Abstract:
The present invention relates to compounds of the formula                            
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Y are defined as in the specification, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the invention are useful in the treatment or alleviation of inflammation and other inflammation associated disorders, such as arthritis, colon cancer, and Alzheimer&#39;s disease in mammals, preferably humans, dogs, cats and livestock.

Description:
This application claims the benefit of U.S. Provisional No. 60/168,698, filed on Dec. 3, 1999. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention relates to acetylene derivatives, methods of treatment and pharmaceutical compositions for the treatment of cyclooxygenase mediated diseases. The compounds of this invention inhibit the biosynthesis of prostaglandins by intervention of the action of the enzyme cyclooxygenase on arachidonic acid, and are therefore useful in the treatment or alleviation of inflammation, other inflammation associated disorders, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock. 
     Nonsteroidal anti-inflammatory drugs (NSAID&#39;s) are widely used in treating pain and the signs and symptoms of arthritis because of their analgesic and anti-inflammatory activity. It is accepted that common NSAID&#39;s work by blocking the activity of cyclooxygenase (COX), also known as prostaglandin G/H synthase (PGHS), the enzyme that converts arachidonic acid into prostanoids. Prostaglandins, especially prostaglandin E 2  (PGE 2 ), which is the predominant eicosanoid detected in inflammation conditions, are mediators of pain, fever and other symptoms associated with inflammation. Inhibition of the biosynthesis of prostaglandins has been a therapeutic target of anti-inflammatory drug discovery. The therapeutic use of conventional NSAID&#39;s is, however, limited due to drug associated side effects, including life threatening ulceration and renal toxicity. An alternative to NSAID&#39;s is the use of corticosteroids; however, long term therapy can also result in severe side effects. 
     The use of NSAID&#39;s in dogs and cats has been more limited than that in humans, e.g., only three such NSAID&#39;s have been approved by the Food and Drug Administration, Committee on Veterinary Medicine (FDA/CVM), for use in dogs in the United States, i.e., ETOGESIC® (etodolac), ARQUEL®) (meclofenamic acid) and RIMADYL® (carprofen). Consequently, there is less experience and knowledge in veterinary medicine about safety and efficacy issues surrounding the use of NSAID&#39;s in dogs. In veterinary medicine, for example, the most common indication for NSAID&#39;s is the treatment of degenerative joint disease (DJD), which in dogs often results from a variety of developmental diseases, e.g., hip dysplasia and osteochondrosis, as well as from traumatic injuries to joints. In addition to the treatment of chronic pain and inflammation, NSAID&#39;s are also useful in dogs for treating post-surgical acute pain, as well as for treating clinical signs associated with osteoarthritis. 
     Two forms of COX are now known, a constitutive isoform (COX-1) and an inducible isoform (COX-2) of which expression is upregulated at sites of inflammation (Vane, J. R.; Mitchell, J. A.; Appleton, I.; Tomlinson, A.; Bishop-Bailey, D.; Croxtoll, J.; Willoughby, D. A.  Proc. Natl. Acad. Sci. USA,  1994, 91, 2046). COX-1 is thought to play a physiological role and to be responsible for gastrointestinal and renal protection. On the other hand, COX-2 appears to play a pathological role and is believed to be the predominant isoform present in inflammation conditions. A pathological role for prostaglandins has been implicated in a number of human disease states including rheumatoid arthritis and osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular diseases, dysmenorrhea, premature labor, nephritis, nephrosis, atherosclerosis, hypotension, shock, pain, cancer, and Alzheimer disease. It is believed that compounds that selectively inhibit the biosynthesis of prostaglandins by intervention of the induction phase of the inducible enzyme COX-2 and/or by intervention of the activity of the enzyme COX-2 on arachidonic acid would provide alternate therapy to the use of NSAID&#39;s or corticosteroids in that such compounds would exert anti-inflammatory effects without the adverse side effects associated with COX-1 inhibition. 
     A variety of sulfonylbenzene compounds which inhibit COX have been disclosed in patent publications (WO 97/16435, WO 97/14691, WO 96/19469, WO 96/36623, WO 96/03392, WO 96/03387, WO 97/727181, WO 96/936617, WO 96/19469, WO 96/08482, WO 95/00501, WO 95/15315, WO 95/15316, WO 95/15317, WO 95/15318, WO 97/13755, EP 0799523, EP 418845, and EP 554829). Especially important is International Publication Number WO 97/11704, which discloses pyrazole compounds substituted by optionally substituted aryl. 
     SUMMARY OF THE INVENTION 
     The present invention relates to compounds of the formula                           
     wherein 
     n is one or two; 
     X is CR 7  or N; 
     Y is CR 8 or N; 
     R 1  is (C 1 -C 6 )alkyl or —NH 2 ; 
     R 2  is hydrogen, halo (more preferably chloro or fluoro, most preferably fluoro), (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbon formamidyl, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl, N—(C 1 -C 6 )alkylaminocarbonyl, N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl, N—(C 6 -C 10 )arylaminocarbonyl, N,N—[(C 6 -C 10 )aryl] 2 aminocarbonyl, N—(C 1 - 6 )alkyl-N—(C 6 -C 10 )arylaminocarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryloxy, morpholino-carbonyl, (C 1 -C 6 )alkoxycarbonylamino or (C 1 - 6 )alkylcarbonylamino; 
     wherein said R 2  (C 1 -C 6 )alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C 1 - 6 )alkoxy, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl, N—(C 1 -C 6 )alkylaminocarbonyl, N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl, N—(C 6 -C 10 )arylaminocarbonyl, N,N—[(C 6 -C 10 )aryl] 2 aminocarbonyl, N—(C 1 -C 6 )alkyl-N—(C 6 -C 10 )arylaminocarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryloxy, morpholino-carbonyl, (C 1 -C 6 )alkoxycarbonylamino or (C 1 -C 6 )alkylcarbonylamino; 
     R 3  is hydrogen, halo (more preferably chloro or fluoro, most preferably fluoro), (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl, formyl, formamidyl, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl, N—(C 1 -C 6 )alkylaminocarbonyl, N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl, N—(C 6 -C 10 )arylaminocarbonyl, N,N—[(C 6 -C 10 )aryl] 2 aminocarbonyl, N—(C 1 -C 6 )alkyl-N—(C 6 -C 10 )arylaminocarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryloxy, morpholino-carbonyl, (C 1 -C 6 )alkoxycarbonylamino or (C 1 -C 6 )alkylcarbonylamino; 
     wherein said R 3  (C 1 -C 6 )alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C 1 -C 6 )alkoxy, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl, N—(C 1 -C 6 )alkylaminocarbonyl, N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl, N—(C 6 -C 10 )arylaminocarbonyl, N,N—[(C 6 -C 10 )aryl] 2 aminocarbonyl, N—(C 1 -C 6 )alkyl-N—(C 6 -C 10 )arylaminocarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 1 )heteroaryl, (C 2 -C 9 )heteroaryloxy, morpholino-carbonyl, (C 1 -C 6 )alkoxycarbonylamino or (C 1 -C 6 )alkylcarbonylamino; 
     R 4  is hydrogen, (C 1 -C 6 )alkyl, —(CH 2 ) m —(C 6 -C 10 )aryl, —(CH 2 -C 9 ) m —(C 2 -C 9 )heteroaryl, wherein m is an integer from 0 to 4; 
     wherein said —(CH 2 ) m —(C 6 -C 10 aryl, —(CH 2 ) m —(C 2 -C 9 )heteroaryl may optionally be substituted with one to three substituents independently selected from halo (preferably fluoro or chloro); hydroxy; mercapto; (C 1 -C 6 )alkyl; (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms (preferably fluoro); (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; cyano; formyl; (C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )alkyl-(C═O)—O—; (C 1 -C 6 )alkoxy-(C═O)—; aminocarbonyl; N—(C 1 -C 6 )alkylaminocarbonyl; N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl; nitro; amino; (C 1 -C 6 )alkylamino; [(C 1 -C 6 )alkyl] 2 amino; or (C 1 C 6 )alkyl-S—; 
     wherein said R 4  (C 1 -C 6 )alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C 1 -C 6 )alkoxy, cyano, nitro, C 1 -C 6 )alkoxycarbonyl, aminocarbonyl, N—(C 1 -C 6 )alkylaminocarbonyl, N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl, N—(C 6 -C 10 )arylaminocarbonyl, N,N—[(C 6 -C 10 )aryl] 2 aminocarbonyl, N—(C 1 -C 6 )alkyl-N—(C 6 -C 10 )arylaminocarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryloxy, morpholino-carbonyl, (C 1 -C 6 )alkoxycarbonylamino, (C 1 -C 6 )alkylcarbonylamino or (C 1 -C 6 )cycloalkylamino; 
     R 5  is hydrogen, halo (more preferably chloro or fluoro, most preferably fluoro), (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl, formyl, formamidyl, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl, N—(C 1 -C 6 )alkylaminocarbonyl, N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl, N—(C 6 -C 10 )arylaminocarbonyl, N,N—[(C 6 -C 10 )aryl] 2 aminocarbonyl, N—(C 1 -C 6 )alkyl-N—(C 6 -C 10 )arylaminocarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryloxy, morpholino-carbonyl, (C 1 -C 6 )alkoxycarbonylamino or (C 1 -C 6 )alkylcarbonylamino; 
     wherein said R 5  (C 1 -C 6 )alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C 1 -C 6 )alkoxy, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl, N—(C 1 -C 6 )alkylaminocarbonyl, N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl, N—(C 6 -C 10 )arylaminocarbonyl, N,N—[(C 6 -C 10 )aryl] 2 aminocarbonyl, N—(C 1 -C 6 )alkyl-N—(C 6 -C 10 )arylaminocarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryloxy, morpholino-carbonyl, (C 1 -C 6 )alkoxycarbonylamino or (C 1 -C 6 )alkylcarbonylamino; 
     R 6  is hydrogen, halo (more preferably chloro or fluoro, most preferably fluoro), (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl, formyl, formamidyl, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl, N—(C 1 -C 6 )alkylaminocarbonyl, N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl, N—(C 6 -C 10 )arylaminocarbonyl, N,N—[(C 6 -C 10 )aryl] 2 aminocarbonyl, N—(C 1 -C 6 )alkyl-N—(C 6 -C 10 )arylaminocarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryloxy, morpholino-carbonyl, (C 1 -C 6 )alkoxycarbonylamino or (C 1 -C 6 )alkylcarbonylamino; 
     wherein said R 6  (C 1 -C 6 )alkyl may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C 1 -C 6 )alkoxy, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl, N—(C 1 -C 6 )alkylaminocarbonyl, N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl, N—(C 6 -C 10 )arylaminocarbonyl, N,N—[(C 6 -C 10 )aryl] 2 aminocarbonyl, N—(C 1 -C 6 )alkyl-N—(C 6 -C 10 )arylaminocarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryloxy, morpholino-carbonyl, (C 1 -C 6 )alkoxycarbonylamino or (C 1 -C 6 )alkylcarbonylamino; 
     R 7  is hydrogen; halo (preferably fluoro or chloro); hydroxy; mercapto; (C 1 -C 6 )alkyl; (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms (preferably fluoro); (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; cyano; formyl; (C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )alkyl-(C═O)—O—; —CO 2 H; (C 1 -C 6 )alkoxycarbonyl; aminocarbonyl; N—(C 1 -C 6 )alkylaminocarbonyl; N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl; nitro; amino; (C 1 -C 6 )alkylamino; [(C 1 -C 6 )alkyl] 2 amino; or (C 1 -C 6 )alkyl S—; 
     wherein said R 7  (C 1 -C 6 )alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C 1 -C 6 )alkoxy, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl, N—(C 1 -C 6 )alkylaminocarbonyl, N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl, N—(C 6 -C 10 )arylaminocarbonyl, N,N—[(C 6 -C 10 )aryl] 2 aminocarbonyl, (C 1 -C 6 )alkyl-N—(C 6 -C 10 )arylaminocarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryloxy, morpholino-carbonyl, (C 1 -C 6 )alkoxycarbonylamino or (C 1 -C 6 )alkylcarbonylamino; 
     R 8  is hydrogen; halo (preferably fluoro or chloro); hydroxy; mercapto; (C 1 -C 6 )alkyl; (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms (preferably fluoro); (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; cyano; formyl; (C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )alkyl-(C═O)—O—; —CO 2 ; (C 1 -C 6 )alkoxycarbonyl; aminocarbonyl; N—(C 1 -C 6 )alkylaminocarbonyl; N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl; nitro; amino; (C 1 -C 6 )alkylamino; [(C 1 -C 6 )alkyl] 2 amino; or (C 1 -C 6 )alkyl S—; 
