-lH-pyrazol-3-yl]-N-(3- methylbenzyl)propanamide (Compound No. 71);
3-[l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-(3- methylbenzyl)propanamide (Compound No. 72);
N-(3 -Chlorobenzyl) -3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 - yl]propanamide (Compound No. 73); N-(3-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l-(pyridin-2-yl)-lH-pyrazol-3- yl]propanamide (Compound No. 74);
3 - [5-(3 -Fluorophenyl)- 1 -(pyridin-2-yl)- 1 H-pyrazol-3 -yl] -N-(pyridin-2-ylmethyl) propanamide (Compound No. 75);
3-[5-(3-Fluorophenyl)-l-(pyridin-2-yl)-lH-pyrazol-3-yl]-N-[3-(morpholin-4- yl)propyl]propanamide (Compound No. 76);
3-[5-(3-Fluorophenyl)-l-(pyridin-2-yl)-lH-pyrazol-3-yl]-N-[2-(morpholin-4- yl)ethyl]propanamide (Compound No. 77);
3 - [5 -(3 -Fluorophenyl)- 1 -(pyridin-2-yl)- 1 H-pyrazol-3 -yl] -N-(pyridin-3 -ylmethyl) propanamide (Compound No. 78);
3-[ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(pyridin-2- ylmethyl)propanamide (Compound No. 79);
3 - [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N- [3 -(morpholin-4- yl)propyl]propanamide (Compound No. 80);
3- [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-[2-(morpholin-4- yl)ethyl]propanamide (Compound No. 81);
3 - [ 1 -(4-Cyanophenyl)-5 -(3-fluorophenyl)- 1 H-pyrazol-3-yl ] -JV-(pyridin-3 - ylmethyl)propanamide (Compound No. 82);
3-[l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-(pyridin-2- ylmethyl)propanamide (Compound No. 83);
3 - [ 1 -(4-Methoxyphenyl)-5-phenyl- 1 H-pyrazol-3 -yl] -N- [3 -(morpholin-4-yl)propyl] propanamide (Compound No. 84);
3 - [ 1 -(4-Methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3-yl] -N- [2-(morpholin-4-yl)ethyl] propanamide (Compound No. 85);
3-[l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-[2-(4- methylpiperazin-l-yl)ethyl]propanamide (Compound No. 86);
N-{[(2i?)-l-Ethylpyrrolidin-2-yl]methyl}-3-[l-(4-fluorophenyl)-5-(3- methoxyphenyl)-l H-pyrazol-3 -yl]propanamide (Compound No. 87);
3-[l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-[2-(2- oxoimidazolidin-l-yl)ethyl]propanamide (Compound No. 88);
3- [ 1 -(4-Fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [3 -(2- oxopyrrolidin-l-yl)propyl]propanamide (Compound No. 89);
3 - [ 1 -(4-Fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3-yl] -N-(pyridin-2- ylmethyl)propanamide (Compound No. 90);
3-[l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-(pyridin-4- ylmethyl)propanamide (Compound No. 91);
3 - [ 1 -(4-Fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3-methylbenzyl) propanamide (Compound No. 92); N-(3-Chlorobenzyl)-3-[l-(4-fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 93);
N-(3 -Fluorobenzyl)-3 - [ 1 -(4-fluorophenyl)-5-(3 -methoxyphenyl)- lH-pyrazol-3 -yl] propanamide (Compound No. 94);
3 - [ 1 -(4-Fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [2-(morpholin-4- yl)ethyl]propanamide (Compound No. 95);
3 - [ 1 -(4-Fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [3 -(morpholin-4- yl)propyl]propanamide (Compound No. 96);
N-(3-Chlorobenzyl)-3-[l-(4-methoxyphenyl)-5-(pyridin-3-yl)-lH-pyrazol-3-yl] propanamide (Compound No. 97);
3-[l-(4-Methoxyphenyl)-5-( yridin-3-yl)-lH-pyrazol-3-yl]-N-(3-methylbenzyl) propanamide (Compound No. 98);
N-(3-Fluorobenzyl)-3-[l-(4-methoxyphenyl)-5-(pyridin-3-yl)-lH-pyrazol-3-yl] propanamide (Compound No. 99);
N-Benzyl-3 -[ 1 -(4-methoxyphenyl)-5-(pyridin-3 -yl)- 1 H-pyrazol-3 -yl]propanamide (Compound No. 100);
3 -[ 1 -(4-Methoxyphenyl)-5 -(pyridin-3 -yl)- 1 H-pyrazol-3 -yl ] -N-(pyridin-2-ylmethyl) propanamide (Compound No. 101);
3 - [ 1 -(4-Methoxyphenyl)-5 -(pyridin-3 -yl)- 1 H-pyrazol-3 -yl]-N-(pyridin-4-ylmethyl) propanamide (Compound No. 102);
3-[l-(4-Methoxyphenyl)-5-(pyridin-3-yl)-lH-pyrazol-3-yl]-N-[2-(2- oxoimidazolidin-l-yl)ethyl]propanamide (Compound No. 103);
3 - [ 1 -(4-Methoxyphenyl)-5-(pyridin-3-yl)- 1 H-pyrazol-3-yl] -N- [3 -(2-oxopyrrolidin- l-yl)propyl]propanamide (Compound No. 104);
N- [( 1 -Ethy lpyrrolidin-2-yl)methyl ] -3 - [ 1 -(4-methoxypheny l)-5 -(pyridin-3 -y 1)- 1 H- pyrazol-3-yl]propanamide (Compound No. 105);
3 - [ 1 -(4-Methoxyphenyl)-5-(pyridin-3 -yl)- lH-pyrazol-3 -yl ] -N- [3 -(morpholin-4- yl)propyl]propanamide (Compound No. 106);
N-[(2-Chloropyridin-4-yl)methyl]-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 107);
N-[(6-Chloropyridin-3 -yl)methyl] -3-[5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 108);
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl ] -N-(pyridin-2- ylmethyl)propanamide (Compound No. 109);
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [(6- methylpyridin-2-yl)methyl]propanamide (Compound No. 110);
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(pyridin-4- ylmethyl)propanamide (Compound No. I l l); N-Benzyl-3-[l-(4-fluorophenyl)-5-(3-niethoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 1 12);
Ethyl 4- { 3 - [3 -(benzylamino)-3 -oxopropyl] -5 -(3 -fluorophenyl)- 1 H-pyrazol- 1 - yl}benzoate (Compound No. 1 13);
Ethyl 4- [5 -(3 -fluorophenyl)-3 - { 3-oxo-3 - [(pyridin-2-ylmethyl)amino]propyl } - 1 H- pyrazol-l-yl]benzoate (Compound No. 1 14);
Ethyl 4-[5-(3-fluorophenyl)-3-{3-oxo-3-[(pyridin-4- ylmethyl)amino]propyl}-lH- pyrazol-l-yl]benzoate (Compound No. 1 15);
Ethyl 4-[5-(3 -fluorophenyl)-3 -(3 -oxo-3 - { [2-(2-oxoimidazolidin- 1 - yl)ethyl]amino}propyl)-l H-pyrazol- l-yl]benzoate (Compound No. 1 16);
Ethyl 4- [5 -(3 - fluorophenyl)-3 -(3 -oxo-3 - { [3 -(2-oxopyrrolidin- 1 - yl)propyl]amino}propyl)-lH-pyrazol-l-yl]benzoate (Compound No. 1 17);
Ethyl 4-[5-(3-fluorophenyl)-3-(3-{ [(1 -methylpyrrolidin-2-yl)methyl]amino}-3- oxopropyl)-l H-pyrazol- l-yl]benzoate (Compound No. 1 18);
Ethyl 4- [3 -(3 - { [(6-chloropyridin-3 -yl)methyl] amino } -3 -oxopropyl)-5 -(3 - fluorophenyl)- 1 H-pyrazol- l-yl]benzoate (Compound No. 1 19);
Ethyl 4- [5-(3 -fluorophenyl)-3 -(3 - { [3-(morpholin-4-yl)propyl]amino } -3 - oxopropyl)- 1 H-pyrazol- 1 -yljbenzoate (Compound No. 120);
Ethyl 4- [5-(3 -fluorophenyl)-3 -(3 - { [(3 -methylpyridin-2-yl)methyl]amino } -3- oxopropyl)-l H-pyrazol- 1 -yljbenzoate (Compound No. 121);
4-[3-{3-[(3 -Chlorobenzyl)amino] -3 -oxopropyl } -5 -(3 -fluorophenyl)- 1 H-pyrazol- 1 - yl]benzoic acid (Compound No. 122);
4- [5-(3 -Fluorophenyl)-3 - {3 - [(3 -methylbenzyl)amino]-3 -oxopropyl } - 1 H-pyrazol- 1 - yfjbenzoic acid (Compound No. 123);
4-[3-{3-[(3-Fluorobenzyl)amino]-3-oxopropyl} -5-(3-fluorophenyl)-l H-pyrazol- 1 - yljbenzoic acid (Compound No. 124);
N- [( 1 -Ethylpyrrolidin-2-yl)methyl] -3- [ 1 -(4-fluorophenyl)-5-(3 -methoxyphenyl)- lH-pyrazol-3-yl]propanamide (Compound No. 125);
Ethyl 4-[3-{3-[(3 -chlorobenzyl)amino] -3 -oxopropyl } -5 -(3 -fluorophenyl)- 1 H- pyrazol-1 -yljbenzoate (Compound No. 126);
Ethyl 4- [5 -(3 -fluorophenyl)-3 - { 3- [(3-methylbenzyl)amino] -3-oxopropyl } - 1 H- pyrazol-1 -yljbenzoate (Compound No. 127);
3- [l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-[(6- methylpyridin-2-yl)methyl]propanamide (Compound No. 128);
Ethyl 4- [3 - { 3 - [(3 -fluorobenzyl)amino] -3 -oxopropyl } -5 -(3 -fluorophenyl)- 1 H- pyrazol-1 -yljbenzoate (Compound No. 129);
4- {3-[3-(Benzylamino)-3-oxopropyl]-5-(3-fluorophenyl)- 1 H-pyrazol- 1 -yl} benzoic acid (Compound No. 130); 4-[5 -(3 -Fluorophenyl)-3 -(3 -oxo-3 - { [2-(2-oxoimidazolidin- 1 - yl)ethyl]amino}propyl)-lH-pyrazol-l-yl]benzoic acid (Compound No. 131);
4- [5 -(3 -Fluorophenyl)-3 -(3 -oxo-3 - { [3-(2-oxopyrrolidin- 1 - yl)propyl] amino } propyl)- 1 H
-pyrazol-l-yl]benzoic acid (Compound No. 132);
4-{3-[3-({[(2i?)-l-Ethylpyrrolidin-2-yl]methyl}amino)-3-oxopropyl]-5-(3- fluorophenyl)-lH-pyrazol-l-yl} benzoic acid (Compound No. 133);
4- [3 -(3- { [(6-Chloropyridin-3 -yl)methyl] amino } -3 -oxopropyl)-5 -(3 -fluorophenyl)- lH-pyrazol-l-yl]benzoic acid (Compound No. 134);
4- [5-(3 -Fluorophenyl)-3 -(3 - { [3-(morpholin-4-yl)propyl] amino } -3 -oxopropyl)- 1 H- pyrazol-l-yl]benzoic acid (Compound No. 135);
4-[5 -(3 -Fluorophenyl)-3 -(3 - { [(6-methylpyridin-2-yl)methyl]amino } -3 -oxopropyl)- lH-pyrazol-l-yl] benzoic acid (Compound No. 136);
N-(3 -Chlorobenzyl)-3 - [5 -(3 -cyanophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 137);
3 - [5 -(3 -Cyanophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -methylbenzyl) propanamide (Compound No. 138);
3 - [5-(3 -Cyanophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -fluorobenzyl) propanamide (Compound No. 139);
N-Benzyl-3-[5-(3-cyanophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (CompoundNo.140);
3-[5-(3-Aminophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3-methylbenzyl) propanamide (Compound No. 141);
3-[5-(3-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N- [2-(4- methylpiperazin-l-yl)benzyl]propanamide (Compound No. 142);
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [3 -(4- methylpiperazin-l-yl)benzyl]propanamide (Compound No. 143);
3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-[3-(4- methylpiperazin-l-yl)benzyl]propanamide (Compound No. 144);
Methyl 3 -[( { 3- [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)methyl]benzoate (Compound No. 145);
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [4-(4- methylpiperazin-l-yl)benzyl]propanamide (Compound No. 146);
3 - { 5- [3 -(Aminomethyl)phenyl] - 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl} -N-(3 -fluorobenzyl)propanamide (Compound No. 147);
3 - { 5 - [3 -( Aminomethyl)phenyl] - 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl } -N-(3 - methylbenzyl)propanamide (Compound No. 148);
N-(3 -Chlorobenzyl)-3 - [5-(3-fluorophenyl)- 1 -(4-methoxy-2-methylphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 149); N-(3 -Fluorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methoxy-2-methylphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 150);
{4-[3-{3-[(3 -Chlorobenzy l)amino] -3 -oxopropyl } - 5 -(3 -fluorophenyl)- 1 H-pyrazol- 1 -yl]phenoxy} acetic acid (Compound No. 151 );
N-Benzyl-3-[l-(4-methoxyphenyl)-5-(pyrazin-2-yl)-lH-pyrazol-3-yl]propanamide (Compound No. 152);
3-[5- {3-[(Acetylamino)methyl]phenyl} - 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N- (3-fluorobenzyl)propanamide (Compound No. 153);
3 - [5 - { 3 - [( Acetylamino)methyl]phenyl } - 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- (3 -methylbenzyl)propanamide (Compound No . 154);
3 - [( { 3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)methyl]benzoic acid (Compound No. 155);
(4- { 3 - [3-(Benzylamino)-3 -oxopropyl] -5 -(3 -fluorophenyl)- lH-pyrazol- 1 - yl}phenoxy)acetic acid (Compound No. 156);
{4-[3-{3-[(3 -Fluorobenzyl)amino] -3 -oxopropyl } -5 -(3 -fluorophenyl)- 1 H-pyrazol- l-yl]phenoxy} acetic acid (Compound No. 157);
{ 4- [3 - { 3 - [(2-Chlorobenzyl)amino] -3 -oxopropyl } -5 -(3 -fluorophenyl)- 1 H-pyrazol- l-yl]phenoxy} acetic acid (Compound No. 158);
{ 4- [3 - { 3 - [(2-Fluorobenzyl)amino] -3 -oxopropyl } -5 -(3 -fluorophenyl)- 1 H-pyrazol- l-yl]phenoxy} acetic acid (Compound No. 159);
3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-{ [2-(4- methylpiperazin-l -yl)pyridin-4-yl] methyl }propanamide (Compound No. 160);
3-[5-(3-Fluorophenyl)- l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-iV-[5-methyl-2-(4- methylpiperazin-l -yl)benzyl]propanamide (Compound No. 161);
N-(5 -Fluoro-2-methylbenzyl)-3 -[5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 162);
N-(2,3 -Difluorobenzyl)-3 - [5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 163);
N-(2,4-Dichlorobenzyl)-3 - [5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 164);
N-(3 ,5-Difluorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 165);
N-Benzyl-3 - { 5-(3 -fluorophenyl)- 1 - [4-(2-hydroxyethoxy)phenyl] - 1 H-pyrazol-3 -yl} propanamide (Compound No. 166);
N-(3-Chlorobenzyl)-3-{5-(3-fluorophenyl)-l -[4-(2-hydroxyethoxy)phenyl]-lH- pyrazol-3-yl}propanamide (Compound No. 167);
N-(2,5-Dimethylbenzyl)-3-[5-(3-fluorophenyl)-l -(4-methoxyphenyl)-lH-pyrazol- 3-yl]propanamide (Compound No. 168); N- [2-Fluoro-4-(4-methylpiperazin- 1 -yl)benzyl] -3- [5-(3 -fluorophenyl)- 1 -(4- methoxyphenyl)-lH-pyrazol-3-yl]propanamide (Compound No. 169);
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N- [(5 - methylpyridin-3-yl)methyl]propanamide (Compound No. 170);
N-(3 -Chlorobenzyl) -3 - [5 -(3 -fluorophenyl)- 1 -(4-hydroxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 171);
3- [5 -(3 -Fluorophenyl)- 1 -(4-hydroxyphenyl)- lH-pyrazol-3 -yl] -N-(3 -methylbenzyl) propanamide (Compound No. 172);
{4- [5 -(3 -Fluorophenyl)-3 - { 3 - [(3 -methylbenzyl)amino] -3 -oxopropyl } - 1 H-pyrazol- l-yl]phenoxy} acetic acid (Compound No. 173);
N-(2-Fluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(2-hydroxyethoxy)phenyl] - 1 H- pyrazol-3-yl} propanamide (Compound No. 174);
N-(3 -Fluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 -[4-(2-hydroxyethoxy)phenyl] - 1 H- pyrazol-3-yl}propanamide (Compound No. 175);
3 - { 5 -(3 -Fluorophenyl)- 1 - [4-(2-hydroxyethoxy)pheny1 ] - 1 H-pyrazol-3 -yl } -N-(3 - methylbenzyl)propanamide (Compound No. 176);
iV-(2-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-hydroxyphenyl)-lH-pyrazol-3 -yl]propanamide (Compound No. 177);
iV-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-hydroxyphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 178);
iV-(3-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-hydroxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 179);
N-(3 -Fluorobenzyl)-3 - { 1 -(4-methoxyphenyl)-5-[3 -( 1 H-tetrazol-5-yl)phenyl] - 1 H- pyrazol-3-yl} propanamide (Compound No. 180);
3-{ l-(4-Methoxyphenyl)-5-[3-(lH-tetrazol-5-yl)phenyl]-lH-pyrazol-3-yl}-N-(3 -methylbenzyl)propanamide (Compound No. 181);
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxy-2-methylphenyl)- 1 H-pyrazol-3 -yl]-N-(3 -methylbenzyl)propanamide (Compound No. 182);
3 - { 5 -(3 -Fluorophenyl)- 1 - [4-(hydroxymethyl)phenyl] - 1 H-pyrazol-3 -yl } -N-(3 -methylbenzyl)propanamide (Compound No. 183);
N-(3 ,5 -Dimethylbenzyl)-3 -[5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-
3- yl]propanamide (Compound No. 184);
N- [3 -Chloro-4-(4-methylpiperazin- 1 -yl)benzyl] -3 - [5-(3 -fluorophenyl)- 1 -(4- methoxyphenyl)-l H-pyrazol-3 -yl]propanamide (Compound No. 185);
4- [5-(3 -Fluorophenyl)-3 - { 3 - [(3 -methylbenzyl)amino] -3 -oxopropyl } - 1 H-pyrazol- 1 - yl]benzamide (Compound No. 186);
iV-(3-Chlorobenzyl)-3-{5-(3-fluorophenyl)-l-[4-(hydroxymethyl)phenyl]-lH- pyrazol-3-yl} propanamide (Compound No. 187); N-(3 ,5-Dichlorobenzyl)-3-[5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3- yl]propanamide (Compound No. 188);
3-[5-(3-Fluorophenyl)-l -(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3-methylphenyl) propanamide (Compound No. 189);
N-(3 -Fluorophenyl)-3-[5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 190);
iV-(3 -Chlorophenyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3-yl] propanamide (Compound No . 191 ) ;
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [3 - (hydroxymethyl)benzyl]propanamide (Compound No. 192);
3-[5-(3-Fluorophenyl)-l-(2-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3- methylbenzyl)propanamide (Compound No. 193);
N-(3 -Fluorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(2-methoxyphenyl)- 1 H-pyrazol-3-yl] propanamide (Compound No. 194);
iV-(3-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l -(2-methoxyphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 195);
N-(3-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methylphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 196);
N-(3 -Fluorobenzyl)-3 - [5 -(3 -fluorophenyl)- 1 -(4-methylphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 197);
3-[5-(3-Fluorophenyl)-l-(4-methylphenyl)-lH-pyrazol-3-yl]-N-(3-methylbenzyl) propanamide (Compound No. 198);
N-Benzyl-3 - [5-(3 -fluorophenyl)- 1 -(4-methylphenyl)- 1 H-pyrazol-3 -yl]propanamide (Compound No. 199);
N-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methylphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 200);
N-(2-Fluorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(2-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 201);
3 - [5 -(3 -Fluorophenyl)- 1 -(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl ] -N-(3 -methylbenzyl) propanamide (Compound No. 202);
N-(3 -Fluorobenzyl)-3- [5-(3 -fluorophenyl)- 1 -(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 203);
N-(3 -Chlorobenzyl)-3- [5 -(3 -fluorophenyl)- 1 -(3 -methoxyphenyl)- 1 H-pyrazol-3-yl] propanamide (Compound No. 204);
N-(3 -Chloro-2-fluorobenzyl)-3 - [5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 205);
N-(3-Fluoro-5-methylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 206); N-(5-Chloro-2-fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 207);
N-(3 -Chloro-2,6-difluorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 208);
N-(3-Chloro-2-methylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 209);
N-(3-Chloro-4-fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 210);
N-(2-Chloro-6-fluoro -3 -methylbenzyl)-3 - [5 -(3 -fluorophenyl)- 1 -(4- methoxyphenyl)-l H-pyrazol-3 -yljpropanamide (Compound No. 21 1);
N-(3-Chlorobenzyl)-3-[5-(2-fluorophenyl)- 1 -(4-methoxyphenyl)- lH-pyrazol-3-yl] propanamide (Compound No. 212);
N-(3 -chlorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 -[4-(trifluoromethyl)phenyl] - 1 H- pyrazol-3-yl} propanamide (Compound No. 213);
N-(3 ,5 -Difluorobenzyl)-3 - [5-(2-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3- yl] propanamide (Compound No. 214);
3 - { 5-(3 -Fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H-pyrazol-3-yl} -N-(3 -methylbenzyl)propanamide (Compound No. 215);
N-(3 ,4-Dichlorobenzyl)-3 - [5-(2-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 216);
3 - [5-(2-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -methylbenzyl) propanamide (Compound No. 217);
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [(5 -methyl-3- phenyl-l,2-oxazol-4-yl)methyl]propanamide (Compound No. 218);
N-(3-Fluorobenzyl)-3-[5-(2-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 219);
N-(2,5-Dimethylbenzyl)-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol- 3-yl]propanamide (Compound No. 220);
N-(2-Fluorobenzyl)-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 221);
N-(3 -Fluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 -[4-(trifluoromethoxy)phenyl] - 1 H- pyrazol-3-yl} propanamide (Compound No. 222);
N-(3-Fluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 -[4-(trifluoromethyl)phenyl] - 1 H- pyrazol-3-yl} propanamide (Compound No. 223);
N-(3 -Chlorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethoxy)phenyl] - 1 H- pyrazol-3-yl}propanamide (Compound No. 224);
N-Benzyl-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 225); 7V-(2-Fluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 -[4-(trifluoromethyl)phenyl] - 1 H- pyrazol-3-yl}propanamide (Compound No. 226);
JV-(3 ,5-Difluorobenzyl)-3 - [5-(2,3 -difluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 227);
JV-(3 ,5 -Difluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H- pyrazol-3-yl}propanamide (Compound No. 228);
N-(3-Chlorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(2-methylpropoxy)phenyl] - 1H- pyrazol-3-yl}propanamide (Compound No. 229);
3-[5-(2,3-Difluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3- fluorobenzyl)propanamide (Compound No . 230) ;
7V-(2-Fluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 -[4-(trifluoromethoxy)phenyl] - 1 H- pyrazol-3-yl}propanamide (Compound No. 231);
3-[5-(2,3-Difluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(2,5- dimethylbenzyl)propanamide (Compound No. 232);
JV-(3 -Chlorobenzyl)-3 - [5-(2,3 -difluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 233);
JV-(3 , 5 -Difluorobenzyl)-3 -{ 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethoxy)pheny] ]- 1 H- pyrazol-3-yl}propanamide (Compound No. 234);
3 - { 5 -(3 -Fluorophenyl)- 1 - [4-(trifluoromethoxy)phenyl] - 1 H-pyrazol-3 -yl } -7V-(3 - methylbenzyl)propanamide (Compound No. 235);
JV-(3 ,4-Dichlorobenzyl)-3 - [5-(2,3 -difluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 236);
7V-Benzyl-3 - [5-(2,3 -difluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3- yljpropanamide (Compound No. 237);
N-(2,5-Dimethylbenzyl)-3-{5-(3-fluorophenyl)-l-[4-(trifluoromethoxy)phenyl]- 1 H-pyrazol-3 -yl}propanamide (Compound No. 238);
N-(3 ,4-Dichlorobenzyl)-3- { 5-(3 -fluorophenyl)- 1 - [4-(trifluoromethoxy)phenyl] - 1 H -pyrazol-3-yl}propanamide (Compound No. 239);
3 -[5 -(2,3 -Difluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -JV-(3 - methylbenzyl)propanamide (Compound No. 240);
3-[5-(2,3-Difluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(2- fluorobenzyl)
propanamide (Compound No. 241);
JV-(3 ,4-Dichlorobenzyl)-3- { 5-(3 -fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H- pyrazol-3-yl}propanamide (Compound No. 242);
7V-(3 ,4-Dichlorobenzyl)-3 - [5-(3-fluorophenyl)- 1 -(4-methylphenyl)- 1 H-pyrazol-3 - yljpropanamide (Compound No. 243);
N-(3,5-Difluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methylphenyl)-lH-pyrazol-3- yi]
propanamide (Compound No. 244); N-(2,5-Dimethylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-methylphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 245);
N-Benzyl-3 - { 5-(3 -fluorophenyl)- 1 -[4-(trifluoromethyl)phenyl]- 1 H-pyrazol-3 -yl } propanamide (Compound No. 246);
N-(2,5-Dimethylbenzyl)-3-{5-(3-fluorophenyl)-l-[4-(trifluoromethyl)phenyl]-lH- pyrazol-3-yl}propanamide (Compound No. 247);
N-(5 -Chloro-2-methylbenzyl)-3 - [5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 248);
3 -[5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-[(5 -methyl- 1 ,2- oxazol-3-yl)methyl]propanamide (Compound No. 249);
3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-(3-fluorobenzyl) propanamide (Compound No. 250);
3 - [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl]-N-(2,3-difluorobenzyi) propanamide (Compound No.251);
3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-(3,5-difluorobenzyl) propanamide (Compound No. 252);
3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-(2,5- dimethylbenzyl)propanamide (Compound No.253);
-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-(3-fluoro-5- methylbenzyl)propanamide (Compound No. 254);
N-(3 -Chlorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5-(4-methylphenyl)- 1 H-pyrazol-3-yl ] propanamide (Compound No. 255);
N-(3-fluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -(4-methylphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 256);
