Abstract:
Corticotropin releasing factor (CRF) antagonists of Formula (I) ##STR1## and their use in treating psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorders, supranuclear palsy and eating disorders.

Description:
This application claims the benefit of U.S. Provisional Application No. 60/026,373, filed Sep. 16, 1996. 
    
    
     FIELD OF THE INVENTION 
     This invention relates to novel compounds and pharmaceutical compositions, and to methods of using same in the treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorders, supranuclear palsy and eating disorders. 
     BACKGROUND OF THE INVENTION 
     Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)]. 
     Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and eating disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer&#39;s disease, Parkinson&#39;s disease, Huntington&#39;s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)]. 
     In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)]. 
     There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces &#34;anxiolytic-like&#34; effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the &#34;anxiogenic&#34; effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)]. 
     The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF 9-41 ) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces &#34;anxiolytic-like&#34; effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)]. 
     DuPont Merck PCT application WO95/10506 describes corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. 
     European patent application 0 576 350 A1 by Elf Sanofi describes corticotropin releasing factor antagonist compounds useful in the treatment of CNS and stress disorders. 
     Pfizer patent applications WO 94/13676, WO 94/13677, WO 94/13661, WO 95/33750, WO 95/34563, WO 95/33727 describe corticotropin releasing factor antagonist compounds useful in the treatment of CNS and stress disorders. 
     All of the aforementioned references are hereby incorporated by reference. 
     The compounds and the methods of the present invention provide for the production of compounds capable of inhibiting the action of CRF at its receptor protein in the brain. These compounds would be useful in the treatment of a variety of neurodegenerative, neuropsychiatric and stress-related disorders such as affective disorders, anxiety, depression, post-traumatic stress disorders, supranuclear palsy, seizure disorders, stroke, irritable bowel syndrome, immune suppression, Alzheimer&#39;s disease, gastrointestinal disease, anorexia nervosa or other eating disorders, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorders and fertility problems. It is further asserted that this invention may provide compounds and pharmaceutical compositions suitable for use in such a method. 
     SUMMARY OF THE INVENTION 
     This invention is a class of novel compounds which are CRF receptor antagonists and which can be represented by Formula (I): ##STR2## or a pharmaceutically acceptable salt form thereof, wherein Z is CR 2  or N; 
     when Z is CR 2  : 
     Y is NR 4 , O or S(O) n  ; 
     Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, indolinyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, benzothiazolyl, indazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 4 R 5  groups; wherein Ar is attached to Y through an unsaturated carbon; 
     R 1  is H, halo, C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 8  cycloalkyl, C 1  -C 4  haloalkyl, aryl, heterocyclyl, --CN, --OR 7 , --SH, --S(O) n  R 13 , --COR 7 , --CONR 6  R 7 , --CO 2  R 7 , --OC(O)R 13 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , or --NR 6  R 7 , wherein C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl or C 3  -C 8  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, halo, C 1  -C 4  haloalkyl, --CN, --OR 7 , --SH, --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --OC(O)R 13 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7 , --CONR 6  R 7 , aryl and heterocyclyl; 
     R 2  is H, C 1  -C 4  alkyl, C 2  -C 4  alkenyl, C 2  -C 4  alkynyl, C 3  -C 6  cycloalkyl, halo, --CN, C 1  -C 4  haloalkyl, --NR 9  R 10 , --NR 9  COR 10 , --NR 9  CO 2  R 10 , --OR 11 , --SH or --S(O) n  R 12  ; 
     R 3  is C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 8  cycloalkyl, C 1  -C 4  haloalkyl, aryl, heterocyclyl, --CN, --OR 7 , --S(O) 2  R 13 , --COR 7 , --CO 2  R 7 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --CONR 6  R 7 , --NR 8  CO 2  R 7 , or --NR 6  R 7 , 
     wherein C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl or C 3  -C 8  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, halo, C 1  -C 4  haloalkyl, --CN, --OR 7 , --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7 , --CONR 6  R 7 , aryl and heterocyclyl, 
     with the proviso that when R 3  is aryl, Ar is not imidazolyl; 
     R 4  is H, C 1  -C 6  alkyl, C 2  -C 6  alkenyl or C 2  -C 6  alkynyl, wherein C 2  -C 6  alkenyl or C 2  -C 6  alkynyl is optionally substituted with C 1  -C 4  alkyl or C 3  -C 6  cycloalkyl and wherein C 1  -C 6  alkyl is optionally substituted with C 1  -C 4  alkyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, --OR 7 , --S(O) n  R 12 , --CO 2  R 7 , --NR 6  R 7  or --NR 9  COR 10  ; 
     R 5  is independently selected at each occurrence from C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, aryl, heterocyclyl, --NO 2 , halo, --CN, C 1  -C 4  haloalkyl, --NR 6  R 7 , --NR 8  COR 7 , --NR 8  CO 2  R 7 , --OR 7 , --COR 7 , --CO 2  R 7 , --CONR 6  R 7 , --CON(OR 9 )R 7 , --SH, and --S(O) n  R 13 , wherein C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 6  cycloalkyl and C 4  -C 12  cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, --NO 2 , halo, --CN, --OR 7 , --COR 7 , --CO 2  R 7 , --CONR 6  R 7 , --NR 6  R 7 , --NR 8  COR 7 , --NR 8  CO 2  R 7  and --S(O) n  R 13  ; 
     R 6  and R 7  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, aryl, aryl(C 1  -C 4  alkyl)-, heterocyclyl, heterocyclyl(C 1  -C 4  alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or --NR 6  R 7  taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine; 
     wherein C 1  -C 4  alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C 1  -C 4  alkoxy groups; 
     R 8  is independently at each occurrence H or C 1  -C 4  alkyl; 
     R 9  and R 10  are independently at each occurrence selected from H, C 1  -C 4  alkyl and C 3  -C 6  cycloalkyl; 
     R 11  is H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, or C 3  -C 6  cycloalkyl; 
     R 12  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl or --NR 6  R 7  ; 
     R 13  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, --NR 6  R 7 , aryl, aryl(C 1  -C 4  alkyl)-, heterocyclyl or heterocyclyl(C 1  -C 4  alkyl)-; 
     R 14  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, --NR 15  R 16  ; 
     R 15  and R 16  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl and C 4  -C 12  cycloalkylalkyl; or --NR 15  R 16  taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine; 
     aryl is phenyl, biphenyl or naphthyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, halo, C 1  -C 4  haloalkyl, --CN, --OR 15 , --SH, --S(O) n  R 14 , --COR 15 , --CO 2  R 15 , --OC(O)R 14 , --NO 2 , --NR 8  COR 15 , --N(COR 15 ) 2 , --NR 8  CONR 15  R 16 , --NR 8  CO 2  R 15 , --NR 15  R 16  and --CONR 15  R 16  ; 
     heterocyclyl is 5- to 10-membered heterocyclic ring which may be saturated, partially unsaturated or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein the heterocyclic ring is substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, halo, C 1  -C 4  haloalkyl, --CN, --OR 15 , --SH, --S(O) n  R 14 , --COR 15 , --CO 2  R 15 , --OC(O)R 14 , --NR 8  COR 15 , --N(COR 15 ) 2 , --NR 8  CONR 15  R 16 , --NR 8  CO 2  R 15 , --NR 15  R 16 , and --CONR 15  R 16  ; and 
     n is independently at each occurrence 0, 1 or 2; 
     and wherein, when Z is N: 
     Y is NR 4 , O or S(O) n  ; 
     Ar, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , aryl, heterocyclyl, heterocyclyl and n are as defined above, but 
     R 3  is C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 8  cycloalkyl, C 1  -C 4  haloalkyl, aryl, heterocyclyl, --CN, --S(O) 2  R 13 , --CO 2  R 7 , --COR 7  or --CONR 6  R 7 , 
     wherein C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl or C 3  -C 8  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, halo, C 1  -C 4  haloalkyl, --CN, --OR 7 , --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7 , --CONR 6  R 7 , aryl and heterocyclyl, 
     with the proviso that when R 3  is aryl, Ar is not imidazolyl. 
     [3] Preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein: 
     Z is CR 2  ; 
     Y is NR 4  or O; 
     Ar is phenyl or pyridyl, each substituted with 0 to 4 R 5  groups; 
     R 1  is H, halo, C 1  -C 4  alkyl, cyclopropyl, C 1  -C 4  haloalkyl, --CN, --NR 6  R 7 , --CONR 6  R 7 , --OR 7 , --COR 7 , --CO 2  R 7  or --S(O) n  R 13 , wherein C 1  -C 4  alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, C 3  -C 6  cycloalkyl, halo, --CN, --OR 7 , --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --NR 8  COR 7 , --NR 8  CO 2  R 7 , --NR 6  R 7  and aryl; 
     R 2  is H, C 1  -C 4  alkyl, halo, C 1  -C 4  haloalkyl; 
     R 3  is C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 8  cycloalkyl, C 1  -C 4  haloalkyl, aryl, heterocyclyl, --CN, --OR 7 , --S(O) 2  R 13 , --COR 7 , --CO 2  R 7 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --CONR 6  R 7 , --NR 8  CO 2  R 7 , or --NR 6  R 7 , 
     wherein C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl or C 3  -C 8  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, halo, --CN, --OR 7 , --S(O) n  R l3 , --CO 2  R 7 , --NR 8  COR 7 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7 , aryl and heterocyclyl; 
     R 4  is H, C 1  -C 6  alkyl or C 2  -C 6  alkenyl, wherein C 1  -C 6  alkyl is optionally substituted with C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, --OR 7 , --S(O) n  R 12 , --CO 2  R 7 , --NR 6  R 7  or --NR 9  COR 10  ; 
     R 5  is independently selected at each occurrence from C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 6  cycloalkyl, C 4  -C 8  cycloalkylalkyl, aryl, heterocyclyl, C 1  -C 4  haloalkyl, halo, --CN, --NO 2 , --NR 6  R 7 , --COR 7 , --OR 7 , --CONR 6  R 7 , --CON(OR 9 )R 7 , CO 2  R 7  and --S(O) n  R 13 , 
     wherein C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 6  cycloalkyl and C 4  -C 8  cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, --NO 2 , halo, --CN, --NR 6  R 7 , COR 7 , --OR 7 , --CONR 6  R 7 , CO 2  R 7  and --S(O) n  R 13  ; 
     R 6  and R 7  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, aryl, aryl(C 1  -C 4  alkyl)-, heterocyclyl, heterocyclyl(C 1  -C 4  alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or --NR 6  R 7  taken together as a whole is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; 
     wherein C 1  -C 4  alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C 1  -C 4  alkoxy groups; 
     R 8  is independently at each occurrence H or C 1  -C 4  alkyl; 
     R 9  and R 10  are independently at each occurrence selected from H, C 1  -C 4  alkyl and C 3  -C 6  cycloalkyl; 
     R 11  is H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, or C 3  -C 6  cycloalkyl; 
     R 12  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl or --NR 6  R 7  ; 
     R 13  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, --NR 6  R 7 , aryl, aryl(C 1  -C 4  alkyl)-, heterocyclyl or heterocyclyl(C 1  -C 4  alkyl)-; 
     R 14  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, --NR 15  R 16  ; 
     R 15  and R 16  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl and C 4  -C 12  cycloalkylalkyl; or --NR 15  R 16  taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine; 
     aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --COR 15 , --CO 2  R 15 , --NO 2 , --NR 8  COR 15 , --NR 8  CONR 15  R 16 , --NR 8  CO 2  R 15  and --NR 15  R 16  ; 
     heterocyclyl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --CO 2  R 15 , --NO 2 , --NR 8  COR 15 , --NR 8  CONR 15  R 16 , --NR 8  CO 2  R 15 , and --NR 15  R 16  ; and 
     n is independently at each occurrence 0, 1 or 2. 