     wherein said R 8  (C 1 -C 6 )alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C 1 -C 6 )alkoxy, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl, N—(C 1 -C 6 )alkylaminocarbonyl, N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl, N—(C 6 -C 10 )arylaminocarbonyl, N,N—[(C 6 -C 10 )aryl] 2 aminocarbonyl, N—(C 1 -C 6 )alkyl-N—(C 6 -C 10 )arylaminocarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryloxy, morpholino-carbonyl, (C 1 -C 6 )alkoxycarbonylamino or (C 1 -C 6 )alkylcarbonylamino; 
     and the pharmaceutically acceptable salts of such compounds. 
     The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula 1. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts. 
     The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (eg., potassium and sodium) and alkaline earth metal cations (eg., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. 
     The compounds of this invention include all stereoisomers (eg., cis and trans isomers) and all optical isomers of compounds of the formula I (eg., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers. 
     The compounds of the invention also exist in different tautomeric forms. This invention relates to all tautomers of formula 1. 
     The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. 
     Unless otherwise indicated, the alkyl, referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tertiary-butyl), and they may also be cyclic (e.g., cyclopropyl, or cyclobutyl); optionally substituted by 1 to 3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C 1 -C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C 1 -C 6 )alkyl. The phrase “each of said alkyl” as used herein refers to any of the preceding alkyl moieties within a group such alkoxy, alkenyl or alkylamino. Preferred alkyls include (C 1 -C 4 )alkyl, most preferably methyl. 
     Unless otherwise indicated, halogen includes fluoro, chloro, bromo or iodo, or fluoride, chloride, bromide or iodide. 
     As used herein, the term “halo-substituted alkyl” refers to an alkyl radical as described above substituted with one or more halogens included, but not limited to, chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C 1 -C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C 1 -C 6 )alkyl. 
     As used herein, the term “alkenyl” means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C 1 -C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C 1 -C 6 )alkyl. 
     As used herein, the term “(C 2 -C 6 )alkynyl” is used herein to mean straight or branched hydrocarbon chain radicals having one triple bond including, but not limited to, ethynyl, propynyl, butynyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C 1 -C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C 1 -C 6 )alkyl. 
     As used herein, the term “carbonyl” (as used in phrases such as alkylcarbonyl or alkoxycarbonyl) refers to the joinder of the &gt;C═O moiety to a second moiety such as an alkyl or amino group (i.e. an amido group). Alkoxycarbonylamino refers to an alkyl carbamate group. The carbonyl group is also equivalently defined herein as (C═O). Alkylcarbonylamino refers to groups such as acetamide. 
     As used herein, the term “aryl” means aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like; optionally substituted by 1 to 3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C 1 -C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C 1 -C 6 )alkyl. 
     As used herein, the term “heteroaryl” refers to an aromatic heterocyclic group usually with one heteroatom selected from O, S and N in the ring. In addition to said heteroatom, the aromatic group may optionally have up to four N atoms in the ring. For example, heteroaryl group includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), tetrazole, quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C 1 -C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C 1 -C 6 )alkyl. Particularly preferred heteroaryl groups include pyridyl, thienyl, furyl, thiazolyl and pyrazolyl (these heteroaryls are most preferred of the R 4  heteroaryls). 
     “A suitable substituent” is intended to mean a chemically and pharmaceutically acceptable functional group i.e., a moiety that does not negate the inhibitory activity of the inventive compounds. Such suitable substituents may be routinely selected by those skilled in the art. Illustrative examples of suitable substituents include, but are not limited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy or heteroaralkoxy groups, —CO 2 H groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups dialkylamino carbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, an arylsulfonyl groups and the like. 
     An embodiment of the present invention includes compounds of formula I, referred to as the Arylsulfonyl Group of compounds, wherein X and Y are both carbon. Another embodiment of the present invention includes compounds of formula I, referred to as the Pyridin-2-yl-sulfonyl Group of compounds, wherein X is nitrogen and Y is carbon. Another embodiment of the present invention includes compounds of formula I, referred to as the Pyridin-3-yl-sulfonyl Group of compounds, wherein Y is nitrogen and X is carbon. Another embodiment of the present invention includes compounds of formula I, referred to as the Pyridazin-2-yl-sulfonyl Group of compounds, wherein X and Y are both nitrogen. 
     Another embodiment of the present invention includes compounds of formula I, referred to as the Acetylene Group of compounds, wherein R 4  is hydrogen. Another embodiment of the present invention includes compounds of formula I, referred to as the Alkylacetylene Group of compounds, wherein R 4  is (C 1 -C 6 )alkyl. Another embodiment of the present invention includes compounds of formula I, referred to as the Arylacetylene Group of compounds, wherein R 4  is —(CH 2 ) m —(C 6 -C 10 )aryl. Another embodiment of the present invention includes compounds of formula I, referred to as the Heteroarylacetylene Group of compounds, wherein R 4  is —(CH 2 ) m —(C 2 -C 9 )heteroaryl. 
     Subgeneric embodiments of the present invention of the Arylsulfonyl Group of compounds are expressly contemplated by the present invention. Such subgeneric embodiments within the Arylsulfonyl Group of compounds include the Arylsulfonyl Group in combination with each of the R 4  groups (i.e. Acetylene-Arylsulfonyl Group, Alkylacetylene-Arylsulfonyl Group, Arylacetylene-Arylsulfonyl Group and Heteroarylacetylene-Arylsulfonyl Group. 
     Subgeneric embodiments of the present invention of the Pyridin-2-yl-sulfonyl Group of compounds are expressly contemplated by the present invention. Such subgeneric embodiments within the Pyridin-2-yl-sulfonyl Group of compounds include the Pyridin-2-yl-sulfonyl Group in combination with each of the R 4  groups (i.e. Acetylene-Pyridin-2-yl-sulfonyl Group, Alkylacetylene-Pyridin-2-yl-sulfonyl Group, Arylacetylene-Pyridin-2-yl-sulfonyl Group and Heteroarylacetylene-Pyridin-2-yl-sulfonyl Group. 
     Subgeneric embodiments of the present invention of the Pyridin-3-yl-sulfonyl Group of compounds are expressly contemplated by the present invention. Such subgeneric embodiments within the Pyridin-3-yl-sulfonyl Group of compounds include the Pyridin-3-yl-sulfonyl Group in combination with each of the R 4  groups (i.e. Acetylene-Pyridin-3-yl-sulfonyl Group, Alkylacetylene-Pyridin-3-yl-sulfonyl Group, Arylacetylene-Pyridin-3-yl-sulfonyl Group and Heteroarylacetylene-Pyridin-3-yl-sulfonyl Group. 
     Subgeneric embodiments of the present invention of the Pyridazin-2-yl-sulfonyl Group of compounds are expressly contemplated by the present invention. Such subgeneric embodiments within the Pyridazin-2-yl-sulfonyl Group of compounds include the Pyridazin-2-yl-sulfonyl Group in combination with each of the R 4  groups (i.e. Acetylene-Pyridazin-2-yl-sulfonyl Group, Alkylacetylene-Pyridazin-2-yl-sulfonyl Group, Arylacetylene-Pyridazin-2-yl-sulfonyl Group and Heteroarylacetylene-Pyridazin-2-yl-sulfonyl Group. 
     Preferred compounds of this invention are those of the formula (I) wherein X is CR 7  and Y is nitrogen. 
     Other preferred compounds of this invention are those of the formula (I) wherein X is nitrogen and Y is CR 8 . 
     Other preferred compounds of this invention are those of the formula (I) wherein X is CR 7  and Y is CR 8 , more preferably wherein R 7  and R 8  are each independently selected from hydrogen, (C 1 -C 4 )alkyl and halogen, more preferably hydrogen and methyl. 
     Other preferred compounds of this invention are those of the formula (I) wherein R 1  is (C 1 -C 6 )alkyl (preferably methyl) or —NH 2 . 
     Other preferred compounds of this invention are those of the formula (I) wherein R 4  is hydrogen or optionally substituted (C 1 -C 6 )alkyl, —(CH 2 ) m —(C 6 -C 10 )aryl or —(CH 2 ) m —(C 2 -C 9 )heteroaryl. More preferred compounds are those wherein the R 4 -acetylene group is in the para or meta position, more preferably the R 4 -acetylene group is in the para position. Most preferred R 4  groups are hydrogen and (C 1 -C 6 )alkyl. 
     Preferred optionally substituted —(CH 2 ) m —(C 6 -C 10 )aryl, —(CH 2 ) m —(C 2 -C 9 )heteroaryl are those optionally substituted with zero or one substituent selected from halo (preferably fluoro or chloro); hydroxy; mercapto; (C 1 -C 6 )alkyl; (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms (preferably fluoro); (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; cyano; formyl; (C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )alkyl-(C═O)—O— and (C 1 -C 6 )alkoxycarbonyl; more preferably from halo (preferably fluoro or chloro); hydroxy; (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms (preferably fluoro); most preferably halo, (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy. 
     Preferred optionally substituted (C 1 -C 6 )alkyl are those optionally substituted with one to three substituents (preferably one substituent) independently selected from halo, hydroxy, (C 1 -C 6 )alkoxy, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxycarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroaryl and (C 2 -C 9 )heteroaryloxy, more preferably halo, hydroxy, (C 1 -C 6 )alkoxy and (C 6 -C 10 )aryloxy, most preferably halo and (C 1 -C 6 )alkoxy. 
     Other preferred compounds of this invention are those of the formula (I) wherein R 5  is H or methyl. 
     Other preferred compounds of this invention are those of the formula (I) wherein R 6  is CF 3  or CF 2 H. 
     Other preferred compounds of this invention are those of the formula (I) wherein R 3  is hydrogen, halo (more preferably chloro or fluoro, most preferably fluoro), (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl, formyl, formamidyl, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl, N—(C 1 -C 6 )alkylaminocarbonyl, N,N—[(C 1 -C 6 )alkyl] 2 aminocarbonyl, N—(C 6 -C 10 )arylaminocarbonyl, N,N—[(C 6 -C 10 )aryl] 2 aminocarbonyl, (C 1 -C 6 )alkyl-N—(C 6 -C 10 )arylaminocarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryloxy, morpholino-carbonyl, (C 1 -C 6 )alkoxyaminocarbonyl or (C 1 -C 6 )alkylcarbonylamino; 
     Examples of specific preferred compounds of the formula I are the following: 
     4-[5-(4-Ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-benzenesulfonamide, 
     4-[5-(3-Ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-benzenesulfonamide, 
     4-[5-(4-Ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2-fluoro-benzenesulfonamide, 
     2-Aminosulfonyl-5-[5-(4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     2-Aminosulfonyl-5-[5-(3-ethynyl-phenyl)3trifluoromethylpyrazol-1-yl]-pyridine, 
     2-Methylsulfonyl-5-[5-(4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     5-Methylsulfonyl-2-[5-(4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-y]-pyridine, 
     2-Aminosulfonyl-5-[5-(3-ethynyl-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     5-Methylsulfonyl-2-[5-(4-ethyny-phenyl)-3-difluoromethyl-pyrazol-1-yl]-pyridine, 
     4-[5-(3-Ethynyl-4-methoxy-phenyl)-3-difluoromethyl-pyrazol-1-yl]-benzenesulfonamide, 