3 -[ 1 -(4-Methoxyphenyl)-5-(4-methylphenyl)- 1 H-pyrazol-3 -yl] -N-(3 - methylbenzyl)propanamide (Compound No. 257);
N-Benzyl-3-[l-(4-methoxyphenyl)-5-(4-methylphenyl)-lH-pyrazol-3- yl] propanamide (Compound No.258);
N-(3,4-Dichlorobenzyl)-3-[l-(4-methoxyphenyl)-5-(4-methylphenyl)-lH-pyrazol- 3-yl]propanamide (Compound No. 259);
N-(2,5-Dimethylbenzyl)-3-[l-(4-methoxyphenyl)-5-(4-methylphenyl)-lH-pyrazol- 3-yl]propanamide (Compound No. 260);
N-(3 ,5-Difluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5-(4-methylphenyl)- 1 H-pyrazol- 3-yl]propanamide (Compound No. 261);
N-(2,3 -Difluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -(4-methylphenyl)- 1 H-pyrazol-
3-yl]propanamide (Compound No. 262);
N-(2-Fluorobenzyl)-3- [ 1 -(4-methoxyphenyl)-5 -(4-methylphenyl)- 1 H-pyrazol-3-yl] propanamide (Compound No. 263); N-Benzyl-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide(Compound No. 264);
N-(3 -Fluorobenzyl)-3 - [5-(4-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide(Compound No. 265);
N-(3-Chlorobenzyl)-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl] propanamide(Compound No. 266);
3-[5-(4-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3-methylbenzyl) propanamide(Compound No. 267);
N-(2,3-Difluorobenzyl)-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide(Compound No. 268);
N-(3,5-difluorobenzyl)-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 269);
N-(2,5 -Dimethylbenzyl)-3 - [5-(4-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol- 3-yl]propanamide(Compound No. 270);
N-(3,4-dichlorobenzyl)-3-[5-(4-fluorophenyl)-l -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide(Compound No. 271);
N-(3-Fluoro-5-methylbenzyl)-3 - [5 -(4-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanamide(Compound No. 272);
N-(2-Fluorobenzyl)-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl] propanamide(Compound No. 273);
N-(3 -Fluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 - yl]propanamide(Compound No. 274);
N-(3 ,5-Difluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 - yl]propanamide(Compound No. 275);
N-(2,3-Difluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 - yl]propanamide(Compound No. 276);
N-(2,5-Dimethylbenzyl)-3-[l-(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3- yl]propanamide(Compound No. 277);
N-(2,3 -Dichlorobenzyl)-3 - [ 1 -(4-methoxyphenyl)- 5 -phenyl- 1 H-pyrazol-3 - yl]propanamide(Compound No. 278);
N-(3 -Fluoro-5-methylbenzyl)-3 -[ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 -yl] propanamide(Compound No. 279);
N-(3-Fluoro-5-methylbenzyl)-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide(Compound No. 280); and
pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof.
The compound of general Formula 1 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 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 therapeutically effective amount of one or more compounds of Formula 1 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 , 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, β2- 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
Figure imgf000030_0001
Formula 1 Formula 5
{when ring A is (un)substituted
phenyl and n=l }
The compound of Formula 1 can be prepared according to Scheme I. Thus, reacting a compound of Formula 2 (wherein Ring B and R2 are same as defined earlier) with succinic anhydride gives a compound of Formula 3 which is then cyclised with compound of Formula 4 (wherein R1 is same as defined earlier) to give a compound of Formula 5. The coupling of a compound of Formula 5 with a compound of Formula 6 (wherein R3 and R4 is same as defined earlier) gives a compound of Formula l(when Ring A is (un)substituted phenyl and n=l).
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-ethyldiisoproylamine, 4-N,N- dimethylaminopyridine, N-methylmorpholine or 2,6-lutidine in the presence of polar solvents selected from methanol, ethanol, propanol, /so-propanol or butanol.
The coupling of a compound of Formula 5 with a compound of Formula 6 to form a compound of Formula 1 can be carried out using amine selected from triethylamine, N,N-dimethylaminopyridine,2,6-lutidine, 1 -methylpiperidine, N-ethyldiisoproylamine, N,N-diisopropylethylamine or N-methylmorpholine, in the presence of a 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, dicyclohexyl carbodiimide, 1 -(3 -dimethylaminopropyl)-3 - ethylcarbodiimide hydrochloride,chlorotripyrrolidinophosphoniumhexafluorophosphate or (benzotriazol- 1 -yloxy)tra-(dimethylamino)phosphonium hexafluorophosphate.
The compound of Formula 9 (Path A), Formula 12 (Path B) and Formula 15 (Path C) can be prepared according to Scheme II. The deprotection of a compound of Formula 7 gives a compound of Formula 8 which on coupling with compound of Formula 6 gives a compound of Formula 9. The reaction with a compound of Formula 9 with a compound of Formula 10 gives a compound of Formula 1 1 which finally on hydrolysis gives a compound of Formula 12. The reaction of compound of Formula 9 with a compound of Formula 13 gives a compound of Formula 14 which finally on deprotection gives a compound of Formula 15.
The deprotection of a compound of Formula 7 to form a compound of Formula 8 can be carried out in the presence of deprotecting agents, for example, Pd/C with ammonium formate, Pd/C with triethylsilane, Pd/C in the presence of hydrogen in one or more polar solvent, selected from methanol, ethanol, propanol, isopropanol, and the like.
The reaction of a compound of Formula 8 with a compound of Formula 6 to form a compound of Formula 9 can be carried out under similar conditions as for compound of Formula 5 with a compound of Formula 6 to form a compound of Formula 1 (Scheme I).
The reaction of a compound of Formula 9 with a compound of Formula 10 to form a compound of Formula 1 1 can be carried out using base such as sodium hydride, lithium hydride or potassium hydride in the presence of solvent, for example, NJf- dimethylformamide, dimethylsulfoxide, acetonitrile or tetrahydrofuran. The hydrolysis of a compound of Formula 11 to form a compound of Formula 12 can be carried out in a solvent selected from methanol, ethanol, tetrahydrofuran, 1 ,4-dioxane, water or mixture(s) thereof in the presence of a base, for example, lithium hydroxide, potassium hydroxide, sodium hydroxideor cesium hydroxide.
The reaction of a compound of Formula 9 with a compound of Formula 13 to form a compound of Formula 14 can be carried in solvents selected from, NJf'- dimethylformamide, dimethylsulfoxide, acetonitrile or tetrahydrofuran in the presence of base, for example, lithium hydride, sodium hydride or potassium hydride.
Scheme II
Figure imgf000032_0001
Formula 12
The deprotection of a compound of Formula 14 to form a compound of Formula 15 can be carried out in the presence of one or more organic solvents selected from
tetrahydrofuran, diethyl ether, 1,4-dioxane, dichloromethane and chloroform or a mixture thereof using base, for example, tetraw-butyl ammonium fluoride, hydrochloric acid or sodium fluoride.
Scheme III
Figure imgf000033_0001
hormula 10 Formula 17 Formula 18
{Formula I when
R2 is N02} The compound of Formula 18 can be prepared according to Scheme III. The reduction of a compound of Formula 16 gives a compound of Formula 17 which upon coupling with a compound of Formula 6 gives a compound of Formula 18.
The reduction of a compound of Formula 16 to form a compound of Formula 17 can be carried out in the presence of one or more solvents selected from methanol, ethanol, propanol, isopropanol, using reducing agent, for example, Pd/C in the presence of hydrogen, lithium aluminium hydride, Raney Nickel in hydrazine hydrate or zinc, tin or iron in the presence of hydrochloric acid.
The coupling of a compound of Formula 17 with a compound of Formula 6 to form a compound of Formula 18 can be carried out under similar conditions as for compound of Formula 6 with a compound of Formula 5 to give a compound of Formula 1.
Scheme IV
The compound of Formula 20 (Path D), Formula 21 (Path E) and Formula 22 (Path F) can be prepared according to Scheme IV. The reduction of a compound of Formula 19 gives a compound of Formula 20 (Path D) which upon acylation with a compound of Formula 20a (wherein R7 is alkyl or aryl and U is leaving group for example, halide, acyloxy or aryloxy) gives a compound of Formula 22 (Path F). The reaction of a compound of Formula 19 with sodium azide gives a compound of Formula 21 (Path E).
The reduction of a compound of Formula 19 to give a compound of Formula 20 can be carried out in presence of one or more reducing agents, for example, potassium borohydride in the presence of Raney Nickel, Nickel (II) chloride in combination with sodium borohydride, lithium aluminum hydride, Pd/C in the presence of hydrogen, Boron reagent using solvent selected from ethanol, methanol, propanol, wo-propanol.
Figure imgf000034_0001
{Formula I when R2 is -CN}
Figure imgf000034_0002
Formula 21 Formula 22
The reaction of compound of Formula 19 with sodium azide to give a compound of Formula 21 which can be carried out in the presence of organic base, for example, triethylamine, N,7V-dimethylaminopyridine,2,6-lutidine, 1-methylpiperidine, N,N- diisopropylethylamine or N-methylmorpholine, in one or more solvent selected from toluene, dimethoxymethane, xylene, or mixture thereof.
The 7V-acylation of a compound of Formula 20 with a compound of Formula 20a to form a compound of Formula 22 can be carried in the presence of a base, for example, triethylamine, pyridine, N-ethyldiisopropylamine, N-methylmorpholine, 4- dimethylaminopyridine, 1-methylimidazole, 1,2,4-triazole using relatively polar including polar aprotic solvent, for example, dimethylformamide, dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethylsulphoxide, N,7V-dimethyl acetamide, trifluoroethanol, l-methyl-2- pyrrolidinone, 1,1, 1,3,3,3, -hexafluoro-2-propanol,or mixture thereof. Scheme V
Figure imgf000035_0001
Formula 24
Figure imgf000035_0002
Formula 26
Formula 25
The compound of Formula 24 (Path G), 25 (Path H) and 26 (Path I) can be prepared according to Scheme V. The hydrolysis of compound of Formula 23 gives a compound of Formula 24 which on amidation gives a compound of Formula 25. The reduction of a compound of Formula 23 gives a compound of Formula 26.
The hydrolysis of compound of Formula 23 (Path G) to form a compound of Formula 24 can be carried out in a solvent selected from, for example, methanol, ethanol, tetrahydrofuran, 1 ,4-dioxane, water or mixture(s) thereof in the presence of a base, for example, lithium hydroxide, potassium hydroxide or sodium hydroxide.
The compound of Formula 24 can be coupled with ammonium carbonate to form a compound of Formula 25 using base, for example, triethylamine, N- ethyldiisopropylamine, N,N-dimethylaminopyridine,2,6-lutidine, 1-methylpiperidine, N,N- diisopropylethylamine or N-methylmorpholine, in the presence of a 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, dicyclohexyl carbodimide, l-(3-dimethylaminopropyl)-3- ethylcarbodimide hydrochloride,chlorotripyrrolidinophosphoniumhexafluorophosphate or (benzotriazol- 1 -yloxy)trw-(dimethylamino)phosphonium hexafluorophosphate.
The reduction of a compound of Formula 23 to form a compound of Formula 26 can be carried out using reducing agents, for example, sodium borohydride, potassium borohydride, lithium aluminium hydride, diisobutylaluminium hydride or B¾ (Borane) in the presence of polar aprotic solvents, for example, tetrahydrofuran, diethylether, 1,4- dioxane, dimethylformamide, acetonitrile or mixture(s) thereof or in the presence of protic solvents, for example, methanol, ethanol, isopropanol, water or mixture(s) thereof.
Scheme VI
Figure imgf000036_0001
Formula 9 Formula 27 Formula 28
{Formula 1 when Rl is -OH}
The reaction of compound of Formula 9 (wherein R2, R3 and R4 are the same as defined earlier) with a compound of Formula 27 (wherein R8 is methyl, ethyl, propyl, iso- propyl, wo-butyl, butylpentyl, hexyl, heptyl, octyl) to form a compound of Formula 27.
The coupling of a compound of Formula 9 with a compound of Formula 27 to give a compound of Formula 28 can be carried out in the presence of a redox couple. The oxidizing part of the redox couple is selected from the group 1,1 '-(azodicarbonyl) piperidine (ADDP), 4,7-dimethyl-3,5,7-hexahydro-l,2,4,7-tetrazocin-3,8-dione (DHTD), N,N,A^N'-tetramethylazodicarboxamide (TMAD), Ν,Ν,Ν',Ν'- tetraisopropylazodicarboxamide (TIP A), diethyl azodicarboxylate (DEAD), di-t- butylazodicarboxylate or diisopropylazodicarboxylate (DIAD). The reduction part of the redox couple is phosphine, such as, for example, trialkylphosphine (such as
tributylphosphine), triarylphosphine [such as, triphenylphosphine, p- (dimethylaminophenyl)diphenylphosphine], tricycloalkylphosphine (such as,
triscyclohexylphosphine) or tetraheteroarylphosphine. The phosphine reagents with a combination of aryl, alkyl, or heteroaryl substituents may also be used (such as, diphenylpyridylphosphine) in solvent selected from toluene, xylene, diethyl ether, tetrahydrofuran or N,N'-dimethylformamide.
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 accelerators, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol mono stearate or mixtures thereof; adsorbents, for example, Kaolin; lubricants, for example, talc, calcium stearate, magnesium stearate, solid
polyethyleneglycol, sodium lauryl 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 coca 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 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 1
Figure imgf000039_0001
A
/ (R>)x
Wherein R3 is hydrogen and n is one
Figure imgf000039_0002
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Table 2
Figure imgf000058_0002
(Ri)x wherein n is one and R3 and R4 together with the nitrogen combine to form a heterocycle rin
Figure imgf000058_0003
Figure imgf000059_0001
Experimental
Various solvents used were dried using drying reagents according to procedures described in the literature. Wherever room temperature or ambient temperature is mentioned, it refers to the range 25°C to 30°C.
Synthesis of Intermediates
Synthesis of 5-Methyl-2-(4-Methyl-Piperazin-l-Yl)Benzylamine
To a solution of 2-fluoro-5-methylbenzonitrile (2g, 14.81 mmoles) in dry DMSO (20 ml) were added dried potassium carbonate (4 g, 29.63 mmoles) and 4- methylpiperazine (2.22 g, 22.22 mmoles) and heated at 90°C for 12 hours. After completion of reaction, solvent was evaporated under vacuum, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2S04, filtered and evaporated under vacuum to afford the title compound as light yellow oil.
Yield: 1.8 g.
Mass spectrum (m/z, +ve ion mode): 220 [M++l]
The following compounds can be prepared using similar procedure:
3 -Chloro-4-(4-methyl-piperazin- 1 -yl)-benzylamine;
2-Fluoro-4-(4-methyl-piperazin- 1 -yl)-benzylamine;
[2-(4-Methyl-piperazin-l-yl)-pyridin-4-yl]-methylamine;
4-(4-Methyl-piperazin- 1 -yl)-benzylamine;
3 -(4-Methyl-piperazin- 1 -yl)-benzylamine;
2-(4-Methyl-piperazin- 1 -yl)-benzylamine. Synthesis of (2-Bromoethoxy)(Tg^Butyl)Dimethylsilane
To a solution of 2-bromoethanol (2 g, 16.13 mmoles) in dry DMF (10 ml) was added imidazole (2.19 g, 32.25 mmoles) and stirred at room temperature for 10 minutes. To this solution was added tert-butyldimethylsilyl chloride (3.62 g, 24.19 mmoles) at room temperature and stirred for 12 hours at room temperature. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated solution of ammonium chloride, water and brine, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford the title compound as colorless oil. Yield: 2.8 g.
Mass spectrum (m/z, +ve ion mode): 216 [M++l]
Synthesis of l-(6-Chloropyridin-3-Yl)Methanamine
To a solution of 6-chloropyridin-3-carbonitrile (1 g, 7.21 mmoles) in ethanol (15 ml) was added potassium borohydride (1.55 g, 28.87 mmoles) and Raney Nickel (0.5 g) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and then at 40°C for 2 hours. After completion, the reaction mixture was filtered through a prewashed celite pad in ethanol and concentrated. It was then diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated solution of ammonium chloride, water and brine, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford the title compound as brown oil. Yield: 0.7 g.
Mass spectrum (m/z, +ve ion mode): 143 [M++l]
The following compounds can be prepared using similar procedure:
1 -(6-Methylpyridin-2-yl)methanamine;
l-(2-Chloropyridin-4-yl)methanamine;
l-(4-Methylpyridin-2-yl)methanamine. Synthesis of Ethyl 4-Hydrazinylbenzoate
To a solution of 4-carboxyphenyl hydrazine (1 g, 6.55 mmoles) in ethanol (10 ml) was added ethanolic HCl (10 %, 20 ml) and heated at 80°C for 10 hours. After completion, the reaction mixture was allowed to cool to room temperature and the solid so obtained was filtered at pump. The solid was washed with diethyl ether and dried to afford the title compound as white shiny crystals. Yield: 1 g.
Mass spectrum (m/z, +ve ion mode): 181 [M++l] Synthesis of 3-(AminomethvDBenzoic Acid
To a solution of 3-cyanobenzoic acid (2 g, 13.59 mmoles) in methanol (20 ml) was added Raney Nickel (0.4 g) at 0°C and kept it under hydrogen atmosphere using H2 balloon at room temperature for 16 hours. After completion, the reaction mixture was filtered through a prewashed celite pad in methanol and washed with methanol. The solvent was evaporated under vacuum to afford the title compound as colourless syrup. Yield: 2 g
Mass spectrum (m/z, +ve ion mode): 152 [M++l]
Synthesis of Methyl 3-(Aminomethyl)Benzoate
To an ice cold solution of 3-(aminomethyl)benzoic acid (2 g, 13.23 mmoles) in dry methanol(39 ml) was added thionyl chloride (1.92 ml, 26.47 mmoles) dropwise. The reaction mixture was allowed to reflux for 6 hours. After completion of reaction, the solvents were evaporated under reduced pressure to afford a residue. A solution of sodium bicarbonate was added to the residue till effervescence ceased to evolve and then extracted with ethyl acetate. The resulting organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford the title compound as thick yellow syrup. Yield: 1.2 g
Mass spectrum (m/z, +ve ion mode): 166 [M++l]
Synthesis of [3-(Aminomethyl)Phenyll Methanol
To a solution of 3-(hydroxymethyl)benzonitrile (1 g, 7.51 mmoles) in ethanol (20 ml) was added potassium borohydride (0.81 g, 15.02 mmoles) and Raney Nickel (0.5 g) at room temperature. The reaction mixture was allowed to stir at room temperature for 15 minutes and then at 40°C for 2 hours. After completion, the reaction mixture was filtered through a prewashed celite pad in ethanol and concentrated. It was then diluted with water and extracted with ethyl acetate. The resulting organic layer was washed with a saturated solution of ammonium chloride, water and brine, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford the title compound as brown oil. Yield: 0.8 g
Mass spectrum (m/z, +ve ion mode): 138 [M++l]
Example 1 : Synthesis of S-rS-G-FluorophenylVl-^-Methoxyphenvn-lH-Pyrazol-S-Yll- N-(3-Methylbenzyl)Propanamide (Compound No. 22) Scheme I
Step A: Preparation of 6-(3-fluorophenyl)-4, 6-dioxohexanoic acid In a three-necked round bottom flask was taken 3-fluoroacetophenone (30g, 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 mmoles) dropwise at -78°C and allowed to stir at the same temperature for one hour.
Succinic anhydride (43.43 g 434.32 mmoles) dissolved in dry THF (200 ml) was added dropwise into the reaction mixture at the same temperature under an argon atmosphere. The reaction mixture was allowed to stir at -78°C for one hour and then at room
temperature for 2 hours. After completion, the reaction mixture was diluted by addition of water and concentrated hydrochloric acid was added until the pH became acidic (pH~4) and then extracted with ethyl actetate. The reaction mixture was extracted with ethyl actetate. The resulting organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated 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-Pyrazol-3- Yll Propanoic Acid
To a solution of compound obtained from step a (11 g, 46.21 mmoles) in dry ethanol (110 ml) was added 4-methoxyphenyl hydrazine (8 g, 46.21 mmoles) and triethylamine (12.8 ml, 92.43 mmoles) at room temperature. The reaction mixture was allowed to stir at room temperature for 4 hours to 5 hours. After the completion of reaction, solvent was evaporated under vacuum, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated 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: Preparation of 3-[5-(3-Fluorophenyl)-l-(4-Methoxyphenyl)-lH-Pyrazol-3- Yil-N-(3-Methylbenzyl)Propanamide
To a solution of compound obtained from Step b (0.5 g, 1.46 mmoles) were added
1-hydroxybenzotriazole (HOBT, 0.79 g, 5.87 mmoles), N-ethyldiisopropyl amine (Hunig's base, 1.00 ml, 5.87 mmoles) and 3-methylbenzyl amine (0.27 ml, 2.20 mmoles) in DMF (3 ml) at room temperature. The reaction mixture was allowed to stir at room temperature for 5 minutes and then l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HC1, 1.126 g, 5.87 mmoles) was added. The reaction mixture was stirred at room temperature for 12 hours. After the completion of reaction, solvent was evaporated under vacuum, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford an oily residue which was purified through column chromatography eluting with ethyl acetate: hexane (2:3) to afford the title compound as white solid. Yield: 0.6 g 1H NMR (400 MHz, DMSO-<¾: δ 8.40 (brm, 1H, -NH & D20 exchangeable), 7.41-7.35 (m, 1H, Ar-H), 7.19-7.11 (m, 4H, Ar-H), 7.05-6.95 (m, 7H, Ar-H), 6.50 (s, 1H, -CH), 4.26-4.25 (d, J= 4.00 Hz, -NHBn), 3.78 (s, 3H, -OCH3), 2.92-2.88 (2H, t, J= 8.00 Hz, CH2), 2.58-2.54 (2H, t, J= 8.00 Hz, CH2) and 2.23 (s, 2H, -CH3).
Mass spectrum (m/z, +ve ion mode): 444[M++1]
Example la: Synthesis of N-(3-ChlorobenzylV3-[5-(3-Fluorophenyl)-l-(4- Methoxyphenyl lH-Pyrazol-3-Y11Propanamide (Compound No. 20) Scheme I
Step 1: Synthesis of 6-(3-Fluorophenyl)-4,6-Dioxohexanoic Acid
The procedure is similar to Step A of Example 1.
Step 2: Synthesis of 3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-l//-pyrazol-3-yl] propanoic acid
The procedure is similar to Step B of Example 1.
Step 3: Synthesis of iV-(3-Chlorobenzyl)-3-[5-(3-Fluorophenyl)-l-(4-Methoxyphenyl)- liT-Pyrazol-S-YlJPropanamide