     [4] More preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein: 
     Z is CR 2  ; 
     Y is NR 4  ; 
     Ar is phenyl or pyridyl, each substituted with 0 to 4 R 5  groups; 
     R 1  is H, halo, C 1  -C 4  alkyl, cyclopropyl, C 1  -C 3  haloalkyl, --CN, --NR 6  R 7 , --CONR 6  R 7 , --COR 7 , --CO 2  R 7 , --OR 7  or --S(O) n  R 13  wherein C 1  -C 4  alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C 3  -C 4  cycloalkyl, halo, --CN, --OR 7 , --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --NR 6  R 7  ; 
     R 2  is H; 
     R 3  is C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl or aryl, wherein C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl or C 3  -C 6  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, halo, --CN, --OR 7 , --S(O) n  R 13 , --CO 2  R 7 , --NR 8  COR 7 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7  and aryl; 
     R 4  is H, allyl, or C 1  -C 4  alkyl, wherein C 1  -C 4  alkyl is optionally substituted with C 1  -C 4  alkyl, --OR 7 , --S(O) 2  R 12 , --CO 2  R 7 , --NR 6  R 7  or --NR 9  COR 10  ; 
     R 5  is independently selected at each occurrence from C 1  -C 6  alkyl, aryl, heterocyclyl, C 1  -C 4  haloalkyl, halo, --CN, --NO 2 , --NR 6  R 7 , --COR 7 , --OR 7 , --CONR 6  R 7 , --CON(OR 9 )R 7 , --CO 2  R 7  and --S(O) n  R 13 , wherein C 1  -C 6  alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, --NO 2 , halo, --CN, --NR 6  R 7 , COR 7 , --OR 7 , --CONR 6  R 7 , CO 2  R 7  and --S(O) n  R 13  ; 
     R 6  and R 7  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl and C 2  -C 8  alkoxyalkyl; 
     wherein C 1  -C 4  alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C 1  -C 4  alkoxy groups; 
     R 8 , R 9  and R 10  are independently at each occurrence H or C 1  -C 4  alkyl; 
     R 12  and R 13  are independently at each occurrence C 1  -C 4  alkyl or --NR 6  R 7  ; 
     R 14  is C 1  -C 4  alkyl or --NR 15  R 16  ; 
     R 15  and R 16  are independently at each occurrence H, C 1  -C 4  alkyl or C 2  -C 8  alkoxyalkyl; 
     aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --COR 15 , --CO 2  R 15 , --NO 2  and --NR 15  R 16  ; and 
     n is independently at each occurrence 0, 1 or 2. 
     [5] Even more preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein: 
     Z is CR 2  ; 
     Y is NR 4  ; 
     Ar is phenyl or pyridyl, each substituted with 2 to 4 R 5  groups; 
     R 1  is H, Cl, Br, methyl, ethyl, cyclopropyl, or --CN, 
     R 2  is H; 
     R 3  is C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl or aryl, wherein C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl or C 3  -C 6  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, C 3  -C 6  cycloalkyl, --CF 3 , halo, --CN, --OR 7 , and aryl; 
     R 4  is H, methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, n-butyl, or allyl; 
     R 5  is independently selected at each occurrence from methyl, ethyl, i-propyl, n-propyl, aryl, --CF 3 , halo, --CN, --N(CH 3 ) 2 , --C(═O)CH 3 , --OCH 3 , --OCH 2  CH 3 , --OCF 3 , and --S(O) 2  CH 3  ; 
     R 14  is C 1  -C 4  alkyl or --NR 15  R 16  ; 
     R 15  and R 16  are independently at each occurrence H, C 1  -C 4  alkyl or C 2  -C 8  alkoxyalkyl; 
     aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --COR 15 , --CO 2  R 15 , --NO 2  and --NR 15  R 16  ; and 
     n is independently at each occurrence 0, 1 or 2. 
     [6] Specifically preferred compounds of this invention are compounds of Formula (I), pharmaceutically acceptable salts and pro-drug forms thereof, which are: 
     3-[(2,4-Dibromophenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 
     3-[[2-Bromo-4-(1-methylethyl)phenyl]amino]-5-Chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 
     3-[(2,4-Dibromophenyl)ethylamino]-5-Chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 
     3-[[2-Bromo-4-(1-methylethyl)phenyl]ethylamino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 
     3-[(2,4,6-Trimethylphenyl)amino]-5-Chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 
     3-[(2,4,6-Trimethylphenyl)ethylamino]-5-Chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 
     (+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     3-[(2-Bromo-4,6-dimethoxyphenyl)amino]-5-Chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 
     3-[(2-Cyano-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2-Bromo-4,6-dimethoxyphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2-Chloro-4,6-dimethoxyphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone; 
     (+/-)-3-[(4,6-Dimethyl-2-iodophenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     3-[(2-Cyano-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2-Bromo-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone; 
     (+/-)-3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(4-Acetyl-2,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2-Acetyl-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(4,6-Dimethyl-2-thiomethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone; 
     (+/-)-3-[(4,6-Dimethyl-2-methylsulfonylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(4-Chloro-2-iodo-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     3-[(2,4,6-Trimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(2,4,6-Trimethylphenyl)amino]-5-Chloro-1-phenyl-2(1H)-pyrazinone; 
     (+/-)-3-[(2,4-Dibromophenyl)amino]-5-methyl-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)-3-[[2-Bromo-4-(1-methylethyl)phenyl]amino]-5-methyl-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone; 
     (+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     3-[(2,4,6-Trimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(2,4-Dichloro-6-methylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(2,4-Dichloro-6-methylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(2,4-Dibromo-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     3-[(2,4,6-Trimethylphenyl)amino]-5-Chloro-1-[1-(2-methoxyethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2 (1H)-pyrazinone; 
     (+/-)-3-[[2,4-Dimethyl-6-(methoxymethyl)phenyl]amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[[2,4-Dimethyl-6-(methoxymethyl)phenyl]amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[[2,4-Dimethyl-6-(methoxymethyl)phenyl]amino]-5-Chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[[2,4-Dimethyl-6-(methoxymethyl)phenyl]amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     (+/-)3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-Chloro-1-(2-methoxy-1-methylethyl)-2(1H)-pyrazinone; 
     (+/-)3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-Chloro-1-(2-methoxy-1-methylethyl)-2(1H)-pyrazinone; 
     (+/-)3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-Chloro-1-[1-(ethoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-Chloro-1-(2-ethoxy-1-methylethyl)-2(1H)-pyrazinone; and 
     (+/-)3-[(4-Bromo-2,6-difluorophenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2-Bromo-4,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,4-Dimethyl-6-thiomethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,4-Dimethyl-6-methylsulfonylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,6-Dimethyl-4-(N,N-dimethylamino)phenyl)-amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,4-Dichloro-6-methylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(4-Chloro-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,6-Dimethyl-4-methoxyphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(2,6-Dimethyl-4-methylsulfonylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     (+/-)-3-[(4-Acetyl-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 
     3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(4-Acetyl-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(2,6-Dimethyl-4-methylsulfonylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(2,6-Dimethyl-4-(N,N-dimethylamino)phenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(4,6-Dimethyl-2-(N,N-dimethylamino)phenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     (+/-)3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)3-[(2,6-Dimethyl-4-methylsulfonylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     (+/-)3-[(4-Bromo-6-methoxy-2-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 
     3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(2,6-Dimethyl-4-methylsulfonylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 
     3-[(4-Bromo-6-methoxy-2-methylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; and 
     3-[(2,4,6-Trimethylphenyl)amino]-5-methyl-1-(1-ethylpropyl)-2(1H)-pyrazinone. 