     5-(4-Ethynyl-phenyl)-3-trifluoromethyl-1-(4-methylsulfonylphenylypyrazole, and 
     4-[5-(3-Ethynyl-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2-fluoro-benzenesulfonamide. 
     Other compounds of formula I include the following: 
     4-[5-(3-Methyl-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-benzenesulfonamide, 
     4-(5-(3-Fluoro-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl-benzenesulfonamide, 
     4-[5-(3-Chloro-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-benzenesulfonamide, 
     5-(3-Methyl-4-ethynyl-phenyl)-1-( 4 -methylsulfonylphenyl)-3-trifluoromethyl-pyrazole, 
     5-(3-Fluoro-4-ethynyl-phenyl)-1-(4-methylsulfonylphenyl)-3-trifluoromethyl-pyrazole, 
     5-(3-Chloro-4-ethynyl-phenyl)-1-(4-methylsulfonylphenyl)-3-trifluoromethyl-pyrazole, 
     5-Methylsulfonyl-2-[5-(3-methyl-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     5-Methylsulfonyl-2-[5-(3-fluoro-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     5-Methylsulfonyl-2-[5-(3-chloro-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     2-Methylsulfonyl-5-[5-(3-methyl-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     2-Methylsulfonyl-5-[5-(3-chloro-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     2-Methylsulfonyl-5-[5-(3-fluoro-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     2-Aminosulfonyl-5-[5-(3-methyl-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     2-Aminosulfonyl-5-[5-(3-fluoro-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     2-Aminosulfonyl-5-[5-(3-chloro-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     5-Aminosulfonyl-2-[5-(3-methyl4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     5-Aminosulfonyl-2-[5-(3-fluoro4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     5-Aminosulfonyl-2-[5-(3-chloro-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     5-Aminosulfonyl-2-[5-(4-ethynyl-phenyl)3-trifluoromethyl-pyrazol-1-yl]-pyridine, 
     4-[5-(3-Methyl4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2-fluoro-benzenesulfonamide, 
     4-[5-(3-Chloro4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2-fluoro-benzenesulfonamide, 
     4-[5-(3-Fluoro-4-ethynyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2-fluoro-benzenesulfonamide, 
     5-[3-Ethynyl-4-(1,3-thiazol-4-yl)-phenyl]-3-trifluoromethyl-1-(4-methylsulfonylphenyl)-pyrazole, 
     5-[3-Ethynyl-4-(furan-2-yl)-phenyl]-3-trifluoromethyl-1-(4-methylsulfonylphenyl)-pyrazole, 
     5-[3-Ethynyl-4-(1,3-thiazol-4-yl )-phenyl]-3-trifluoromethyl-1-(4-aminosulfonylphenyl)-pyrazole, 
     5-[3-Ethynyl-4-(furan-2-yl)-phenyl]-3-trifluoromethyl-1-(4-aminosulfonylphenyl)-pyrazole, 
     5-[3-Ethynyl-4-(1,3-th iazol-4-yl)-phenyl]-3-trifluoromethyl-1-[2-(5-methylsulfonyl)-pyridyl]-pyrazole, 
     5-[3-Ethynyl-4-(1,3-thiazol-4-yl)-phenyl]-3-trifluoromethyl-1-[5-(2-methylsulfonyl)-pyridyl]-pyrazole, 
     5-[3-Ethynyl-4-(furan-2-yl)-phenyl]-3-trifluoromethyl-1-[2-(5-methylsulfonyl)-pyridyl]-pyrazole, 
     5-[3-Ethynyl-4-(furan-2-yl)-phenyl]-3-trifluoromethyl-1-[5-(2-methylsulfonyl)-pyridyl]pyrazole, 
     5-[3-Ethynyl-4-(1,3-thiazol-4-yl)-phenyl]-3-trifluoromethyl-1-[2-(5-aminosulfonyl)-pyridyl]-pyrazole, 
     5-[3-Ethynyl-4-(1,3-thiazol-4-yl)-phenyl]-3-trifluoromethyl-1-[5-(2-aminosulfonyl)-pyridyl]-pyrazole, 
     5-[3-Ethynyl-4-(furan-2-yl)-phenyl]-3-trifluoromethyl-1-[2-(5-aminosulfonyl)-pyridyl]-pyrazole, 
     5-[3-Ethynyl-4-(furan-2-yl)-phenyl]-3-trifluoromethyl-1-[5-(2-aminosulfonyl)-pyridyl]-pyrazole, 
     5-[3-Ethynyl-4-(furan-2-yl)-phenyl]-3-trifluoromethyl-pyrazol-1-yl]-2-fluoro-benzenesulfonamide, and 
     5-[3-Ethynyl-4-(1,3-thiazol-4-yl)-phenyl]-3-trifluoromethyl-pyrazol-1-yl]-2-fluoro-benzenesulfonamide. 
     The present invention also relates to a pharmaceutical composition for the treatment of a condition selected from the group consisting of arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), fever (including rheumatic fever and fever associated with influenza and other viral infections), common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn&#39;s disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer&#39;s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostrate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin&#39;s disease; aplastic anemia, skin cancer and familiar adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington&#39;s disease, Parkinson&#39;s disease, migraine, depression, peripheral neuropathy, pain (including low back and neck pain, headache and toothache), gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, bums, diabetes (including types I and II diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats), sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Beheet&#39;s syndrome, hypersensitivity, kidney disease, Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoan diseases (such as malaria, giardia, coccidia), reproductive disorders (preferably in livestock) and septic shock in a mammal, preferably a human, cat, livestock or a dog, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in such treatment and a pharmaceutically acceptable carrier. 
     The present invention also relates to a pharmaceutical composition for the treatment of a disorder or condition that can be treated by selectively inhibiting COX-2 in a mammal, preferably a human, cat, livestock or dog, comprising a COX-2 selective inhibiting effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     The present invention also relates to a method for treating a condition selected from the group consisting of arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), fever (including rheumatic fever and fever associated with influenza and other viral infections), common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn&#39;s disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer&#39;s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostrate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin&#39;s disease; aplastic anemia, skin cancer and familiar adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington&#39;s disease, Parkinson&#39;s disease, migraine, depression, peripheral neuropathy, pain (including low back and neck pain, headache and toothache), gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes (including types I and II diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats), sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet&#39;s syndrome, hypersensitivity, kidney disease, Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoan diseases (such as malaria, giardia, coccidia), reproductive disorders (preferably in livestock) and septic shock in a mammal, preferably a human, cat, livestock or a dog, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition. 
     The present invention also relates to a method for treating a disorder or condition that can be treated or prevented by selectively inhibiting COX-2 in a mammal, preferably a human, cat, livestock or a dog, comprising administering to a mammal requiring such treatment a COX-2 selective inhibiting effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. 
     This invention also relates to a method of or a pharmaceutical composition for treating inflammatory processes and diseases comprising administering a compound of formula I of this invention or its salt to a mammal including a human, cat, livestock or dog, wherein said inflammatory processes and diseases are defined as above, and said inhibitory compound is used in combination with one or more other therapeutically active agents under the following conditions: 
     A. where a joint has become seriously inflamed as well as infected at the same time by bacteria, fungi, protozoa, and/or virus, said inhibitory compound is administered in combination with one or more antibiotic, antifungal, antiprotozoal, and/or antiviral therapeutic agents; 
     B. where a multi-fold treatment of pain and inflammation is desired, said inhibitory compound is administered in combination with inhibitors of other mediators of inflammation, comprising one or more members independently selected from the group consisting essentially of: 
     (1) NSAID&#39;s; 
     (2) H 1 -receptor antagonists; 
     (3) kinin-B 1 - and B 2 -receptor antagonists; 
     (4) prostaglandin inhibitors selected from the group consisting of PGD-, PGF-PGI 2 -, and PGE-receptor antagonists; 
     (5) thromboxane A 2  (TXA 2 —) inhibitors; 
     (6) 5-, 12- and 15-, lipoxygenase inhibitors; 
     (7) leukotriene LTC 4 —, LTD 4 /LTE 4 —, and LTB 4 —, inhibitors; 
     (8) PAF-receptor antagonists; 
     (9) gold in the form of an aurothio group together with one or more hydrophilic groups; 
     (10) immunosuppressive agents selected from the group consisting of cyclosporine, azathioprine, and methotrexate; 
     (11) anti-inflammatory glucocorticoids; 
     (12) penicillamine; 
     (13) hydroxychloroquine; 
     (14) anti-gout agents including colchicine; xanthine oxidase inhibitors including allopurinol; and uricosuric agents selected from probenecid, sulfinpyrazone, and benzbromarone; 
     C. where older mammals are being treated for disease conditions, syndromes and symptoms found in geriatric mammals, said inhibitory compound is administered in combination with one or more members independently selected from the group consisting essentially of: 
     (1) cognitive therapeutics to counteract memory loss and impairment; 
     (2) anti-hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, hypertension, myocardial ischemia, angina, congestive heart failure, and myocardial infarction, selected from the group consisting of: 
     a. diuretics; 
     b. vasodilators; 
     c. β-adrenergic receptor antagonists; 
     d. angiotensin-II converting enzyme inhibitors (ACE-inhibitors), alone or optionally together with neutral endopeptidase inhibitors; 
     e. angiotensin II receptor antagonists; 
     f. renin inhibitors; 
     g. calcium channel blockers; 
     h. sympatholytic agents; 
     i. α 2 -adrenergic agonists; 
     j. α-adrenergic receptor antagonists; and 
     k. HMG-CoA-reductase inhibitors (anti-hypercholesterolemics); 
     (3) antineoplastic agents selected from: 
     a. antimitotic drugs selected from: 
     i. vinca alkaloids selected from: 
     [1] vinblastine, and 
     [2] vincristine; 
     (4) growth hormone secretagogues; 
     (5) strong analgesics; 
     (6) local and systemic anesthetics; and 
     (7) H 2 -receptor antagonists, proton pump inhibitors, and other gastroprotective agents. 
     The term “treating”, as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, refers to the act of treating, as “treating” is defined immediately above. 
     The term “livestock animals” as used herein refers to domesticated quadrupeds, which includes those being raised for meat and various byproducts, e.g., a bovine animal including cattle and other members of the genus Bos, a porcine animal including domestic swine and other members of the genus Sus, an ovine animal including sheep and other members of the genus Ovis, domestic goats and other members of the genus Capra; domesticated quadrupeds being raised for specialized tasks such as use as a beast of burden, e.g., an equine animal including domestic horses and other members of the family Equidae, genus Equus, or for searching and sentinel duty, e.g., a canine animal including domestic dogs and other members of the genus Canis; and domesticated quadrupeds being raised primarily for recreational purposes, e.g., members of Equus and Canis, as well as a feline animal including domestic cats and other members of the family Felidae, genus Felis. 
     “Companion animals” as used herein refers to cats and dogs. As used herein, the term “dog(s)” denotes any member of the species  Canis familiaris , of which there are a large number of different breeds. While laboratory determinations of biological activity may have been carried out using a particular breed, it is contemplated that the inhibitory compounds of the present invention will be found to be useful for treating pain and inflammation in any of these numerous breeds. Dogs represent a particularly preferred class of patients in that they are well known as being very susceptible to chronic inflammatory processes such as osteoarthritis and degenerative joint disease, which in dogs often results from a variety of developmental diseases, e.g., hip dysplasia and osteochondrosis, as well as from traumatic injuries to joints. Conventional NSAID&#39;s, if used in canine therapy, have the potential for serious adverse gastrointestinal reactions and other adverse reactions including kidney and liver toxicity. Gastrointestinal effects such as single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestine, are usually debilitating, but can often be severe or even fatal. 