To a solution of compound obtained from Step 2 (0.5 g, 1.46 mmoles) were added
1 -hydroxybenzotriazole (HOBT, 0.79 g, 5.87 mmoles), N-ethyldiisopropyl amine (Hunig's base, 1.00 ml, 5.87 mmoles) and 3-chlorobenzyl amine (0.27 ml, 2.20 mmoles) in DMF (3 ml) at room temperature. The reaction mixture was allowed to stir at room temperature for
5 minutes and then l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI.HC1, 1.13 g, 5.87 mmoles) was added. The reaction mixture was stirred at room temperature for 12 hours. After the completion of reaction, solvent was evaporated under vacuum, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford an oily residue which was purified through column chromatography eluting with ethyl acetate: hexane (2:3) to afford the title compound as white solid. Yield: 0.6 g
1H NMR (400 MHz, DMSO-i¾: δ 8.45 (t, J= 5.96 Hz, 1H, -NH & D20 exchangeable),
7.39-7.33 (m, 1H, Ar-H), 7.27-7.24 (m, 3H, Ar-H), 7.17-7.13 (m, 4H, Ar-H), 6.99-6.93
(m, 4H, Ar-H), 6.48 (s, 1H,-CH), 4.28 (d, J= 5.96 Hz, -NHBn), 3.76 (s, 3H, -OCH3), 2.88
(2H, t, J= 7.36 Hz, -CH2) and 2.56 (2H, t, J= 7.36 Hz, -CH2).
Mass spectrum (m/z, +ve ion mode): 466 [M++l+2] and 464 [M++l].
The compounds mentioned below were prepared by following the same route of synthesis as above.
3-[5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N-(4- fluorobenzyl)propanamide (Compound No. 1);
Mass spectrum (m/z, +ve ion mode): 394 [M++l].
3 - [5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2,3 -dichlorobenzyl) propanamide (Compound No. 2 );
Mass spectrum (m/z, +ve ion mode): 445 [M++l].
3 - [5 -Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2,4-dichlorobenzyl) propanamide (Compound No. 3);
Mass spectrum (m/z, +ve ion mode): 445 [M++l].
N-(2-Chlorobenzyl)-3-[5-cyclopropyl-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 4);
Mass spectrum (m/z, +ve ion mode): 410 [M++l].
3 - [5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2- fluorobenzyl)propanamide (Compound No. 5);
Mass spectrum (m/z, +ve ion mode): 394 [M++l].
3- [5 -Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2-phenoxyethyl) propanamide (Compound No. 6);
Mass spectrum (m/z, +ve ion mode): 406 [M++l].
3-[5-Cyclopropyl-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[2- (trifluoromethyl)benzyl] propanamide (Compound No. 7);
Mass spectrum (m/z, +ve ion mode): 444 [M++l].
3- [5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 ,4-dichlorobenzyl) propanamide (Compound No. 8);
Mass spectrum (m/z, +ve ion mode): 445 [M++l].
N-(3 -Chlorobenzyl)-3- [5-cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl] propanamide (Compound No. 9);
Mass spectrum (m/z, +ve ion mode): 410 [M++l].
3 - [5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3-methylbenzyl) propanamide (Compound No. 10); Mass spectrum (m/z, +ve ion mode): 390 [M++l].
N-Benzyl-3 - [5-cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3-yl]propanamide (Compound No. 1 1);
Mass spectrum (m/z, +ve ion mode): 376 [M++l].
3-[5-Cyclopropyl-l -(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(thiophen-2-ylmethyl) propanamide (Compound No. 12);
Mass spectrum (m/z, +ve ion mode): 382 [M++l].
jV-(3-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 13);
Mass spectrum (m/z, +ve ion mode): 448 [M++l].
N-(2-Fluorobenzyl)-3 -[5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 14);
Mass spectrum (m/z, +ve ion mode): 448 [M++l].
3- [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(thiophen-2- ylmethyl)propanamide (Compound No. 15);
Mass spectrum (m/z, +ve ion mode): 436 [M++l].
3- [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl ] -N- [2-(thiophen-2- yl)ethyl]propanamide (Compound No. 16);
Mass spectrum (m/z, +ve ion mode): 450 [M++l].
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl ] -N-(2-phenoxyethyl) propanamide (Compound No. 17);
Mass spectrum (m/z, +ve ion mode): 460 [M++l].
iV-Benzyl-3 - [5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- lH-pyrazol-3- yl]propanamide (Compound No. 18);
Mass spectrum (m/z, +ve ion mode): 430 [M++l].
N-(2-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 19) ;
Mass spectrum (m/z, +ve ion mode): 464 [M++l].
N-(3-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 20);
Mass spectrum (m/z, +ve ion mode): 464 [M++l].
3-[5-(3-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3-yl]-/V-(2-methylbenzyl) propanamide (Compound No. 21);
Mass spectrum (m/z, +ve ion mode): 444 [M++l].
3- [5-(3-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl ] -N-(3 -methylbenzyl) propanamide (Compound No. 22);
Mass spectrum (m/z, +ve ion mode): 444 [M++l]. 3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[2-(4- methylpiperazin-l-yl)ethyl]propanamide (Compound No. 23);
Mass spectrum (m/z, +ve ion mode): 466 [M++l].
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [2-(2- oxoimidazolidin-l-yl)ethyl]propanamide (Compound No. 24);
Mass spectrum (m/z, +ve ion mode): 452 [M++l].
N-Benzyl-3 -[5 -(3 -fluorophenyl)- 1 -phenyl- lH-pyrazol-3 -yljpropanamide
(Compound No. 25);
Mass spectrum (m/z, +ve ion mode): 400 [M++l .].
N-(2-Chlorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl]propanamide (Compound No. 26);
Mass spectrum (m/z, +ve ion mode): 434 [M++l]. iV-(2-Fluorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -y l jpropanamide (Compound No. 27);
Mass spectrum (m/z, +ve ion mode): 418 [M++l].
3- [5 -(3 -Fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl] -N- [2-(trifluoromethyl)benzyl] propanamide (Compound No. 28);
Mass spectrum (m/z, +ve ion mode): 468 [M++l].
N-(3 -Fluorobenzyl)-3 - [5-(3-fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl]propanamide (Compound No. 29);
Mass spectrum (m/z, +ve ion mode): 418 [M++l].
3 - [5 -(3 -Fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl] - N-(3 - methylbenzyl)propanamide (Compound No. 30);
Mass spectrum (m/z, +ve ion mode): 414 [M++l].
3-[5-(3-Fluorophenyl)-l-phenyl-lH-pyrazol-3-yl]-N-[2-(4-methylpiperazin-l- yl)ethyl]propanamide (Compound No. 31);
Mass spectrum (m/z, +ve ion mode): 436 [M++l].
3 - [5 -(3 -Fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl] - 1 -(pyrrolidin- 1 -yl)propan- 1 -one (Compound No. 32);
Mass spectrum (m/z, +ve ion mode): 364 [M++l].
3 - [5 -(3 -Fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl] - 1 -(piperidin- 1 -yl)propan- 1 -one (Compound No. 33);
Mass spectrum (m/z, +ve ion mode): 378 [M^+l].
3- [5-(3 -Fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl] - 1 -(morpholin-4-yl)propan- 1 -one (Compound No. 34);
Mass spectrum (m/z, +ve ion mode): 380 [M++l].
N-(3 -Chlorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl]propanamide (Compound No. 35);
Mass spectrum (m/z, +ve ion mode): 434 [M++l]. 3-[5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N-(3- fluorobenzyl)propanamide (Compound No. 36);
Mass spectrum (m/z, +ve ion mode): 394 [M++l].
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3-yl] - 1 -(morpholin-4- yl)propan-l-one (Compound No. 37);
Mass spectrum (m/z, +ve ion mode): 410 [M++l].
3-[5-(3-Fluorophenyl)-l -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-l -(piperidin- 1 - yl)propan-l-one (Compound No. 38);
Mass spectrum (m/z, +ve ion mode): 408 [M++l].
3- [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl ] -N-(4-methylbenzyl) propanamide (Compound No. 39);
Mass spectrum (m/z, +ve ion mode): 444 [M++l].
N-(4-Chlorobenzyl)-3 - [5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 40);
Mass spectrum (m/z, +ve ion mode): 464 [M++l].
N-(3 , 4-Dichlorobenzyl)-3 - [5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-
3-yl]propanamide (Compound No. 41);
Mass spectrum (m/z, +ve ion mode): 409 [M++l].
N-Benzyl-3 - [ 1 -(4-methoxyphenyl)-5-phenyl- 1 H-pyrazol-3 - yl]propanamide(Compound No. 42);
Mass spectrum (m/z, +ve ion mode): 412 [M++l].
N-(2-Fluorobenzyl)-3-[l-(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3- yl] propanamide (Compound No. 43);
Mass spectrum (m/z, +ve ion mode): 430 [M++l].
N-(2-Chlorobenzyl)-3 -[ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 - yl] propanamide (Compound No. 44);
Mass spectrum (m/z, +ve ion mode): 446 [M++l].
3-[l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-(2- methylbenzyl)propanamide (Compound No. 45);
Mass spectrum (m/z, +ve ion mode): 426 [M++l].
3-[l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-(2- phenoxyethyl)propanamide (Compound No. 46);
Mass spectrum (m/z, +ve ion mode): 442 [M++l].
3- [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2-phenylethyl) propanamide (Compound No. 47);
Mass spectrum (m/z, +ve ion mode): 444 [M++l].
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(tetrahydrofuran- 2-ylmethyl)propanamide (Compound No. 48);
Mass spectrum (m/z, +ve ion mode): 424 [M++l].
N-(2,3 -Dihydro- 1 -benzofuran-5-ylmethyl)-3 - [5-(3 -fluorophenyl)- 1 -(4- methoxyphenyl)-lH-pyrazol-3-yl]propanamide (Compound No. 49);
Mass spectrum (m/z, +ve ion mode): 472 [M++ 1.]. N-(2, 3 -Dichlorobenzyl)-3 - [5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-
3-yl]propanamide (Compound No. 50);
Mass spectrum (m/z, +ve ion mode): 499 [M++l].
N-(4-Chlorobenzyl)-3-[l-(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3- yl]propanamide (Compound No. 51);
Mass spectrum (m/z, +ve ion mode): 446 [M++l].
N-(4-Fluorobenzyl)-3-[l-(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3- yl]propanamide (Compound No. 52);
Mass spectrum (m/z, +ve ion mode): 430 [M++l].
3-[ 1 -(4-Methoxyphenyl)-5-phenyl- lH-pyrazol-3-yl]-7V-(4- methylbenzyl)propanamide (Compound No. 53);
Mass spectrum (m/z, +ve ion mode): 426 [M^+l].
3 - [ 1 -(4-Methoxyphenyl)- 5 -phenyl- 1 H-pyrazol-3 -y 1] -N-(thiophen-3 - ylmethyl)propanamide (Compound No. 54);
Mass spectrum (m/z, +ve ion mode): 418 [M++l].
3-[l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-[2-(thiophen-2-yl)ethyl] propanamide (Compound No. 55);
Mass spectrum (m/z, +ve ion mode): 432 [M++l].
3 - [ 1 -(4-Methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3-yl] -N- [2-(2-oxoimidazolidin- 1 - yl)ethyl]propanamide (Compound No. 56);
Mass spectrum (m/z, +ve ion mode): 434 [M++l].
N-Benzyl-3-[l-(4-cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]propanamide (Compound No. 57);
Mass spectrum (m/z, +ve ion mode): 425 [M++l].
3- [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -y I ] -N-(2-fluorobenzyl) propanamide (Compound No. 58);
Mass spectrum (m/z, +ve ion mode): 443 [M++l].
N-(2-Chlorobenzyl)-3-[l-(4-cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 59);
Mass spectrum (m/z, +ve ion mode): 459 [M++l].
3 -[ 1 -(4-Cyanophenyl)-5-(3-fluorophenyl)- 1 H-pyrazol-3 -yl]-N-(2-methylbenzyl) propanamide (Compound No. 60);
Mass spectrum (m/z, +ve ion mode): 439 [M++l].
3- [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(2-phenoxy ethyl) propanamide (Compound No. 61);
Mass spectrum (m/z, +ve ion mode): 455[M++1].
N-(4-Chlorobenzyl)-3 - [ 1 -(4-cyanophenyl)-5 -(3 -fluorophenyl)- lH-pyrazol-3 -yl] propanamide (Compound No. 62);
Mass spectrum (m/z, +ve ion mode): 459 [M++l].
3 - [ 1 -(4-Cyanophenyl)-5 -(3-fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(4-fluorobenzyl) propanamide (Compound No. 63);
Mass spectrum (m/z, +ve ion mode): 443 [M++l]. 3 - [ 1 -(4-Cyanophenyl)-5 -(3-fluorophenyl)- 1 H-pyrazol-3 -yl]-N-(4-methylbenzyl) propanamide (Compound No.64);
Mass spectrum (m/z, +ve ion mode): 439 [M++l].
3- [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(thiophen-2- ylmethyl)propanamide (Compound No. 65);
Mass spectrum (m/z, +ve ion mode): 431 [M++l].
3 - [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl]-N- [2-(thiophen-2- yl)ethyl]propanamide (Compound No. 66);
Mass spectrum (m/z, +ve ion mode): 445 [M++l].
3-[l -(4-Cyanophenyl)-5-(3-fluorophenyl)- lH-pyrazol-3-yl]-N-[2-(2- oxoimidazolidin-l-yl)ethyl]propanamide (Compound No. 67);
Mass spectrum (m/z, +ve ion mode): 447 [M++l .].
3- [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- lH-pyrazol-3 -yl] -N-(3 -methylbenzyl) propanamide (Compound No. 68);
Mass spectrum (m/z, +ve ion mode): 439 [M++l].
N-(3 -Chlorobenzyl)-3 -[ 1 -(4-cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] propanamide(Compound No. 69);
Mass spectrum (m/z, +ve ion mode): 459 [M++l].
N-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)- 1 -(4-methoxy-2-methylphenyl)- 1H- pyrazol-3-yl]propanamide (Compound No. 70);
Mass spectrum (m/z, +ve ion mode): 462 [M++l].
3-[5-(3-Fluorophenyl)- 1 -(pyridin-2-yl)- lH-pyrazol-3-yl]-N-(3- methylbenzyl)propanamide (Compound No. 71);
Mass spectrum (m/z, +ve ion mode): 415 [M++l].
3-[ 1 -(4-Methoxyphenyl)-5-phenyl- 1 H-pyrazol-3 -yl]-N-(3 - methylbenzyl)propanamide (Compound No. 72);
Mass spectrum (m z, +ve ion mode): 426 [M++l].
N-(3 -Chlorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5-phenyl- 1 H-pyrazol-3- yl]propanamide (Compound No. 73);
Mass spectrum (m/z, +ve ion mode): 446 [M++l].
N-(3 -Chlorobenzy l)-3 - [5-(3 -fluorophenyl)- 1 -(pyridin-2-yl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 74);
Mass spectrum (m/z, +ve ion mode): 435 [M++l].
3-[5-(3-Fluorophenyl)-l-^yridin-2-yl)-lH-pyrazol-3-yl]-N-^yridin-2-ylmethyl) propanamide (Compound No. 75);
Mass spectrum (m z, +ve ion mode): 402 vT+l].
3 - [5-(3 -Fluorophenyl)- 1 -(pyridin-2-yl)- 1 H-pyrazol-3 -yl] -N- [3 -(morpholin-4- yl)propyl]propanamide (Compound No. 76);
Mass spectrum (m/z, +ve ion mode): 438 [M++l].
3-[5-(3-Fluorophenyl)-l-(pyridin-2-yl)-lH-pyrazol-3-yl]-N-[2-(morpholin-4- yl)ethyl]propanamide (Compound No. 77);
Mass spectrum (m/z, +ve ion mode): 424 [M++l]. 3 - [5 -(3 -Fluorophenyl)- 1 -(pyridin-2-yl)- 1 H-pyrazol-3 -yl] -JV-(pyridin-3 -ylmethyl) propanamide (Compound No. 78);
Mass spectrum (m/z, +ve ion mode): 402 [M++l].
3 - [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(pyridin-2- ylmethyl)propanamide (Compound No. 79);
Mass spectrum (m/z, +ve ion mode): 426 [M++l].
3 - [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N- [3 -(morpholin-4- yl)propyl]propanamide (Compound No. 80);
Mass spectrum (m/z, +ve ion mode): 462 [M++l].
3 - [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N- [2-(morpholin-4- yl)ethyl]propanamide (Compound No. 81);
Mass spectrum (m/z, +ve ion mode): 448 [M++l].
3-[ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(pyridin-3 - ylmethyl)propanamide (Compound No. 82);
Mass spectrum (m/z, +ve ion mode): 426 [M++l].
3 - [ 1 -(4-Methoxyphenyl)- 5 -phenyl- 1 H-pyrazol-3 -yl] -N-(pyridin-2- ylmethyl)propanamide (Compound No. 83);
Mass spectrum (m/z, +ve ion mode): 413 [M++l].
3 - [ 1 -(4-Methoxyphenyl)-5-phenyl- lH-pyrazol-3-yl] -N- [3 -(morpholin-4-yl)propyl] propanamide (Compound No. 84);
Mass spectrum (m/z, +ve ion mode): 449 [M++l].
3-[l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-[2-(morpholin-4-yl)ethyl] propanamide (Compound No. 85);
Mass spectrum (m/z, +ve ion mode): 435 [M++l].
3 - [ 1 -(4-Fluorophenyl)-5 -(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [2-(4- methylpiperazin-l-yl)ethyl]propanamide (Compound No. 86);
Mass spectrum (m/z, +ve ion mode): 466 [M++l].
iV-{[(2i?)-l-Ethylpyrrolidin-2-yl]methyl}-3-[l-(4-fluorophenyl)-5-(3- methoxyphenyl)-lH-pyrazol-3-yl]propanamide (Compound No. 87);
Mass spectrum (m/z, +ve ion mode): 451 [M++l].
3 - [ 1 -(4-Fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [2-(2- oxoimidazolidin-l-yl)ethyl]propanamide (Compound No. 88);
Mass spectrum (m/z, +ve ion mode): 452 [M++l].
3-[l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-[3-(2- oxopyrrolidin-l-yl)propyl]propanamide (Compound No. 89);
Mass spectrum (m/z, +ve ion mode): 465 [M++l].
3- [ 1 -(4-Fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl] -JV-(pyridin-2- ylmethyl)propanamide (Compound No. 90);
Mass spectrum (m/z, +ve ion mode): 431 [M++l].
3-[l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-(pyridin-4- ylmethyl)propanamide (Compound No. 91);
Mass spectrum (m/z, +ve ion mode): 431 [M++l] 3 - [ 1 -(4-Fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -methyl benzyl)propanamide (Compound No. 92);
Mass spectrum (m/z, +ve ion mode): 444 [M++l].
N-(3-Chlorobenzyl)-3 - [ 1 -(4-fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3-yl] propanamide (Compound No. 93);
Mass spectrum (m/z, +ve ion mode): 464 [M++l].
N-(3-Fluorobenzyl)-3 - [ 1 -(4-fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 94);
Mass spectrum (m/z, +ve ion mode): 448 [M++l].
3-[l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-[2-(morpholin-4- yl)ethyl]propanamide (Compound No. 95);
Mass spectrum (m z, +ve ion mode): 453 [M++l],
3 - [ 1 -(4-Fluorophenyl)-5-(3-methoxyphenyl)- 1 H-pyrazol-3-yl] -N- [3 -(morpholin-4- yl)propyl]propanamide (Compound No. 96);
Mass spectrum (m/z, +ve ion mode): 467 [M++l].
N-(3 -Chlorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5-(pyridin-3 -yl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 97);
Mass spectrum (m/z, +ve ion mode): 447 [M++l].
3- [ 1 -(4-Methoxyphenyl)-5-(pyridin-3-yl)- 1 H-pyrazol-3 -yl] -JV-(3 -methylbenzyl) propanamide (Compound No. 98);
Mass spectrum (m/z, +ve ion mode): 427 [M++l].
N-(3-Fluorobenzyl)-3-[l-(4-methoxyphenyl)-5-(pyridin-3-yl)-lH-pyrazol-3-yl] propanamide (Compound No. 99);
Mass spectrum (m/z, +ve ion mode): 431 [M++l].
iV-Benzyl-3 - [ 1 -(4-methoxyphenyl)-5-(pyridin-3 -yl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 100);
Mass spectrum (m/z, +ve ion mode): 413 [M++l].
3 - [ 1 -(4-Methoxyphenyl)-5-(pyridin-3-yl)- 1 H-pyrazol-3 -yl] -N-(pyridin-2-ylmethyl) propanamide (Compound No. 101);
Mass spectrum (m/z, +ve ion mode): 414 [M++l].
3-[l -(4-Methoxyphenyl)-5-(pyridin-3-yl)-lH-pyrazol-3-yl]-N-(pyridin-4-ylmethyl) propanamide (Compound No. 102);
Mass spectrum (m/z, +ve ion mode): 414 [M++l].
3-[l -(4-Methoxyphenyl)-5-(pyridin-3-yl)-lH-pyrazol-3-yl]-N-[2-(2- oxoimidazolidin-l-yl)ethyl]propanamide (Compound No. 103);
Mass spectrum (m/z, +ve ion mode): 435 [M^+l]
3 - [ 1 -(4-Methoxyphenyl)-5-(pyridin-3 -yl)- 1 H-pyrazol-3 -yl] -N- [3 -(2-oxopyrrolidin- l-yl)propyl]propanamide (Compound No. 104);
Mass spectrum (m/z, +ve ion mode): 448 [M++l].
JV-[(1 -Ethy lpyrrolidin-2-yl)methyl] -3 - [ 1 -(4-methoxypheny 1)- 5 -(pyridin-3 -yl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 105);
Mass spectrum (m/z, +ve ion mode): 434 [M++l]. 3 - [ 1 -(4-Methoxyphenyl)-5-(pyridin-3-yl)- 1 H-pyrazol-3 -yl] -N- [3 -(morpholin-4- yl)propyl]propanamide (Compound No. 106);
Mass spectrum (m/z, +ve ion mode): 450 [M++l].
N- [(2-Chloropyridin-4-yl)methyl] -3 -[5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H -pyrazol-3-yl]propanamide (Compound No. 107);
Mass spectrum (m/z, +ve ion mode): 465 [M++l].
N-[(6-Chloropyridin-3 -yl)methyl] -3 -[5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H -pyrazol-3-yl]propanamide (Compound No. 108);
Mass spectrum (m/z, +ve ion mode): 465 [M++l].
3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(pyridin-2- ylmethyl)propanamide (Compound No. 109);
Mass spectrum (m/z, +ve ion mode): 431 [M++l].
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [(6- methylpyridin-2-yl)methyl]propanamide (Compound No. 110);
Mass spectrum (m/z, +ve ion mode): 445 [M++l].
3 -[5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3-yl] -N-(pyridin-4- ylmethyl)propanamide (Compound No. I l l);
Mass spectrum (m/z, +ve ion mode): 431 [M++l].
N-Benzyl-3 -[ 1 -(4-fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 112);
Mass spectrum (m/z, +ve ion mode): 430 [M++l].
Ethyl 4- { 3 - [3 -(benzylamino)-3 -oxopropyl]-5-(3 -fluorophenyl)- 1 H-pyrazol- 1 - yl}benzoate (Compound No. 113);
Mass spectrum (m/z, +ve ion mode): 472 [M++l].
Ethyl 4-[5-(3-fluorophenyl)-3-{3-oxo-3-[(pyridin-2-ylmethyl)amino]propyl}-lH- pyrazol-l-yl]benzoate (Compound No. 114);
Mass spectrum (m/z, +ve ion mode): 473 [M++l].
Ethyl 4- [5-(3-fluorophenyl)-3 - { 3 -oxo-3- [(pyridin-4- ylmethyl)amino]propyl } - 1 H- pyrazol-l-yl]benzoate (Compound No. 115);
Mass spectrum (m/z, +ve ion mode): 473 [M++l]
Ethyl 4- [5-(3 -fluorophenyl)-3 -(3 -oxo-3 - { [2-(2-oxoimidazolidin- 1 - yl)ethyl]amino}propyl)-lH-pyrazol-l-yl]benzoate (Compound No. 116);
Mass spectrum (m/z, +ve ion mode): 494 [M++l].
Ethyl 4- [5 -(3 -fluorophenyl)^ -(3 -oxo-3 -{ [3 -(2-oxopyrrolidin-l- yl)propyl]amino}propyl)-lH-pyrazol-l-yl]benzoate (Compound No. 117);
Mass spectrum (m/z, +ve ion mode): 507 [M++l].
Ethyl 4-[5-(3-fluorophenyl)-3-(3- { [(1 -methylpyrrolidin-2-yl)methyl]amino}-3- oxopropyl)-l H-pyrazol- l-yl]benzoate (Compound No. 118);
Mass spectrum (m/z, +ve ion mode): 479 [M++l].
Ethyl 4-[3 -(3 - { [(6-chloropyridin-3 -yl)methyl] amino } -3 -oxopropyl)-5 -(3- fluorophenyl)-lH-pyrazol-l-yl]benzoate (Compound No. 119;
Mass spectrum (m/z, +ve ion mode): 507 [M++l]. Ethyl 4-[5-(3-fluorophenyl)-3-(3-{[3-(morpholin-4-yl)propyl]amino}-3- oxopropyl)-lH-pyrazol-l-yl]benzoate (Compound No. 120);
Mass spectrum (m/z, +ve ion mode): 509 [M++l].
Ethyl 4- [5-(3-fluorophenyl)-3 -(3- { [(3 -methylpyridin-2-yl)methy l]amino } -3 - oxopropyl)-lH-pyrazol-l-yl]benzoate (Compound No. 121);
Mass spectrum (m/z, +ve ion mode): 487 [M++l].
N- [( 1 -Ethylpyrrolidin-2-yl)methyl] -3 - [ 1 -(4-fluorophenyl)-5-(3 -methoxyphenyl)- lH-pyrazol-3-yl]propanamide (Compound No. 125);
Mass spectrum (m/z, +ve ion mode): 451 [M++l].
Ethyl 4- [3 - { 3 - [(3-chlorobenzyl)amino] -3-oxopropyl } -5 -(3 -fluorophenyl)- 1H- pyrazol-l-yl]benzoate (Compound No. 126);
Mass spectrum (m/z, +ve ion mode): 506 [M++l].
Ethyl 4-[5-(3-fluorophenyl)-3- {3-[(3-methylbenzyl)amino]-3-oxopropyl} - 1H- pyrazol-l-yl]benzoate (Compound No. 127);
Mass spectrum (m/z, +ve ion mode): 486 [M++l].
3- [ 1 -(4-Fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl]-N- [(6- methylpyridin-2-yl)methyl]propanamide (Compound No. 128);
Mass spectrum (m/z, +ve ion mode): 445 [M++l].
Ethyl 4- [3 - { 3 - [(3 -fluorobenzyl)amino] -3-oxopropyl } -5 -(3 -fluorophenyl)- 1 H- pyrazol-l-yl]benzoate (Compound No. 129);
Mass spectrum (m/z, +ve ion mode): 490 [M++l].
JV-(3 -Chlorobenzyl)-3 - [5-(3-cyanophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl ] propanamide (Compound No. 137);
Mass spectrum (m/z, +ve ion mode): 471 [M^+l].
3-[5-(3-Cyanophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-jV-(3-methylbenzyl) propanamide (Compound No. 138);
Mass spectrum (m/z, +ve ion mode): 451 pvT+l].
3- [5-(3 -Cyanophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -fluorobenzyl) propanamide (Compound No. 139);
Mass spectrum (m/z, +ve ion mode): 455 [M++l].
jV-Benzyl-3 - [5 -(3 -cyanophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 140);
Mass spectrum (m/z, +ve ion mode): 437 [M++l].