     [7] A second embodiment of preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein: 
     Z is CR 2  ; 
     Y is NR 4  or O; 
     Ar is phenyl or pyridyl, each substituted with 0 to 4 R 5  groups; 
     R 1  is H, halo, C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 8  cycloalkyl, C 1  -C 4  haloalkyl, aryl, heterocyclyl, --CN, --OR 7 , --SH, --S(O) n  R 13 , --COR 7 , --CONR 6  R 7 , --CO 2  R 7 , --OC(O)R 13 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , or --NR 6  R 7 , 
     wherein C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl or C 3  -C 8  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, halo, C 1  -C 4  haloalkyl, --CN, --OR 7 , --SH, --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --OC(O)R 13 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7 , --CONR 6  R 7 , aryl and heterocyclyl; 
     R 2  is H, C 1  -C 4  alkyl, halo, C 1  -C 4  haloalkyl; 
     R 3  is C 1  -C 4  alkyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl and --NR 6  R 7 , 
     wherein C 1  -C 4  alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, halo, --CN, --OR 7 , --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7  and --CONR 6  R 7  ; 
     R 4  is H, C 1  -C 6  alkyl or C 2  -C 6  alkenyl, wherein C 1  -C 6  alkyl is optionally substituted with C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, --OR 7 , --S(O) n  R 12 , --CO 2  R 7 , --NR 6  R 7  or --NR 9  COR 10  ; 
     R 5  is independently selected at each occurrence from C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, aryl, heterocyclyl, --NO 2 , halo, --CN, C 1  -C 4  haloalkyl, --NR 6  R 7 , --NR 8  COR 7 , --NR 8  CO 2  R 7 , --OR 7 , --COR 7 , --CO 2  R 7 , --CONR 6  R 7 , --CON(OR 9 )R 7  and --S(O) n  R 13 , wherein C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 6  cycloalkyl and C 4  -C 12  cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, --NO 2 , halo, --CN, --OR 7 , --COR 7 , --CO 2  R 7 , --CONR 6  R 7 , --NR 6  R 7 , --NR 8  COR 7 , --NR 8  CO 2  R 7  and --S(O) n  R 13  ; 
     R 6  and R 7  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, aryl, aryl(C 1  -C 4  alkyl)-, heterocyclyl, heterocyclyl (C 1  -C 4  alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or --NR 6  R 7  taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine; 
     wherein C 1  -C 4  alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C 1  -C 4  alkoxy groups; 
     R 8  is independently at each occurrence H or C 1  -C 4  alkyl; 
     R 9  and R 10  are independently at each occurrence selected from H, C 1  -C 4  alkyl and C 3  -C 6  cycloalkyl; 
     R 11  is H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, or C 3  -C 6  cycloalkyl; 
     R 12  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl or --NR 6  R 7  ; 
     R 13  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, --NR 6  R 7 , aryl, aryl(C 1  -C 4  alkyl)-, heterocyclyl or heterocyclyl(C 1  -C 4  alkyl)-; 
     R 14  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, --NR 15  R 16  ; 
     R 15  and R 16  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl and C 4  -C 12  cycloalkylalkyl; or --NR 15  R 16  taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine; 
     aryl is phenyl or naphthyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --COR 15 , --CO 2  R 15 , --NO 2 , --NR 8  COR 15 , --NR 8  CONR 15  R 16 , --NR 8  CO 2  R 15  and --NR 15  R 16  ; 
     heterocyclyl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --CO 2  R 15 , --NO 2 , --NR 8  COR 15 , --NR 8  CONR 15  R 16 , --NR 8  CO 2  R 15 , and --NR 15  R 16  ; and 
     n is independently at each occurrence 0, 1 or 2. 
     [8] More preferred compounds of the second embodiment of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein: 
     Z is CR 2  ; 
     Y is NR 4  ; 
     Ar is phenyl or pyridyl, each substituted with 0 to 4 R 5  groups; 
     R 1  is H, halo, C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, aryl, heterocyclyl, --CN, --OR 7 , --S(O) n  R 13 , --COR 7 , --CONR 6  R 7 , --CO 2  R 7  or --NR 6  R 7 , 
     wherein C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl or C 3  -C 6  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, halo, C 1  -C 4  haloalkyl, --CN, --OR 7 , --SH, --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --OC(O)R 13 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7 , --CONR 6  R 7 , aryl and heterocyclyl; 
     R 2  is H; 
     R 3  is C 1  -C 4  alkyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl and --NR 6  R 7   1 , 
     wherein C 1  -C 4  alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, halo, --CN, --OR 7 , --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7  and --CONR 6  R 7  ; 
     R 4  is H, allyl, or C 1  -C 4  alkyl, wherein C 1  -C 4  alkyl is optionally substituted with C 1  -C 4  alkyl, --OR 7 , --S(O) 2  R 12 , --CO 2  R 7 , --NR 6  R 7  or --NR 9  COR 10  ; 
     R 5  is independently selected at each occurrence from C 1  -C 6  alkyl, aryl, heterocyclyl, C 1  -C 4  haloalkyl, halo, --CN, --NO 2 , --NR 6  R 7 , --COR 7 , --OR 7 , --CONR 6  R 7 , --CON(OR 9 )R 7 , --CO 2  R 7  and --S(O) n  R l3 , wherein C 1  -C 6  alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, --NO 2 , halo, --CN, --NR 6  R 7 , COR 7 , --OR 7 , --CONR 6  R 7 , CO 2  R 7  and --S(O) n  R 13  ; 
     R 6  and R 7  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl and C 2  -C 8  alkoxyalkyl; 
     wherein C 1  -C 4  alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C 1  -C 4  alkoxy groups; 
     R 8 , R 9  and R 10  are independently at each occurrence H or C 1  -C 4  alkyl; 
     R 12  and R 13  are independently at each occurrence C 1  -C 4  alkyl or --NR 6  R 7  ; 
     R 14  is C 1  -C 4  alkyl or --NR 15  R 16  ; 
     R 15  and R 16  are independently at each occurrence H, C 1  -C 4  alkyl or C 2  -C 8  alkoxyalkyl; 
     aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --COR 15 , --CO 2  R 15 , --NO 2  and --NR 15  R 16  ; and 
     n is independently at each occurrence 0, 1 or 2. 
     [10] A third embodiment of preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein: 
     Z is N; 
     Y is NR 4  or O; 
     Ar is phenyl or pyridyl, each substituted with 0 to 4 R 5  groups; 
     R 1  is H, halo, C 1  -C 4  alkyl, C 3  -C 6  cycloalkyl, aryl, --CN, C 1  -C 4  haloalkyl, --NR 6  R 7 , --CONR 6  R 7 , --OR 7 , --COR 7 , --CO 2  R 7  or --S(O) n  R 13 , 
     wherein C 1  -C 4  alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 3  alkyl, C 3  -C 6  cycloalkyl, halo, --CN, --OR 7 , --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --NR 8  COR 7 , --NR 8  CO 2  R 7 , --NR 6  R 7  and aryl; 
     R 3  is C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 8  cycloalkyl, C 1  -C 4  haloalkyl, aryl, heterocyclyl, --CN, --S(O) 2  R 13 , --COR 7 , --CO 2  R 7  or --CONR 6  R 7 , 
     wherein C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl or C 3  -C 8  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, halo, --CN, --OR 7 , --S(O) n  R l3 , --CO 2  R 7 , --NR 8  COR 7 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7 , aryl and heterocyclyl; 
     R 4  is H, C 1  -C 6  alkyl or C 2  -C 6  alkenyl, wherein C 1  -C 6  alkyl is optionally substituted with C 1  -C 4  alkyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, --OR 7 , --S(O) n  R 12 , --CO 2  R 7 , --NR 6  R 7  or --NR 9  COR 10  ; 
     R 5  is independently selected at each occurrence from C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 6  cycloalkyl, C 4  -C 8  cycloalkylalkyl, aryl, heterocyclyl, C 1  -C 4  haloalkyl, halo, --CN, --NO 2 , --NR 6  R 7 , --COR 7 , --OR 7 , --CONR 6  R 7 , --CON(OR 9 )R 7 , CO 2  R 7  and --S(O) n  R 13 , 
     wherein C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 6  cycloalkyl and C 4  -C 8  cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, --NO 2 , halo, --CN, --NR 6  R 7 , COR 7 , --OR 7 , --CONR 6  R 7 , CO 2  R 7  and --S(O) n  R 13  ; 
     R 6  and R 7  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, aryl, aryl(C 1  -C 4  alkyl)-, heterocyclyl, heterocyclyl(C 1  -C 4  alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or --NR 6  R 7  taken together as a whole is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; 
     wherein C 1  -C 4  alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C 1  -C 4  alkoxy groups; 
     R 8  is independently at each occurrence H or C 1  -C 4  alkyl; 
     R 9  and R 10  are independently at each occurrence selected from H, C 1  -C 4  alkyl and C 3  -C 6  cycloalkyl; 
     R 11  is H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, or C 3  -C 6  cycloalkyl; 
     R 12  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl or --NR 6  R 7  ; 
     R 13  is C 1  -C 4  alkyl, C 1  14 C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, --NR 6  R 7 , aryl, aryl(C 1  -C 4  alkyl)-, heterocyclyl or heterocyclyl(C 1  -C 4  alkyl)-; 
     R 14  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, --NR 15  R 16  ; 
     R 15  and R 16  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl and C 4  -C 12  cycloalkylalkyl; or --NR 15  R 16  taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine; 
     aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --COR 15 , --CO 2  R 15 , --NO 2 , --NR 8  COR 15 , --NR 8  CONR 15  R 16 , --NR 8  CO 2  R 15  and --NR 15  R 16  ; 
     heterocyclyl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --CO 2  R 15 , --NO 2 , --NR 8  COR 15 , --NR 8  CONR 15  R 16 , --NR 8  CO 2  R 15  and --NR 15  R 16  ; and 
     n is independently at each occurrence 0, 1 or 2. 