     The term “treating reproductive disorders (preferably in livestock)” as used herein refers to the use of the COX-2 inhibitors of the invention in mammals, preferably livestock animals (cattle, pigs, sheep, goats or horses) during the estrus cycle to control the time of onset of estrus by blocking the uterine signal for lysis of the corpus luteum, i.e. F-series prostaglandins, then removing the inhibition when the onset of estrus is desired. There are settings where it is useful to control or synchronize the time of estrus, especially when artificial insemination or embryo transfer are to be performed. Such use also includes enhancing the rate of embryo survival in pregnant livestock animals. Blocking F-series prostaglandin release can have several beneficial actions including reducing uterine contractions, enhancing uteroplacental bloodflow, supporting recognition of pregnancy, and postponing lysis of the corpus luteum at the time when estrus would have occurred had the animal not become pregnant (around Day 21 of pregnancy). Such treatment also abrogates the effects of stress on reproduction. For example reductions in fertility caused by excessive heat, negative energy balance and other stresses which have a COX-2 mediated component, as does abortion induced by stress such as heat, transportation, co-mingling, palpation, infection, etc. Such treatment is also useful to control the time of parturition, which is accompanied by release of F-series prostaglandins that lead to lysis of the corpus luteum. Inhibition of COX-2 would block the onset of premature labor in livestock animals, allowing the offspring time to mature before birth. Also there are settings where controlling the time of parturition is a useful tool for management of pregnant animals. 
     The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as  2 H,  3 H,  13 C,  14 C,  15 N,  18 O,  17 O,  31 P,  32 P,  18 S,  18 F, and  36 Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as  3 H and  14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e.,  3 H, and carbon-14, i.e.,  14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,  2 H, can afford certain therapeutic and diagnostic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. 
     This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the formula I. This invention also encompasses methods of treating or preventing disorders that can be treated or prevented by the selective inhibition of COX-2 comprising administering prodrugs of compounds of the formula I. Compounds of formula I having free amino, amido, hydroxy, carboxylic acid ester, sulfonamide or carboxylic groups (especially alkyl-S— and alkyl-(S═O)—) can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, omithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain. Prodrugs also include metabolically labile groups such as ethers, acetates, mercaptans and sulfoxides. 
     One of ordinary skill in the art will appreciate that the compounds of the invention are useful in treating a diverse array of diseases. One of ordinary skill in the art will also appreciate that when using the compounds of the invention in the treatment of a specific disease that the compounds of the invention may be combined with various existing therapeutic agents used for that disease. 
     For the treatment of rheumatoid arthritis, the compounds of the invention may be combined with agents such as TNF-α inhibitors such as anti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules (such as Enbrel®), low dose methotrexate, lefunimide, hydroxychloroquine, d-penicilamine, auranofin or parenteral or oral gold. 
     The compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAID&#39;s) such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib and rofecoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc. 
     The active ingredient of the present invention may be administered in combination with inhibitors of other mediators of inflammation, comprising one or more members selected from the group consisting essentially of the classes of such inhibitors and examples thereof which include, matrix metalloproteinase inhibitors, aggrecanase inhibitors, TACE inhibitors, leucotriene receptor antagonists, IL-1 processing and release inhibitors, IL-1 ra, H 1 -receptor antagonists; kinin-B 1 - and B 2 -receptor antagonists; prostaglandin inhibitors such as PGD-, PGF-PGI 2 -, and PGE-receptor antagonists; thromboxane A 2  (TXA2-) inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene LTC 4 -, LTD 4 /LTE 4 -, and LTB 4 -inhibitors; PAF-receptor antagonists; gold in the form of an aurothio group together with various hydrophilic groups; immunosuppressive agents, e.g., cyclosporine, azathioprine, and methotrexate; anti-inflammatory glucocorticoids; penicillamine; hydroxychloroquine; anti-gout agents, e.g., colchicine, xanthine oxidase inhibitors, e.g., allopurinol, and uricosuric agents, e.g., probenecid, sulfinpyrazone, and benzbromarone. 
     The compounds of the present invention may also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine, and antimetabolites such as methotrexate. 
     The compounds of the present invention may also be used in combination with anti-hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, including hypertension, myocardial ischemia including angina, congestive heart failure, and myocardial infarction, selected from vasodilators such as hydralazine, β-adrenergic receptor antagonists such as propranolol, calcium channel blockers such as nifedipine, α 2 -adrenergic agonists such as clonidine, α-adrenergic receptor antagonists such as prazosin, and HMG-CoA-reductase inhibitors (anti-hypercholesterolemics) such as lovastatin or atorvastatin. 
     The active ingredient of the present invention may also be administered in combination with one or more antibiotic, antifungal, antiprotozoal, antiviral or similar therapeutic agents. 
     The compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as L-dopa, requip, mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists and inhibitors of neuronal nitric oxide synthase), and anti-Alzheimer&#39;s drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate. 
     The compounds of the present invention may also be used in combination with osteoporosis agents such as roloxifene, lasofoxifene, droloxifene or fosomax and immunosuppressant agents such as FK-506 and rapamycin. 
     The present invention also relates to the formulation of the active agents of the present invention alone or with one or more other therapeutic agents which are to form the intended combination, including wherein said different drugs have varying half-lives, by creating controlled-release forms of said drugs with different release times which achieves relatively uniform dosing; or, in the case of non-human patients, a medicated feed dosage form in which said drugs used in the combination are present together in admixture in said feed composition. There is further provided in accordance with the present invention co-administration in which the combination of drugs is achieved by the simultaneous administration of said drugs to be given in combination; including co-administration by means of different dosage forms and routes of administration; the use of combinations in accordance with different but regular and continuous dosing schedules whereby desired plasma levels of said drugs involved are maintained in the patient being treated, even though the individual drugs making up said combination are not being administered to said patient simultaneously. 
     DETAILED DESCRIPTION OF THE INVENTION 
     Compounds of the formula I may be prepared according to the following reaction schemes and discussion. Unless otherwise indicated, R 1  through R 8 , X and n in the reaction schemes and discussion that follow are as defined above.                                                     
     Scheme 1 illustrates a method of synthesizing compounds of the formula I. Referring to Scheme 1, a compound of the formula I is prepared from a compound of formula II, wherein L 1  is bromo or iodo, by reaction with a trimethylsilyl acetylide of the formula                           
     in the presence of a catalyst, a base and a solvent. Palladium is the preferred catalyst (for example, ((C 6 H 5 ) 3 P) 4 Pd or Pd 2 (dba) 3 ), wherein dba refers to dibenzylidene acetone. A catalytic amount of Cul is usually used for the reaction. Suitable bases include alkyl amines such as triethylamine. Suitable solvents for the aforesaid reaction include neat, acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone, preferably dimethylformamide. This reaction is conveniently run at about 20° C. to about 160° C., preferably about 60° C. to about 130° C. 
     The compound of formula II is prepared by reaction of a compound of the formula III with a compound of the formula                           
     (prepared according to the methods of Scheme 2 or commercially available or prepared by methods known to those skilled in the art) under acidic, neutral, or basic conditions preferably in the presence of acid or the acid salt of the compound of formula VI in a suitable solvent. Suitable solvents include alcohols, such as ethanol, methanol, propanol, isopropanol, trifluoroethanol or butanol; dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP), preferably an alcohol, most preferably ethanol trifluoroethanol, or isopropanol. Suitable acids include hydrochloric acid, trifluoroacetic acid, acetic acid, and sulfuric acid. This reaction is generally carried out at a temperature from about 0° C. to about 140° C., preferably at about the reflux temperature of the polar solvent. 
     The compound of formula III is prepared from a compound of the formula IV by reaction with a compound of the formula                           
     wherein L is a leaving group, in the presence of a base and a solvent. Examples of compounds of formula V include ester or ester equivalents such as acylimidazole, dialkylamide and dialkylacetal, preferably ester and acylimidazole. Suitable bases include potassium carbonate (K 2 CO 3 ), sodium carbonate (Na 2 CO 3 ), sodium hydride (NaH), sodium methoxide, potassium-tert-butoxide, lithium diisopropylamide, pyrrolidine and piperidine, preferably sodium methoxide. These reactions can be carried out in a solvent such as di-(alkyl)ether (preferably dimethylether), tetrahydrofuran (THF), methanol, dichloromethane, methyl tert-butyl ether, dimethylformamide (DMF), dimethylacetamide (DMA) or DMSO, preferably dimethoxyethane (DME). Reaction temperatures can range from about 0° C. to about 150° C., preferably from about 20° C. to about 25° C. 
     Compounds of formula IV are commercially available or can be made by methods well known to those of ordinary skill in the art. Compounds of formula III can be prepared by the method described in  Aust. J. Chem.,  1977, 30 , 229 and  Heterocycles,  1990, 31, 1951 and which are incorporated by reference. The regio isomeric pyrazole (la′) can be also prepared from the corresponding 1,3-diketone and heteroarylhydrazine according to other methods well known in the art. 
     Scheme 2 refers to the preparation of compounds of the formula VI which are intermediates used in Scheme 1. Referring to Scheme 2, compounds of the formula VI are prepared from compounds of the formula VII by reaction with hydrazine in the presence of a polar solvent. Suitable solvents include alcohols, such as ethanol, methanol, propanol or butanol; dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP), preferably an alcohol, most preferably ethanol. This reaction is generally carried out at a temperature from about 0° C. to about 140° C., preferably at about the reflux temperature of the polar solvent. Preferably the product is isolated as a salt, such as a hydrochoride salt. 