3- [5-(3-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [2-(4- methylpiperazin-l-yl)benzyl]propanamide (Compound No. 142);
Mass spectrum (m/z, +ve ion mode): 528 [M++l].
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -JV-[3 -(4- methylpiperazin-l-yl)benzyl]propanamide (Compound No. 143);
Mass spectrum (m/z, +ve ion mode): 528 [M++l].
3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-[3-(4- methylpiperazin-l -yl)benzyl]propanamide (Compound No. 144);
Mass spectrum (m/z, +ve ion mode): 523 [M^+l]. Methyl 3 - [( { 3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)methyl]benzoate (Compound No. 145);
Mass spectrum (m/z, +ve ion mode): 488 [M++l].
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-[4-(4- methy lpiperazin- 1 -y l)benzyl] propanamide (Compound No . 146);
Mass spectrum (m/z, +ve ion mode): 528 [M++l].
N-(3 -Chlorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methoxy-2-methylphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 149);
Mass spectrum (m/z, +ve ion mode): 478 [M++l].
N-(3 -Fluorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methoxy-2-methylphenyl 1 H- pyrazol-3-yl] propanamide (Compound No. 150);
Mass spectrum (m/z, +ve ion mode): 462 [M++l].
N-Benzyl-3-[l-(4-methoxyphenyl)-5-(pyrazin-2-yl)-lH-pyrazol-3-yl]propanamide (Compound No. 152);
Mass spectrum (m/z, +ve ion mode) : 414 [M++ 1 ] .
3-[({3-[5-(3-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)methyl]benzoic acid (Compound No. 155);
Mass spectrum (m/z, +ve ion mode): 474 [M++l].
3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-{[2-(4- methylpiperazin-l-yl)pyridin-4-yl]methyl}propanamide (Compound No. 160);
Mass spectrum (m/z, +ve ion mode): 529 [M++l].
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [5 -methyl-2-(4- methylpiperazin-l-yl)benzyl]propanamide (Compound No. 161);
Mass spectrum (m/z, +ve ion mode): 542 [M++l].
N-(5-Fluoro-2-methylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 162);
Mass spectrum (m/z, +ve ion mode): 462 [M++l].
N-(2,3 -Difluorobenzyl)-3 -[5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 163);
Mass spectrum (m/z, +ve ion mode): 466 [M++l].
N-(2, 4-Dichlorobenzyl)-3 -[5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-
3-yl]propanamide (Compound No. 164);
Mass spectrum (m/z, +ve ion mode): 499 [M++l].
N-(3 ,5-Difluorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yljpropanamide (Compound No. 165);
Mass spectrum (m/z, +ve ion mode): 466 [M++l].
iV-(2,5-Dimethylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-
3 -yljpropanamide (Compound No. 168);
Mass spectrum (m/z, +ve ion mode): 458 [M++l].
N- [2-Fluoro-4-(4-methy lpiperazin- 1 -yl)benzyl] -3 - [5 -(3 -fluorophenyl)- 1 -(4
-methoxyphenyl)-l H-pyrazol-3 -yljpropanamide (Compound No. 169);
Mass spectrum (m/z, +ve ion mode): 546 [M++l]. 3 -[5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [(5 - methylpyridin-3-yl)methyl]propanamide (Compound No. 170);
Mass spectrum (m/z, +ve ion mode): 445 [M++l].
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxy-2 -methylphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -methylbenzyl)propanamide (Compound No. 182);
Mass spectrum (m/z, +ve ion mode): 458 [M++l].
N-(3 , 5-Dimethylbenzyl)-3-[5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-
3-yl]propanamide (Compound No. 184);
Mass spectrum (m/z, +ve ion mode): 458 [M++l].
N- [3 -Chloro-4-(4-methylpiperazin- 1 -yl)benzyl]-3 - [5-(3 -fluorophenyl)- 1 -(4
-methoxyphenyl)-lH-pyrazol-3-yl]propanamide (Compound No. 185);
Mass spectrum (m/z, +ve ion mode): 563 [M++l].
N-(3 , 5-Dichlorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol- 3-yl]propanamide (Compound No. 188);
Mass spectrum (m/z, +ve ion mode): 499 [M++l].
3 - [5-(3-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -methylphenyl) propanamide (Compound No. 189);
Mass spectrum (m/z, +ve ion mode): 430 [M++l]
N-(3 -Fluorophenyl)-3 - [5 -(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 190);
Mass spectrum (m/z, +ve ion mode): 434 [M++l].
N-(3 -Chlorophenyl)-3 - [5 -(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 191);
Mass spectrum (m/z, +ve ion mode): 450 [M++l].
3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[3- (hydroxymethyl)benzyl]propanamide (Compound No. 192);
Mass spectrum (m/z, +ve ion mode): 460 [M++l].
3-[5-(3 -Fluorophenyl)- 1 -(2-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -methyl benzyl)propanamide (Compound No. 193);
Mass spectrum (m/z, +ve ion mode): 444 [M++l].
N-(3-Fluorobenzyl)-3 - [5 -(3-fluorophenyl)- 1 -(2-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 194);
Mass spectrum (m/z, +ve ion mode): 448 [M++l].
N-(3 -Chlorobenzyl)-3 - [5 -(3-fluorophenyl)- 1 -(2-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 195);
Mass spectrum (m/z, +ve ion mode): 464 [M++l].
vV-(3 -Chlorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methylphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 196);
Mass spectrum (m/z, +ve ion mode): 448 [M++l].
N-(3 -Fluorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methylphenyl)- 1 H-pyrazol-3-yl] propanamide (Compound No. 197);
Mass spectrum (m/z, +ve ion mode): 432 [M++l]. 3 - [5 -(3 -Fluorophenyl)- 1 -(4-methylphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -methylbenzyl) propanamide (Compound No. 198);
Mass spectrum (m/z, +ve ion mode): 428 [M++l]
N-Benzyl-3- [5 -(3 -fluorophenyl)- 1 -(4-methylphenyl)- 1 H-pyrazol-3 -yl]propanamide (Compound No. 199);
Mass spectrum (m/z, +ve ion mode): 414 [M++l].
N-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methylphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 200);
Mass spectrum (m/z, +ve ion mode): 432 [M++l].
N-(2-Fluorobenzyl)-3- [5-(3 -fluorophenyl)- 1 -(2 -methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 201);
Mass spectrum (m/z, +ve ion mode): 448 [M++ 1 ].
3-[5-(3-Fluorophenyl)-l-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3-methyl benzyl)propanamide (Compound No. 202);
Mass spectrum (m/z, +ve ion mode): 444 [M++l].
N-(3 -Fluorobenzyl)-3 - [5-(3-fluorophenyl)- 1 -(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 203);
Mass spectrum (m/z, +ve ion mode): 448 [M++l].
N-(3 -Chlorobenzyl) -3 - [5 -(3 -fluorophenyl)- 1 -(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl ] propanamide (Compound No. 204);
Mass spectrum (m/z, +ve ion mode): 464 [M++l].
N-(3-Chloro-2-fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 205);
Mass spectrum (m z, +ve ion mode): 484[M++l+2] and 482[M++1]
N-(3 -Fluoro-5 -methylbenzyl)-3 -[5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 206);
Mass spectrum (m/z, +ve ion mode): 462 [M++l].
jV-(5-Chloro-2-fluorobenzyl)-3- [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl]propanamide (Compound No. 207);
Mass spectrum (m z, +ve ion mode): 484[M++l+2] and 482[M++1]
N-(3 -Chloro-2,6-difluorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl] propanamide (Compound No. 208);
Mass spectrum (m/z, +ve ion mode): 502[M++l+2] and 500[M++1]
N-(3-Chloro-2-methylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 209);
Mass spectrum (m/z, +ve ion mode): 480[M +1+2] and 478[M++1]
N-(3-Chloro-4-fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl] propanamide (Compound No. 210);
Mass spectrum (m/z, +ve ion mode): 484[M++l+2] and 482[M++1]
N-(2-Chloro-6-fluoro-3-methylbenzyl)-3-[5-(3-fluorophenyl)-l-(4- methoxyphenyl)-lH-pyrazol-3-y]]propanamide (Compound No. 211);
Mass spectrum (m/z, +ve ion mode): 498[M+ 1+2] and 496[M+ +1] N-(3 -Chlorobenzyl)-3 - [5 -(2-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -y 1] propanamide (Compound No. 212);
Mass spectrum (m/z, +ve ion mode): 466[M++l+2] and 464[M++1]
N-(3 -Chlorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H- pyrazol-3-yl} propanamide (Compound No. 213);
Mass spectrum (m/z, +ve ion mode): 504[M++l+2] and 502[M++1]
N-(3, 5-Difluorobenzyl)-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-
3-yl]propanamide (Compound No. 214);
Mass spectrum (m/z, +ve ion mode): 466 [M++l].
3 - { 5 -(3 -Fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H-pyrazol-3 -y 1 } -N-(3 - methyl benzyl)propanamide (Compound No. 215);
Mass spectrum (m/z, +ve ion mode): 482 [M++l].
N-(3,4-Dichlorobenzyl)-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 216);
Mass spectrum (m/z, +ve ion mode): 502 [M++ 1+2+2], 500 [M++l+2] and 498 [M++l]
3-[5-(2-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3-methylbenzyl) propanamide (Compound No. 217);
Mass spectrum (m/z, +ve ion mode): 444 [M++l].
3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3-yl] -N-[(5 -methyl-3 - phenyl- l,2-oxazol-4-yl)methyl]propanamide (Compound No. 218);
Mass spectrum (m/z, +ve ion mode): 511 [M++l].
N-(3 -Fluorobenzyl)-3 - [5-(2-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 219);
Mass spectrum (m/z, +ve ion mode): 448 [M++l].
N-(2, 5-Dimethylbenzyl)-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-
3-yl]propanamide (Compound No. 220);
Mass spectrum (m/z, +ve ion mode): 458 [M++l].
N-(2-Fluorobenzyl)-3 - [5 -(2-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 221);
Mass spectrum (m/z, +ve ion mode): 448 [M++l].
N-(3-Fluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethoxy)phenyl] - 1 H- pyrazol-3-yl} propanamide (Compound No. 222);
Mass spectrum (m/z, +ve ion mode): 502 [M++l].
N-(3 -Fluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethy l)phenyl] - 1 H- pyrazol-3-yl}propanamide (Compound No. 223);
Mass spectrum (m/z, +ve ion mode): 486 [M++l].
N-(3 -Chlorobenzy l)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethoxy)pheny 1] - 1 H- pyrazol-3-yl}propanamide (Compound No. 224);
Mass spectrum (m/z, +ve ion mode): 520[M++l+2] and 518[M++1]
N-Benzyl-3 - [5-(2-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 225); Mass spectrum (m/z, +ve ion mode): 430 [M++l].
N-(2-Fluorobenzyl)-3 - { 5-(3 -fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H- pyrazol-3-yl}propanamide (Compound No. 226);
Mass spectrum (m/z, +ve ion mode): 486 [M++l].
N-(3,5-Difluorobenzyl)-3-[5-(2,3-difluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 227);
Mass spectrum (m/z, +ve ion mode): 484 [M++l].
N-(3 , 5 -Difluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H- pyrazol-3-yl}propanamide (Compound No. 228);
Mass spectrum (m/z, +ve ion mode): 504[M+ +1]
3- [5-(2,3 -Difluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -JV-(3 - fluorobenzyl)
propanamide (Compound No. 230);
Mass spectrum (m/z, +ve ion mode): 466 [M++l].
N-(2-Fluorobenzyl)-3-{5-(3-fluorophenyl)-l -[4-(trifluoromethoxy)phenyl]-lH- pyrazol-3-yl}propanamide (Compound No. 231);
Mass spectrum (m/z, +ve ion mode): 502 [M++l ].
3- [5-(2,3 -Difluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2,5 - dimethylbenzyl)propanamide (Compound No. 232);
Mass spectrum (m/z, +ve ion mode): 476 [M++l].
N-(3-Chlorobenzyl)-3-[5-(2,3-difluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 233);
Mass spectrum (m/z, +ve ion mode): 484[M++l+2] and 482[M++1]
N-(3,5-Difluorobenzyl)-3- {5-(3 -fluorophenyl)- 1 -[4-(trifluoromethoxy)phenyl]- IH -pyrazol-3-yl}propanamide (Compound No. 234);
Mass spectrum (m/z, +ve ion mode): 520 [M++l].
3 - { 5 -(3 -Fluorophenyl) - 1 - [4-(trifluoromethoxy)phenyl] - 1 H-pyrazol-3 -yl } -N-(3 - methyl benzyl)propanamide (Compound No. 235);
Mass spectrum (m/z, +ve ion mode): 498 [M++l].
N-(3,4-Dichlorobenzyl)-3-[5-(2,3-difluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 236);
Mass spectrum (m/z, +ve ion mode): 520[M++l+2+2], 518[M++l+2] and
516[M++1]
N-Benzyl-3-[5-(2,3-difluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yljpropanamide (Compound No. 237);
Mass spectrum (m/z, +ve ion mode): 448 [M++l].
N-(2,5-Dimethylbenzyl)-3-{5-(3-fluorophenyl)-l-[4-(trifluoromethoxy)phenyl]-lH -pyrazol-3-yl}propanamide (Compound No. 238);
Mass spectrum (m/z, +ve ion mode): 512 [M++l].
N-(3 ,4-Dichlorobenzyl)-3 - { 5-(3 -fluorophenyl)- 1 - [4-(trifluoromethoxy)phenyl] - IH
-pyrazol-3-yl}propanamide (Compound No. 239); Mass spectrum (m/z, +ve ion mode): 556[M++l+2+2], 554[M++l+2] and
552[M++1]
3-[5-(2,3-Difluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3- methylbenzyl)propanamide (Compound No. 240);
Mass spectrum (m/z, +ve ion mode): 462 [M++l].
3 - [5-(2, 3 -Difluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2- fluorobenzyl)propanamide (Compound No. 241);
Mass spectrum (m/z, +ve ion mode): 466 [M++l].
JV-(3 ,4-Dichlorobenzyl)-3- { 5-(3 -fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H- pyrazol-3-yl}propanamide (Compound No. 242);
Mass spectrum (m/z, +ve ion mode): 540[M+ +1+2+2], 538[M+ +1+2] and 536[M+ +1]
N-(3 ,4-Dichlorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methylphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 243);
Mass spectrum (m/z, +ve ion mode): 486[M+ +1+2+2], 484[M+ +1+2] and 482[M+
+1]
N-(3 ,5 -Difluorobenzyl)-3 - [5 -(3 -fluorophenyl)- 1 -(4-methylphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 244);
Mass spectrum (m/z, +ve ion mode): 450[M+ +1]
N-(2,5-Dimethylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-methylphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 245);
Mass spectrum (m/z, +ve ion mode): 442[M+ +1]
N-Benzyl-3 - { 5 -(3-fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl]- 1 H-pyrazol-3-yl } propanamide (Compound No. 246);
Mass spectrum (m/z, +ve ion mode): 468 [M+ +1]
N-(2 , 5 -Dimethylbenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H -pyrazol-3-yl} propanamide (Compound No. 247);
Mass spectrum (m/z, +ve ion mode): 496[M+ +1]
N-(5-Chloro-2-methylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 248);
Mass spectrum (m/z, +ve ion mode): 478 [M+ +1]
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-[(5 -methyl- 1 ,2- oxazol-3-yl)methyl]propanamide (Compound No. 249);
Mass spectrum (m/z, +ve ion mode): 434.46 [M+ +1]
3 - [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(3 -fluorobenzyl) propanamide (Compound No. 250);
Mass spectrum (m/z, +ve ion mode): 443 [M+ +1]
3 -[ 1 -(4-Cyanophenyl)-5 -(3-fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(2,3 -difluorobenzyl) propanamide (Compound No.251);
Mass spectrum (m/z, +ve ion mode): 461 [M+ +1]
3 - [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(3 ,5-difluorobenzyl) propanamide (Compound No. 252); Mass spectrum (m/z, +ve ion mode): 461 [M+ +1]
3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-(2,5- dimethylbenzyl)propanamide (Compound No.253);
Mass spectrum (m/z, +ve ion mode): 453 [M+ +1]
3 - [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(3 -fluoro-5- methylbenzyl)propanamide (Compound No. 254);
Mass spectrum (m/z, +ve ion mode): 457 [M+ +1]
N-(3-Chlorobenzyl)-3-[l-(4-methoxyphenyl)-5-(4-methylphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 255);
Mass spectrum (m/z, +ve ion mode): 461 [M++l+2] and 459[M++1]
N-(3 -fluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -(4-methylphenyl)- 1 H-pyrazol-3 -yl ] propanamide (Compound No. 256);
Mass spectrum (m/z, +ve ion mode): 444 [M+ +1]
3 - [ 1 -(4-Methoxypheny l)-5-(4-methylphenyl)- 1 H-pyrazol-3 -yl] -N-(3 - methylbenzyl)propanamide (Compound No. 257);
Mass spectrum (m/z, +ve ion mode): 440 [M+ +1]
N-Benzyl-3 - [ 1 -(4-methoxyphenyl)-5-(4-methylphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No.258);
Mass spectrum (m/z, +ve ion mode): 426 [M+ +1]
JV-(3 ,4-Dichlorobenzyl)-3 -[ 1 -(4-methoxyphenyl)-5 -(4-methylphenyl)- 1 H-pyrazol- 3-yl]propanamide (Compound No. 259);
Mass spectrum (m/z, +ve ion mode): 498 [M++ 1+2+2], 496[M++l+2] and
494[M++1]
N-(2,5-Dimethylbenzyl)-3-[l-(4-methoxyphenyl)-5-(4-methylphenyl)-lH-pyrazol-
3-yl]propanamide (Compound No. 260);
Mass spectrum (m/z, +ve ion mode): 454 [M+ +1]
N-(3 ,5-Difluorobenzyl)-3 -[ 1 -(4-methoxyphenyl)-5-(4-methylphenyl)- lH-pyrazol-
3-yl]propanamide (Compound No. 261);
Mass spectrum (m/z, +ve ion mode): 462.36 [M+ +1]
N-(2,3 -Difluorobenzyl)-3 -[ 1 -(4-methoxyphenyl)-5-(4-methylphenyl)- lH-pyrazol-
3-yl]propanamide (Compound No. 262);
Mass spectrum (m/z, +ve ion mode): 462 [M+ +1]
N-(2-Fluorobenzyl)-3-[l-(4-methoxyphenyl)-5-(4-methylphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 263);
Mass spectrum (m/z, +ve ion mode): 444 [M+ +1]
N-benzyl-3 - [5-(4-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide(Compound No. 264);
Mass spectrum (m/z, +ve ion mode): 430 [M+ +1]
N-(3-fluorobenzyl)-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl] propanamide(Compound No. 265);
Mass spectrum (m/z, +ve ion mode): 448 [M+ +1] N-(3 -chlorobenzyl)-3 - [5-(4-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 266);
Mass spectrum (m/z, +ve ion mode): 465[M++l+2] and 463[M++1]
3 - [5 -(4-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3-yl] -N-(3-methylbenzyl) propanamide(Compound No. 267);
Mass spectrum (m/z, +ve ion mode): 444 [M+ +1]
iV-(2,3-difluorobenzyl)-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide(Compound No. 268);
Mass spectrum (m/z, +ve ion mode): 466 [M1" +1]
iV-(3,5-difluorobenzyl)-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 269);
Mass spectrum (m/z, +ve ion mode): 466 [M+ +1]
iV-(2,5-dimethylbenzyl)-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide(Compound No. 270);
Mass spectrum (m z, +ve ion mode): 458 [M+ +1]
N-( ,4-dichlorobenzyl)-3 - [5 -(4-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 271);
Mass spectrum (m/z, +ve ion mode): 502[M++l+2+2], 500[M++l+2] and
498[M++1]
iV-(3-fluoro-5-methylbenzyl)-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide(Compound No. 272);
Mass spectrum (m z, +ve ion mode): 462 [M+ +1]
N-(2-fluorobenzyl)-3 - [5-(4-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide(Compound No. 273);
Mass spectrum (m/z, +ve ion mode): 448 [M+ +1]
iV-(3-fluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 - yl]propanamide(Compound No. 274);
Mass spectrum (m/z, +ve ion mode): 430 [M+ +1]
iV-(3,5-difluorobenzyl)-3-[l-(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3- yl]propanamide(Compound No. 275);
Mass spectrum (m/z, +ve ion mode): 448 [M+ +1]
N-(2,3-difluorobenzyl)-3-[l-(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3- yl]propanamide(Compound No. 276);
Mass spectrum (m/z, +ve ion mode): 448 [M+ +1]
iV-(2,5-dimethylbenzyl)-3-[l-(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3- yl]propanamide(Compound No. 277);
Mass spectrum (m/z, +ve ion mode): 440 [M1" +1]
N-(2,3 -dichlorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 - yl]propanamide(Compound No. 278);
Mass spectrum (m/z, +ve ion mode): 484[M++l+2+2], 482[M++l+2] and
480[M++1] N-(3 -fluoro-5 -methylbenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 -yl] propanamide(Compound No. 279);
Mass spectrum (m/z, +ve ion mode): 444 [M+ +1 ]
N-(3-fluoro-5-methylbenzyl)-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 280).
Mass spectrum (m/z, +ve ion mode): 462 [M+ +1]
Example 2 : Preparation of N-(3-Fluorobenzyl -3-[5-(3-Fluorophenyl -l-(4- Hydroxyphenyl)-lH-Pyrazol-3-Yl]Propanamide (Compound No. 179);(Scheme II, Path A)
Step A: Preparation of 3-[5-(3-Fluorophenyl)-l-(4-Hydroxyphenyl)-lJi-r-Pyrazol-3- Yl] Propanoic Acid
To a solution of 3-{ l-[4-(benzyloxy)phenyl]-5-(3-fluorophenyl)-lH-pyrazol-3-yl} propanoic acid (1 g, 2.40 mmoles) in methanol (10 ml) were added palladium on carbon (10% wet, 0.5 g) and ammonium formate (0.74 g, 12.02 mmoles) at room temperature. The reaction mixture was allowed to stir at 60°C for 4 hours. After completion, the reaction mixture was filtered through a prewashed celite pad and washed with ethyl acetate. The solvent was evaporated under vacuum, diluted with water and extracted with ethyl acetate. The resulting organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford the title compound as white solid. Yield: 0.70 g.
Mass spectrum (m/z, +ve ion mode): 327 [M++l].
Step B: Preparation of N-(3-Fluorobenzyl)-3-[5-(3-Fluorophenyl)-l-(4
-Hydroxyphenyl)-l//-Pyrazol-3-Yl]Propanamide
1-Hydroxybenzotriazole (HOBT, 0.16 g, 1.23 mmoles), N-ethyldiisopropyl amine
(Hunig's base, 0.33 ml, 1.84 mmoles) and 3-fluorobenzyl amine (0.057 ml, 0.46 mmoles) were added to a solution of compound obtained from Step a (0.1 g, 0.31 mmoles) in DMF (2 ml) at room temperature. The reaction mixture was allowed to stir at room temperature for about 5 minutes and then (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HC1, 0.23 g, 1.23 mmoles) was added to it. The reaction mixture was again stirred at room temperature for about 12 hours. After completion of the reaction, solvent was evaporated under vacuum, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford an oily residue which was purified through flash column chromatography eluting with ethyl acetate :dichloromethane (3:7) to afford the title compound as white solid. Yield: 0.07 g.
1H NMR (400 MHz, DMSO-i¾: δ 9.77 (s, IH, -OH), 8.48 (t, J- 4.00 Hz, IH, -NH), 7.34- 7.47 (m, IH, Ar-H), 7.28 (q, J= 7.07 Hz, IH, Ar-H), 7.16 (t, J= 8.08 Hz, IH, Ar-H), 6.93 - 7.09 (m, 7H, Ar-H), 6.77 (d, J= 8.59 Hz, 2H, Ar-H), 6.49 (s, IH, -CH), 4.31 (d, J= 5.56 Hz, 2H, -NHBn), 2.90 (t, J= 7.20 Hz, 2H, -CH2) and 2.58 (t, J= 7.33 Hz, 2H, -CH2). Mass spectrum (m/z, +ve ion mode): 434 [M++l].
The compounds mentioned below were prepared by following the same route of synthesis as above: N-(3 -Chlorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-hydroxyphenyl)- lH-pyrazol-3 -yl] propanamide (Compound No. 171);
Mass spectrum (m/z, +ve ion mode): 450 [M++l].
3 - [5-(3 -Fluorophenyl)- 1 -(4-hydroxyphenyl)- 1 H-pyrazol-3-yl] -N-(3-methylbenzyl) propanamide (Compound No. 172);
Mass spectrum (m/z, +ve ion mode): 430 [M++l].
N-(2-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-hydroxyphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 177);
Mass spectrum (m/z, +ve ion mode): 450 [M++l].
N-(2-Fluorobenzyl)-3 -[5-(3 -fluorophenyl)- 1 -(4-hydroxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 178).
Mass spectrum (m/z, +ve ion mode): 434 [M++l].
Example 3 : Preparation of (4- [3 - { 3 - \(3 -Fluorobenzyl) Aminol -3 -Oxopropyl ) -5 -(3 -Fluorophenyl)-lH-Pyrazol-l-Y11Phenoxyl Acetic Acid (Compound No. 157); (Scheme II, Path B)
Step A: Preparation of Methyl{4-[3-{3-[(3-Fluorobenzyl)Amino]-3-Oxopropyl}-5-(3 -Fluoro Phenyl)-lH-Pyrazol-l-Yl]Phenoxy}Acetate