     [11] More preferred compounds of the third embodiment of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein: 
     Z is N; 
     Y is NR 4  ; 
     Ar is phenyl or pyridyl, each substituted with 0 to 4 R 5  groups; 
     R 1  is H, halo, C 1  -C 4  alkyl, C 1  -C 3  haloalkyl, cyclopropyl, --CN, --NR 6  R 7 , --CONR 6  R 7 , --COR 7 , --CO 2  R 7 , --OR 7  or --S(O) n  R 13 , 
     wherein C 1  -C 4  alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C 3  -C 4  cycloalkyl, halo, --CN, --OR 7 , --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --NR 6  R 7  ; 
     R 3  is C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl or aryl, 
     wherein C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl or C 3  -C 6  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, halo, --CN, --OR 7 , --S(O) n  R 13 , --CO 2  R 7 , --NR 8  COR 7 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7  and aryl; 
     R 4  is H, allyl, or C 1  -C 4  alkyl, wherein C 1  -C 4  alkyl is optionally substituted with C 1  -C 4  alkyl, --OR 7 , --S(O) 2  R 12 , CO 2  R 7 , --NR 6  R 7  or --NR 9  COR 10  ; 
     R 5  is independently selected at each occurrence from C 1  -C 6  alkyl, aryl, heterocyclyl, C 1  -C 4  haloalkyl, halo, --CN, --NO 2 , --NR 6  R 7 , --COR 7 , --OR 7 , --CONR 6  R 7 , --CON(OR 9 )R 7 , --CO 2  R 7  and --S(O) n  R 13 , wherein C 1  -C 6  alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, --NO 2 , halo, --CN, --NR 6  R 7 , COR 7 , --OR 7 , --CONR 6  R 7 , CO 2  R 7  and --S(O) n  R 13  ; 
     R 6  and R7 are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl and C 2  -C 8  alkoxyalkyl; 
     wherein C 1  -C 4  alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C 1  -C 4  alkoxy groups; 
     R 8 , R 9  and R 10  are independently at each occurrence H or C 1  -C 4  alkyl; 
     R 12  and R 13  are independently at each occurrence C 1  -C 4  alkyl or --NR 6  R 7  ; 
     R 14  is C 1  -C 4  alkyl or --NR 15  R 16  ; 
     R 15  and R 16  are independently at each occurrence H, C 1  -C 4  alkyl or C 2  -C 8  alkoxyalkyl; 
     aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --COR 15 , --CO 2  R 15 , --NO 2  and --NR 15  R 16  ; and 
     n is independently at each occurrence 0, 1 or 2. 
     [12] Even more preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein: 
     Z is N; 
     Y is NR 4  ; 
     Ar is phenyl or pyridyl, each substituted with 2 to 4 R 5  groups; 
     R 1  is H, methyl, ethyl, cyclopropyl, --CF 3 , or --N(CH 3 ) 2  ; 
     R 3  is C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl or aryl, wherein C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl or C 3  -C 6  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, C 3  -C 6  cycloalkyl, --CF 3 , halo, --CN, --OR 7 , and aryl; 
     R 4  is H, methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, n-butyl, or allyl; 
     R 5  is independently selected at each occurrence from methyl, ethyl, i-propyl, n-propyl, aryl, --CF 3 , halo, --CN, --N(CH 3 ) 2 , --C(═O)CH 3 , --OCH 3 , --OCH 2  CH 3 , --OCF 3 , and --S(O) 2  CH 3  ; 
     R 14  is C 1  -C 4  alkyl or --NR 15  R 16  ; 
     R 15  and R 16  are independently at each occurrence H, C 1  -C 4  alkyl or C 2  -C 8  alkoxyalkyl; 
     aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --COR 15 , --CO 2  R 15 , --NO 2  and --NR 15  R 16  ; and 
     n is independently at each occurrence 0, 1 or 2. 
     [13] A fourth embodiment of preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein: 
     Z is N; 
     Y is NR 4  or O; 
     Ar is phenyl or pyridyl, each substituted with 0 to 4 R 5  groups; 
     R 1  is H, halo, C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 8  cycloalkyl, C 1  -C 4  haloalkyl, aryl, heterocyclyl, --CN, --OR 7 , --SH, --S(O) n  R 13 , --COR 7 , --CONR 6  R 7 , --CO 2  R 7 , --OC(O)R 13 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , or --NR 6  R 7 , wherein C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl or C 3  -C 8  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, halo, C 1  -C 4  haloalkyl, --CN, --OR 7 , --SH, --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --OC(O)R 13 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7 , --CONR 6  R 7 , aryl and heterocyclyl; 
     R 3  is C 1  -C 4  alkyl, --CN, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, --OR 7 , --COR 7 , --CO 2  R 7  or --CONR 6  R 7 , 
     wherein C 1  -C 4  alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, halo, --CN, --OR 7 , --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --NR 8  COR 7 , --N (COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7  and --CONR 6  R 7  ; 
     R 4  is H, C 1  -C 6  alkyl or C 2  -C 6  alkenyl, wherein C 1  -C 6  alkyl is optionally substituted with C 1  -C 4  alkyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, --OR 7 , --S(O) n  R 12 , --CO 2  R 7 , --NR 6  R 7  or --NR 9  COR 10  ; 
     R 5  is independently selected at each occurrence from C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, aryl, heterocyclyl, --NO 2 , halo, --CN, C 1  -C 4  haloalkyl, --NR 6  R 7 , --NR 8  COR 7 , --NR 8  CO 2  R 7 , --OR 7 , --COR 7 , --CO 2  R 7 , --CONR 6  R 7 , --CON(OR 9 )R 7  and --S(O) n  R 13 , wherein C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 2  -C 10  alkynyl, C 3  -C 6  cycloalkyl and C 4  -C 12  cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, --NO 2 , halo, --CN, --OR 7 , --COR 7 , --CO 2  R 7 , --CONR 6  R 7 , --NR 6  R 7 , --NR 8  COR 7 , --NR 8  CO 2  R 7  and --S(O) n  R 13  ; 
     R 6  and R 7  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, aryl, aryl(C 1  -C 4  alkyl)-, heterocyclyl, heterocyclyl(C 1  -C 4  alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or NR 6  R 7  taken together as a whole is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; 
     wherein C 1  -C 4  alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C 1  -C 4  alkoxy groups; 
     R 8  is independently at each occurrence H or C 1  -C 4  alkyl; 
     R 9  and R 10  are independently at each occurrence selected from H, C 1  -C 4  alkyl and C 3  -C 6  cycloalkyl; 
     R 11  is H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, or C 3  -C 6  cycloalkyl; 
     R 12  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl or --NR 6  R 7  ; 
     R 13  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, --NR 6  R 7 , aryl, aryl(C 1  -C 4  alkyl)-, heterocyclyl or heterocyclyl(C 1  -C 4  alkyl)-; 
     R 14  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl, C 4  -C 12  cycloalkylalkyl, --NR 15  R 16  ; 
     R 15  and R 16  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 2  -C 8  alkoxyalkyl, C 3  -C 6  cycloalkyl and C 4  -C 12  cycloalkylalkyl; or --NR 15  R 16  taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine; 
     aryl is phenyl or naphthyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --COR 15 , --CO 2  R 15 , --NO 2 , --NR 8  COR 15 , --NR 8  CONR 15  R 16 , --NR 8  CO 2  R 15  and --NR 15  R 16  ; 
     heterocyclyl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --CO 2  R 15 , --NO 2 , --NR 8  COR 15 , --NR 8  CONR 15  R 16 , --NR 8  CO 2  R 15 , and --NR 15  R 16  ; and 
     n is independently at each occurrence 0, 1 or 2. 
     [14] More preferred compounds of the fourth embodiment of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein: 
     Z is N; 
     Y is NR 4  ; 
     Ar is phenyl or pyridyl, each substituted with 0 to 4 R 5  groups; 
     R 1  is H, halo, C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, aryl, heterocyclyl, --CN, --OR 7 , --S(O) n  R 13 , --COR 7 , --CONR 6  R 7 , --CO 2  R 7  or --NR 6  R 7 , 
     wherein C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl or C 3  -C 6  cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, halo, C 1  -C 4  haloalkyl, --CN, --OR 7 , --SH, --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --OC(O)R 13 , --NR 8  COR 7 , --N(COR 7 ) 2 , --NR 8  CONR 6  R 7 , --NR 8  CO 2  R 7 , --NR 6  R 7 , --CONR 6  R 7 , aryl and heterocyclyl; 
     R 3  is C 1  -C 4  alkyl, --CN, C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, --OR 7 , --COR 7  or --CO 2  R 7 , 
     wherein C 1  -C 4  alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C 3  -C 6  cycloalkyl, C 1  -C 4  haloalkyl, halo, --CN, --OR 7 , --S(O) n  R 13 , --COR 7 , --CO 2  R 7 , --NR 8  COR 7 , --NR 6  R 7  and --CONR 6  R 7  ; 
     R 4  is H, allyl, or C 1  -C 4  alkyl, wherein C 1  -C 4  alkyl is optionally substituted with C 1  -C 4  alkyl, --OR 7 , --S(O) 2  R 12 , --CO 2  R 7 , --NR 6  R 7  or --NR 9  COR 10  ; 
     R 5  is independently selected at each occurrence from C 1  -C 6  alkyl, aryl, heterocyclyl, C 1  -C 4  haloalkyl, halo, --CN, --NO 2 , --NR 6  R 7 , --COR 7 , --OR 7 , --CONR 6  R 7 , --CON(OR 9 )R 7 , --CO 2  R 7  and --S(O) n  R 13 , wherein C 1  -C 6  alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, --NO 2 , halo, --CN, --NR 6  R 7 , COR 7 , --OR 7 , --CONR 6  R 7 , CO 2  R 7  and --S(O) n  R 13  ; 
     R 6  and R 7  are independently selected at each occurrence from H, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl and C 2  -C 8  alkoxyalkyl; 
     wherein C 1  -C 4  alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C 1  -C 4  alkoxy groups; 
     R 8 , R 9  and R 10  are independently at each occurrence H or C 1  -C 4  alkyl; 
     R 12  and R 13  are independently at each occurrence C 1  -C 4  alkyl or --NR 6  R 7  ; 
     R 14  is C 1  -C 4  alkyl or --NR 15  R 16  ; 
     R 15  and R 16  are independently at each occurrence H, C 1  -C 4  alkyl or C 2  -C 8  alkoxyalkyl; 
     aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C 1  -C 4  alkyl, halo, --CN, --OR 15 , --S(O) n  R 14 , --COR 15 , --CO 2  R 15 , --NO 2  and --NR 15  R 16  ; and 
     n is independently at each occurrence 0, 1 or 2. 
     A fifth embodiment of this invention is the method of treating affective disorders, anxiety, depression, post-traumatic stress disorders, supranuclear palsy, seizure disorders, stroke, irritable bowel syndrome, immune suppression, Alzheimer&#39;s disease, gastrointestinal disease, anorexia nervosa or other eating disorders, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of Formula I. 