     The compound of formula VII is prepared from a compound of the formula VIII by reaction with an oxidizing reagent in the presence of a solvent. Suitable oxidants include meta-chloroperbenzoic acid, hydrogen peroxide, sodium perborate, or Oxone® (Oxone® is preferred). Suitable solvents or solvent mixtures include methanol-water, dioxane-water, tetrahydrofuran-water, methylene chloride, or chloroform, preferably methanol-water. Suitable temperatures for the aforesaid reaction range from about 0° C. to about 60° C., preferably the temperature may range from about 20° C. to about 25° C. (i.e. room temperature). The reaction is complete within about 0.5 hours to about 24 hours, preferably about 16 hours. 
     The compound of the formula VIII is prepared from a compound of formula IX by reaction with a disulfide or methyl alkylthiolsulfonate of the formula R 1 S—L, wherein L is alkylthio or methylsulfonate, in the presence or absence of a base in a polar solvent. Suitable bases include, alkyllithium such as n-butyllithium, and suitable solvents include ether, benzene and THF. This reaction is generally carried out at a temperature from about −78° C. to 0° C. for from about 1 to 8 hours. 
     Unless indicated otherwise, the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere). 
     The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained. 
     The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts. 
     Those compounds of the formula I which are also acidic in nature, e.g., wherein R 2 , R 4 , R 5  or R 6  include a —COOH, tetrazole or other acidic moiety, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I. These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields. 
     METHOD FOR ASSESSING BIOLOGICAL ACTIVITIES 
     The activity of the compounds of the formula (I) of the present invention was demonstrated by the following assays. 
     Human in Vitro Assays 
     Human Cell-based COX-1 Assay 
     Human peripheral blood obtained from healthy volunteers was diluted to 1/10 volume with 3.8% sodium citrate solution. The platelet-rich plasma immediately obtained was washed with 0.14 M sodium chloride containing 12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA. Platelets were then washed with platelet buffer (Hanks buffer (Ca free) containing 0.2% BSA and 20 mM Hepes). Finally, the human washed platelets (HWP) were suspended in platelet buffer at the concentration of 2.85×10 8  cells/ml and stored at room temperature until use. The HWP suspension (70 μl aliquots, final 2.0×10 7  cells/ml) was placed in a 96-well U bottom plate and 10 μl aliquots of 12.6 mM calcium chloride added. Platelets were incubated with A23187 (final 10 μM, Sigma) with test compound (0.1-100 μM) dissolved in DMSO (final concentration; less than 0.01%) at 37° C. for 15 minutes. The reaction was stopped by addition of EDTA (final 7.7 mM) and TxB2 in the supernatant quantitated by using a radioimmunoassay kit (Amersham) according to the manufacturer&#39;s procedure. 
     Human Cell-based COX-2 Assay 
     The human cell based COX-2 assay was carried out as previously described (Moore etal.,  Inflam. Res.,  45, 54, 1996). Confluent human umbilical vein endothelial cells (HUVECs, Morinaga) in a 96-well flat bottom plate were washed with 80 ml of RPMI1640 containing 2% FBS and incubated with hIL-1β (final concentration 300 U/ml, R &amp; D Systems) at 37° C. for 24 hr. After washing, the activated HUVECs were incubated with test compound (final concentration; 0.1 nM-1 μM) dissolved in DMSO (final concentration; less than 0.01%) at 37° C. for 20 minutes and stimulated with A23187 (final concentration 30 mM) in Hanks buffer containing 0.2% BSA, 20 mM Hepes at 37° C. for 15 minutes. 6-Keto-PGF 1α , stable metabolite of PGI2, in the supernatant was quantitated by using a radioimmunoassay method (antibody; Preseptive Diagnostics, SPA; Amersham). 
     Canine in Vitro Assays 
     The following canine cell based COX 1 and COX-2 assays have been reported in Ricketts et al.,  Evaluation of Selective Inhibition of Canine Cyclooxygenase  1 and 2 by  Carprofen and Other Nonsteroidal Anti - inflammatory Drugs,  American Journal of Veterinary Research, 59 (11), 1441-1446. 
     Protocol for Evaluation of Canine COX-1 Activity 
     Test drug compounds were solubilized and diluted the day before the assay was to be conducted with 0.1 mL of DMSO/9.9 mL of Hank&#39;s balanced salts solution (HBSS), and stored overnight at 4° C. On the day that the assay was carried out, citrated blood was drawn from a donor dog, centrifuged at 190×g for 25 minutes at room temperature, and the resulting platelet-rich plasma was then transferred to a new tube for further procedures. The platelets were washed by centrifuging at 1500×g for 10 minutes at room temperature. The platelets were washed with platelet buffer comprising Hank&#39;s buffer (Ca free) with 0.2% bovine serum albumin (BSA) and 20 mM HEPES. The platelet samples were then adjusted to 1.5×10 7  mL, after which 50 μl of calcium ionophore (A23187) together with a calcium chloride solution were added to 50 μl of test drug compound dilution in plates to produce final concentrations of 1.7 μM A23187 and 1.26 mM Ca. Then, 100 μl of canine washed platelets were added and the samples were incubated at 37° C. for 15 minutes, after which the reaction was stopped by adding 20 μl of 77 mM EDTA. The plates were then centrifuged at 2000×g for 10 minutes at 4° C., after which 50 μl of supernatant was assayed for thromboxane B 2  (TXB 2 ) by enzyme-immunoassay (EIA). The pg/mL of TXB 2  was calculated from the standard line included on each plate, from which it was possible to calculate the percent inhibition of COX-1 and the IC 50  values for the test drug compounds. 
     Protocol for Evaluation of Canine COX-2 Activity 
     A canine histocytoma (macrophage-like) cell line from the American Type Culture Collection designated as DH82, was used in setting up the protocol for evaluating the COX-2 inhibition activity of various test drug compounds. There was added to flasks of these cells 10 μg/mL of LPS, after which the flask cultures were incubated overnight. The same test drug compound dilutions as described above for the COX-1 protocol were used for the COX-2 assay and were prepared the day before the assay was carried out. The cells were harvested from the culture flasks by scraping, and were then washed with minimal Eagle&#39;s media (MEM) combined with 1% fetal bovine serum, centrifuged at 1500 rpm for 2 minutes, and adjusted to a concentration of 3.2×10 5  cells/mL. To 50 μl of test drug dilution there was added 50 μl of arachidonic acid in MEM to give a 10 μM final concentration, and there was added as well 100 μl of cell suspension to give a final concentration of 1.6×10 5  cells/mL. The test sample suspensions were incubated for 1 hour and then centrifuged at 1000 rpm for 10 minutes at 4° C., after which 50 μl aliquots of each test drug sample were delivered to EIA plates. The EIA was performed for prostaglandin E 2  (PGE 2 ), and the pg/mL concentration of PGE 2  was calculated from the standard line included on each plate. From this data it was possible to calculate the percent inhibition of COX-2 and the IC 50  values for the test drug compounds. Repeated investigations of COX-1 and COX-2 inhibition were conducted over the course of several months. The results are averaged, and a single COX-1: COX-2 ratio is calculated. 
     Whole blood assays for COX-1 and COX-2 are known in the art such as the methods described in C. Brideau, et al.,  A Human Whole Blood Assay for Clinical Evaluation of Biochemical Efficacy of Cyclooxygenase Inhibitors, Inflammation Research,  Vol. 45, pp. 68-74 (1996). These methods may be applied with feline, canine or human blood as needed. 
     In Vivo Assays 
     Carrageenan Induced Foot Edema in Rats 
     Male Sprague-Dawley rats (5 weeks old, Charles River Japan) were fasted overnight. A line was drawn using a marker above the ankle on the right hind paw and the paw volume (V0) was measured by water displacement using a plethysmometer (Muromachi). Animals were given orally either vehicle (0.1% methyl cellulose or 5% Tween 80) or a test compound (2.5 ml per 100 g body weight). One hour later, the animals were then injected intradermally with λ-carrageenan (0.1 ml of 1% w/v suspension in saline, Zushikagaku) into right hind paw (Winter et al.,  Proc. Soc. Exp. Biol. Med.,  111, 544, 1962; Lombardino et al.,  Arzneim. Forsch.,  25, 1629, 1975) and three hours later, the paw volume (V3) was measured and the increase in volume (V3-V0) calculated. Since maximum inhibition attainable with classical NSAID&#39;s is 60-70%, ED30 values were calculated. 
     Gastric Ulceration in Rats 
     The gastric ulcerogenicity of test compound was assessed by a modification of the conventional method (Ezer et al.,  J. Pharm. Pharmacol.,  28, 655, 1976; Cashin et al.,  J. Pharm. Pharmacol.,  29, 330-336, 1977). Male Sprague-Dawley rats (5 weeks old, Charles River Japan), fasted overnight, were given orally either vehicle (0.1% methyl cellulose or 5% Tween 80) or a test compound (1 ml per 100 g body weight). Six hours after, the animals were sacrificed by cervical dislocation. The stomachs were removed and inflated with 1% formalin solution (10 ml). Stomachs were opened by cutting along the greater curvature. From the number of rats that showed at least one gastric ulcer or hemorrhaging erosion (including ecchymosis), the incidence of ulceration was calculated. Animals did not have access to either food or water during the experiment. 
     Canine Whole Blood Ex Vivo Determinations of COX-1 and COX-2 Activity Inhibition 
     The in vivo inhibitory potency of a test compound against COX-1 and COX-2 activity may be evaluated using an ex vivo procedure on canine whole blood. Three dogs were dosed with 5 mg/kg of the test compound administered by oral gavage in 0.5% methylcellulose vehicle and three dogs were untreated. A zero-hour blood sample was collected from all dogs in the study prior to dosing, followed by 2- and 8-hour post-dose blood sample collections. Test tubes were prepared containing 2μL of either (A) calcium ionophore A23187 giving a 50 μM final concentration, which stimulates the production of thromboxane B 2  (TXB 2 ) for COX-1 activity determination; or of (B) lipopolysaccharide (LPS) to give a 10 μg/mL final concentration, which stimulates the production of prostaglandin E 2  (PGE 2 ) for COX-2 activity determination. Test tubes with unstimulated vehicle were used as controls. A 500 μL sample of blood was added to each of the above-described test tubes, after which they were incubated at 37° C. for one hour in the case of the calcium ionophore-containing test tubes, and overnight in the case of the LPS-containing test tubes. After incubation, 10 μL of EDTA was added to give a final concentration of 0.3%, in order to prevent coagulation of the plasma which sometimes occurs after thawing frozen plasma samples. The incubated samples were centrifuged at 4° C. and the resulting plasma sample of ˜200 μL was collected and stored at −20° C. in polypropylene 96-well plates. In order to determine endpoints for this study, enzyme immunoassay (EIA) kits available from Cayman were used to measure production of TXB 2  and PGE 2 , utilizing the principle of competitive binding of tracer to antibody and endpoint determination by colorimetry. Plasma samples were diluted to approximate the range of standard amounts which would be supplied in a diagnostic or research tools kit, i.e., 1/500 for TXB 2  and 1/750 for PGE 2 . 
     The data set out in Table 2 below show how the percent inhibition of COX-1 and COX-2 activity is calculated based on their zero hour values. The data is expressed as treatment group averages in pg/ml of TXB 2  and PGE 2  produced per sample. Plasma dilution was not factored in said data values. 
     The data in Table 2 show that, in this illustration, at the 5 mg/kg dose there was significant COX-2 inhibition at both timepoints. The data in Table 2 also show that at the 5 mg/kg dose there was no significant inhibition of COX-1 activity at the timepoints involved. Accordingly, the data in Table 2 clearly demonstrates that at the 5 mg/kg dosage concentration this compound possesses good COX-2 selectivity. 
     