Into a three neck round bottom flask was taken sodium hydride (60% dispersion in oil, 0.006 g, 0.15 mmoles) in dry DMF (2 ml) under an argon atmosphere and cooled to 0°C. To it was added a solution of V-(3-fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4- hydroxyphenyl)-lH-pyrazol-3-yl]propanamide(0.067 g, 0.15 mmoles) in DMF (1 ml) dropwise at 0°C and stirred at the same temperature for 30 minutes. Methyl bromoacetate (0.023 ml, 0.15 mmoles) was then added dropwise into the reaction mixture at the same temperature under an argon atmosphere. After the addition was over, there action mixture was allowed to stir at room temperature for one hour and diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to obtain 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: 0.06 g.
Mass spectrum (m/z, +ve ion mode): 506 [M++l].
Step B: Preparation of {4-[3-{3-[(3-Fluorobenzyl)Amino]-3-Oxopropyl}-5-(3
-Fluorophenyl)-l//-Pyrazol-l-Yl]Phenoxy}Acetic Acid
To a solution of compound obtained from Step a (0.06 g, 0.12 mmoles) in THF: MeOH: water (1 ml; 5:3:2) was added lithium hydroxide (0.01 g, 0.25 mmoles) and stirred at room temperature for 2 hours. The solvent was evaporated under vacuum and IN HCl solution was added until the pH became acidic (pH~3). The reaction mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over anhydrous Na2S04, filtered and evaporated under vacuum to afford the title compound as white solid. Yield: 0.03 g.
1H NMR (400 MHz, DMSO-i¾ δ 8.48 (t, J= 4.00 Hz, 1H, -NH), 7.33-7.45 (m, 1H, Ar- H), 7.22-7.33 (m, 1H, Ar-H), 6.88-7.20 (m, 12H, Ar-H), 6.74 (d, J= 7.83 Hz, 1H, Ar-H), 6.50 (s, 1H,
-CH), 4.70 (s, 2H, -OC¾), 4.30 (d, J= 5.05 Hz, 2H, -NHBn), 2.90 (t, J= 6.82 Hz, 2H, - CH2), and 2.58 (t, J= 7.20 Hz, 2H, -CH2).
Mass spectrum (m/z, +ve ion mode): 492 [M++l].
The compounds mentioned below were prepared by following the same route of synthesis as above:
{4-[3-{3-[(3-Chlorobenzyl)amino]-3-oxopropyl}-5-(3-fluorophenyl)-lH-pyrazol- 1 -yl]phenoxy} acetic acid (Compound No. 151);
Mass spectrum (m/z, +ve ion mode): 508 [M++l].
(4- { 3 -[3 -(Benzylamino)-3 -oxopropyl] -5 -(3 -fluorophenyl)- 1 H-pyrazol- 1 - yl}phenoxy)acetic acid (Compound No. 156);
Mass spectrum (m/z, +ve ion mode): 474 [M++l].
{4-[3-{3-[(2-Chlorobenzyl)amino]-3-oxopropyl}-5-(3-fluorophenyl)-lH-pyrazol- l-yl]phenoxy} acetic acid (Compound No. 158);
Mass spectrum (m/z, +ve ion mode): 508 [M^+l].
{4- [3 - { 3 - [(2-Fluorobenzyl)amino] -3 -oxopropyl } -5 -(3 -fluorophenyl)- 1 H-pyrazol- 1 -yl]phenoxy} acetic acid (Compound No. 159);
Mass spectrum (m/z, +ve ion mode): 492 [M++l ]. {4- [5-(3 -Fluorophenyl)-3 - { 3 - [(3 -methylbenzyl)amino] -3 -oxopropyl } -7H-pyrazol- l-yl]phenoxy} acetic acid (Compound No. 173).
Mass spectrum (m/z, +ve ion mode): 488 []ν +1]. Example 4: Preparation of N-G-FluorobenzylV3-(5-i3-Fluorophenviy 1-Γ4-(2
-Hydroxyethoxy)Phenyl1-lH-Pyrazol-3-Yl|Propanamide (Compound No. 175);(Scheme II, Path O
Step A: Preparation of 3-{l-[4-(2-{[Ji?rt-Butyl(Diniethyl)Silyl]Oxy}Ethoxy)Phenyl]-5 -(3-Fluorophenyl)-lH-Pyrazol-3-Yl}-N-(3-Fluorobenzyl)Propanamide
In a three neck round bottom flask was taken sodium hydride (60% dispersion in oil, 0.007 g, 0.184 mmoles) in dry DMF (1 ml) under an argon atmosphere and cooled to 0°C. To it was added a solution of N-(3-fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4- hydroxyphenyl)-lH-pyrazol-3-yl]propanamide (0.08 g, 0.18 mmoles) in DMF (1 ml) dropwise at 0°C and stirred at the same temperature for 30 minutes. (2-Bromoethoxy)(tert- butyl)dimethylsilane (0.044 ml, 0.18 mmoles) was then added dropwise into the reaction mixture at the same temperature under an argon atmosphere. After the addition was over, reaction mixture was allowed to stir at room temperature for one hour. 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 evaporated under vacuum. The crude product so obtained was purified through column chromatography over silica gel (100 to 200) eluting with ethyl acetate :hexane (1 :5) to afford the title compound as off white solid. Yield: 0.08 g.
Mass spectrum (m/z, +ve ion mode): 592 [M++l].
Step B: Preparation of 7V-(3-Fluorobenzyl)-3-{5-(3-Fluorophenyl)-l-[4-(2
-Hydroxyethoxy) Phenyl] -lH-Pyrazol-3-Yl}Propanamide
To a solution of compound obtained from Step a(0.08 g, 0.13 mmoles) in dry THF (2 ml) was added tetrabutylammonium fluoride (1M soln in THF, 0.3 ml, 0.28 mmoles) and stirred at room temperature for 2 hours. The solvent was evaporated under vacuum, diluted with water and extracted with ethyl acetate. The resulting organic layer was washed with water, dried over anhydrous Na2S04, filtered and evaporated under vacuum to afford a residue which upon column chromatography over silica gel (100-200) in methanol :dichloromethane (1 :49) afforded the title compound as white solid. Yield: 0.02 g- 1H NMR (400 MHz, DMSO-i¾): δ 8.49 (t, J= 4.0 Hz, IH, -NH), 7.41-7.35 (m, IH, Ar-H), 7.30-7.25 (m, IH, Ar-H), 7.19-7.14 (m, 3H, Ar-H), 7.07-6.95 (m, 7H, Ar-H), 6.51 (s, IH, - CH), 4.90 (t, J= 4.0 Hz, IH, OH), 4.31 (d, J= 4.0 Hz, 2H, -OCH2), 4.00 (d, J= 4.0 Hz, 2H, -CH20), 3.72 (d, J= 4.0 Hz, 2H, -NHBn), 2.91 (t, J= 8.0 Hz, 2H, -CH2) and 2.59 (t, J = 8.0 Hz, 2H, -CH2).
Mass spectrum (m/z, +ve ion mode): 478 [M++l].
The compounds mentioned below were prepared by following the same route of synthesis as above:
N-Benzyl-3- { 5-(3-fluorophenyl)- 1 -[4-(2 -hydroxy ethoxy)phenyl]- 1 H-pyrazol-3-yl} propanamide (Compound No. 166);
Mass spectrum (m/z, +ve ion mode): 460 [M++l].
N-(3-Chlorobenzyl)-3-{5-(3-fluorophenyl)-l-[4-(2-hydroxyethoxy)phenyl]-lH- pyrazol-3-yl} propanamide (Compound No. 167);
Mass spectrum (m/z, +ve ion mode): 494 [M++l].
N-(2-Fluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(2-hydroxyethoxy)phenyl] - 1 H- pyrazol-3-yl}propanamide (Compound No. 174);
Mass spectrum (m/z, +ve ion mode): 478 [M++l].
3 - { 5 -(3 -Fluorophenyl)- 1 - [4-(2-hydroxyethoxy)pheny] ] - 1 H-pyrazol-3 -yl} -N-(3 -methylbenzyl)propanamide (Compound No. 176).
Mass spectrum (m/z, +ve ion mode): 474 [M++l].
Example 5: Preparation of 3-r5-(3-Aminophenvn-l-(4-Methoxyphenyl)-lH-Pyrazol-3 -Y11-iV-(3 -Methyl BenzvOPropanamide (Compound No. 141): (Scheme IIP
Step A: Synthesis of 3-[5-(3-Aminophenyl)-l-(4-Methoxyphenyl)-l^-Pyrazol-3- Yl] Propanoic Acid
To a solution of 3-[l-(4-methoxyphenyl)-5-(3-nitrophenyl)-lH-pyrazol-3- yl]propanoic acid (0.1 g, 0. 27 mmoles) in methanol (5 ml) was added palladium on carbon (10%, wet, 0.05 g) and stirred under hydrogen atmosphere at room temperature for 4 hours. After completion, the reaction mixture was filtered through a pre washed celite pad and the solvent was evaporated under vacuum to afford the title compound as light brown solid. Yield: 0.07 g
Mass spectrum (m/z, +ve ion mode): 338 [M++l].
Step B: Synthesis of 3-[5-(3-Aminophenyl)-l-(4-Methoxyphenyl)-lH-Pyrazol-3-Yl] -N-(3-Methylbenzyl)Propanamide 1-Hydroxybenzotriazole (HOBT, 0.16 g, 1.18 mmoles), N-ethyldiisopropyl amine (Hunig's base, 0.20 ml, 1.18 mmoles) and 3-methylbenzyl amine (0.05 ml, 0.44 mmoles) were added to a solution of compound(0.1 g, 0.29 mmoles) obtained from Step a in DMF (2 ml) at room temperature. The reaction mixture was allowed to stir at room temperature for about 5 minutes and then l-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI.HC1, 0.227 g, 1.186 mmoles) was added to it. The reaction mixture was again stirred at room temperature for about 12 hours. After completion, the solvent was evaporated under vacuum, diluted with water and extracted with ethyl acetate. The resulting organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford an oily residue which was purified through flash column chromatography eluting with ethyl acetate :dichloromethane (3:7) to afford the title compound as white solid. Yield: 0.07 g.
1H NMR (400 MHz, DMSO-^): δ 8.35 (t, 1H, J= 8.0 Hz, -NH & D20 exchangeable), 7.13-7.1 1 (m, 3H, Ar-H), 7.02-6.99 (m, 3H, Ar-H), 6.94-6.89 (m, 3H, Ar-H), 6.49-6.44 (m, 2H, Ar-H), 6.26 (s, 1H, -CH), 6.22-6.20 (m, 1H, Ar-H), 5.12 (brs, 2H, -NH2& D20 exchangeable), 4.24 (d, J= 4.0 Hz, 2H, -NHBn), 3.74 (s, 3H, -OCH3), 2.85 ( t, J= 8.0 Hz, 2H, -CH2), 2.53 (t, J= 8.0 Hz, 2H, -CH2) and 2.27 (s, 3H, -CH3).
Mass spectrum (m/z, +ve ion mode): 441 [M++1]. Example 6: Preparation of 3-{5-r3- Aminomethvf)Phenyl1-l-r4-MethoxyphenylVlH
-Pyrazol-3-Yl>-N-r3-FluorobenzvnPropanamide (Compound No. 148 (Scheme IV, Path D)
To a solution of 3-[5-(3-cyanophenyl)-l -(4-methoxyphenyl)-lH-pyrazol-3-yl]-N- (3-fluorobenzyl)propanamide (0.1 g, 0.22 mmoles) in ethanol (3ml) were added potassium borohydride (0.023 g, 0.40 mmoles) and Raney Nickel (0.1 g, w/w) at room temperature. The reaction mixture was allowed to stir at room temperature for 15 minutes and then at 40°C for 2 hours. After completion, the reaction mixture was filtered through a prewashed celite pad in ethanol, washed with ethanol and concentrated to afford the title compound as brown oil.Yield: 0.04 g
1H NMR (400 MHz, DMSO-<¾: δ 8.39 (t, 1H, J= 8.0 Hz, -NH), 7.29-7.21 (m, 3H, Ar-H), 7.15-7.1 1 (m, 3H, Ar-H), 7.04-7.02 (m, 3H, Ar-H), 6.94-6.89 (m, 3H, Ar-H), 6.42 (s, 1H, - CH), 4.25 (d, J= 4.0 Hz, -NHBn), 3.76 (s, 3H, -OCH3), 3.66 (s, 2H, -CH2Ph), 2.90 (t, J= 8.0 Hz, 2H, -CH2), 2.57 (t, J= 8.0 Hz, 2H, -CH2) and 1.99 (s, 3H, Ar-CH3).
Mass spectrum (m/z, +ve ion mode): 455 [M++l].
The compound mentioned below was prepared by following the same route of synthesis as above.
3-{5-[3-(Aminomethyl)phenyl]-l-(4-methoxyphenyl)-lH-pyrazol-3-yl}-N-(3 -fluorobenzyl)propanamide (Compound No. 147).
Mass spectrum (m/z, +ve ion mode): 459 [M++l]. Example 7: Preparation of 3-{ l-(4-MethoxyphenylV5-r3-(lH-Tetrazol-5-YnPhenyll-lH- Pyrazol-3-Yl)-N-r3-MethylbenzvnPropanamide iCompound No. 18 (Scheme IV, Path
E)
To a solution of 3-{5-[3-(aminomethyl)phenyl]-l-(4-methoxyphenyl)-lH-pyrazol- 3-yl}-N-(3-fluorobenzyl)propanamide (0.1 g, 0.22 mmoles) in dry toluene (5 ml) were added sodium azide (0.042 g, 0.66 mmoles) and triethylamine hydrochloride (0.09 g, 0.66 mmoles) at room temperature. The reaction mixture was refluxed at 70°C for 12 hours. After the completion of reaction, solvent was evaporated under vacuum, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford the title compound as white solid. Yield: 0.02 g.
1H NMR (400 MHz, DMSO-<¾: δ 8.38 (t, J= 4.00 Hz, 1H, -NH), 8.00-7.96 (m, 2H, -NH & Ar-H), 7.53 (t, J- 8.0 Hz, 1H, Ar-H), 7.25-7.23 (m, 2H, Ar-H), 7.18 (d, J= 8.0 Hz, 2H, Ar-H), 7.1 1 -6.92 (m, 4H, Ar-H), 6.74 (d, J= 8.0 Hz, 2H, Ar-H), 6.53 (s, 1H, -CH), 4.24 (d, J= 4.0 Hz, -NHBn), 3.74 (s, 3H, -OCH3), 2.92 (t, J= 8.0 Hz, 2H, -CH2), 2.56 (t, J= 8.0 Hz, 2H, -CH2) and 2.20 (s, 3H, -CH3).
Mass spectrum (m/z, +ve ion mode): 494 [M++l].
The compound mentioned below was prepared by following the same route of synthesis as above.
N-(3-Fluorobenzyl)-3-{ l -(4-methoxyphenyl)-5-[3-(lH-tetrazol-5-yl)phenyl]-lH- pyrazol-3-yl}propanamide (Compound No. 180).
Mass spectrum (m/z, +ve ion mode): 498 [M++l]. Example 8: Preparation of 3-r5-{3-r('Acetylamino')Methyl1Phenyl}-l-f4-Methoxyphenvn- lH-Pyrazol-3-Yll-N-(3-MethylbenzvnPropanamide (Compound No. 154 (Scheme IV. Path F)
To a solution of 3-{5-[3-(aminomethyl)phenyl]-l-(4-methoxyphenyl)-lH-pyrazol- 3-yl}-N-(3-fluorobenzyl)propanamide (0.1 g, 0.22 mmoles) in dry pyridine (2 ml) was added acetic anhydride (0.067 g, 0.66 mmoles) and stirred at room temperature for 2 hours. After the completion of reaction, solvent was evaporated under vacuum, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford an oily residue which was then triturated with hexane to afford the title compound as white solid. Yield: 0.06 g.
1H NMR (400 MHz, DMSO-c/6): δ 8.37 (t, J= 4.0 Hz, 1H, -NH), 8.26 (br m, 1H, -NH), 7.25-7.23 (m, 1H, Ar-H), 7.18-7.16 (m, 1H, Ar-H), 7.11-7.09 (m, 4H, Ar-H), 7.02-6.98 (m, 4H, Ar-H), 6.92-6.90 (m, 2H, Ar-H), 6.39 (s, IH, -CH), 4.24 (d, J= 4.0 Hz, -NHBn), 4.18 (d, J= 4.0 Hz, -NHBn), 3.75 (s, 3H, -OCH3), 2.87 (t, J= 8.0 Hz, 2H, -CH2), 2.54 (t, J = 8.0 Hz, 2H, -CH2), 2.21 (s, 2H, -COCH3) and 1.79 (s, 3H, Ar-CH3).
Mass spectrum (m/z, +ve ion mode): 497 [M++l].
The compound mentioned below was prepared by following the same route of synthesis as above.
3-[5-{3-[(Acetylamino)methyl]phenyl}-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N- (3-fluorobenzyl)propanamide (Compound No. 153).
Mass spectrum (m/z, +ve ion mode): 501 [M++l].
Example 9: Preparation of 4-[3-{3-[(3-Fluorobenzyl)Amino1-3-Oxopropyl>-5-(3
-FluorophenylVlH-Pyrazol-l-YllBenzoic Acid (Compound No. 124 : (Scheme V. Path G To a solution of ethyl 4-[3-{3-[(3-fluorobenzyl)(methyl)amino]-3-oxopropyl}-5- (3 -fluorophenyl)- lH-pyrazol-l-yl]benzoate (0.07 g, 0.14 mmoles) in THF: MeOH: water (0.6 ml; 5:3:2) was added lithium hydroxide (0.011 g, 0.27 mmoles) and stirred at room temperature for 2 hours. After the completion of reaction, solvent was evaporated under vacuum, IN HCl solution was added till the pH became acidic (pH~2) and then extracted with ethyl acetate. The resulting organic layer was washed with water, dried over anhydrous Na2S04, filtered and evaporated under vacuum to afford the title compound as white solid. Yield: 0.03 g. 1H NMR (400 MHz, DMSO-c¼): δ 8.47 (t, J= 4.0 Hz, 1H, -NH), 7.92 (d, J= 8.0 Hz, 2H, Ar-H), 7.43-7.37 (m, IH, Ar-H), 7.32 (d, J= 8.0 Hz, 2H, Ar-H), 7.28-7.20 (m, 2H, Ar-H), 7.07-6.98 (m, 5H, Ar-H), 6.55 (s, IH, -CH), 4.29 (d, J= 4.0 Hz, -NHBn), 2.92 (t, J= 8.0 Hz, 2H, -CH2) and 2.59 (t, J= 8.0 Hz, 2H, -CH2).
Mass spectrum (m/z, +ve ion mode): 462 [M++l].
The compounds mentioned below were prepared by following the same route of synthesis as above:
4-[3-{3-[(3-Chlorobenzyl)amino]-3-oxopropyl}-5-(3-fluorophenyl)-lH-pyrazol-l- yl]benzoic acid (Compound No. 122);
Mass spectrum (m/z, +ve ion mode): 478 [M++l].
4- [5 -(3 -Fluorophenyl)-3 - { 3 - [(3 -methylbenzyl)amino] -3 -oxopropyl } - 1 H-pyrazol- 1 - yl] benzoic acid (Compound No. 123);
Mass spectrum (m/z, +ve ion mode): 456 [M++l].
4- { 3 - [3 -(Benzylamino)-3 -oxopropyl] -5 -(3-fluorophenyl)- 1 H-pyrazol- 1 -yl } benzoic acid (Compound No. 130);
Mass spectrum (m/z, +ve ion mode): 444 [M++l].
4- [5 -(3 -Fluorophenyl)-3 -(3-0X0-3 - { [2-(2-oxoimidazolidin- 1 - yl)ethyl]amino}propyl)-lH-pyrazol-l-yl]benzoic acid (Compound No. 131);
Mass spectrum (m/z, +ve ion mode): 466 [M++l].
4-[5-(3-Fluorophenyl)-3-(3-oxo-3-{[3-(2-oxopyrrolidin-l- yl)propyl]amino}propyl)-lH-pyrazol-l-yl]benzoic acid (Compound No. 132); Mass spectrum (m/z, +ve ion mode): 479 [M++l].
4- { 3 - [3 -( { [(2R)- 1 -Ethylpyrrolidin-2-yl] methyl } amino)-3 -oxopropyl] -5 -(3 - fluorophenyl)-lH-pyrazol-l-yl}benzoic acid (Compound No. 133);
Mass spectrum (m z, +ve ion mode): 465 [M++l].
4- [3 -(3 - { [(6-Chloropyridin-3 -yl)methyl] amino } -3 -oxopropyl)-5-(3 -fluorophenyl)- 1 H-pyrazol- l-yl]benzoic acid (Compound No. 134);
Mass spectrum (m/z, +ve ion mode): 479 [M++l ].
4- [5-(3 -Fluorophenyl)-3 -(3- { [3 -(morpholin-4-yl)propyl]amino } -3 -oxopropyl)- 1 H- pyrazol-l-yl]benzoic acid (Compound No. 135);
Mass spectrum (m/z, +ve ion mode): 481 [M++l].
4- [5-(3 -Fluorophenyl)-3 -(3 - { [(6-methylpyridin-2-yl)methyl]amino } -3 -oxopropyl)- 1 H-pyrazol- 1-yl] benzoic acid (Compound No. 136).
Mass spectrum (m/z, +ve ion mode): 459 [M++l ].
Example 10: Preparation of 4- 5-(3-Fluorophenyl)-3-{3-r 3-Methylbenzyl)Amino]-3 -Oxopropyl)-lH-Pyrazol-l-Yl]Benzamide (Compound No. 186^; (Scheme V. Path H) 1-Hydroxybenzotriazole (HOBT, 0.24 g, 1.79 mmoles), N-ethyldiisopropyl amine (Hunig's base, 0.31 ml, 1.18 mmoles) and ammonium carbonate (0.052 g, 0.54 mmoles) were added to a solution of 4-[5-(3-fluorophenyl)-3-{3-[(3-methylbenzyl)amino]-3- oxopropyl}-lH-pyrazol-l-yl]benzoic acid (0.2 g, 0.45 mmoles) in DMF (2 ml) at room temperature. The reaction mixture was stirred at room temperature for about 5 minutes and then l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HC1, 0.34 g, 1.18 mmoles) was added into it. The reaction mixture was again stirred at room
temperature for about 12 hours. After completion of the reaction, solvent was evaporated under vacuum, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford an oily residue which was purified through flash column chromatography eluting with ethyl acetate: methanol (19: 1) to afford the title compound as white solid. Yield: 0.180 g.
1H NMR (400 MHz, DMSO-c/6): δ 8.41 (t, J= 4.0 Hz, IH, -NH), 8.04-8.05 (brm, 1H, - NH), 7.89-7.87 (m, 2H, Ar-H), 7.45-7.41 (m, 2H, Ar-H), 7.31-7.22 (m, 3H, Ar-H), 7.1 1- 7.01 (m, 6H, -NH & Ar-H), 6.56 (s, 1H, -CH), 4.26 (d, J= 4.0 Hz, -NHBn), 2.93 (t, J= 8.0 Hz, 2H, -CH2), 2.58 (t, J= 8.0 Hz, 2H, -CH2) and 2.28 (s, 3H, -CH3).
Mass spectrum (m/z, +ve ion mode): 457 [M++l]. Example 1 1 : Preparation of 3-{5-(3-Fluorophenyl -l- 4-(Hvdroxymethvf)Phenyl1-lH-
Pyrazol-3-Yl>-N-(3-MethylbenzvnPropanamide iCompound No. 183^): (Scheme V. Path Γ)
To an ice-colded solution of ethyl 4-[5-(3-fluorophenyl)-3-{3-[(3- methylbenzyl)amino]-3-oxopropyl}-lH-pyrazol-l-yl]benzoate (0.2 g, 0.41 mmoles) in dry distilled THF was added lithium aluminium hydride (2 M solution in THF, 0.41 ml, 1.03 mmoles) dropwise with constant stirring. The reaction mixture was allowed to stir at 0°C for 30 minutes. After the completion of reaction, a saturated solution of Na2S04was added dropwise with constant stirring at 0°C until a white gelatinous precipitate was obtained. The reaction mixture was filtered through a prewashed celite pad and washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford an oily residue which was purified through flash column chromatography eluting with ethyl acetate:hexane (4: 1) to afford the title compound as white solid. Yield: 0.14 g 1H NMR (400 MHz, OMSO-d6): δ 8.39 (t, J= 5.81 Hz, 1H, -NH & D20 exchangeable), 7.29 - 7.46 (m, 3H, Ar-H), 7.06 - 7.24 (m, 4H, Ar-H), 6.93 - 7.06 (m, 5H, Ar-H), 6.51 (s, 3H, -CH), 5.28 (t, J= 5.56 Hz, 1H, -OH & D20 exchangeable), 4.51 (d, J= 4.80 Hz, 2H, - NHBn), 4.16 - 4.34 (m, 2H, -CH2OH), 2.90 (t, J= 7.45 Hz, 2H, -CH2), 2.56 (t, J= 7.58 Hz, 2H, -CH2) and 2.22 (s, 3H, Ar-CH3).
Mass spectrum (m/z, +ve ion mode): 444 [M++l].
The compound mentioned below was prepared by following the same route of synthesis as above:
N-(3-Chlorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(hydroxymethyl)phenyl] - 1 H-pyrazol- 3 -yl}propanamide (Compound No. 187).
Mass spectrum (m/z, +ve ion mode): 464 [M++l].
Example 12: Preparation of N-(3-Chlorobenzyl)-3-(5-(3-Fluorophenyl -l-r4- (2Methylpropoxy Phenyll-lH-Pyrazol-3-Yl>Propanamide (Compound No 229) (Scheme VI)
To a solution of N-(3-chlorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-hydroxyphenyl)- lH-pyrazol-3-yl]propanamide (0.04 g, 0.09 mmoles) in toluene (3 ml) in a 5 ml vial was added triphenylphosphine(0.04 g, 0.18 mmoles), wobutyl alcohol (0.009 ml, 0.13 mmoles) and l,r-(azodicarbonyl)dipiperidine (ADDP), (0.02 ml, 0.18 mmoles). The reaction mixture was kept in microwave synthesizer at 130°C for 45 minutes. After the completion of reaction, solvent was evaporated under vacuum and the residue so obtained was purified by flash chromatography eluting with ethyl acetate: dichloromethane (3:7) to afford the title compound as white solid. Yield: 0.0 lg
1H NMR (400 MHz, DMSO-c/6): δ 8.48 (t, J= 5.90 Hz, 1H, -NH), 7.38 (td, J- 6.40, 8.09 Hz, 1H, Ar-H), 7.23-7.31 (m, 3H, Ar-H), 7.10-7.22 (m, 4H, Ar-H), 6.88-7.03 (m, 4H, Ar- H), 6.49 (s, 1H, -CH), 4.29 (d, J= 5.77 Hz, 2H, -OCH2), 3.76 (d, J= 6.27 Hz, 2H, - NHBn), 2.90 (t, J= 7.53 Hz, 2H, -CH2), 2.54 (t, J= 7.54 Hz, 2H, -CH2), 2.01-1.98 (m, 1H, -CH(CH3)2) and 0.98 (d, J= 6.53 Hz, 6H).
Mass spectrum (m/z, +ve ion mode): 508 [M++l+2] and 506 [M+ +1].
Pharmacological Activity
5 LO Enzyme assay
The NCEs/standard compounds were diluted in DMSO (20 μΐ) of TEC buffer (50 mM Tris; pH 7.5, 2 mM EDTA, 2 mM CaCl2) 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 (H2DCFDA) (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 nm excitation/520 nm emission. The % inhibition and IC50 were calculated.
The IC50 values of compounds (Compound No. 20, 22, 41,69, 165,168) ranged from 10 nM to 500nM. Some compounds showed IC50 in the range of 0.5μΜ to 5μΜ. 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 χ 106 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 Mg2+& Ca2+ (5 μΐ of 1M MgCl2 + 5 μΐ of 1M CaCl2 + 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 LTB4 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 ¾DCFDA 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 enzyme were appropriately diluted in reaction buffer and added in the plate. The reaction mixture was incubated for 30 minutes. Subsequently, ΙΟμΜ of ¾DCFDA 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 χ 105 g for 60 minutes at 4°C to prepare the membranes. Protein was estimated using Bradford estimation and stored at -80°C until use. Radio ligand binding assay was performed using [3H] 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 fluorescence was monitored at Exc 535 nm and Em 590 nm, respectively. All assays were run in duplicate. % inhibition was calculated using control wells.
Ex vivo effect of Compound No. 20 and Compound No. 22 in A23187 induced LTB4 release from blood using Wistar rats
Wistar rats weighing 180-200 g were obtained. Animals were maintained on standard laboratory chow (Harlan Teklad, Oxon, UK) and water ad libitum with a 12 hour day/night schedule. All animal experiments were conducted according to the Guidelines of Experimental Animal Care issued by the Committee for Purpose of Control and
Supervision of Experiments on Animals (CPCSEA).
Overnight fasted animals were randomized to different treatment groups to obtain uniform average body weight among different treatment groups. On the day of study, animals were either treated with vehicle or test compound or Standard compound
(atreleuton/zileuton-1/5 hour, blood was collected from the retro-orbital sinus under light anesthesia in heparinised tubes. Blood samples (200μ1) were challenged with A23187 (l(^g/mi) in a 96 well plate and incubated at 37°C for 30 minutes. In another well, blood was challenged with saline (vehicle for A23187) and served as negative controls. After 30 minutes of incubation 80μΙ, of cold methanol was added to each well, centrifuged at 8,000 rpm for 10 minutes at 4°C to separate plasma. Plasma leukotriene B4 concentrations were determined using commercially available ELISA kit. A23187 induced LTB4 released was corrected for basal release by subtracting the LTB4 obtained in corresponding
unchallenged wells. Results were expressed as mean ± SEM for each treatment group. Effect of treatment/standard drug was compared with vehicle control using ANOVA followed by Dunnett's multiple comparison test, p <0.05 was considered statistically significant.

