Pyrazole ether derivatives as anti-inflammatory/analgesic agents

Abstract

The present invention relates to compounds of the formula wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, 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's disease in mammals, preferably humans, dogs, cats and livestock animals.

1 - 26 . (Cancelled).  
     
     
         27 . A method for treating a condition selected from the group consisting of arthritis, fever, common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, 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, aortic aneurysm, periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, 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, myasthenia gravis, polymyositis, myositis, bursitis, bums, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases, sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease, Rickettsial infections, Protozoan diseases, reproductive disorders, and septic shock in a mammal, comprising administering to said mammal a treatment effective amount of a compound of the formula  
       
         
           
           
               
               
           
         
         wherein  
         A is O, S, SO, SO 2  or NR 4 :  
         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, hydroxy, mercapto, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl (C 2-6 )alkynyl, (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms. (C 1-6 )alkyl-(C═O)—, formyl, formamidyl, cyano, nitro, amino, (C 1 -C 6 )alkylamino, [(C 1-6 )alkyl] 2 amino (C 1 -C 6 )alkyl-S—, —CO_H, (C 1 -C 6 )alkoxy-(C═O)—, (C 1 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 1 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N—(C═O)—, (C 6 -C 10 )aryl-NH—(C═O)—, [(C 6 -C 10  aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl-]N—(C═O)—, (C 1 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryl, (C 6 -C 10 ) 4 aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic. (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 1 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— or (C 6 -C 10 )aryl-(C═O)—NH—,  
         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 -C 6 )alkoxy, cyano, nitro, —CO 2 H (C 1 -Cr 6 )alkoxy-(C═O)—, (C 1 -C 10 )cycloalkyl-(C═O)—O—. (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (—O—(C═O—, HN—(C═O)—, (C 1 -C 6 )alkyl-NH—(C═O)—, [(C 1-6 )alkyl] 2 -N—(C═O)—, (C 6 -C 10 )aryl-NH—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-(C 6 -C 10 )aryl-N—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— and (C 6 -C 10 )aryl-(C═O)—NH—;  
         R 3  is selected from the group consisting of (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 10 )cycloalkyl, (C 1 -C 9 )heteroaryl and (C 1 -C 9 )heterocyclic;  
         wherein each of said R 3  (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 10 )cycloalkyl, (C 1 -C 9 )heteroaryl or (C 1 C 9 )heterocyclic groups may optionally be substituted with one to three substituents independently selected from halo, amino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 ) alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cyano, nitro, —OCF 3 , —CF 3 , (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 3 -C 10 )cycloalkyl, (C 1 -C 9 )heterocyclic, (C 6 -C 10 )aryloxy, (C 1 -C 9 )heteroaryloxy, (C 3 -C 10 )cycloalkoxy and (C 1 -C 9 )heterocyclic-O—; wherein each of said (C 6 -C 10 )aryl, (C 3 -C 10 )cycloalkyl, (C 1 -C 9 )heterocyclic and (C 1 -C 9 )heteroaryl substituents may optionally be substituted with one to three moieties independently selected from halo, amino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cyano, nitro, —OCF 3  and —CF 3 ; wherein said amino substituent or moiety may optionally be substituted by one or two elements independently selected from optionally substituted (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 10 )cycloalkyl, (C 1 -C 9 )heterocyclic and (C 1 -C 9 )heteroaryl, wherein said elements are optionally substituted by halo, amino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, —OCF 3  or —CF 3 ;  
         R 4  is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkyl-(C═O)— or (C 1-6 )alkyl-O—(C═O)—;  
         R 5  is hydrogen, halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-(C═O)—, formyl, formamidyl, cyano, nitro, —CO_H, (C 1 -C 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O— (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl]-N—(C═O)—, (C 6 -C 10 )aryl-HN—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl-]N—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 1 -C 6 )alkoxyiminyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-[(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— or (C 6 -C 10 )aryl-(C═O)—NH—;  
         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 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O— (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N—(C═O)—, (C 6 -C 10 )aryl-NH—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl-]N-(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N—(C═O)-, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, ( 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— and (C 6 -C 10 )aryl-(C═O)—NH—;  
         R 6  is hydrogen, halo (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-(C═O)—, formyl, formamidyl, cyano, nitro, amino, (C 1 -C 6 )alkylamino. [(C 1 -C 6 )alkyl] 2 amino; (C 1 -C 6 )alkyl-S—, (C 1 -C 6 )alkyl-(S═O)—, (C 1 -C 6 )alkyl-SO 2 —, —CO 2 H, (C 1 -C 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O— (C 1 -C 9 )heterocyclic-(C═O)—O— (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)— (C 1 -C 9 )heteroaryl-O—(C═O)—. (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H?N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N-(C═O)—, (C 6 -C 10 )aryl-HN—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl-]N-(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 1 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— or (C 6 -C 10 )aryl-(C═O)—NH—,  
         wherein said R 6  (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_H, (C 1 -C 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N—(C═O)—. (C 6 -C 10 )aryl—HN—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl]-N—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N-(C═O)—, [(C 1 -C 9 )heteroaryl]-N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 1 -C 10 )cycloalkyloxy, (C 1 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1-9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— and (C 6 -C 10 )aryl-(C═O)—NH—;  
         R 7  is hydrogen, halo, hydroxy, mercapto, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms, (C 2 -C 6 )alkenyl. (C 2 -C 6 )alkynyl, cyano, formyl, formamidyl, (C 1 -C 6 )alkyl-(C═O)—, (C 1 -C 6 )alkyl-(C═O)—O—, —CO_H, (C 1 - 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10  cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, R 9 )alkyl] 2 -N—(C═O)—, nitro, amino, (C 1 -C 6 )alkylamino, [(C 1 -C 6 alkyl] 2 amino, (C 1 -C 6 )alkyl-S—, (C 6 -C 10 )aryl-NH—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)-, (C 3 -C 10 )cycloalkyl, (C 3 C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—. (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— or (C 6 -C 1   0 )aryl-(C═O)—NH—,  
         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 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N—(C═O)—, (C 6 -C 10 )aryl-NH—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl-]N-(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— and (C 6 -C 10 )aryl-(C==O)—NH—;  
         R 8  is hydrogen, halo, hydroxy mercapto, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cyano, formyl, formamidyl, (C 1 -C 6 )alkyl-(C═O)—, (C 1 -C 6 )alkyl-(C═O)—O—, —CO_H, (C 1 -C 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N—(C═O)—, nitro, amino, (C 1 -C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 amino, (C 1 -C 6 )alkyl-S—, (C 6 -C 10 )aryl-NH—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl-]N—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )cycloalkyl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O), (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )hetero cyclic, (C 1  C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-C═O—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— or (C 6 -C 10 )aryl-(C═O)—NH—; or a pharmaceutically acceptable salt thereof.  
       