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
             
               
             
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
             
             
               
                 COX-1 ACTIVITY INHIBITION-Group Averages 
               
             
          
           
               
                   
                 TXB 2  Pg/mL/Well 
                 Percent Inhibition 
                   
               
             
          
           
               
                 Hour 
                 0-hour 
                 2-hour 
                 8-hour 
                 2-hour 
                 8-hour 
               
               
                   
               
               
                 Untreated 
                  46 
                  45 
                 140 
                 2% 
                 0% 
               
               
                 5 mg/kg 
                  41 
                  38 
                 104 
                 7% 
                 0% 
               
               
                   
               
             
          
           
               
                 COX-2 ACTIVITY INHIBITION-Group Averages 
               
             
          
           
               
                   
                 PGE 2  Pg/mL/Well 
                 Percent Inhibition 
                   
               
             
          
           
               
                 Hour 
                 0-hour 
                 2-hour 
                 8-hour 
                 2-hour 
                 8-hour 
               
               
                   
               
               
                 Untreated 
                 420 
                 486 
                 501 
                 0% 
                 0% 
               
               
                 5 mg/kg 
                 711 
                 165 
                 350 
                 77%  
                 51%  
               
               
                   
               
             
          
         
       
     
     COX inhibition is observed when the measured percent inhibition is greater than that measured for untreated controls. The percent inhibition in the above table is calculated in a straightforward manner in accordance with the following equation:          %                 Inhibition                   (     2        -        hour     )       =         (         PGE   2                   at                 t     =   0     )     -     (         PGE   2                   at                 t     =   2     )         (         PGE   2                   at                 t     =   0     )                              
     Data Analysis 
     Statistical program packages, SYSTAT (SYSTAT, INC.) and StatView (Abacus Cencepts, Inc.) for Macintosh were used. Differences between test compound treated group and control group were tested for using ANOVA. The IC50 (ED30) values were calculated from the equation for the log-linear regression line of concentration (dose) versus percent inhibition. 
     Most compounds prepared in the Working Examples as described hereinafter were tested by at least one of the methods described above, and showed IC 50  values of 0.001 μM to 3 μM with respect to inhibition of COX-2 in either the canine or human assays. 
     COX-2 selectivity can be determined by ratio in terms of IC 50  value of COX-1 inhibition to COX-2 inhibition. In general, it can be said that a compound showing a COX-2/COX-1 inhibition ratio of more than 5 has good COX-2 selectivity. 
     The compounds of the formula (I) of this invention can be administered via oral, parenteral, anal, buccal or topical routes to mammals (including humans, dogs, cats, horses and livestock). 
     In general, these compounds are most desirably administered to humans in doses ranging from 0.01 mg to 100 mg per kg of body weight per day, although variations will necessarily occur depending upon the weight, sex and condition of the subject being treated, the disease state being treated and the particular route of administration chosen. However, a dosage level that is in the range of from 0.1 mg to 10 mg per kg of body weight per day, single or divided dosage is most desirably employed in humans for the treatment of above-mentioned diseases. 
     These compounds are most desirably administered to said non-human mammals, e.g. dogs, cats, horses or livestock in an amount, expressed as mg per kg of body weight of said member per day, ranging from about 0.01 mg/kg to about 20.0 mg/kg/day, preferably from about 0.1 mg/kg to about 12.0 mg/kg/day, more preferably from about 0.5 mg/kg to about 10.0 mg/kg/day, and most preferably from about 0.5 mg/kg to about 8.0 mg/kg/day. 
     The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, trochees, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5% to 70% by weight, preferably 10% to 50% by weight. 
     For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tablefting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof. 
     A preferred composition for dogs comprises an ingestible liquid peroral dosage form selected from the group consisting of a solution, suspension, emulsion, inverse emulsion, elixir, extract, tincture, and concentrate, optionally to be added to the drinking water of the dog being treated. Any of these liquid dosage forms, when formulated in accordance with methods well known in the art, can either be administered directly to the dog being treated, or may be added to the drinking water of the dog being treated. The concentrate liquid form, on the other hand, is formulated to be added first to a given amount of water, from which an aliquot amount may be withdrawn for administration directly to the dog or addition to the drinking water of the dog. 
     A preferred composition provides delayed-, sustained-, and/or controlled-release of said anti-inflammatory selective COX-2 inhibitor. Such preferred compositions include all such dosage forms which produce ≧80% inhibition of COX-2 isozyme activity and result in a plasma concentration of said inhibitor of at least 3 fold the COX-2 IC 50  for at least 4 hours; preferably for at least 8 hours; more preferably for at least 12 hours; more preferably still for at least 16 hours; even more preferably still for at least 20 hours; and most preferably for at least 24 hours. Preferably, there is included within the above-described dosage forms those which produce ≧80% inhibition of COX-2 isozyme activity and result in a plasma concentration of said inhibitor of at least 5 fold the COX-2 IC 50  for at least 4 hours, preferably for at least 8 hours, more preferably for at least 12 hours, still more preferably for at least 20 hours, and most preferably for at least 24 hours. More preferably, there is included the above-described dosage forms which produce≧90% inhibition of COX-2 isozyme activity and result in a plasma concentration of said inhibitor of at least 5 fold the COX-2 IC 50  for at least 4 hours, preferably for at least 8 hours, more preferably for at least 12 hours, still more preferably for at least 20 hours, and most preferably for at least 24 hours. 
     For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH&gt;8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice. 
     The compounds of formula (I) may also be administered in the form of suppositories for rectal or vaginal administration of the active ingredient. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature (for example, 10° C. to 32° C.) but liquid at the rectal temperature and will melt in the rectum or vagina to release the active ingredient. Such materials are polyethylene glycols, cocoa butter, suppository and wax. 
     For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner. 
     For transdermal administration, transdermal patches prepared in accordance with well known drug delivery technology may be prepared and applied to the skin of a mammal, preferably a human or a dog, to be treated, whereafter the active agent by reason of its formulated solubility characteristics migrates across the epidermis and into the dermal layers of the skin where it is taken up as part of the general circulation, ultimately providing systemic distribution of the active ingredient over a desired, extended period of time. Also included are implants which are placed beneath the epidermal layer of the skin, i.e. between the epidermis and the dermis of the skin of the patient being treated. Such an implant will be formulated in accordance with well known principles and materials commonly used in this delivery technology, and may be prepared in such a way as to provide controlled-, sustained-, and/or delayed-release of the active ingredient into the systemic circulation of the patient. Such subepidermal (subcuticular) implants provide the same facility of installation and delivery efficiency as transdermal patches, but without the limitation of being subject to degradation, damage or accidental removal as a consequence of being exposed on the top layer of the patient&#39;s skin. 
    