Claims

Claims:
1. A compound of Formula 1
Figure imgf000096_0001
Formula 1
including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof,
wherein
Ring A is selected from phenyl, pyridine, pyrazine, triazine, tetrazole, thiazole, imidazole and oxazole each of which is optionally substituted by one or more substituents independently selected from R1;
Ring B is selected from phenyl, C3.10 cycloalkyl and a 6-10 membered heteroaryl each of which is optionally substituted by one or more substituents independently selected from R2;
Rlis selected from the group consisting of hydrogen, hydroxy, d-C5alkyl, d- C5alkoxy, CN, halogen, CF3, nitro, -C=0, d-dalkylamino, d-C3alkyl-OH, CORf, heteroaryl, NRfRq, COORf, CONRfRq and -ORd wherein Rd is d-C5aikyl, d-C3alkyl-COORf or d-C3alkyl-OH;
R2 is selected from the group consisting of hydrogen, hydroxy, d-C5alkyl, d- dalkoxy, CN, halogen, CF3, heteroaryl, Ci-dalkylamino, NRfRq, d-dalkyl- NHCO-d-C5alkyl and COORf;
Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and Rf and Rq may together form a ring system together with the heteroatom to which they are attached;
R3 is hydrogen or R3 and R4 together with the nitrogen atom to which they are attached forms a C5-1oring system wherein 1-3 carbon atom in the ring are replaced by heteroatom selected from N, O or S and the ring system can optionally be substituted by one or more substituents independently selected from R5; R4 is selected from the group consisting of -(CH2)m-(0)s-phenyl, -(CH2)m-(0)s- heterocyclyl or -(CH2)m-(0)s-heteroaryl, wherein each of phenyl, heterocyclyl and heteroaryl is optionally substituted by one or more substituents selected from R5; R5 is selected from the group consisting of hydrogen, halogen, d-Csalkyl, nitro, CF3, -C=0, COORf, hydroxyalkyl, piperazine, d-C3alkyl-COORf, d-C3alkyl-CO NRfRq, d-C alkyl-piperazine and phenyl;
n is an integer 1-2;
m is an integer 0-3;
s is an integer 0-1 ; and
x is an integer 1-3.
2. A compound according to claim 1 , having the structure of Formula la:
Figure imgf000097_0001
Formula la
including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof
wherein
R4 can be phenyl, heterocyclyl, heteroaryl optionally substituted with one or more substituents selected from R5;
Ring A, Ring B, R1 , R2 , R5 and x are same as defined in claim 1.
3. A compound according to claim 1 , having the structure of Formula lb:
Figure imgf000097_0002
Formula lb
including pharmaceutically acceptable salts, pharmaceutically acceptable solvates, and stereoisomers, thereof wherein
R4 can be phenyl, heterocyclyl, heteroaryl optionally substituted with one or more substituents selected from R5;
Ring A, Ring B, R1 R2, R5and x are same as defined in claim 1.
4. A compound according to claim 1, having the structure of Formula Ic:
Figure imgf000098_0001
Formula lc
including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof
wherein
R4' can be phenyl, heterocyclyl, heteroaryl optionally substituted with one or more substituents selected from R5;
Ring A, Ring B, R1 R2, R5 and x are same as defined in claim 1.
5. A compound according to claim 1, having the structure of Formula Ic:
Figure imgf000098_0002
Formula Id
including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof
wherein s is selected from pyrrolidine, piperidine and morpholine;
Ring A, Ring B, R1 R2, R5 and x are same as defined in claim 1.
6. A compound, which is:
3-[5-Cyclopropyl-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-iV-(4- fluorobenzyl)propanamide (Compound No. 1); 3 - [5 -Cyclopropyl- 1 -(4-methoxypheny 1)- 1 H-pyrazol-3 -yl] -N-(2,3 -dichlorobenzyl) propanamide (Compound No. 2 );
3-[5-Cyclopropyl- 1 -(4-methoxyphenyl)- lH-pyrazol-3-yl]-N-(2,4-dichlorobenzyl) propanamide (Compound No. 3);
iV-(2-Chlorobenzyl)-3 - [5-cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 4);
3-[5-Cyclopropyl-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(2- fluorobenzyl)propanamide (Compound No. 5);
3 - [5-Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(2-phenoxyethyl) propanamide (Compound No. 6);
3-[5-Cyclopropyl- 1 -(4-methoxyphenyl)- lH-pyrazol-3-yl]-N-[2- (trifluoromethyl)benzyl]propanamide (Compound No. 7);
3-[5-Cyclopropyl-l -(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3,4-dichlorobenzyl) propanamide (Compound No. 8);
JV-(3 -Chlorobenzyl)-3 - [5-cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl] propanamide (Compound No. 9);
3 -[5 -Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N-(3-methylbenzyl) propanamide (Compound No . 10);
N-Benzyl-3-[5-cyclopropyl-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]propanamide (Compound No. 11);
3-[5-Cyclopropyl- 1 -(4-methoxyphenyl)- lH-pyrazol-3-yl]-N-(thiophen-2-yl methyl)propanamide (Compound No. 12);
N-(3-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 13);
N-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-7H-pyrazol-3 -yl] propanamide (Compound No. 14);
3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(thiophen-2- ylmethyl)propanamide (Compound No. 15);
3-[5-(3-Fluorophenyl)- 1 -(4-methoxyphenyl)- lH-pyrazol-3-yl]-N-[2-(thiophen-2- y l)ethy 1] propanamide (Compound No . 16);
3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(2-phenoxyethyl) propanamide (Compound No. 17);
N-Benzyl-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 18);
iV-(2-Chlorobenzyl)-3 - [5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 19);
N-(3-Chlorobenzyl)-3-[5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 20); 3-[5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N-(2-methylbenzyl) propanamide (Compound No. 21);
3-[5-(3-FIuorophenyI)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3-methyIbenzyl) propanamide (Compound No. 22);
3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[2-(4- methylpiperazin- 1 -yl)ethyl]propanamide (Compound No. 23);
3-[5-(3-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N-[2-(2- oxoimidazolidin-l-yl) ethyljpropanamide (Compound No. 24);
N-Benzyl-3-[5-(3-fluorophenyl)-l-phenyl-lH-pyrazol-3-yl]propanamide
(Compound No. 25);
N-(2-Chlorobenzyl)-3-[5-(3-fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl]propanamide (Compound No. 26);
N-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-phenyl-lH-pyrazol-3-yl]propanamide (Compound No. 27);
3 - [5 -(3 -Fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl ] -N- [2-(trifluoromethyl)benzyl] propanamide (Compound No. 28);
N-(3 -Fluorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl]propanamide (Compound No. 29);
3-[5-(3-Fluorophenyl)-l-phenyl-lH-pyrazol-3-yl]-N-(3- methylbenzyl)propanamide (Compound No. 30);
3-[5-(3-Fluorophenyl)-l-phenyl-lH-pyrazol-3-yl]-N-[2-(4-methylpiperazin-l- yl)ethyl]propanamide (Compound No. 31);
-[5-(3 -Fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3-yl] - 1 -(pyrrolidin- 1 -yl)propan- 1 -one (Compound No. 32);
3 -[5-(3 -Fluorophenyl)- 1 -phenyl- 1 H-pyrazol-3 -yl]- 1 -(piperidin- 1 -yl)propan- 1-one (Compound No. 33);
3-[5-(3-Fluorophenyl)-l-phenyl-lH-pyrazol-3-yl]-l-(morpholin-4-yl)propan-l-one (Compound No. 34);
jV-(3-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l-phenyl-lH-pyrazol-3-yl]propanamide (Compound No. 35);
3- [5 -Cyclopropyl- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]- V-(3 - fluorobenzyl)propanamide (Compound No. 36);
3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-l-(morpholin-4- yl)propan- 1-one (Compound No. 37);
3-[5-(3-Fluorophenyl)-l -(4-methoxyphenyl)- 1 H-pyrazol-3-yl]- 1 -(piperidin- 1 - yl)propan- 1 -one (Compound No. 38);
3-[5-(3-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl.]- V-(4-methylbenzyl) propanamide (Compound No. 39); 80 N-(4-Chlorobenzyl)-3- [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]
81 propanamide (Compound No. 40);
82 N-(3 ,4-Dichlorobenzyl)-3 - [5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -
83 yl]propanamide (Compound No. 41);
84 N-Benzyl-3 - [ 1 -(4-methoxyphenyl)-5-phenyl- 1 H-pyrazol-3 -yl]propanamide
85 (Compound No. 42);
86 N-(2-Fluorobenzyl)-3-[l-(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3-
87 yl] propanamide (Compound No. 43);
88 N-(2-Chlorobenzyl)-3-[l-(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3-
89 yl]propanamide (Compound No. 44);
90 3-[l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-(2-
91 methylbenzyl)propanamide (Compound No. 45);
92 3-[l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-(2-
93 phenoxyethyl)propanamide (Compound No. 46);
94 3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(2-phenylethyl)
95 propanamide (Compound No. 47);
96 3 - [5-(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(tetrahydrofuran-
97 2-ylmethyl)propanamide (Compound No. 48);
98 N-(2,3-Dihydro- 1 -benzofuran-5-ylmethyl)-3-[5-(3-fluorophenyl)- 1 -(4-
99 methoxyphenyl)-lH-pyrazol-3-yl]propanamide (Compound No. 49);
100 N-(2,3-Dichlorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-
101 yl]propanamide (Compound No. 50);
102 N-(4-Chlorobenzyl)-3-[l-(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3-
103 yl]propanamide (Compound No. 51 );
104 N-(4-Fluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 -
105 yl]propanamide (Compound No. 52);
106 3-[l -(4-Methoxyphenyl)-5-phenyl- lH-pyrazol-3-yl]-N-(4-
107 methylbenzyl)propanamide (Compound No. 53);
108 3-[l -(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-(thiophen-3-
109 ylmethyl)propanamide (Compound No . 54);
1 10 3-[l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-[2-(thiophen-2-yl)ethyl]
1 1 1 propanamide (Compound No. 55);
1 12 3 - [ 1 -(4-Methoxyphenyl)- 5 -phenyl- 1 H-pyrazol-3 -yl] -N- [2-(2-oxoimidazolidin- 1 -
1 13 yl)ethyl]propanarnide (Compound No. 56);
114 N-Benzyl-3-[l -(4-cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]propanamide
115 (Compound No. 57);
1 16 3-[l -(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-(2-fluorobenzyl)
1 17 propanamide (Compound No. 58); N-(2-Chlorobenzyl)-3-[l-(4-cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 59);
3- [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -vV-(2-methylbenzyl) propanamide (Compound No. 60);
3 - [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(2-phenoxy ethyl) propanamide (Compound No. 61);
N-(4-Chlorobenzyl)-3-[l-(4-cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl] propanamide (Compound No . 62) ;
3- [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(4-fluorobenzyl) propanamide (Compound No. 63);
3 - [ 1 -(4-Cyanophenyl)- 5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(4-methylbenzyl) propanamide (Compound No.64);
3 -[ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- lH-pyrazol-3 -yl] -N-(thiophen-2- ylmethyl)propanamide (Compound No. 65);
3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-[2-(thiophen-2- yl)ethyl]propanamide (Compound No. 66);
3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-[2-(2- oxoimidazolidin-l-yl)ethyl] propanamide (Compound No. 67);
3-[ 1 -(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-(3-methylbenzyl) propanamide (Compound No. 68);
N-(3-Chlorobenzyl)-3-[l-(4-cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl] propanamide (Compound No . 69) ;
N-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxy-2-methylphenyl)-lH- pyrazol-3 -yl] propanamide (Compound No . 70) ;
3-[5-(3-Fluorophenyl)-l-(pyridin-2-yl)-lH-pyrazol-3-yl]-N-(3- methylbenzyl)propanamide (Compound No. 71);
3-[ 1 -(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-(3- methylbenzyl)propanamide (Compound No. 72);
N-(3 -Chlorobenzyl)-3- [ 1 -(4-methoxyphenyl)-5-phenyl- 1 H-pyrazol-3- yl] propanamide (Compound No. 73);
N-(3-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l-(pyridin-2-yl)-lH-pyrazol-3- yl] propanamide (Compound No. 74);
3-[5-(3-Fluorophenyl)-l-(pyridin-2-yl)-lH-pyrazol-3-yl]-N-(pyridin-2-ylmethyl) propanamide (Compound No. 75);
3 - [5 -(3 -Fluorophenyl)- 1 -(pyridin-2-yl)- 1 H-pyrazol-3 -yl] -N- [3 -(morpholin-4- yl)propyl]propanamide (Compound No. 76);
3-[5-(3-Fluorophenyl)-l-(pyridin-2-yl)-lH-pyrazol-3-yl]-N-[2-(morpholin-4- yl)ethyl]propanamide (Compound No. 77); 156 3- [5-(3 -Fluorophenyl)- 1 -(pyridin-2-yl)- 1 H-pyrazol-3 -yl] -N-(pyridin-3 -ylmethyl)
157 propanamide (Compound No. 78);
158 3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-iV-(pyridin-2-
159 ylmethyl)propanamide (Compound No. 79);
160 3- [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N- [3-(morpholin-4-
161 yl)propyl]propanamide (Compound No. 80);
162 3- [ 1 -(4-Cyanophenyl)-5-(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N- [2-(morpholin-4-
163 yl)ethyl]propanamide (Compound No. 81 );
164 3-[ 1 -(4-Cyanophenyl)-5-(3-fluorophenyl)- lH-pyrazol-3-yl]-N-(pyridin-3-
165 ylmethyl)propanamide (Compound No. 82);
166 3-[l -(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-iV-(pyridin-2-
167 ylmethyl)propanamide (Compound No. 83);
168 3 -[ 1 -(4-Methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3-y 1] -N- [3 -(morpholin-4-yl)propyl]
169 propanamide (Compound No. 84);
170 3-[l-(4-Methoxyphenyl)-5-phenyl-lH-pyrazol-3-yl]-N-[2-(morpholin-4-yl)ethyl]
171 propanamide (Compound No. 85);
172 3-[l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-[2-(4-
173 methylpiperazin- 1 -yl)ethyl]propanamide (Compound No. 86);
174 N-{ [(2R)- 1 -Ethylpyrrolidin-2-yl]methyl} -3-[ 1 -(4-fluorophenyl)-5-(3-
175 methoxyphenyl)- lH-pyrazol-3-yl]propanamide (Compound No. 87);
176 3-[ 1 -(4-Fluorophenyl)-5-(3-methoxyphenyl)- lH-pyrazol-3-yl]-N-[2-(2-
177 oxoimidazolidin-l-yl)ethyl]propanamide (Compound No. 88);
178 3-[l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-[3-(2-
179 oxopyrrolidin- 1 -yl)propyl]propanamide (Compound No. 89);
180 3-[l -(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-(pyridin-2-
181 ylmethyl)propanamide (Compound No. 90);
182 3-[l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-7V-(pyridin-4-
183 ylmethyl)
184 propanamide (Compound No. 91 );
185 3-[l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3-methylbenzyl)
186 propanamide (Compound No. 92);
187 N-(3-Chlorobenzyl)-3-[l-(4-fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]
188 propanamide (Compound No. 93);
189 N-(3 -Fluorobenzyl)-3 - [ 1 -(4-fluorophenyl)-5 -(3 -methoxyphenyl)- 1 H-pyrazol-3-yl]
190 propanamide (Compound No. 94);
191 3-[l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-iV-[2-(morpholin-4-
192 yl)ethyl] propanamide (Compound No. 95);
193 3-[l-(4-Fluorophenyl)-5-(3-methoxyphenyl)-lH-pyrazol-3-yl]-N-[3-(morpholin-4-
194 yl)propyl] propanamide (Compound No. 96); 195 N-(3-Chlorobenzyl)-3-[l-(4-methoxyphenyl)-5-(pyridin-3-yl)-lH-pyrazol-3-yl]
196 propanamide (Compound No. 97);
197 3- [ 1 -(4-Methoxyphenyl)-5 -(pyridin-3 -yl)- 1 H-pyrazol-3 -yl] -N-(3-methylbenzyl)
198 propanamide (Compound No. 98);
199 N-(3 -Fluorobenzyl)-3 - [ 1 -(4-methoxypheny l)-5 -(pyridin-3 -yl)- 1 H-pyrazol-3 -yl]
200 propanamide (Compound No. 99);
201 N-Benzyl-3-[l-(4-methoxyphenyl)-5-(pyridin-3-yl)-lH-pyrazol-3-yl]propanamide
202 (Compound No. 100);
203 3-[ 1 -(4-Methoxyphenyl)-5-(pyridin-3-yl)- 1 H-pyrazol-3 -yl]-N-(pyridin-2-ylmethyl)
204 propanamide (Compound No. 101);
205 3-[l-(4-Methoxyphenyl)-5-(pyridin-3-yl)-lH-pyrazol-3-yl]-N-(pyridin-4-ylmethyl)
206 propanamide (Compound No. 102);
207 3-[l-(4-Methoxyphenyl)-5-(pyridin-3-yl)-lH-pyrazol-3-yl]-N-[2-(2-
208 oxoimidazolidin-l-yl)ethyl]propanamide (Compound No. 103);
209 3-[ 1 -(4-Methoxyphenyl)-5-(pyridin-3-yl)- lH-pyrazol-3-yl]-N-[3-(2-oxopyrrolidin-
210 1 -y l)propy l]propanamide (Compound No . 104) ;
21 1 JV- [( 1 -Ethy lpyrrolidin-2-y l)methy 1] -3 - [ 1 -(4-methoxypheny l)-5 -(pyridin-3 -y 1)- 1 H-
212 pyrazol-3-yl]propanamide (Compound No. 105);
213 3- [ 1 -(4-Methoxyphenyl)-5 -(pyridin-3 -yl)- 1 H-pyrazol-3 -yl] -N- [3 -(morpholin-4-
214 yl)propyl]propanamide (Compound No. 106);
215 N-[(2-Chloropyridin-4-yl)methyl] -3 - [5-(3 -fluorophenyl)- 1 -(4-methoxypheny 1)- 1 H
216 -pyrazol-3-yl]propanamide (Compound No. 107);
217 N-[(6-Chloropyridin-3-yl)methyl]-3-[5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1H
218 -pyrazol-3-yl]propanamide (Compound No. 108);
219 3- [5-(3-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3-yl]-N-(pyridin-2-
220 ylmethyl)propanamide (Compound No. 109);
221 3-[5-(3-Fluorophenyl)-l -(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[(6-
222 methylpyridin-2-yl)methyl]propanamide (Compound No. 1 10);
223 3- [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(pyridin-4-
224 ylmethyl)propanamide (Compound No. I l l);
225 N-Benzyl-3 - [ 1 -(4-fluorophenyl)-5 -(3 -methoxyphenyl)- 1 H-pyrazol-3 -
226 yl]propanamide (Compound No. 1 12);
227 Ethyl 4- { 3 - [3 -(benzylamino)-3-oxopropyl ] -5-(3 -fluorophenyl)- 1 H-pyrazol- 1 -
228 yl}benzoate (Compound No. 1 13);
229 Ethyl 4- [5-(3-fluorophenyl)-3 - { 3 -oxo-3 - [(pyridin-2-ylmethyl)amino]propyl } - 1 H-
230 pyrazol-l-yl]benzoate (Compound No. 1 14);
231 Ethyl 4-[5-(3-fluorophenyl)-3-{3-oxo-3-[(pyridin-4- ylmethyl)amino]propyl}-lH-
232 pyrazol-l-yl]benzoate (Compound No. 1 15); 233 Ethyl 4-[5-(3 -fluorophenyl)-3 -(3 -oxo-3 - { [2-(2-oxoimidazolidin- 1 -
234 yl)ethyl]amino}propyl)-lH-pyrazol-l-yl]benzoate (Compound No. 116);
235 Ethyl 4-[5-(3-fluorophenyl)-3-(3-oxo-3-{[3-(2-oxopyrrolidin-l-
236 yl)propyl]amino}propyl)-lH-pyrazol-l-yl]benzoate (Compound No. 117);
237 Ethyl 4- [5-(3 -fluorophenyl)^ -(3 - { [( 1 -methylpyrrolidin-2-yl)methyl] amino } -3 -
238 oxopropyl)- lH-pyrazol-l-yl]benzoate (Compound No. 118);
239 Ethyl 4-[3 -(3- { [(6-chloropyridin-3 -yl)methyl] amino } -3 -oxopropyl)-5 -(3 -
240 fluorophenyl)- lH-pyrazo -yl]benzoate (Compound No. 119);
241 Ethyl 4-[5-(3-fluorophenyl)-3-(3-{ [3-(morpholin-4-yl)propyl]amino}-3-
242 oxopropyl)- 1 H-pyrazol- l-yl]benzoate (Compound No. 120);
243 Ethyl 4- [5 -(3-fluorophenyl)-3 -(3 - { [(3 -methylpyridin-2-yl)methyl]amino } -3 -
244 oxopropyl)- 1 H-pyrazol- 1 -yl]benzoate (Compound No . 121);
245 4-[3-{3 - [(3 -Chlorobenzy l)amino] -3 -oxopropyl } -5 -(3 -fluorophenyl)- 1 H-pyrazol- 1 -
246 yljbenzoic acid (Compound No. 122);
247 4-[5-(3 -Fluorophenyl)-3 - { 3 - [(3 -methy lbenzyl)amino] -3 -oxopropyl } - 1 H-pyrazol- 1 -
248 yljbenzoic acid (Compound No. 123);
249 4-[3-{3-[(3-Fluorobenzyl)amino]-3-oxopropyl}-5-(3-fluorophenyl)-lH-pyrazol-l-
250 yljbenzoic acid (Compound No. 124);
251 N-[(l-Ethylpyrrolidin-2-yl)methyl]-3-[l-(4-fluorophenyl)-5-(3-methoxyphenyl)-
252 lH-pyrazol-3-yl]propanamide (Compound No. 125);
253 Ethyl 4-[3-{3-[(3-chlorobenzyl)amino]-3-oxopropyl}-5-(3-fluorophenyl)-lH-
254 pyrazol-l-yl]benzoate (Compound No. 126);
255 Ethyl 4- [5 -(3 -fluorophenyl)-3 - { 3 - [(3 -methy lbenzy l)amino] -3 -oxopropyl } - 1 H-
256 pyrazol-l-yl]benzoate (Compound No. 127);
257 3- [ 1 -(4-Fluorophenyl)-5-(3 -methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- [(6-
258 methy lpyridin-2-yl)methyl]propanamide (Compound No. 128);
259 Ethyl 4-[3 - { 3 - [(3 -fluorobenzy l)amino] -3 -oxopropyl } -5 -(3 -fluorophenyl)- 1 H-
260 pyrazol-l-yl]benzoate (Compound No. 129);
261 4- { 3 - [3 -(Benzylamino)-3 -oxopropyl ] -5-(3 -fluorophenyl)- 1 H-pyrazol- 1 -yl } benzoic
262 acid (Compound No. 130);
263 4- [5-(3 -Fluorophenyl)-3-(3 -oxo-3 - { [2-(2-oxoimidazolidin- 1 -
264 yl)ethyl]amino}propyl)-lH-pyrazol-l-yl]benzoic acid (Compound No. 131);
265 4- [5-(3 -Fluorophenyl)-3 -(3-0X0-3 - { [3-(2-oxopyrrolidin- 1 -
266 yl)propyl] amino} propyl)- 1H
267 -pyrazol-1 -yljbenzoic acid (Compound No. 132);
268 4-{3-[3-({[(2^)-l-Ethylpyrrolidin-2-yl]methyl}amino)-3-oxopropyl]-5-(3-
269 fluorophenyl)- 1 H-pyrazol- 1 -yl } benzoic acid (Compound No . 133);
270 4- [3 -(3- { [(6-Chloropyridin-3 -yl)methyl]amino} -3 -oxopropyl)-5-(3 -fluorophenyl)-
271 1 H-pyrazol- 1 -yljbenzoic acid (Compound No. 134); 272 4- [5 -(3 -Fluorophenyl)-3 -(3- { [3 -(morpholin-4-yl)propyl] amino } -3 -oxopropyl)- 1 H-
273 pyrazol-l-yl]benzoic acid (Compound No. 135);
274 4-[5-(3-Fluorophenyl)-3-(3-{[(6-methylpyridin-2-yl)methyl]amino}-3-oxopropyl)-
275 lH-pyrazol-l-yl]benzoic acid (Compound No. 136);
276 N-(3-Chlorobenzyl)-3-[5-(3-cyanophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]
277 propanamide (Compound No. 137);
278 3 - [5 -(3 -Cyanophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -methylbenzyl)
279 propanamide (Compound No. 138);
280 3- [5 -(3 -Cyanophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -fluorobenzyl)
281 propanamide (Compound No. 139);
282 N-Benzyl-3 - [5 -(3 -cyanophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -
283 yl]propanamide (Compound No . 140);
284 3- [5-(3 - Aminophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -methyl
285 benzy propanamide (Compound No. 141);
286 3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[2-(4-
287 methylpiperazin- 1 -yl) benzyl]propanamide (Compound No . 142) ;
288 3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[3-(4-
289 methylpiperazin- 1 -yl)benzyl]propanamide (Compound No. 143);
290 3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-[3-(4-
291 methylpiperazin- 1 -yl)benzyl]propanamide (Compound No. 144);
292 Methyl 3-[({3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-
293 yl]propanoyl}amino)methyl]benzoate (Compound No. 145);
294 3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[4-(4-
295 methylpiperazin- 1 -yl)benzyl]propanamide (Compound No. 146);
296 3 - { 5 - [3 -( Aminomethyl)pheny 1] - 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl } -N-(3
297 -fluorobenzyl)propanamide (Compound No. 147);
298 3-{5-[3-(Aminomethyl)phenyl]-l-(4-methoxyphenyl)-lH-pyrazol-3-yl}-N-(3
299 -methylbenzyl)propanamide (Compound No. 148);
300 N-(3-Chlorobenzyl)-3-[5-(3-fluorophenyl)- 1 -(4-methoxy-2-methylphenyl)- 1H-
301 pyrazol-3-yl]propanamide (Compound No. 149);
302 N-(3-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxy-2-methylphenyl)-lH-
303 pyrazol-3-yl]propanamide (Compound No. 150);
304 {4-[3-{3 - [(3 -Chlorobenzyl)amino] -3 -oxopropyl } - 5 -(3 -fluorophenyl)- 1 H-pyrazol-
305 l-yl]phenoxy} acetic acid (Compound No. 151);
306 N-Benzyl-3 -[ 1 -(4-methoxyphenyl)-5-(pyrazin-2-yl)- 1 H-pyrazol-3 -yl]propanamide
307 (Compound No. 152);
308 3-[5-{3 - [( Acety lamino)methy l]phenyl } - 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-
309 (3-fluorobenzyl)propanamide (Compound No. 153); 3 - [5 - { 3 - [( Acetyl amino)methyl]phenyl } - 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N- (3-methyl benzyl)propanamide (Compound No. 154);
3 - [( { 3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanoyl}amino)methyl]benzoic acid (Compound No. 155);
(4-{3-[3-(Benzylamino)-3-oxopropyl]-5-(3-fluorophenyl)-lH-pyrazol-l- yl}phenoxy)acetic acid (Compound No. 156);
{4-[3-{3-[(3 -Fluorobenzyl)amino] -3 -oxopropyl } - 5 -(3 -fluorophenyl)- 1 H-pyrazol- 1 -yl]phenoxy} acetic acid (Compound No. 157);
{4-[3-{3-[(2-Chlorobenzyl)amino]-3-oxopropyl}-5-(3-fluorophenyl)-lH-pyrazol- 1 -yl]phenoxy} acetic acid (Compound No. 158);
{4-[3-{3 - [(2-Fluorobenzyl)amino] -3 -oxopropyl } - 5 -(3 -fluorophenyl)- 1 H-pyrazol- 1 -yl]phenoxy} acetic acid (Compound No. 159);
3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-{[2-(4- methylpiperazin-1 -yl) pyridin-4-yl]methyl}propanamide (Compound No. 160); 3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[5-methyl-2-(4- methyl piperazin-l-yl)benzyl]propanamide (Compound No. 161);
N-(5-Fluoro-2-methylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 162);
N-(2,3-Difluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 163);
N-(2,4-Dichlorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 164);
_V-(3, 5 -Difluorobenzyl)-3- [5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yl]propanamide (Compound No. 165);
N-Benzyl-3 - { 5-(3 -fluorophenyl)- 1 - [4-(2-hydroxyethoxy)phenyl] - 1 H-pyrazol-3 -yl } propanamide (Compound No. 166);
N-(3 -Chlorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(2-hydroxyethoxy)phenyl] - 1 H- pyrazol-3-yl}propanamide (Compound No. 167);
N-(2,5-Dimethylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol- 3 -yl]propanamide (Compound No. 168);
N-[2-Fluoro-4-(4-methylpiperazin- 1 -yl)benzyl]-3-[5-(3-fluorophenyl)- 1 -(4
-methoxyphenyl)- 1 H-pyrazol-3 -yl]propanamide (Compound No. 169);
3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[(5- methylpyridin-3-yl)methyl]propanamide (Compound No. 170);
N-(3 -Chlorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-hydroxyphenyl)- 1 H-pyrazol-3 -yl] propanamide (Compound No. 171);
3 - [5 -(3 -Fluorophenyl)- 1 -(4-hydroxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3-methylbenzyl) propanamide (Compound No. 172); 348 {4- [5 -(3 -Fluorophenyl)-3 - { 3 - [(3 -methylbenzyl)amino] -3 -oxopropyl } - 1 H-pyrazol-
349 l-yl]phenoxy}acetic acid (Compound No. 173);
350 N-(2-Fluorobenzyl)-3-{5-(3-fluorophenyl)-l-[4-(2-hydroxyethoxy)phenyl]-lH-
351 pyrazol-3-yl}propanamide (Compound No. 174);
352 N-(3-Fluorobenzyl)-3-{5-(3-fluorophenyl)-l-[4-(2-hydroxyethoxy)phenyl]-lH-
353 pyrazol-3-yl}propanamide (Compound No. 175);
354 3-{5-(3-Fluorophenyl)-l-[4-(2-hydroxyethoxy)phenyl]-lH-pyrazol-3-yl}-N-(3
355 -methylbenzyl)propanamide (Compound No. 176);
356 N-(2-Chlorobenzyl)-3 - [5 -(3 -fluorophenyl)- 1 -(4-hydroxyphenyl)- 1 H-pyrazol-3 -yl]
357 propanamide (Compound No . 177);
358 N-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-hydroxyphenyl)-lH-pyrazol-3-yl]
359 propanamide (Compound No. 178);
360 N-(3 -Fluorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-hydroxyphenyl)- 1 H-pyrazol-3 -yl]
361 propanamide (Compound No . 179);
362 N-(3-Fluorobenzyl)-3-{ l-(4-methoxyphenyl)-5-[3-(lH-tetrazol-5-yl)phenyl]-lH-
363 pyrazol-3-yl} propanamide (Compound No. 180);
364 3-{ l-(4-Methoxyphenyl)-5-[3-(lH-tetrazol-5-yl)phenyl]-lH-pyrazol-3-yl}-N-(3
365 -methylbenzyl)propanamide (Compound No. 181);
366 3-[5-(3-Fluorophenyl)- 1 -(4-methoxy-2-methylphenyl)-l H-pyrazol-3-yl]-JV-(3
367 -methylbenzyl)propanamide (Compound No. 182);
368 3-{5-(3-Fluorophenyl)-l-[4-(hydroxymethyl)phenyl]-lH-pyrazol-3-yl}-N-(3
369 -methylbenzyl)propanamide (Compound No . 183);
370 N-(3,5-Dimethylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-
371 3-yl]propan amide (Compound No. 184);