     
     
         28 . A method for treating a disorder or condition that can be treated by selectively inhibiting COX-2 in a mammal, comprising administering to a mammal having a disorder or condition that can be treated by selectively inhibiting COX-2 a COX-2 selective inhibiting effective amount of a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 A is O, S, SO, SO 2  or NR 4 ;  
 X is CR 7  or N  
 Y is CR 8  or N. 
 R 1  is (C 1 -C 6 )alkyl or —NH 2 ;  
 
 R is hydrogen, halo, hydroxy, mercapto, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms, (C 1 -C 6 )alkyl-(C═O)—, formyl, formamidyl, cyano, nitro, amino, (C 1 -C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 amino, (C 1 -C 6 )alkyl-S—, —CO 2 H, (C 1 -C 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 —N—(C═O)—, (C 6 -C 10 )aryl-NH—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl-]N—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 —N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 —N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)-, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)— (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH— (C 1 -C 9 )heterocyclic-(C═O)—NH— or (C 6 -C 10 )aryl-(C═O)—NH—.  
 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 -C 6 )alkoxy, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 1 -C 9 )aryl-(C═O)—O—, (C 6 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, N 2 H-(C═O)—, (C 1 -C 6 )alkyl-NH—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N—(C═O)—, (C 6 -C 10 )aryl-NH—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl-]N-(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl]-N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryloxy, (C 6 -C 10 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— and (C 6 -C 10 )aryl-(C═O)—NH—;  
 R 3  is selected from the group consisting of (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 10 )cycloalkyl. (C 1 -C 9 )heteroaryl and (C 1 -C 9 )heterocyclic;  
 wherein each of said R 3  (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 10 )cycloalkyl, (C 1 -C 9 )heteroaryl or (C 1 -C 9 )heterocyclic groups may optionally be substituted with one to three substituents independently selected from halo, amino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cyano, nitro, —OCF 3 , —CF 3 , (C 6 -C 10 )heteroaryl, (C 1 -C 9 )heteroaryl, (C 3 -C 10 )cycloalkyl, (C 1 -C 9 )heterocyclic, (C 6 -C 10 )aryloxy (C 1 -C 9 )heteroaryloxy, (C 3 -C 10 )cycloalkoxy and (C 1 -C 9 )heterocyclic-O—, wherein each of said (C 6 -C 10 )aryl, (C 3 -C 10 )cycloalkyl, (C 1 -C 9 )heterocyclic and (C 1 -C 9 )heteroaryl substituents may optionally be substituted with one to three moieties independently selected from halo, amino, hydroxy, (C 1 -C 6 )alkoxy, ( 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cyano, nitro, —OCF 3  and —CF 1 ; wherein said amino substituent or moiety may optionally be substituted by one or two elements independently selected from optionally substituted (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 10 )cycloalkyl, (C 1 -C 9 )heterocyclic and (C 1 -C 6 )heteroaryl, wherein said elements are optionally substituted by halo, amino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, —OCF_or —CF 3 ;  
 R 4  is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkyl-(C═O)— or (C 1 -C 6 )alkyl-O—(C═O)—:  
 R 5  is hydrogen, halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-(C═O)—, formyl, formamidyl, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 —N—(C═O)—, (C 6 -C 10 )aryl-HN—(C═O)—, [(C 6 -C 10)aryl]   2 -N-(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl-]N—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 9 —N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 1 -C 6 )alkoxyiminyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— or (C 6 -C 10 )aryl-(C═O)—NH—;  