    
     EXAMPLES 
     The following examples contain detailed descriptions of the methods of the preparation of compounds of formula (I). These detailed descriptions fall within the scope of the invention and serve to exemplify the above described general synthetic procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended to restrict the scope of the present invention. 
     The invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all operations were carried out at room or ambient temperature, that is, in the range of 18-25° C.; evaporation of solvent was carried out using a rotary evaporator under reduced pressure with a bath of up to 60° C.; reactions were monitored by thin layer chromatography (tlc) and reaction times are given for illustration only; melting points (m.p.) given are uncorrected (polymorphism may result in different melting points); structure and purity of all isolated compounds were assured by at least one of the following techniques: tlc (Merck silica gel 60 F-254 precoated plates), mass spectrometry, nuclear magnetic resonance (NMR) or infrared spectroscopy (IR). IR data were obtained on a FTIR 8200 (SHIMAZU Spectrometer). Yields are given for illustrative purposes only. Flash column chromatography was carried out using Merck silica gel 60 (230-400 mesh ASTM). Low-resolution mass spectral data (EI) were obtained on a Automass 120 (JEOL) mass spectrometer. Liquid Chromatography data was collected on a Hewlett Packard 1100 Liquid Chromatography/Mass Selective Detector (LC/MSD). Analysis was performed on a Luna C-18 column with dimensions of 3.0×150 mm. The flow rate was 0.425 ml/minute running a gradient of 50% 0.1% aqueous formic acid and 50% acetonitrile to 100% acetonitrile in 15 minutes. The ionization type for the mass detector of the Mass Spectrophotometer was atmospheric pressure electrospray in the positive ion mode with a fragmentor voltage of 50 volts. NMR data was determined at 270 MHz (JEOL JNM-LA 270 spectrometer) using deuterated chloroform (99.8% D), methanol (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, etc. 
     The following abbreviations are used: 
     THF: tetrahydrofuran 
     CH 2 Cl 2 : dichloromethane 
     NaHCO 3 : sodium bicarbonate 
     HCl: hydrogen chloride 
     MgSO 4 : magnesium sulfate 
     Na 2 SO 4 : sodium sulfate 
     DME: dimethoxyethane 
     n-BuLi: n-butyllithium 
     DMF: dimethylformamide 
     Example 1 
     5-Methylsulfonyl-2-[5-(4-acetylenylphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]pyridine 
     Step 1: 5-Methylsulfonyl-2-[5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]pyridine 
     4,4,4-Trifluoro-1-(4-bromophenyl)1,3-butanedione (600 mg) (prepared according to the method of Thomas D. Penning, et al.;  J. Med. Chem.,  1997, 40, 1347-1365.) and 2-hydrazino-5-(methylsulfonyl)pyridine hydrochloride (420 mg) were mixed in ethanol (40 mL), and the resulting solution was refluxed for 3 days. Upon cooling, white precipitates came out. The white precipitates were collected by filtration and purified by flash chromatography using 70:30 of methylene chloride and hexane to give the title compound (450 mg). 
     Step 2: 5-Methylsulfonyl-2-[5-(4-acetylenyl-phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]pyridine 
     5-Methylsulfonyl-2-[5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]pyridine (230 mg), Cul (5 mg), Pd(PPh 3 ) 4  (30 mg) were mixed in triethylamine (2.5 mL), followed by the addition of trimethylsilyl acetylene (0.182 mL), and the reaction mixture was heated at 80° C. for 2 hours. TLC in 1:1 of ethyl acetate/hexane showed complete conversion of the starting material to the product. The solvent was removed in vacuo to give the crude product. This crude material was then dissolved in methanol (2.5 mL), followed by the addition of potassium carbonate (20 mg). The reaction mixture was stirred at room temperature for 30 minutes. After filtration, the solvent was removed in vacuo to give the crude product which was purified by flash chromatography using 70:30 of methylene chloride/hexane to give the title compound (41 mg). 
     The following examples were prepared by an analogous procedure to that of Example 1, except where indicated. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                 Example 
                 Structure 
                 HPLC 
                 HRMS 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8.224 
                 392.3 
               
               
                   
               
               
                 3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8.053 
                 392.3 
               
               
                   
               
               
                 4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8.639 
                 410.3 
               
               
                   
               
               
                 5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 7.147 
                 393.2 
               
               
                   
               
               
                 6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                 392.9 
               
               
                   
               
               
                 7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8.944 
                 392.3 
               
               
                   
               
               
                 8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 9.597 
                 392.3 
               
               
                   
               
               
                 9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 6.714 
                 423.3 
               
               
                   
               
               
                 10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 7.742 
                 374.2 
               
               
                   
               
               
                 11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 7.630 
                 422.3 
               
               
                   
               
               
                 12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 6.565 
                 374.2 
               
               
                   
               
               
                 13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8.125 
                 440.3 
               
               
                   
               
             
          
         
       
     