372 N-[3-Chloro-4-(4-methylpiperazin-l-yl)benzyl]-3-[5-(3-fluorophenyl)-l-(4
373 -methoxyphenyl)- 1 H-pyrazol-3 -yl]propanamide (Compound No. 185);
374 4-[5-(3 -Fluorophenyl)-3- { 3 - [(3 -methylbenzyl)amino]-3 -oxopropyl } - 1 H-pyrazol- 1 -
375 yl]benzamide (Compound No. 186);
376 N-(3-Chlorobenzyl)-3-{5-(3-fluorophenyl)-l-[4-(hydroxymethyl)phenyl]-lH-
377 pyrazol-3-yl} propanamide (Compound No. 187); .
378 N-(3 ,5 -Dichlorobenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -
379 yl]propanamide (Compound No. 188);
380 3 - [5 -(3 -Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3-yl] -vV-(3-methylphenyl)
381 propanamide (Compound No. 189);
382 N-(3 -Fluorophenyl)-3 - [5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]
383 propanamide (Compound No. 190);
384 N-(3-Chlorophenyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]
385 propanamide (Compound No. 191); 386 3-[5-(3-Fluorophenyl)- l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[3-
387 (hydroxymethyl)
388 benzyl]propanamide (Compound No. 192);
389 3- [5-(3 -Fluorophenyl)- 1 -(2-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -methylbenzyl)
390 propanamide (Compound No. 193);
391 N-(3-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(2-methoxyphenyl)-lH-pyrazol-3-yl]
392 propanamide (Compound No. 194);
393 N-(3 -Chlorobenzyl)-3 - [5-(3-fluorophenyl)- 1 -(2-methoxyphenyl)- 1 H-pyrazol-3 -yl]
394 propanamide (Compound No. 195);
395 N-(3-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methylphenyl)-lH-pyrazol-3-yl]
396 propanamide (Compound No. 196);
397 N-(3-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methylphenyl)-lH-pyrazol-3-yl]
398 propanamide (Compound No . 197);
399 3-[5-(3-Fluorophenyl)- 1 -(4-methylphenyl)- lH-pyrazol-3-yl]-N-(3-methylbenzyl)
400 propanamide (Compound No. 198);
401 N-Benzyl-3-[5-(3-fluorophenyl)-l-(4-methylphenyl)-lH-pyrazol-3-yl]propanamide
402 (Compound No. 199);
403 N-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)- 1 -(4-methylphenyl)- 1 H-pyrazol-3 -yl]
404 propanamide (Compound No. 200);
405 N-(2-Fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(2-methoxyphenyl)-lH-pyrazol-3-yl]
406 propanamide (Compound No. 201);
407 3 -[5 -(3 -Fluorophenyl)- 1 -(3-methoxyphenyl)- 1 H-pyrazol-3 -yl]-N-(3 -methylbenzyl)
408 propanamide (Compound No. 202);
409 N-(3-Fluorobenzyl)-3-[5-(3-fluorophenyl)- 1 -(3-methoxyphenyl)- lH-pyrazol-3-yl]
410 propanamide (Compound No. 203);
41 1 N-(3-Chlorobenzyl)-3-[5-(3-fluorophenyl)-l-(3-methoxyphenyl)-lH-pyrazol-3-yl]
412 propanamide (Compound No. 204);
413 N-(3-Chloro-2-fluorobenzyl)-3-[5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-
414 pyrazol-3-yl]propanamide (Compound No. 205);
415 N-(3-Fluoro-5-methylbenzyl)-3-[5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- 1H-
416 pyrazol-3-yl]propanamide (Compound No. 206);
417 N-(5-Chloro-2-fluorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methoxyphenyl)-lH-
418 pyrazol-3-yl]propanamide (Compound No. 207);
419 N-(3-Chloro-2,6-difluorobenzyl)-3-[5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1H-
420 pyrazol-3-yl]propanamide (Compound No. 208);
421 N-(3-Chloro-2-methylbenzyl)-3 - [5-(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-
422 pyrazol-3-yl]propanamide (Compound No. 209);
423 N-(3 -Chloro-4-fluorobenzyl)-3 -[5 -(3 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-
424 pyrazol-3-yl]propanamide (Compound No. 210); 425 N-(2-Chloro-6-fluoro-3-methylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-
426 methoxyphenyl)-l H-pyrazol-3 -yl]propanamide (Compound No. 211);
427 N-(3-Chlorobenzyl)-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]
428 propanamide (Compound No. 212);
429 N-(3 -chlorobenzyl)-3 - { 5-(3 -fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H-
430 pyrazol-3-yl} propanamide (Compound No. 213);
431 N-(3,5-Difluorobenzyl)-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-
432 yl]propanamide (Compound No. 214);
433 3-{5-(3-Fluorophenyl)-l-[4-(trifluoromethyl)phenyl]-lH-pyrazol-3-yl}-N-(3
434 -methylbenzyl)propanamide (Compound No. 215);
435 N-(3,4-Dichlorobenzyl)-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-
436 yl]propanamide (Compound No. 216);
437 3-[5-(2-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3-methylbenzyl)
438 propanamide (Compound No . 217) ;
439 3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[(5-methyl-3-
440 phenyl- 1 ,2-oxazol-4-yl)methyl]propanamide (Compound No. 218);
441 N-(3 -Fluorobenzyl)-3-[5-(2 -fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]
442 propanamide (Compound No . 219) ;
443 N-(2,5-Dimethylbenzyl)-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-
444 3-yl]propanamide (Compound No. 220);
445 N-(2-Fluorobenzyl)-3-[5-(2-fluorophenyl)-l -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]
446 propanamide (Compound No. 221);
447 N-(3 -Fluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 -[4-(trifluoromethoxy)phenyl] - 1 H-
448 pyrazol-3 -y 1 } propanamide (Compound No . 222) ;
449 N-(3 -Fluorobenzyl)-3- { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H-
450 pyrazol-3 -yl} propanamide (Compound No. 223);
451 N-(3-Chlorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethoxy)phenyl] - 1 H-
452 pyrazol-3 -yl} propanamide (Compound No. 224);
453 N-Benzyl-3-[5-(2-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-
454 yl]propanamide (Compound No. 225);
455 N-(2-Fluorobenzyl)-3-{5-(3-fluorophenyl)-l-[4-(trifluoromethyl)phenyl]-lH-
456 pyrazol-3-yl}propanamide (Compound No. 226);
457 N-(3,5-Difluorobenzyl)-3-[5-(2,3-difluorophenyl)-l-(4-methoxyphenyl)-lH-
458 pyrazol-3 -y]]propanamide (Compound No. 227);
459 N-(3,5-Difluorobenzyl)-3-{5-(3-fluorophenyl)-l-[4-(trifluoromethyl)phenyl]-lH-
460 pyrazol-3 -yl} propanamide (Compound No. 228);
461 _V-(3 -Chlorobenzyl)-3 - { 5 -(3-fluorophenyl)- 1 - [4-(2-methylpropoxy)phenyl] - 1 H-
462 pyrazol-3 -yl} propanamide (Compound No. 229); 463 3-[5-(2,3-Difluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(3-
464 fluorobenzyl)propanamide (Compound No. 230);
465 N-(2-Fluorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 -[4-(trifluoromethoxy)phenyl] - 1 H-
466 pyrazol-3-yl}propanamide (Compound No. 231);
467 3-[5-(2,3-Difluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(2,5-
468 dimethylbenzyl)propanarnide (Compound No. 232);
469 N-(3-Chlorobenzyl)-3-[5-(2,3-difluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-
470 yl]propanamide (Compound No. 233);
471 N-(3,5-Difluorobenzyl)-3-{5-(3-fluorophenyl)-l-[4-(trifluoromethoxy)phenyl]-lH
472 -pyrazol-3-yl}propanamide (Compound No. 234);
473 3-{5-(3-Fluorophenyl)-l-[4-(trifluoromethoxy)phenyl]-lH-pyrazol-3-yl}-N-(3-
474 methylbenzyl)propanarnide (Compound No. 235);
475 iV-(3 ,4-Dichlorobenzyl)-3 - [5-(2,3 -difluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-
476 pyrazol-3-yl]propanamide (Compound No. 236);
477 N-Benzyl-3-[5-(2,3-difluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-
478 yljpropanamide (Compound No. 237);
479 N-(2,5-Dimethylbenzyl)-3- { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethoxy)phenyl]- 1H
480 -pyrazol-3 -yljpropanamide (Compound No. 238);
481 iV-(3 ,4-Dichlorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethoxy)phenyl] - 1 H
482 -pyrazol-3 -yljpropanamide (Compound No. 239);
483 3-[5-(2,3-Difluorophenyl)-l -(4-methoxyphenyl)- lH-pyrazol-3-yl]-N-(3-
484 methylbenzyl)propanamide (Compound No. 240);
485 3-[5-(2,3-Difluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-(2-
486 fluorobenzyl)propanamide (Compound No. 241);
487 iV-(3 ,4-Dichlorobenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H-
488 pyrazol-3 -yl } propanamide (Compound No . 242) ;
489 N-(3,4-Dichlorobenzyl)-3-[5-(3-fluorophenyl)-l-(4-methylphenyl)-lH-pyrazol-3-
490 yljpropanamide (Compound No. 243);
491 _V-(3 ,5 -Difluorobenzyl)-3 - [5-(3-fluorophenyl)- 1 -(4-methylphenyl)- 1 H-pyrazol-3 -
492 yljpropanamide (Compound No. 244);
493 N-(2,5-Dimethylbenzyl)-3-[5-(3-fluorophenyl)-l-(4-methylphenyl)-lH-pyrazol-3-
494 yljpropanamide (Compound No. 245);
495 N-Benzyl-3- { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H-pyrazol-3-yl}
496 propanamide (Compound No. 246);
497 N-(2,5 -Dimethylbenzyl)-3 - { 5 -(3 -fluorophenyl)- 1 - [4-(trifluoromethyl)phenyl] - 1 H-
498 pyrazol-3-yl}propanamide (Compound No. 247);
499 N-(5-Chloro-2-methylbenzyl)-3-[5-(3-fluorophenyl)- 1 -(4-methoxyphenyl)- \H-
500 pyrazol-3 -yljpropanamide (Compound No. 248); 501 3-[5-(3-Fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N-[(5-methyl-l,2-
502 oxazol-3-yl) methyl]propanamide (Compound No. 249);
503 3 - [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl] -N-(3 -fluorobenzyl)
504 propanamide (Compound No. 250);
505 3 - [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl]-N-(2,3 -difluorobenzyl)
506 propanamide (Compound No.251);
507 3 - [ 1 -(4-Cyanophenyl)-5 -(3 -fluorophenyl)- 1 H-pyrazol-3 -yl]-N-(3 ,5-difluorobenzyl)
508 propanamide (Compound No . 252) ;
509 3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-(2,5-
510 dimethylbenzyl)propanamide (Compound No .253 ) ;
51 1 3-[l-(4-Cyanophenyl)-5-(3-fluorophenyl)-lH-pyrazol-3-yl]-N-(3-fluoro-5-
512 methylbenzyl)propanamide (Compound No . 254) ;
513 N-(3 -Chlorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5-(4-methylphenyl)- 1 H-pyrazol-3 -yl]
514 propanamide (Compound No. 255);
515 N-(3 -fluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -(4-methylphenyl)- 1 H-pyrazol-3 -yl]
516 propanamide (Compound No . 256) ;
517 3- [ 1 -(4-Methoxyphenyl)-5-(4-methylphenyl)- 1 H-pyrazol-3 -yl] -N-(3 -
518 methylbenzyl)propanamide (Compound No . 257) ;
519 N-Benzyl-3-[l-(4-methoxyphenyl)-5-(4-methylphenyl)-lH-pyrazol-3-
520 yl] propanamide (Compound No.258);
521 N-(3,4-Dichlorobenzyl)-3-[l-(4-methoxyphenyl)-5-(4-methylphenyl)-lH-pyrazol-
522 3-yl]propanamide (Compound No. 259);
523 N-(2,5-Dimethylbenzyl)-3-[l-(4-methoxyphenyl)-5-(4-methylphenyl)-lH-pyrazol-
524 3-yl]propanamide (Compound No. 260);
525 _V-(3 ,5 -Difluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -(4-methylphenyl)- 1 H-pyrazol-
526 3-yl]propanamide (Compound No. 261);
527 N-(2,3-Difluorobenzyl)-3-[l-(4-methoxyphenyl)-5-(4-methylphenyl)-lH-pyrazol-
528 3-yl]propanamide (Compound No. 262);
529 N-(2-Fluorobenzyl)-3-[l-(4-methoxyphenyl)-5-(4-methylphenyl)-lH-pyrazol-3-yl]
530 propanamide (Compound No. 263);
531 N-Benzyl-3-[5-(4-fluorophenyl)-l -(4-methoxyphenyl)-lH-pyrazol-3-
532 yl]propanamide (Compound No. 264);
533 N-(3-Fluorobenzyl)-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl]
534 propanamide (Compound No. 265);
535 N-(3 -Chlorobenzyl)-3- [5-(4-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl]
536 propanamide (Compound No. 266);
537 3 - [5-(4-Fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 -yl] -N-(3-methylbenzyl)
538 propanamide (Compound No. 267); N-(2,3 -Difluorobenzyl)-3- [5-(4-fluorophenyl)- 1 -(4-methoxyphenyl)- 1 H-pyrazol-3 - yljpropanamide (Compound No. 268);
iV-(3,5-difluorobenzyl)-3-[5-(4-fluorophenyl)-l -(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 269);
N-(2,5-Dimethylbenzyl)-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol- 3-yl]propanamide (Compound No. 270);
N-(3,4-dichlorobenzyl)-3-[5-(4-fluorophenyl)-l -(4-methoxyphenyl)-lH-pyrazol-3- yl]propanamide (Compound No. 271);
N-(3-Fluoro-5-methylbenzyl)-3-[5-(4-fluorophenyl)-l -(4-methoxyphenyl)-lH- pyrazol-3-yl]propanamide (Compound No. 272);
N-(2-Fluorobenzyl)-3-[5-(4-fluorophenyl)-l-(4-methoxyphenyl)-lH-pyrazol-3-yl] propanamide (Compound No. 273);
N-(3-Fluorobenzyl)-3-[l -(4-methoxyphenyl)-5-phenyl-lH-pyrazol-3- yljpropanamide (Compound No. 274);
N-(3 ,5 -Difluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 - yl]propanamide (Compound No. 275);
N-(2,3 -Difluorobenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3- yljpropanamide (Compound No. 276);
N-(2,5-Dimethylbenzyl)-3 - [ 1 -(4-methoxyphenyl)-5 -phenyl- 1 H-pyrazol-3 - yljpropanamide (Compound No. 277);
N-(2,3-Dichlorobenzyl)-3-[l -(4-methoxyphenyl)-5 -phenyl- lH-pyrazol-3- yljpropanamide (Compound No. 278);
V-(3-Fluoro-5-methylbenzyl)-3-[l -(4-methoxyphenyl)-5-phenyl- 1 H-pyrazol-3 -yl] propanamide (Compound No. 279);
N-(3-Fluoro-5-methylbenzyl)-3-[5-(2-fluorophenyl)-l -(4-methoxyphenyl)-lH- pyrazol-3 -yljpropanamide (Compound No. 280);
including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. 7. A pharmaceutical composition comprising therapeutically effective amount of one or more compounds according to any one of the claims 1-6, together with one or more pharmaceutically acceptable carriers, excipient or diluent.
8. A pharmaceutical composition of claim 7, further comprising one or more therapeutic agents selected from COX inhibitors, BLTR antagonists, FLAP inhibitors, muscarinic receptor antagonists, β2 -agonists, p38 MAP Kinase inhibitors, PDE-IV inhibitors or corticosteroids.
9. A method for treating or preventing conditions caused by inflammation and associated pathologies comprising administering to a mammal in need thereof therapeutically effective amount of one or more compounds of claims 1-6, or their pharmaceutical composition of claim 7.
10. A method according to claim 9, wherein conditions caused by 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.
11. A process for preparing compound of Formula I, (when ring A is un(substituted) phenyl and n = 1),
Figure imgf000114_0001
Formula 1
{when ring A is (un)substituted
phenyl and n=l }
comprising:
a) reacting compound of Formula 2 with succinic anhydride
Figure imgf000114_0002
Formula 2
to give compound of Formula 3
Figure imgf000114_0003
Formula 3
b) reacting a compound of Formula 3 with a compound of Formula 4
Figure imgf000114_0004
Formula 4 to give compound of Formula 5
Figure imgf000115_0001
Formula 5
c) coupling of compound of Formula 5 with compound of Formula 6
R3R4NH
Formula 6
to give compound of Formula 1 ;
wherein
Ring B is selected from phenyl, C3-10 cycloalkyl and a 6- 10 membered heteroaryl each of which is optionally substituted by one or more substituents independently selected from R2;
RHs selected from the group consisting of hydrogen, hydroxy, Q-Csalkyl, C\- C5alkoxy, CN, halogen, CF3, nitro, -CO, d-Csalkylamino, CrC3alkyl-OH, CORf, heteroaryl, NRfRq, COORf, CONRfRq and -ORd wherein Rd is Ci-C5alkyl, Ci-C3alkyl-COORf or Ci-C3alkyl-OH.
R2is selected from the group consisting of hydrogen, hydroxy, Ci-Csalkyl, C\- C5alkoxy, CN, halogen,
Figure imgf000115_0002
NRfRq, CrCsalkyl- NHCO-d-Csalkyl and COORf;
Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and Rf and Rq may together form a ring system together with the heteroatom to which they are attached;
R3 is hydrogen or R3 and R4 together with the nitrogen atom to which they are attached forms a Ο5-10 ring system wherein 1 -3 carbon atom in the ring are replaced by heteroatom selected from N, O or S and the ring system can optionally be substituted by one or more substituents independently selected from R5;
R4 is selected from the group consisting of -(CH2)m-(0)s-phenyl,-(CH2)m-(0)s- heterocyclyl or -(CH2)m-(0)s-heteroaryl, wherein each of phenyl, heterocyclyl and heteroaryl is optionally substituted by one or more substituents selected from R5; selected from the group consisting of hydrogen, halogen, Ci-C5alkyl, nitro,
CF3, -C=0, COORf, hydroxyalkyl, piperazine, Ci-C3alkyl-COOR6 C1-C3alkyl- CONRfRq, Q-Csalkyl-piperazine and phenyl;
m is an integer 0-3;
sis an integer 0-1.
12. A process for preparing compound of Formula 12(Formula 1 when ring A is phenyl, R1 is -OCH2COOH and x =1)
Figure imgf000116_0001
Formula 12
comprising:
a) deprotecting of compound of Formula 7
Figure imgf000116_0002
{ Formula 1 when R1 is}
Figure imgf000116_0003
to give compound of Formula 8
Figure imgf000116_0004
Formula 8
b) reacting a compound of Formula 8 with a compound of Formula 6 R3R4NH
10 Formula 6
1 1 to give a compound of Formula 9
Figure imgf000117_0001
9
j 2 {Formula I when R1 is -OH}
13 c) reacting a compound of Formula 9 with a compound of Formula 10
X-(CH2)z-COOEt
4 Formula 10
15 to ive a compound of Formula 11
Figure imgf000117_0002
17 d) hydrolyzing the compound of Formula 11 to gives a compound of Formula 12;
18 wherein
19 R is selected from the group consisting of hydrogen, hydroxy, Ci-Csalkyl, Q- 0 C5alkoxy, CN, halogen, CF3,heteroaryl.Ci-C5alk lamino. NRfRq, Ci-C5alkyl-
21 NHCO-d-Csalkyl and COORf;
2 Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl,
23 aryl, aralkyl, heterocyclyl, heteroaryl and Rf and Rq may together form a ring 4 system together with the heteroatom to which they are attached;
25 R3 is hydrogen or R3 and R4 together with the nitrogen atom to which they are
26 attached forms a C5-10ring system wherein 1-3 carbon atom in the ring are replaced by heteroatom selected from N, O or S and the ring system can optionally be substituted by one or more substituents independently selected from R5;
R4 is selected from the group consisting of -(CH2)m-(0)s-phenyl,-(CH2)m-(0)s- heterocyclyl or -(CH2)m-(0)s-heteroaryl, wherein each of phenyl, heterocyclyl and heteroaryl is optionally substituted by one or more substituents selected from R5; R5 is selected from the group consisting of hydrogen, halogen, Ci-Csalkyl, nitro, CF3, -C=0, COORf, hydroxyalkyl, piperazine, Q-Csalkyl-COORf, CrC3alkyl- CONRfRq, Q-Csalkyl-piperazine and phenyl;
X is a halogen
m is an integer 0-3;
s is an integer 0- 1 ;
z is an integer 1.
13. A process for preparing compound of Formula 15 (Formula 1 when ring A is phenyl, R1 is -OCH2CH2OH and x=l)
Figure imgf000118_0001
Formula 15
comprising:
a) reacting a com ound of Formula 9 with a compound of Formula 13
Figure imgf000118_0002
9 X-(CH2)Z -OTBDMS
{Formula I when R1 is -OH} Formula 13
to give compound of Formula 14
Figure imgf000119_0001
SMDBTO'
Formula 14
which on deprotection give compound of Formula 15;
wherein
R is selected from the group consisting of hydrogen, hydroxy, Q-Csalkyl, C\- C5alkoxy, CN, halogen, CFs eroaryl -Csalkylamino, NRfRq, Q-Qalkyl- NHCO-d-Csalkyl and COORf;
Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and Rf and Rq may together form a ring system together with the heteroatom to which they are attached;
R3 is hydrogen or R3 and R4 together with the nitrogen atom to which they are attached forms a C5-10 ring system wherein 1 -3 carbon atom in the ring are replaced by heteroatom selected from N, O or S and the ring system can optionally be substituted by one or more substituents independently selected from R5;
R4 is selected from the group consisting of -(CH2)m-(0)s-phenyl,-(CH2)m-(0)s- heterocyclyl or -(CH2)m-(0)s-heteroaryl, wherein each of phenyl, heterocyclyl and heteroaryl is optionally substituted by one or more substituents selected from R5; R5 is selected from the group consisting of hydrogen, halogen, CrC5alkyl, nitro, CF3, -C=0, COORf, hydroxyalkyl, piperazine, Q-Csalkyl-COORf, Q-Csalkyl- CONRfRq, Q-Csalkyl-piperazine and phenyl;
X is a halogen
m is an integer 0-3;
s is an integer 0-1 ;
z is an integer 1-2.
14. A process for preparing compound of Formula 18 (Formula 1 when ring A and B are phenyl, n=l and R2 is NH2)
Figure imgf000120_0001
Formula 18
comprising:
a) reducing a compound o Formula 16
Figure imgf000120_0002
Formula 16
{Formula I when
R2 is N02}
to give a compound o Formula 17
Figure imgf000120_0003
Formula 17
b) coupling a compound of Formula 17 with a compound of Formula 6
R3R4NH
Formula 6
to give a compound of Formula 18;
wherein
R1 is selected from the group consisting of hydrogen, hydroxy, Ci-C5alkyl, C\- C5alkoxy, CN, halogen, CF3, nitro, -C=0, C]-C5alkylamino, C C3alkyl-OH, CORf, heteroaryl, NRfRq, COORf, CONRfRq and -ORd wherein Rj is C]-C5alkyl, C]-C3alkyl-COORf or d-C3alkyl-OH; Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and Rf and Rq may together form a ring system together with the heteroatom to which they are attached;
R3 is hydrogen or R3 and R4 together with the nitrogen atom to which they are attached forms a C5-ioring system wherein 1-3 carbon atom in the ring are replaced by heteroatom selected from N, O or S and the ring system can optionally be substituted by one or more substituents independently selected from R5;
R4 is selected from the group consisting of -(CH2)m-(0)s-phenyl,-(CH2)m-(0)s- heterocyclyl or -(CH2)m-(0)s-heteroaryl, wherein each of phenyl, heterocyclyl and heteroaryl is optionally substituted by one or more substituents selected from R5; R5 is selected from the group consisting of hydrogen, halogen, Q-Csalkyl, nitro, CF3, -C=0, COORf, hydroxyalkyl, piperazine, Q-Csalkyl-COORf, CrC3alkyl- CONRfRq, Q-Csalkyl-piperazine and phenyl;
m is an integer 0-3;
s is an integer 0-1.
15. A process for preparing compound of Formula 21 (Formula 1 when ring A and B are phenyl, n=l and R2 is tetrazole) and Formula 22 (Formula 1 when ring A and B are phenyl, n=l and 2 is CH2NHC(=0)R7)
Figure imgf000121_0001
Formula 21 Formula 22
comprising:
a) reacting a compound of Formula 19
Figure imgf000122_0001
formula 19
7 {Formula I when R2 is -CN}
8 with sodium azide to give a compound of Formula 21 ;
9 OR
10 a) reduction of a compound of Formula 19 to give compound of Formula 20
Figure imgf000122_0002
\ \ Formula 20
12 b) acylating a compound of Formula 20 with a compound of Formula 20a
O
R^U
2 Formula 20a
14 to give a compound of Formula 22;
15 wherein
16 R1 is selected from the group consisting of hydrogen, hydroxy, Q-Csalkyl, Q-
17 C5alkoxy, CN, halogen, CF3, nitro, -C=0, Ci-C5alkylamino, Q-Qalkyl-OH,
18 CORf, heteroaryl, NRfRq, COORf, CONRfRq and -ORd wherein Rd is d-C5alkyl,
19 d-Qalkyl-COORf or Q-Qalkyl-OH;
20 Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, 1 aryl, aralkyl, heterocyclyl, heteroaryl and Rf and Rq may together form a ring 2 system together with the heteroatom to which they are attached;
3 R3 is hydrogen or R3 and R4 together with the nitrogen atom to which they are 4 attached forms a C5-10 ring system wherein 1-3 carbon atom in the ring are replaced by heteroatom selected from N, O or S and the ring system can optionally be substituted by one or more substituents independently selected from R5;
R4 is selected from the group consisting of -(CH2)m-(0)s-phenyl,-(CH2)m-(0)s- heterocyclyl or -(CH2)m-(0)s-heteroaryl, wherein each of phenyl, heterocyclyl and heteroaryl is optionally substituted by one or more substituents selected from R5;
R5 is selected from the group consisting of hydrogen, halogen, Q-Csalkyl, nitro,
CF3, -C=0, COORf, hydroxyalkyl, piperazine, Ci-C3alk l-COORf, CpC3alkyl-
CONRfRq, d-Csalkyl-piperazine and phenyl;
R7is alkyl or aryl;
U is halide, acyloxy or aryloxy;
m is an integer 0-3;
s is an integer 0-1.
A process for preparing compound of Formula 26 (Formula 1 when ring A and B are phenyl, n=l and R1 is CH2OH) and Formula 25 (Formula 1 when ring A and B are phenyl, n=l and R1 is C=ONH2)
Figure imgf000123_0001
Formula 26 Formula 25
comprising:
a) reducing of a compound of Formula 23
Figure imgf000124_0001
Formula 23
{Formula I when R1 is -COOEt} to give a compound of Formula 26;
OR
a) hydro lyzing a compound of Formula 23to give compound of Formula 24
Figure imgf000124_0002
Formula 24
b) amidating a compound of Formula 24 to give a compound of Formula 25 ; wherein
R is selected from the group consisting of hydrogen, hydroxy, Ci-Csalkyl, d- C5alkoxy, CN, halogen, CF3, heteroaryl, Q-Csalkylamino, NRfRq, d-C5alkyl- NHCO-d-Cjalkyl and COORf;
Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and Rf and Rq may together form a ring system together with the heteroatom to which they are attached;
R3 is hydrogen or R3 and R4 together with the nitrogen atom to which they are attached forms a C5-10 ring system wherein 1 -3 carbon atom in the ring are replaced by heteroatom selected from N, O or S and the ring system can optionally be substituted by one or more substituents independently selected from R5; R4 is selected from the group consisting of -(CH2)m-(0)s-phenyl,-(CH2)m-(0)s- heterocyclyl or -(CH2)m-(0)s-heteroaryl, wherein each of phenyl, heterocyclyl and heteroaryl is optionally substituted by one or more substituents selected from R5; R5 is selected from the group consisting of hydrogen, halogen, d-C5alkyl, nitro, CF3, -C=0, COORf, hydroxyalkyl, piperazine, Q-Caalkyl-COORf, C C3alkyl- CONRfRq, CpCsalkyl-piperazine and phenyl;
m is an integer 0-3;
s is an integer 0-1.
17. A process for preparing compound of Formula 28, (Formula 1 when ring A is phenyl, n=l and R1 is -OR8)
Figure imgf000125_0001
Formula 28 comprising:
a) coupling of a compound of Formula 9
Figure imgf000125_0002
Formula 9
{Formula 1 when Rl is -OH}
with a compound of Formula 27
R8OH
Formula 27 to give a compound of Formula 28;
wherein
R8is methyl, ethyl, propyl, wo-propyl, wo-butyl, butylpentyl, hexyl, heptyl, octyl; R is selected from the group consisting of hydrogen, hydroxy, Q-Csalkyl,
Figure imgf000126_0001
C5alkoxy, CN, halogen, CF3, heteroaryl, d-Csalkylamino, NRfRq, d-C5alkyl- NHCO-d-Csalkyl and COORf;
Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and Rf and Rq may together form a ring system together with the heteroatom to which they are attached;
R3 is hydrogen or R3 and R4 together with the nitrogen atom to which they are attached forms a C5-i0 ring system wherein 1 -3 carbon atom in the ring are replaced by heteroatom selected from N, O or S and the ring system can optionally be substituted by one or more substituents independently selected from R5;
R4 is selected from the group consisting of -(CH2)m-(0)s-phenyl,-(CH2)m-(0)s- heterocyclyl or -(CH2)m-(0)s-heteroaryl, wherein each of phenyl, heterocyclyl and heteroaryl is optionally substituted by one or more substituents selected from R5; R5 is selected from the group consisting of hydrogen, halogen, Ci-C5alkyl, nitro, CF3, -C=0, COORf, hydroxyalkyl, piperazine, CrC3alkyl-COORf, d-C3alkyl- CONRfRq, d-dalkyl-piperazine and phenyl;
m is an integer 0-3;
s is an integer 0-1.
PCT/IB2011/052695 2010-06-24 2011-06-20 5-lipoxygenase inhibitors WO2011161615A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1479DE2010 2010-06-24
IN1479/DEL/2010 2010-06-24