     A sixth embodiment of this invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I. 
     This invention also includes intermediate compounds useful in preparation of the CRF antagonist compounds and processes for making those intermediates, as described in the following description and claims. 
     The CRF antagonist compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor. 
     DETAILED DESCRIPTION OF INVENTION 
     Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. 
     The term &#34;alkyl&#34; includes both branched and straight-chain alkyl having the specified number of carbon atoms. For example, the term &#34;C 1  -C 10  alkyl&#34; denotes alkyl having 1 to 10 carbon atoms; thus, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl, wherein, for example, butyl can be --CH 2  CH 2  CH 2  CH 3 , --CH 2  CH(CH 3 ) 2 , --CH(CH 3 )CH 2  CH 3  or --CH(CH 3 ) 3 . 
     The term &#34;alkenyl&#34; includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon--Carbon bonds which may occur in any stable point along the chain. For example, the term &#34;C 2  -C 10  alkenyl&#34; denotes alkenyl having 2 to 10 carbon atoms; thus, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl, such as allyl, propargyl, 1-buten-4-yl, 2-buten-4-yl and the like, wherein, for example, butenyl can be, but is not limited to, --CH═CH 2  CH 2  CH 3 , --CH 2  CH═CHCH 3 , --CH 2  CH 2  CH═CH 2 , --CH═C(CH 3 ) 2  or --CH═CHCH═CH 2 . 
     The term &#34;alkynyl&#34; includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon--carbon bonds which may occur in any stable point along the chain. The term &#34;C 2  -C 10  alkynyl&#34; denotes alkynyl having 2 to 10 carbon atoms; thus, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl. 
     The term &#34;haloalkyl&#34; is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted independently with 1 or more halogen, such as, but not limited to, --CH 2  F, --CHF 2 , --CF 3 , --CF 2  Br, --CH 2  CF 3 , --CF 2  CF 3 , --CH(CF 3 ) 2  and the like. 
     The term &#34;alkoxy&#34; represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. 
     The term &#34;cycloalkyl&#34; is intended to include saturated ring groups having the specified number of carbon atoms, including mono-, bi- or poly--Cyclic ring systems, such as cyclopropyl (c-Pr), cyclobutyl (c-Bu), cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, [3.3.0]bicyclooctyl, [2.2.2]bicyclooctyl and so forth. 
     As used herein, the term &#34;heterocyclyl&#34; or &#34;heterocyclic&#34; is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl, isoxazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolinyl, isoxazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzothienyl, 2,3-dihydrobenzofuranyl or 2,3-dihydrobenzothienyl. 
     The term &#34;halo&#34; or &#34;halogen&#34; includes fluoro, chloro, bromo and iodo. 
     The term &#34;substituted&#34;, as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom&#39;s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced. 
     Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By &#34;stable compound&#34; or &#34;stable structure&#34; is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. 
     The term &#34;pharmaceutically acceptable salts&#34; includes acid or base salts of the compounds of formula (I). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. 
     Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington&#39;s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference. 
     &#34;Prodrugs&#34; are considered to be any covalently bonded carriers which release the active parent drug of formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I); and the like. 
     The term &#34;therapeutically effective amount&#34; of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host. 
     Synthesis 
     The pyrazinones and triazinones of this invention can be prepared by one of the general schemes outlined below (Scheme 1-6). 
     Compounds of the Formula (I) wherein Z═CH, Y═NR 4 , R 1  =halogen and R 2  =H can be prepared as shown in Scheme 1. Compounds wherein R 2  is a substituent other than H as defined in the broad scope of the invention can also be prepared as shown in Scheme 1 by using the corresponding R 2  COH substituted aldehydes or ClCHR 2  CN substituted haloacetonitriles. ##STR3## 
     Reaction of a cyanide salt with formaldehyde and the appropriate substituted amine afforded the corresponding aminoacetonitrile which was purified as the hydrochloride salt of Formula (III). Alternatively the same compounds of Formula (III) can be synthesized by reaction of the amine H 2  NR 3  with a haloacetonitrile, such as chloroacetonitrile, in the presence of a base such as a tertiary amine or an inorganic base such as K 2  CO 3  in an organic solvent and isolated as a salt of an inorganic acid by treatment with that acid. Amine salt of Formula (III) was treated with an oxalyl halide, R 1  COCOR 1 , such as oxalyl chloride or bromide to afford the dihalo compound Formula (IV), as described in Vekemans, J.; Pollers-Wieers, C.; Hoornaert, G. J. Heterocyclic Chem. 20, 919, (1982). Compound Formula (IV) can be coupled with an aryl amine H 2  NAr thermally, in the presence of a strong base such as NaH, KN(SiMe 3 ) 2 , LiN(SiMe 3 ) 2  or NaN(SiMe 3 ) 2  in an aprotic organic solvent, or under acid catalysis to give compounds of Formula (V). Compounds of Formula (V) can be alkylated with an alkyl halide R 4  X to afford compounds of Formula (I). 
     Compounds where R 1  =alkyl or substituted alkyl can be prepared according to Scheme 2. ##STR4## Reaction of the intermediate of Formula (IV) in Scheme 1, wherein R 1  =X=halogen in Scheme 2, with an alkyl or aryl thiol, HSR&#34;, in the presence of base such as NaH affords the adduct of Formula (VII), which may then be treated with a trialkylaluminum as described in Hirota, K.; Kitade, Y.; Kanbe, Y.; Maki, Y.; J. Org. Chem. 57, 5268, (1992), in the presence of a palladium catalyst, such as Pd(PPh 3 ) 2  Cl 2 , to give compounds of Formula (VIII). Condensation of compounds of Formula (VIII) with an aryl amine H 2  NAr under thermal, base, or acid catalyzed conditions gives compounds of Formula (IX). Alternatively (VIII) may be oxidized to the corresponding sulfones with an oxidant such as KMnO 4  and then condensed with the arylamines of formula H 2  NAr to give (IX). The use of appropriately substituted aluminum alkyls, or simple transformations of those substituted alkyls can give access to compounds of Formula (I), where R 1  is a substituted alkyl; see Ratovelomanana, V.; Linstrumelle, G.; Tet. Letters 52, 6001 (1984) and references cited therein. 
     Compounds of the Formula (I) wherein Z═CH, Y═O or S(O) n  and R 1  =halogen can be prepared as shown in Scheme 3. ##STR5## 
     Reaction of the dihalo intermediate (IV) from Scheme 1 with a phenoxide or thiophenoxide, formed by treatment of the corresponding phenol or thiophenol with an appropriate base, such as NaH in an aprotic solvent, gives the adduct of Formula (X) or (XI). Adduct (XI) may be further oxidized to the sulfoxide or sulfone of Formula (XII), by treatment with the appropriate oxidant, such as a peroxide, NaIO4 or KMnO4. 
     Compounds of Formula (I) where R 1  =OR, SR and S(O) n  R and Z═CH can be introduced on compounds of Formula (V) by copper or copper salt-catalyzed coupling of the corresponding anions RO -   and RS -   with the pyrazinone bromide. Keegstra, M. A.; Peters, T. H. A.; Brandsma, L.; Tetrahedron, 48, 3633 (1992) describes the addition of phenoxide anions by this method; alternatively, the same conditions can be used for the addition of thiophenoxide anions. Alternatively the same compounds can be synthesized by Scheme 4. ##STR6## 
     In Scheme 4, reaction of an aminoacetonitrile salt (III), described in Scheme 1, with an oxalyl halide ester (XIII) gives the corresponding amide (XIV), which in turn can be converted to the corresponding imidate salt (XV). This can be cyclized under treatment with a base, such as K 2  CO 3  or Et 3  N to the pyrazinedione of Formula (XVI). This can be converted to the corresponding halide (XIX), using a halogenating agent such as POX 3 , oxalyl halide or SOX 2 . Alternatively, (XVI) can be converted to the corresponding mesylate, tosylate or triflate, by treatment with the corresponding mesyl, tosyl, or triflic anhydride. Subsequently, (XIX) can be coupled with an aniline to the corresponding adduct of Formula (XX), under the conditions described in Scheme 1, or (XIX) can be coupled with a phenoxide or thiophenoxide as described in Scheme 3 to yield compounds of Formula (I) wherein Y═O or S(O) n . 
     Compounds of Formula (I) wherein R 1  =substituted N and Z═CH can be introduced on compounds of Formula (XV) by reaction with an amine to form the corresponding amidate (XVII) according to Scheme 5. Subsequently, (XVII) can be cyclized, halogenated, and substituted with the appropriate aniline, phenoxide or thiophenoxide as described in Scheme 4 above. 
     Compounds of Formula I wherein Z═CH and R 1  ═COR 7  or CO 2  R 7  can be synthesized from compounds of Formula (VII) by coupling with the appropriate vinyl aluminum or boron reagent in the presence of a palladium catalyst, such as Pd(PPh 3 ) 2  Cl 2 , and further transformations of the vinyl group, using methods known to one skilled in the art. ##STR7## 
     The compounds of Formula (I) where Z═CH and R 1  or R 3  is a functional group not compatible with the procedures of Schemes 1-5 may be prepared from precursors where the interfering functionality of R 1  or R 3  is protected using methods known to one skilled in the art (see T. W. Green and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Wiley, New York, 1991); or from precursors bearing R 1  or R 3  groups amenable to later conversion into the desired functionality using standard methods (see J. March, Advanced Organic Chemistry, Wiley, New York, 1992). 
     Triazinones of Formula (I) wherein Z═N and Y═NR 4 , O or S(O) n  can be prepared by the synthetic route shown in Scheme 6. 