 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, —COIH (C 1 -C 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N—(C═O)—, (C 6 -C 10 )aryl-NH—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 1 -C 10 )aryl-]N-(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 —N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 C 9 )heterocyclic-(C═O)—NH— and (C 6 -C 10 )aryl-(C═O)—NH—;  
 R 6  is hydrogen, halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-(C═O)—, formyl, formamidyl, cyano, nitro, amino, (C 1 -C 6 )alkylamino; [(C 1 -C 6 )alkyl] 2 amino; (C 1 -C 6 )alkyl-S—, (C 1 -C 6 )alkyl-(S═O)—, (C 1 -C 6 )alkyl-SO 2 —, —CO 2 H, (C 1 -C 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N—(C═O)—, (C 6 -C 10 )aryl-HN—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 19 )aryl-]N-(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— or (C 6 -C 10 )aryl-(C═O)—NH—;  
 wherein said R 6  (C 1 -C 6 )alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxyl (C 1 -C 6 )alkoxy, cyano, nitro, —CO 2 H, (C 1 -C 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N—(C═O)—, (C 6 -C 10 )aryl-HN—(C═O)—, [(C 6 -C 10 )aryl]2—N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl-]N—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N—(C═O)—, [(C 1 C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— and (C 6 -C 10 )aryl-(C═O)—NH—;  
 R 7  is hydrogen, halo, hydroxy, mercapto, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cyano, formyl, formamidyl, (C 1 -C 6 )alkyl-(C═O)—, (C 1 -C 6 )alkyl-(C═O)—O—, —CO 2 H, (C 1 -C 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N—(C═O)—, nitro, amino, (C 1 -C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 amino, (C 1 -C 6 )alkyl-S—, (C 6 -C 10 )aryl-NH—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 6 )aryl-]N—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 3 C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— or (C 6 -C 10 )aryl-(C═O)—NH—;  
 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 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N—(C═O)—, (C 6 -C 10 )aryl-HN—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl-]N-(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, [(C 3 -C 10 )cycloalkyl] 2 -N—(C═O)—, [(C 1 -C 9 )heteroaryl] 2 -N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, ( 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— and (C 6 -C 10 )aryl-(C═O)—NH—,  
 R 8  is hydrogen, halo, hydroxy, mercapto, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cyano, formyl, formamidyl, (C 1 -C 6 )alkyl-(C═O)—, (C 1 -C 6 )alkyl-(C═O)—O—, —CO 2 H, (C 1 -C 6 )alkoxy-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, (C 1 -C 9 )heteroaryl-(C═O)—O—, (C 1 -C 9 )heterocyclic-(C═O)—O—, (C 6 -C 10 )aryl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 1 -C 9 )heteroaryl-O—(C═O)—, (C 1 -C 9 )heterocyclic-O—(C═O)—, (C 6 -C 10 )aryl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-HN—(C═O)—, [(C 1 -C 6 )alkyl]-N—(C═O)—, nitro, amino, (C 1 -C 6 )alkyl amino, [(C 1 -C 6 )alkyl] 2 amino, (C 1 -C 6 )alkyl-S—, (C 6 -C 10 )aryl-NH—(C═O)—, [(C 6 -C 10 )aryl] 2 -N—(C═O)—, (C 1 -C 6 )alkyl-[(C 6 -C 10 )aryl-N—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, (C 1 -C 9 )heteroaryl-NH—(C═O)—, (C 1 -C 9 )heterocyclic-NH—(C═O)—, (C 3 -C 10 )cycloalkyl] 2 -N—(C═O)—, [(C 1 -C 9 )heteroaryl]-N—(C═O)—, [(C 1 -C 9 )heterocyclic] 2 -N—(C═O)—, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C═O)—, (C 3 -C 10 )cycloalkyl, (C 3 C 10 )cycloalkyloxy, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy, (C 1 -C 9 )heteroaryl-(C═O)—, (C 1 -C 9 )heterocyclic, (C 1 -C 9 )heterocyclic-O—, (C 1 -C 9 )heterocyclic-(C═O)—, (C 1 -C 6 )alkocy-(C═O)—NH—, (C 1 C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, (C 1 -C 9 )heteroaryl-(C═O)—NH—, (C 1 -C 9 )heterocyclic-(C═O)—NH— or (C 6 -C 10 )aryl-(C═O)—NH—, or a pharmaceutically acceptable salt thereof.