Publications (1)

Publication Number Publication Date
WO2011161615A1 true WO2011161615A1 (en) 2011-12-29

Family

ID=44504008

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2011/052695 WO2011161615A1 (en) 2010-06-24 2011-06-20 5-lipoxygenase inhibitors

Country Status (1)

Country Link
WO (1) WO2011161615A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019182852A (en) * 2018-04-04 2019-10-24 日本たばこ産業株式会社 Pyrazole compound substituted with heteroaryl and pharmaceutical use thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0248594A2 (en) * 1986-05-29 1987-12-09 Ortho Pharmaceutical Corporation Pharmacologically active 1,5-diaryl-3-substituted-pyrazoles and method for synthesizing the same
WO2001087287A2 (en) 2000-05-19 2001-11-22 Applied Research Systems Ars Holding N.V. Use of pyrazole derivatives for treating infertility
WO2003026649A1 (en) 2001-09-27 2003-04-03 Applied Research Systems Ars Holding N.V. Methods of increasing endogenous testosterone levels
US20060075376A1 (en) 2004-09-15 2006-04-06 Chartered Semiconductor Manufacturing, Ltd. System and method for phase shift assignment
WO2008071456A2 (en) 2006-12-15 2008-06-19 Bayer Schering Pharma Aktiengesellschaft 3-h-pyrazolopyridines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
WO2009069044A1 (en) 2007-11-26 2009-06-04 Pfizer Inc. Pyrazole derivatives as 5-lo inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0248594A2 (en) * 1986-05-29 1987-12-09 Ortho Pharmaceutical Corporation Pharmacologically active 1,5-diaryl-3-substituted-pyrazoles and method for synthesizing the same
WO2001087287A2 (en) 2000-05-19 2001-11-22 Applied Research Systems Ars Holding N.V. Use of pyrazole derivatives for treating infertility
WO2003026649A1 (en) 2001-09-27 2003-04-03 Applied Research Systems Ars Holding N.V. Methods of increasing endogenous testosterone levels
US20060075376A1 (en) 2004-09-15 2006-04-06 Chartered Semiconductor Manufacturing, Ltd. System and method for phase shift assignment
WO2008071456A2 (en) 2006-12-15 2008-06-19 Bayer Schering Pharma Aktiengesellschaft 3-h-pyrazolopyridines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
WO2009069044A1 (en) 2007-11-26 2009-06-04 Pfizer Inc. Pyrazole derivatives as 5-lo inhibitors

Non-Patent Citations (29)

* Cited by examiner, † Cited by third party
Title
AM. J RESPIR CRIT. CARE MED, vol. 157, 1998, pages S210
AM. J RESPIR CRIT. CARE MED., vol. 157, 1998, pages S214
AM. J RESPIR. CRIT. CARE MED, vol. 157, 1998, pages S233
AM. J RESPIR. CRITIC CARE MED, vol. 157, 1998, pages S210
BIOCHEM J, vol. 274, 1991, pages 287 - 292
BR. J. PHARMACOL., vol. 94, 1988, pages 528 - 539
CLIN. EXP. ALLER. REVIEW, vol. 1, 2001, pages 235
CLIN. EXP. ALLER. REVIEWL, 2001, pages 254
CLIN. EXP. ALLERGY REV., vol. 1, 2001, pages 196
CLIN. EXP. ALLERGY REV., vol. 1, 2001, pages 220
CLIN. EXP. ALLERGY REV., vol. 1, 2001, pages 235
CLIN. EXP. ALLERGY REV., vol. 1, 2001, pages 264
CLIN. EXP.ALLERGY REV., vol. 1, 2001, pages 305
CURR. DRUG TARGETS - INFLAMMATION & ALLEW, vol. 1, 2002, pages 23
DRUG SAFETY, vol. 26, 2003, pages 483
DRUG SAFETY, vol. 26, 2003, pages 484
E. BANOGLU ET AL, TURKISH JOURNAL OF CHEMISTRY, vol. 31, no. 6, 2007, pages 677 - 687, XP002658111, ISSN: 1300-0527 *
EMERGING THERAPEUTIC TARGETS, vol. 3, 1999, pages 229
EUR. J PHARM., vol. 607, no. 1-3, 2009, pages 244 - 250
EUR. RESPIR. J, vol. 22, 2003, pages 926
EXPERT OPIN. INVESTIGATIONAL DRUGS, vol. 10, 2000, pages 1361
EXPERT OPIN. THER. PAT., vol. 120, 2010, pages 355 - 75
J MED. CHEM., vol. 52, no. 11, 2009, pages 3474
J. MED. CHEM., vol. 35, 1992, pages 1299 - 1318
J. PHARM., vol. 617, no. 1-3, 2009, pages 59 - 67
J. PHARMACOL. EXP. THER., vol. 285, 1998, pages 946
MED CHEM. LETT., 2010
NEJM, vol. 340, 1999, pages 197
THORAX, vol. 55, 2000, pages S32

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019182852A (en) * 2018-04-04 2019-10-24 日本たばこ産業株式会社 Pyrazole compound substituted with heteroaryl and pharmaceutical use thereof
JP7130588B2 (en) 2018-04-04 2022-09-05 日本たばこ産業株式会社 Heteroaryl-substituted pyrazole compounds and pharmaceutical uses thereof

Similar Documents

Publication Publication Date Title
KR101715190B1 (en) Pharmaceutical compounds
KR101804588B1 (en) Hematopoietic growth factor mimetic small molecule compounds and their uses
US10730863B2 (en) Bridged bicyclic compounds as farnesoid X receptor modulators
AU2006261841B8 (en) Pyrazole based LXR modulators
JP6116245B2 (en) Indoleamine derivatives and related compounds for use in the treatment of neurodegenerative diseases
CA2596527C (en) Igf-1r inhibitors
AU2007333194A1 (en) LXR and FXR modulators
KR20050044407A (en) N,n&#39;-substituted-1,3-diamino-2-hydroxypropane derivatives
KR20030074774A (en) Fused heterocyclic compounds
JP2007514690A (en) Benzazepine derivatives as histamine H3 antagonists
JPWO2006082952A1 (en) Amide compounds
EP3022199A1 (en) Cyanotriazole compounds
EP2074089A2 (en) Organic compounds
KR101386679B1 (en) Novel arylpiperazine-containing imidazole 4-carboxamide derivatives and pharmaceutical composition comprising same
WO2005111003A1 (en) Amino-tetrazoles analogues and methods of use
KR20090009934A (en) Compounds that are agonists of muscarinic receptors and that may be effective in treating pain, alzheimer&#39;s disease and/or schizophrenia
WO2009056556A1 (en) Substitute 1, 6-naphthyridines for use as scd inhibitors
JP2003238566A (en) Condensed heterocyclic compound
AU2006283884B2 (en) (Indol-3-yl)-heterocycle derivatives as agonists of the cannabinoid CB1 receptor
WO2005023782A1 (en) Substituted fused pyrimidine-4(3h)-one compound
KR20220027933A (en) Imidazo[1,2-C]pyrimidine derivatives as PRC2 inhibitors for the treatment of cancer
RU2412181C2 (en) Heteroaryl-substituted amides containing saturated binding group and use thereof as pharmaceutical agents
JP2000026430A (en) 2,5,6-substituted benzimidazole compound derivative
AU2010333829A1 (en) CRTH2 modulators
WO2011161615A1 (en) 5-lipoxygenase inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11743624

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11743624

Country of ref document: EP

Kind code of ref document: A1