     Condensation of a substituted hydrazine with acetamidines or imidates provides amidrazones of Formula (XXX) (Khrustalev, V. A., Zelenin, K. N. Zhurnal Organicheskoi Khimii, Vol. 15, No. 11, 1979, 2280). Cyclization of (XXX) with oxalyl derivatives such as oxalyl chloride provides diones of Formula (XXXI). Treatment of (XXXI) with chlorodehydrating agents such as thionyl chloride, oxalyl chloride or phosphorous oxychloride provides chlorotriazinones of Formula (XXXII), which may be treated with phenols, thiophenols, anilines and their heterocyclic analogs under basic, acidic or thermal conditions to provide compounds of Formula (I) where Z═N and Y═O, S or NH, respectively. In the preceding instance where Y═NH, alkylation of the nitrogen atom with e.g. alkyl iodides provides the related compounds of Formula (I) where Z═N and Y═NR 4 . In the preceding instance where Y═S, oxidation with e.g. mCPBA provides the compounds of Formula (I) where Z═N and Y═S(O) and S(O) 2 . The compounds of Formula (I) where Z═N and R 1  or R 3  is a functional group not compatible with the procedures of Scheme 4 may be prepared from precursors such as amidrazones of Formula (XXX) or substituted hydrazines where the ##STR8## interfering functionality of R 1  or R 3  is protected using methods known to one skilled in the art (see T. W. Green and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Wiley, New York, 1991); or from precursors bearing R 1  or R 3  groups amenable to later conversion into the desired functionality using standard methods (see J. March, Advanced Organic Chemistry, Wiley, New York, 1992). 
     Triazinones of Formula (I) wherein Z═N and Y═NR 4 , O or S(O) n  can also be prepared by the synthetic route shown in Scheme 7 ##STR9## 
     Reaction of ethyl oxalyl chloride with acylated hydrazines of Formula (XXXIV) provides the ethyl oxalyl acylhydrazine derviatives of Formula (XXXV). Compounds of Formula (XXXIV) may be arrived at via condensation of an appropriate ketone or aldehyde with an acylated hydrazide to give acylated hydrazones which may then be reduced under catalytic hydrogenation conditions or by other reducing agents to give the compounds of Formula (XXXIV). The abovementioned acylated hydrazones may also be produced by acylation of a hydrazone made from hydrazine and an appropriate ketone or aldehyde using methods known to one skilled in the art of organic synthesis. Alternatively, compounds of Formula (XXXIV) may also be produced by acylation of an appropriate hydrazine using methods known to one skilled in the art of organic synthesis. 
     The ethyl esters of compound (XXXV) may then be converted to the primary amide derivatives of Formula (XXXVI) by treatment with an ammonia source such as ammonium hydroxide. Cyclization of (XXXVI) to produce the diones of Formula (XXXI) may be achieved by treatment with, for example, iodotrimethylsilane (TMSI) or POCl 3 , or by heating in the presence of a Lewis acid such as ZnCl 2 . The oxo group in the 5 position of the 1,2,4-triazin-5,6-diones of Formula (XXXI) may then be converted to a leaving group using reagents such as trifluoromethanesulfonic anhydride under basic conditions to yield compounds of Formula (XXXVII) which may then be treated with phenols, thiophenols, anilines and their heterocyclic analogs under basic conditions to provide compounds of Formula (I) 
     Additional 1,2,4-triazinone syntheses are disclosed in the literature (A. R. Katritzky and C. W. Rees, Comprehensive Heterocyclic Chemistry, Pergamon Press, New York, Vol. 3, 1984, p. 385) and can be prepared by one skilled in the art. 
     Intermediates, for example ArYH, H 2  NAr, HOAr or HSAr, in the synthesis of compounds of Formula (I) in Schemes 1-6 may be prepared using standard methods known to one skilled in the art (see, D. Barton and W. D. Ollis, Comprehensive Organic Chemistry, Pergamon Press, New York, Vol. 1-6, 1979; A. R. Katritzky and C. W. Rees, Comprehensive Heterocyclic Chemistry, Pergamon Press, New York, Vol. 1-8, 1984; B. Trost and I. Fleming, Comprehensive Organic Synthesis, Pergamon Press, New York, Vol. 1-9, 1991; and DuPont Merck PCT application WO95/10506). 
     All of the aforementioned references are hereby incorporated by reference. 
    
    
     EXAMPLE 1 
     3-[[2-Bromo-4-(1-methylethyl)phenyl]amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone 
     Part A 
     Hydrogen chloride (12M, aq., 3.8 mL), methanol (33 mL), water (30 mL), potassium cyanide (3 g), 1-ethylpropylamine (4 g), and formaldehyde (37% w/v, 3.7 mL) were stirred 18 hours at room temperature. Water (200 mL) was added, and the mixture was extracted with 2×200 mL methylene chloride, which was dried over MgSO4 and concentrated to a light oil (5.57 g). The oil was dissolved in ether and 1N HCl was added. The precipitate was collected on paper and dried to give N-(1-ethylpropyl)-aminoacetonitrile hydrochloride as an off-white solid (6.70 g). 
     Part B: The product from part A (2 g), chloroform (20 mL), and oxalyl chloride (4.68 g) were heated at reflux for 12 hours. The reaction was concentrated to remove excess oxalyl chloride and solvent, and the crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to afford 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone as a white solid (2.09 g). 
     Part C 
     The product from part B (0.68 g) and 2-bromo-4-isopropylaniline (1.24 g) were heated at 140° C. for 5 hours. After cooling, methylene chloride (20 mL)was added, filtered, and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:9) as eluent to afford the title compound. 639 mg. mp 118.5-119.5° C. Elemental analysis: calcd. for C 18  H 23  N 3  OBrCl: C, 52.38; H, 5.626; N, 10.18; Br, 19.36; Cl, 8.599. Found: C, 52.62; H, 5.43; N, 10.13; Br, 19.53; Cl, 8.97. 
     EXAMPLE 2 
     3-[[2-Bromo-4-(1-methylethyl)phenyl]ethylamino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone 
     The product from Example 1 (198 mg), N,N-dimethyl-formamide (5 mL), and sodium hydride (60% in oil, 96 mg) were stirred at room temperature 20 minutes. Iodoethane (112 mg) was added and the reaction was stirred overnight at room temperature and quenched with water (10 mL) and saturated sodium chloride (aq., 10 mL). The mixture was extracted with methylene chloride which was dried and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:19) as eluent to afford the title compound (125 mg). CI-HRMS calcd. for C 20  H 28  N 3  OClBr (M+H) +  : 440.110427. Found: 440.107480. 
     EXAMPLE 3 
     3-[(2,4-Dibromophenyl)amino]-5-Chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone 
     2,4-Dibromoaniline (500 mg), toluene (8 mL), and sodium hydride (60% in oil, 398 mg) were stirred for 10 minutes at room temperature and then 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone (468 mg, Example 1, part B) was added. The reaction was heated at reflux 3 hours, cooled, and quenched with water (50 mL). The mixture was extracted with ethyl acetate (100 mL), which was washed with brine, then dried and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:19) affording 400 mg of material, which was crystallized from ether/hexane to give the title compound (240 mg). Elemental analysis: calcd. for C 15  H 16  N 3  OClBr 2  : C, 40.07; H, 3.597; N, 9.356; Cl, 7.895; Br, 35.55. Found: C, 40.41; H, 3.49; N, 9.34; Cl, 8.27; Br, 35.71. 
     EXAMPLE 4 
     3-[(2,4-Dibromophenyl)ethylamino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 2. Elemental analysis calcd. for C 17  H 20  N 3  OClBr 2  : C,42.75; H,4.22; N, 8.807. Found: C, 42.82; H, 4.14; N, 8.67. 
     EXAMPLE 5 
     3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 3. Elemental analysis calcd. for C 18  H 24  N 3  OCl: C, 64.76; H, 7.256; N, 12.59. Found: C, 64.69; H, 7.03; N, 12.55. 
     EXAMPLE 6 
     3-[(2,4,6-Trimethylphenyl)ethylamino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 2. Elemental analysis calcd. for C 20  H 28  N 3  OCl: C, 66.37; H, 7.808; N, 11.61. Found: C, 66.50; H, 7.69; N, 11.51. 
     EXAMPLE 7 
     (+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 3. Elemental analysis calcd. for C 18  H 24  N 3  O 2  Cl: C, 61.80; H, 6.91; N, 12.01; Cl, 10.13. Found: C, 61.69; H, 7.00; N, 11.93; Cl, 9.87. 
     EXAMPLE 8 
     3-[(2-Bromo-4,6-dimethoxyphenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 3. Elemental analysis calcd. for C 17  H 21  N 3  O 3  BrCl: C, 47.40; H, 4.91; N, 9.765. Found: C, 47.06; H, 4.61; N, 9.56. 
     EXAMPLE 9 
     3-[(2-Cyano-4,6-dimethylphenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone 
     Part A 
     3-[(2-Iodo-4,6-dimethylphenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone was prepared in a manner similar to Example 3. 
     Part B 
     The product from part A (460 mg), N,N-dimethylformamide (8 mL), cuprous cyanide (97 mg), and sodium cyanide were heated at 120° C. for 18 hours and then at 130° C. for 3 hours. After cooling, ethyl acetate (100 mL) was added to the reaction which was then washed with water (50 mL) and brine (50 mL), dried, and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent. The product was then crystallized from methylene chloride/hexane to afford the title compound (235 mg). Elemental analysis calcd. for C 18  H 21  N 4  OCl: C, 62.69; H, 6.148; N, 16.25; Cl, 10.28. Found: C, 62.29; H, 6.27; N, 15.99; Cl, 10.20. 
     EXAMPLE 10 
     (+/-)-3-[(2-Bromo-4,6-dimethoxyphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 3. Elemental analysis calcd. for C 17  H 21  N 3  O 4  BrCl: C, 45.71; H, 4.748; N, 9.416. Found: C, 45.86; H, 4.43; N, 9.26. 
     EXAMPLE 12 
     (+/-)-3-[(2-Iodo-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone 
     Part A 
     Chloroacetonitrile (3.2 mL), 2-amino-1-methoxybutane (10.32 g), and deuterochloroform (50 mL) were stirred and heated at reflux for 48 h. Methylene chloride (100 mL) and sodium hydroxide (aq., 1N, 100 mL) were added to the reaction, the layers separated, and the organic layer concentrated to an oil (3.4 g). The oil was dissolved in ether (100 mL) and HCl/ether (1N, 100 mL) was added. The precipitate was collected on paper affording N-[(1-methoxymethyl)propyl]aminoacetonitrile hydrochloride (6.86 g). 