     Example 14 
     5-(4-Ethylnylphenyl)-1-[4-(Methylsulfonyl)Phenyl]-3-(Trifluoromethyl)-1H-Pyrazole 
     Step 1: 5-(4-Bromophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole 
     A mixture of 1-(4-bromophenyl)-4,4,4-trifluoro-1,3-butanedione (890 mg, 3.0 mmol, Jones, John R. et al.,  J. Chem. Soc., Perkin Trans.  2, 11, 1231 (1975)) and 4-methylsulfonylhydrazine hydrochloride (735 mg, 3.3 mmol, S. Akio et al.,  Eur. J. Med. Chem. Chim. Ther.,  223 (1984)) in ethanol (15 mL) was heated at reflux temperature for 5 hours. The mixture was concentrated and ethyl acetate (50 ml) was added and whole was washed with water, brine and dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give title compound (1.3 g, quant.). 
       1 H-NMR (CDCl 3 ) δ: 7.97 (d, J=8.9 Hz, 2H), 7.55-7.51 (m, 4H), 7.11 (d, J=8.9 Hz, 2), 6.80 (s, 1H), 3.08 (s, 3H). 
     Step 2: 1-[4-(Methylsulfonyl)phenyl]-3-(trifluoromethyl)-5-[4-[(trimethylsilyl)ethyl]phenyl]-1H-pyrazole 
     To a mixture of 5-(4-bromophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole (670 mg, 1.5 mmol, from step 1), triethylamine (10 mL) and dimethylformamide (2 mL) was added copper(I) iodide (15 mg, 0.08 mmol), bis(triphenylphosphine)palladium(II)chloride (105 mg, 0.15 mmol) and (trimethylsilyl)acetylene (221 mg, 2.25 mmol) at room temperature. The mixture was stirred for 4 hours at room temperature and concentrated. The concentrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3), dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give title compound (353 mg, 52%). 
       1 H-NMR (CDCl 3 ) δ: 7.84 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H), 6.80 (s, 1H), 3.06 (s, 3H), 0.25 (s, 9H). 
     Step 3: 5-(4-Ethylnylphenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole. 
     A mixture of 1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-5-[4-[(trimethylsilyl)ethyl]phenyl]-1H-pyrazole (345 mg, 0.77 mmol, from step 3) and potassium carbonate (530 mg, 3.8 mmol) in methanol (10 mL) was stirred for 4 hours at room temperature. The mixture was concentrated and water (30 mL) was added and extracted with ether (20 mL×3), dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:3) to yield a white solid. The solid was washed with hexane to give title compound (216 mg, 72%). 
       1 H-NMR (CDCl 3 ) δ: 7.96 (d, J=8.6 Hz, 2H), 7.55-7.49 (m, 4H), 7.20 (d, J=8.2 Hz, 2H), 6.81 (s, 1H), 3.19 (s, 1H), 3.08 (s, 3H). 
     Analytical Calculated for C 19 H 13 N 2 O 2 F 3 S: C, 58.4; H, 3.36; N, 7.18. Found: C, 58.73; H, 3.65; N, 6.93. 
     The following compounds were prepared utilizing HSS techniques. 
     Example 15 
     1-[4-(Methylsulfonyl)Phenyl]-5-[4-(Phenylethynyl)Phenyl]-3-Trifluoromethyl-1H-Pyrazole 
     To a stirred solution of 1-[4-(methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole (445 mg; 1 mmol) and phenylacetylene (102 mg; 1 mmol) in pyrrolidine (2 mL) was added tetrakis(triphenylphosphine)palladium (35 mg) under a nitrogen atmosphere, and the mixture was heated at 80° C. for 1 hour. After cooling, the volatiles were removed by evaporation. The residue was purified by flash chromatography (SiO 2 ) eluting with ethyl acetate/hexane (1:3) to give the title compound (0.4 g, 86% yield). 
     Melting Point: 170-172° C., MS (EI): 466 (M + ) 
     Example 16 
     5-[4-(1-Hexyn-1-yl)Phenyl]-1-[4-(Methylsulfonyl)Phenyl]-3-Trifluoromethyl-1H-Pyrazole 
     The title compound was prepared according to the procedure of Example 15 using 1-hexyne instead of phenylacetylene. 
     Melting Point:96-98° C., MS (EI): 446 (M + ) 
     Example 17 
     5-[4-(5-Hydroxy-1-Pentyn-1-yl)Phenyl]-1-[4-(Methylsulfonyl)Phenyl]-3-Trifluoromethyl-1H-Pyrazole 
     The title compound was prepared according to the procedure of Example 1 using 4-pentyn-1-ol instead of phenylacetylene. 
     Melting Point:87-90° C., MS (EI): 448 (M + ) 
     Example 18 
     5-[4-(3-Hydroxy-1-Propyn-1-yl)Phenyl]-1-[4-(Methylsulfonyl)Phenyl]-3-Trifluoromethyl-1H-Pyrazole 
     The title compound was prepared according to the procedure of Example 1 using propargyl alcohol instead of phenylacetylene. 
     MS (EI): 420 (M + ) 
     Example 19 
     5-[4-(3-Methoxy-1-Propyn-1-yl)Phenyl]-1-[4-(Methylsulfonyl)Phenyl]-3-Trifluoromethyl-1H-Pyrazole 
     The title compound was prepared according to the procedure of Example 1 using methyl propargyl ether instead of phenylacetylene. 
     MS (EI): 434 (M + ) 
     Example 20 
     5-[4-(3-(Pyrrolidin-1-yl)-1-Propyn-1-yl)Phenyl]-1-[4-(Methylsulfonyl)Phenyl]-3-Trifluoromethyl-1H-Pyrazole 
     The title compound was prepared according to the procedure of Example 1 using propargyl bromide instead of phenylacetylene. 
     MS (EI): 473 (M + ) 
       1 H-NMR (CDCl 3 ) δ; 7.95 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 6.79 (s, 1H), 3.64 (s, 2H), 3.07 (s, 3), 2.72-2.65 (m, 4H), 1.88-1.82 (m, 4H) 
     Example 21 
     5-[4-(2-(2-Pyridyl)Ethyn-1-yl)Phenyl]-1-[4-(Methylsulfonyl)Phenyl]-3-Trifluoromethyl-1H-Pyrazole 
     The title compound was prepared according to the procedure of Example 1 using 2-pyridylacetylene instead of phenylacetylene. 
     MS (EI): 467 (M + ) 
     Preparation 1 
     Preparation of 3-Pyridyl Hydrazines 
     Step 1: 3-Nitro-6-Methylthio)Pyridine 
     2-Mercapto-5-nitro pyridine (20.0 g, 128 mmol) was suspended in water/ethanol (43 mL/13 mL). Sodium carbonate monohydrate (17.49 g, 141 mmol, dissolved in 86 mL of water) was added to the above slurry dropwise. Methyl iodide (20.0 g, 141 mmol) was added to the above mixture and the mixture was stirred at room temperature for one hour. The solid was filtered and washed with water and ethanol to provide the title compound in quantitative yield. 
     Step 2: 3-Nitro-6-Methylsulfonyl)Pyridine 
     3-Nitro-6-(methylthio)pyridine (22.0 g, 129.3 mmol) was dissolved in acetone (140 mL). Sulfuric acid (2N, 230 mL) was then added dropwise to above solution to form a slurry. Potassium permanganate (KMnO 4 ) (26.5 g, 168.1 mmol, dissolved in 500 mL of H 2 O) was added to the above mixture dropwise. The mixture that resulted was stirred at room temperature overnight. The solid was filtered and stirred with a warm mixture of ethanol/methanol (10/1). The insoluble salt was filtered, the filtrate was concentrated to provide a pale yellow solid. The crude product was recrystallized from ethanol to furnish the title compound (17.8 g, 70%). 
     Step 3: 3-Amino-6-(Methylsulfonyl)Pyridine 
     3-Nitro-6-(methylsulfonyl)pyridine (10 g, 49.5 mmol) was suspended in water (200 mL). Iron powder (5.0 g, 89.3 mmol) and acetic acid (0.5 mL) were added to the above mixture. The mixture, which resulted, was heated to reflux for 2 hours. The reaction was monitored by thin layer chromatography (ethyl acetate/hexane, 1/1). The reaction mixture was then cooled to room temperature and a saturated solution of sodium bicarbonate (NaHCO 3 ) (100 mL) was added to the mixture. Ethyl acetate (200 mL) was added to the above mixture and the mixture which resulted was stirred at room temperature for 30 minutes. The mixture was filtered through Celite® and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (200 mL×3). The organic extractions were combined and dried over sodium sulfate. The solvent was removed under reduced pressure to provide the 3-amino-6-(methylsulfonyl)pyridine (6 g, 70.5%). 
     Step 4: 5-Hydrazino-2-(Methylsulfonyl)Pyridine 
     To a solution of 3-amino-6-(methylsulfonyl)pyridine (3.72 g, 21.6 mmol) in concentrated hydrochloric acid (30 mL), sodium nitrite (1.78 g, 25.7 mmol) in water (20 mL) was added dropwise at −10° C. to −15° C. and the mixture was stirred for 2 hours at −10° C to −5° C. (Note: the reaction was monitored by thin layer chromatography to make sure all the starting material was consumed). Tin(II) chloride dihydrate (20 g, 88.6 mmol) in concentrated hydrochloric acid (30 mL) was added dropwise at −5° C. The mixture was stirred 1 hour at −5° C. and then left overnight. The mixture was basified with aqueous sodium hydroxide (pH=9) with ice cooling and tetrahydrofuran (200 mL) was added and stirred for 30 minutes. The mixture was filtered by Celite® and the filtrate was extracted with tetrahydrofuran (200 mL×3). The organic extraction was combined and dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound (3.2 g, 78.8%). 
     5-Hydrazino-2-(methylsulfonyl)pyridine was dissolved in HCl-methanol (10%, 30 mL) and volatiles were removed under reduced pressure. The residue was washed with ether and employed directly to next step without further purification. 
       1 H-NMR (DMSO-d 6 ) 67 : 8.40-8.37 (m, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.55-7.45 (m, 1H), 3.19 (s,3H). 
     Preparation 2 
     Preparation of 2-Pyridyl Hydrazines 
     2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride 
     5-Methylthio-2-bromopyridine. (step1) 
     To a solution of 2,5-dibromopyridine (23.4 g, 0.099 mol) in ether (500 mL), n-BuLi (1.52 M in n-hexane, 68 mL, 0.10 mmol) was added dropwise at −78° C. and the mixture was stirred for 1 hour at the temperature. Dimethyldisulfide (9.8 mL, 0.11 mol) was added slowly at −78° C. and the mixture was stirred for 1 hour at that temperature and further 1 hour at 0° C. The mixture was quenched with aqueous 1N HCl (200 mL) and extracted with ether (100 mL×2), dried over magnesium sulfate (MgSO 4 ), and concentrated in vacuo gave the title compound (18.9 g, 94%). 
       1 H-NMR (CDCl 3 ) δ: 8.24 (dd, J=0.8, 2.5 Hz, 1H), 7.43 (dd, J=2.8, 8.4 Hz, 1H), 7.38 (dd, J=0.8, 8.4 Hz, 1H), 2.50 (s, 3H). 
     5-Methylsulfonyl-2-bromopyridine. (step2) 
     To a solution of 5-methylthio-2-bromopyridine from step 1 (18.9 g, 0.093 mol) in methylene chloride (600 mL), m-chloroperbenzoic acid (48 g, 0.19 mol) was added portionwise at 0° C. and the mixture was stirred for 2 hours at room temperature. Aqueous saturated Na 2 SO 3  (200 mL) was added and stirred for 15 minutes and organic phase was separated and washed with aqueous saturated sodium bicarbonate (NaHCO 3 ) (200 mL), dried over magnesium sulfate (MgSO 4 ), and concentrated in vacuo gave the title compound (20.9 g, 96%). 
       1 H-NMR (CDCl 3 ) δ: 8.91 (d, J=2.6 Hz, 1H), 8.06 (dd, J=2.6, 8.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 3.12 (s, 3H). 
     2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride. (step3) 
     A mixture of 5-methylsulfonyl-2-bromopyridine from step 2 (20.9 g, 0.088 mol) and anhydrous hydrazine (5.6 mL, 0.18 mol) in ethanol (200 mL) was refluxed for 4 hours. After cooled to room temperature the mixture was concentrated. The residual solid was washed with aqueous saturated NaHCO 3  (100 mL) and water (100 mL) and collected by filtration to give pale yellow solid (9.6 g). The solid was treated with 10% methanolic HCl (80 mL) and the precipitate was collected by filtration to give the title compound (9.8 g, 50%). 
       1 H-NMR (DMSO-d 6 ) δ: 8.54 (s, 1H), 7.99 (d, J=8.9 Hz, 1H), 6.94 (d, J=8.9 Hz, 1H), 3.20 (s, 3H). (hydrazine proton was not detected). 
     Preparation 3 
     2-Fluoro-4-Hydrazino-Benzenesulfonamide 
     N-(3-Fluoro-4-sulfamoyl-phenyl)-acetamide (Step 1) 
     Chlorosulfonic acid (200 ml, 3 mol) was added in a 3-necked 1 liter flask, followed by the portionwise addition of N-(3-fluoro-phenyl)-acetamide (91.8 g, 600 mmol) in an ice-water bath. The reaction mixture was then heated at 70° C. for 5 hours, and then cooled down to room temperature. The reaction mixture was diluted with methylene chloride (300 ml), and the resulting mixture was poured into 1 liter of crushed ice. The aqueous layer was extracted with methylene chloride (2×400 ml), and the combined organic layers were concentrated to about 300 ml in vacuo. The residue was cooled in an ice-water bath, and 28% ammonia (120 ml) was slowly added over 1 hour, and the temperature in the reaction flask was maintained between 0° C. to 10° C. The white precipitate was formed, and it was collected by filtration drying under high vacuum (71.0 g, 51%). 
     4-Amino-2-fluoro-benzenesulfonamide (Step 2) 
     To a stirred solution of sodium hydroxide (120 g, 3 mol) in water (500 ml) was added N-(3-Fluoro-4-sulfamoyl-phenyl)-acetamide (69.7 g, 300 mmol). The reaction mixture was stirred at reflux temperature for 3 hours. The solution was then cooled to room temperature, and the pH was adjusted to 6 by addition of 5N HCl solution. Most of the solvent was removed in vacuo, and the product precipitated out. The product was collected by filtration and drying under vacuum at 60° C. (32 g, 56%). 
     2-Fluoro-4-hydrazino-benzenesulfonamide hydrochloride salt (Step 3) 
     To a stirred suspension of 4-Amino-2-fluoro-benzenesulfonamide (15.2 g, 80 mmol) in concentrated hydrochloric acid solution (180 ml) was slowly added NaNO 2  (5.8 g, 84 mmol) in water (180 ml), while maintaining the internal temperature between −15° C. and −20° C. in a dry ice/acetonitrile bath. After the reaction mixture was stirred at −20° C. for 30 minutes, a solution of tin chloride (SnCl 2 ) hydrate (90.3 g, 400 mmol) in concentrated hydrochloric acid solution (100 ml) was added dropwise, and the reaction mixture temperature was maintained between −50° C. and −10° C. with an ice/methanol bath. The stirring was continued at −10° C. for 1 hour and then at room temperature for 4 hours. The pH of the solution was adjusted to 8 by addition of 5 N NaOH solution at 0° C., and the precipitate was removed by filtration through celite. The aqueous layer was extracted with THF (3×600 ml), and the combined organic layers were washed with brine, dried over MgSO 4 , and concentrated in vacuo. The residue was dissolved in 10% methanolic HCl solution, followed by stirring at room temperature for 1 hour. The title compound was collected by filtration (12.5 g, 65%). 
     Preparation 4 
     2-Sulfamyl-5-Hydrazino-Pyridine Hydrochloride Salt 
     2-Sulfamyl-5-amino-pyridine (Step 1) 
     N-(6-Mercapto-pyridin-3-yl)-acetamide (30 g, 17.3 mmol) was dissolved in cold concentrated hydrochloric acid solution (225 ml), followed by the addition of ice water (50 ml). Chlorine was bubbled into solution, and the temperature was kept below 10° C. The solution became dark brown first, and the chlorination was complete after 3 hours when the temperature no longer rose and the color of the solution lightened. The reaction was diluted with ice and water (1.2 kg) while keeping the temperature below 10° C. The product, 5-acetylamino-pyridine-2-sulfonyl chloride, was collected by filtration and air-dried. This was then suspended in chloroform (CHCl 3 ) (200 mL), followed by the addition of 30% ammonia solution (100 ml), and the resulting reaction mixture was stirred for 2 hours. The solvent was removed in vacuo to give a black solid, 2-sulfamyl-5-acetylamino-pyridine. 2-Sulfamyl-5-acetylamino-pyridine was dissolved in 0.85 N NaOH solution (500 ml), and the resulting solution was stirred at refluxing temperature for 3.5 hours. After cooled down to room temperature, the reaction mixture was extracted with 3:1 of CHCl 3 /MeOH solution (3×200 ml). The aqueous layer was neutralized to pH 7, and water was removed in vacuo to give the crude product which was recrystallized from water to afford the title compound (21.6 g, 70%). 
     2-Sulfamyl-5-hydrazino-pyridine hydrochloride salt (Step 2) 
     To a stirred solution of 2-Sulfamyl-5-amino-pyridine (3 g) in concentrated hydrochloric acid solution (23 ml) was added NaNO 2  (1.4 g, 20 mmol) in water (23 ml) while maintaining the temperature between −5° C. and 0° C. After the reaction mixture was stirred at 0° C. for 1.5 hours, SnCl 2  (19 g) in concentrated hydrochloric acid solution (25 ml) was added, and the resulting reaction mixture was stirred at 0° C. for 1 hour, then room temperature overnight. The pH of the reaction solution was adjusted to 8 by addition of NaOH (24 g) in water (30 ml), followed by the addition of THF (200 ml). After stirred at room temperature for 30 minutes, the reaction mixture was filtered through Celite®. The aqueous layer was extracted with THF (3×200 ml) and ethyl acetate (2×200 ml). The combined organic layers were dried with sodium sulfate (Na 2 SO 4 ), and concentrated in vacuo. The product was dissolved in 10% HCl in methanol (50 ml), and the solvent was removed in vacuo to give title compound (2.5 g).