     Part B 
     The title compound was prepared in a manner similar to the product of Example 3. Elemental analysis calcd. for C 17  H 21  N 3  O 2  ClI: C, 44.22; H, 4.58; N, 9.10. Found: C, 44.26; H, 4.60; N, 9.83. 
     EXAMPLE 15 
     (+/-)-3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone 
     To (+/-)-3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone (300 mg) and 4-bromo-2,6-dimethylaniline (238 mg) in THF (anhydrous, 9.4 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1.0 M/THF, 2.6 mL). The mixture was stirred at 0° C. for 10 minutes. Ethyl acetate (100 mL) was added and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO 4  and concentrated and the crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent. The product was then crystallized from ethyl acetate/hexane to afford the title compound (419 mg). Elemental analysis calcd. for C 17  H 21  N 3  O 2  BrCl: C, 49.23; H, 5.10; N, 10.13. Found: C, 49.33; H, 5.05; N, 10.09. 
     EXAMPLE 16 
     (+/-)-3-[(4-Acetyl-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone 
     To the product of Example 15 (250 mg), bis(triphenylphosphine)palladium(II) chloride (11 mg), and tetrakis(triphenylphosphine)palladium(0) (17 mg) in a dry flask under nitrogen was added toluene (1.5 mL) and 1-ethoxyvinyl tributyl tin (260 mg). The reaction was heated at reflux 18 hours, and then concentrated in vacuo. The residue was taken up in ether (15 mL) and saturated aqueous potassium fluoride (15 mL), and filtered. The layers were separated, and the ether layer was stirred with 1N HCl (aq., 15 mL). The layers were separated and the ether layer was dried over MgSO 4  and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (3:7) as eluent to afford the title compound (90 mg). Elemental analysis calcd. for C 19  H 24  N 3  O 3  Cl: C, 60.39; H, 6.40; N, 11.12. Found: C, 60.51; H, 6.31; N, 11.00. 
     EXAMPLE 16a 
     (+/-)-3-[(4-Acetyl-2-methoxy-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 16. Elemental analysis calcd. for C 19  H 24  N 3  O 4  Cl: C, 57.94; H, 6.14; N, 10.67. Found: C, 57.70; H, 5.98; N, 10.41. 
     EXAMPLE 20 
     (+/-)-3-[(4-Chloro-2-iodo-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 3. Elemental analysis calcd. for C 16  H 18  N 3  O 2  Cl 2  I: C, 39.86; H, 3.76; N, 8.725. Found: C, 40.00; H, 3.69; N, 8.64. 
     EXAMPLE 21 
     3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone 
     Part A 
     To serinol (9.90 g) in DMF (200 mL) was added triethyl amine (14.6 mL) and then chlorotriphenylmethane (24.3 g). The reaction mixture was stirred at room temperature for 18 hours. Toluene (800 mL) was added and washed with water (500 mL and 250 mL) and brine (250 mL), and then dried over K 2  CO 3  and concentrated to dryness. The product was crytallized from benzene/hexane (1:1) to afford product (14.57 g). 
     Part B 
     The product from part A (14.57 g), sodium hydroxide (17.5 g), and iodomethane (8.8 mL) were stirred overnight in DMSO (220 mL) at room temperature. Water (500 mL) was added and extracted with ethyl acetate (3×250 mL). The extracts were washed with water (2×250 mL) and brine (200 mL), dried over K 2  CO 3 , and concentrated to give product (14.46 g). 
     Part C 
     The product from part B (14.46 g) and hydrogen chloride (1M/Et 2  O, 84 mL) were stirred in methanol (300 mL) at room temperature for 6 hours. The solution was washed with hexane (3×300 mL), concentrated, and co-evaporated with ethanol affording 2-amino-1,3-methoxypropane (5.69 g). 
     Part D 
     The title compound was prepared in a manner similar the product of Example 3. Elemental analysis calcd. for C 18  H 24  N 3  O 3  Cl: C, 59.09; H, 6.61; N, 11.49. Found: C, 20 59.27; H, 6.53; N, 11.47. 
     EXAMPLE 30a 
     (+/-)-3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 84. Elemental analysis calcd. for C18H24N3O2Cl: C, 61.80; H, 6.91; N, 12.01. Found: C, 61.70; H, 6.94; N, 11.56. 
     EXAMPLE 36 
     3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C 19  H 26  N 3  O 3  Cl: C, 60.07; H, 6.908; N, 11.06. Found: C, 60.22; H, 7.16; N, 10.92. 
     EXAMPLE 36a 
     3-[(4-Bromo-2-methoxy-6-methylphenyl)amino]-5-chloro-l-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C 18  H 23  N 3  O 4  ClBr: C, 46.92; H, 5.03; N, 9.129. Found: C, 47.29; H, 5.03; N, 8.98. 
     EXAMPLE 45a 
     3-[(2-Bromo-6-flouro-4-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C 16  H 18  N 3  O 3  FClBr: C, 44.21; H, 4.17; N, 9.67. Found: C, 44.35; H, 4.25; N, 9.41. 
     EXAMPLE 46a 
     3-[(2-Chloro-4-methoxy-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C 17  H 20  N 3  O 4  C 12:  C, 50.89; H, 5.02; N, 10.47. Found: C, 50.72; H, 5.33; N, 10.37. 
     EXAMPLE 49 
     3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C 18  H 23  N 3  O 3  ClBr: C, 48.61; H, 5.21; N, 9.457. Found: C, 48.59; H, 5.32; N, 9.45. 
     EXAMPLE 53 
     3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C 17  H 21  N 3  O 3  ClBr: C, 47.40; H, 4.91; N, 9.765. Found: C, 47.52; H, 4.99; N, 9.72. 
     EXAMPLE 54 
     3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C 17  H 21  N 3  O 3  Cl 2  : C, 52.86; H, 5.489; N, 10.88. Found: C, 52.89; H, 5.44; N, 10.72. 
     EXAMPLE 77 
     (+/-)-3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C 18  H 24  N 3  O 2  ClS: C, 56.62; H, 6.33; N, 11.00; S, 8.405. Found: C, 56.66; H, 6.19; N, 10.89; S, 8.45. 
     EXAMPLE 79 
     (+/-)-3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C 17  H 21  N 3  O 2  Cl 2  : C, 55.14; H, 5.726; N, 11.35. Found: C, 55.27; H, 5.70; N, 11.25. 
     EXAMPLE 80 
     (+/-)-3-[(4-Bromo-6-methoxy-2-methylphenyl)amino]-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C 17  H 21  N 3  O 3  BrCl: C, 47.40; H, 4.91; N, 9.765. Found: C, 47.91; H, 4.95; N, 9.74. 
     EXAMPLE 81 
     3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C 18  H 24  N 3  O 3  ClS: C, 54.33; H, 6.08; N, 10.56; S, 8.06. Found: C, 54.48; H, 6.01; N, 10.46; S, 7.86. 
     EXAMPLE 83 
     3-[(4-Bromo-2-methoxy-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C 17  H 21  N 3  O 4  ClBr: C, 45.71; H, 4.748; N, 9.416. Found: C, 45.80; H, 4.70; N, 9.39. 
     EXAMPLE 84 
     3-[(2,4,6-Trimethylphenyl)amino]-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone 
     Part A 
     N-(1-ethylpropyl)aminoacetonitrile hydrochloride (1.41 g) and oxalyl bromide (2.0 M/CH 2  Cl 2 , 13 mL) were heated at reflux for 18 hours. The reaction was concentrated to remove excess oxalyl bromide and solvent, and the crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to afford 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone as a white solid (1.19 g). 
     Part B 
     The product from part A (133 mg) and sodium thiomethoxide (29 mg) were combined in THF (1.5 mL) and stirred at 25° C. 4 hours. More sodium thiomethoxide (29 mg) was added and the reaction was stirred for 2 hours more at room temperature. Water (20 mL) was added and extracted with CH 2  Cl 2  (2×20 mL). The organic layers were combined, dried over MgSO 4 , and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexanes (1:4) as eluent to afford 5-bromo-1-(l-ethylpropyl)-3-thiomethyl-2(1H)-pyrazinone (78 mg). 
     Part C 
     The product from part B (200 mg) and Pd(PPh 3 ) 2  Cl 2  (40 mg) were combined in dry THF (6 mL) under inert atmosphere (N 2 ). To that a 2M solution AlMe 3  in hexanes (0.5 mL) was added and the reaction was heated at reflux for one hour. The excess AlMe 3  was quenched with water at 0° C. and the mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The water was separated and extracted with ethyl acetate (50 mL), and the combined EtOAc extracts were washed with brine, dried (MgSO 4 ) and stripped in vacuo. The crude product was chromatographed on silica gel using ethyl acetate/hexanes as eluent (1:9) to give 1-(1-ethylpropyl)-5-methyl-3-thiomethyl-2(1H)-pyrazinone (100 mg). 
     Part D 
     The product from part B (50 mg) and 2,4,6-trimethylaniline (40 mg) were combined in dry THF (2 mL) under inert atmosphere (N 2 ), and cooled to 0° C. To that a 1M solution NaN(SiMe 3 ) 2  in THF (0.5 mL) was added dropwise and the reaction was stirred at 0° C. for 20 min. Then an additional NaN(SiMe 3 ) 2  in THF (0.3 mL) was added and the reaction was stirred at 0° C. for 30 min and at 25° C. for one hour. Then it was quenched with water (30 mL) and extracted with ethyl acetate (80 mL). The ethyl acetate was washed with brine, dried (MgSO 4 ) and stripped in vacuo. The crude product was chromatographed on silica gel using ethyl acetate/hexanes as eluent (1:9) to give 3-[(2,4,6-trimethylphenyl)amino]-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone (40 mg). mp. 109° C. 
     EXAMPLE 84a 
     3-[(2-Chloro-4,6-dimethylphenyl)amino]-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 84. Elemental analysis calcd. for C 18  H 24  N 3  OCl: C, 64.76; H, 7.256; N, 12.59. Found: C, 65.12; H, 7.28; N, 12.33. 
     EXAMPLE 84b 
     3-[(2-Chloro-4-methoxy-6-methylphenyl)amino]-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 84. Elemental analysis calcd. for C 18  H 24  N 3  O 2  Cl: C, 61.80; H, 6.91; N, 12.01. Found: C, 61.72; H, 6.96; N, 11.83. 
     EXAMPLE 84c 
     3-[(2,4,6-Trimethylphenyl)amino]-1-(1-ethylpropyl)-5-ethyl-2(1H)-pyrazinone 
     Part A 
     5-bromo-1-(1-ethylpropyl)-3-thiomethyl-2(1H)-pyrazinone was prepared in a manner similar to Example 84, parts A and B. 
     Part B 
     To the product of part A (2.14 g) and bis(triphenylphosphine)palladium(II) chloride (258 mg) in anhydrous THF (60 mL) under inert atmosphere was added triethyl aluminum (1 M/THF, 14.7 mL). The reaction was heated at reflux 3 hours and then cooled and quenched with water. Ethyl Acetate (200 mL) was added and washed with water and saturated aqueous sodium chloride. The ethyl acetate was dried over MgSO 4  and concentrated in vacuo. The crude product was chromatographed on silica gel using ethyl acetate/hexane (3:17) as eluent to afford 5-ethyl-1-(1-ethylpropyl)-3-thiomethyl-2(1H)-pyrazinone (809 mg). 
     Part C 
     The title compound was prepared in a manner similar to the product of Example 84 using the procuct from part B. Elemental analysis calcd. for C 20  H 29  N 3  O: C, 73.36; H, 8.936; N, 12.83. Found: C, 73.01; H, 8.55; N, 12.69. 
     EXAMPLE 84d 
     3-[(2-Chloro-4,6-dimethylphenyl)amino]-1-(1-ethylpropyl)-5-ethyl-2(1H)-pyrazinone 
     The title compound was prepared in a manner similar to the product of Example 84c. Elemental analysis calcd. for C 19  H 26  N 3  OCl: C, 65.60; H, 7.53; N, 12.08. Found: C, 65.53; H, 7.33; N, 11.92. 
     EXAMPLE 85 
     3-[(2,4,6-Trimethylphenyl)amino]-5-bromo-1-(1-ethylpropyl)-2(1H)-pyrazinone 
     Part A 
     N-(1-ethylpropyl)-aminoacetonitrile hydrochloride (1.41 g) and oxalyl bromide (2.0 M, CH 2  Cl2, 13 mL) were heated at reflux for 18 hours. The reaction was concentrated to remove excess oxalyl bromide and solvent, and the crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to afford 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone as a white solid (1.19 g). 
     Part B 
     Using the product of part A, the title compound was prepared in a manner similar to the product of Example 3. MS m/z 378, (m+H) + , 100%. 
     EXAMPLE 204 
     5-[(2,4,6-Trimethylphenyl)amino]-3-methyl-1-(1-ethylpropyl)-1,2,4-triazine-6(1H)-one 
     Part A 
     3-Pentanone (18.56 g, 0.215 mol), acetic hydrazide (14.8 g, 0.2 mol), and 200 mL of absolute ethanol were placed in a 500 mL flask. The reaction mixture was reluxed for 18 hr and then evaporated to dryness to afford the desired hydrazone of suitable purity. 
     The hydrazone was then dissolved in 200 mL of glacial acetic acid containing 1.0 g of PtO 2  and hydrogenated at 50 psi hydrogen pressure for 14 hr. The mixture was decanted from the catalyst and evaporated to dryness to afford 23.9 g of a colorless oil (83% yield for the two steps). 
     Part B 
     The 1-acetyl-2-(1-ethylpropyl)hydrazine product from Part A (23.9 g, 0.166 mol) was dissolved in CH 2  Cl 2  (200 mL) and to the stirring solution was added triethylamine (27.9 mL, 0.2 mol) and ethyl oxalyl chloride (19 mL, 0.17 mol). After stirring at room temperature for 3 hr, the reaction mixture was poured into water and the organic layer was separated, dried (Na 2  SO 4 ), filtered and evaporated in vacuo. To the resultant oil was added ammonium hydroxide (250 mL), THF (100 mL), and ethanol (50 mL). The flask containing the mixture was sealed with a rubber septum and stirred for 18 hr at room temperature. The mixture was then concentrated in vacuo until the reduced volume of solvent remaining was approximately 100 mL, and a white precipitate had formed. The flask was then placed in the refrigerator for 1 hr. The precipitate was collected by vacuum filtration and washed with small volumes of cold water. 26.3 g of a white solid was collected (73% yield).  1  H NMR (300 MHz, CDCl 3 ): δ7.78 (s, 1H); 6.74 (br s, 1H); 5.6 (br s, 1H); 4.25 (m, 1H); 2.04 (s, 1H); 1.5 (m, 4H); 0.95 (t, 6H, J=7.3 Hz). 
     Part C 
     The 1-oxamyl-1-(3-pentyl)-2-acetylhydrazine product from Part B (2 g, 9.3 mmol) was suspended in chloroform (50 mL) and 2 mL of iodotrimethylsilane was added dropwise. The mixture was allowed to stir at room temperature for 12 hr. The reaction mixture was then partitioned between CH 2  Cl 2  and 1N NaOH. The aqueous layer was separated and made acidic by addition of conc. HCl and then extracted with CH 2  Cl 2 . This organic layer was dried (Na 2  SO 4 ), filtered and evaporated in vacuo to yield 1.2 g of an off-white solid of suitable purity (65% yield).  1  H NMR (300 MHz, CDCl 3 ): δ7.85 (br s, 1H); 4.61 (m, 1H); 2.35 (s, 3H); 1.73 (m, 4H); 0.83 (t, 6H, J=7.3 Hz). 
     Part D 
     To a solution of the triazine dione product from above (198 mg, 1 mmol) in CH 2  Cl 2  (5 mL) was added trifluoromethanesulfonic anhydride (0.19 mL, 1.1 mmol) and 2,4,6-collidine (0.15 mL, 1.1 mmol). The resulting reaction mixture was stirred at room temperature for 30 min., then 2,4,6-trimethylaniline (162 mg, 1.2 mmol) in 5 mL of THF was added followed by addition of 2,4,6-collidine (0.15 mL, 1.1 mmol). The resulting reaction mixture was stirred at room temperature for 1 hr, at which time TLC showed complete reaction. The reaction mixture was partitioned between water and CH 2  Cl 2 . The organic layer was dried (Na 2  SO 4 ), filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc/hexane (1:9) to afford 260 mg of the title compound (83% yield). mp=133-135° C.  1  H NMR (300 MHz, CDCl 3 ): δ7.89 (br s, 1H); 6.94 (s, 2H); 4.72 (m, 1H); 2.31 (s, 3H); 2.19 (s, 9H); 1.9-1.7 (m, 4H); 0.85 (t, 6H, J=7.32 Hz). Mass Spec. (NH 3  --CI): Calc. (M+H)+=315, Obs. (M+H)+=315. 
     EXAMPLE 703 
     (+/-)-5-Chloro-1-[1-(methoxymethyl)propyl]-3-(2,4,6-trimethylphenoxy)-2(1H)-pyrazinone 
     Part A 
     (+/-)-3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone was prepared in a manner similar to Example 12, part A, and Example 1, part B. 
     Part B 
     2,4,6-Trimethylphenol (59 mg) and potassium t-butoxide (48 mg) were added to pyridine (2 mL) at 0° C. The mixture was warmed to ambient temperature and (+/-)-3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(lH)-pyrazinone (98 mg) and copper (I) iodide (19 mg) were added. The reaction mixture was stirred at ambient temperature for three hours and then heated at reflux for three hours and then cooled to 0° C. Ethyl acetate (50 mL) and saturated ammonium chloride (50 mL) were added and the mixture was stirred overnight at ambient temperature. The layers were separated, and the organic layer was washed with 1M ammonium hydroxide (2×50 mL), 1N sodium hydroxide (2×50 mL), 1N hydrochloric acid (2×50 mL), and saturated sodium chloride (50 mL). The ethyl acetate was dried over MgSO 4  and concentrated in vacuo. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to afford the title compound (66 mg). mp=116° C. Elemental analysis calcd. for C 18  H 23  N 2  O 3  Cl: C, 61.62; H, 6.618; N, 7.98. Found: C, 61.45; H, 6.44; N, 7.77. 
     Various analogs synthesized using Schemes 1, 2 and 3 are listed in Table 1. 
     
                                           TABLE 1__________________________________________________________________________ ##STR10##ExNo R.sup.1 R.sup.3    Y  Ar             mp/° C.__________________________________________________________________________1  Cl      Et.sub.2 CH                 NH 2-Br-4-iPr-phenyl                                   118.52  Cl      Et.sub.2 CH                 NEt                    2-Br-4-iPr-phenyl                                   MS = 4403  Cl      Et.sub.2 CH                 NH 2,4-Br.sub.2 -phenyl                                   155.54  Cl      Et.sub.2 CH                 NEt                    2,4-Br.sub.2 -phenyl                                   88.15  Cl      Et.sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl                                   180.86  Cl      Et.sub.2 CH                 NEt                    2,4,6-Me.sub.3 -phenyl                                   93.87  Cl      MeOCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -phenyl                                   153.88  Cl      Et.sub.2 CH                 NH 2-Br-4,6-(MeO).sub.2 -phenyl                                   181.39  Cl      Et.sub.2 CH                 NH 2-CN-4,6-Me.sub.2 -phenyl                                   174.010 Cl      MeOCH.sub.2 (Et)CH                 NH 2-Br-4,6-(MeO).sub.2 -phenyl                                   175.811 Cl      MeOCH.sub.2 (Et)CH                 NH 2-Cl-4,6-(MeO).sub.2 -phenyl12 Cl      MeOCH.sub.2 (Et)CH                 NH 2-I-4,6-Me.sub.2 -phenyl                                   109.413 Cl      MeOCH.sub.2 (Et)CH                 NH 2-CN-4,6-Me.sub.2 -phenyl14 Cl      MeOCH.sub.2 (Et)CH                 NH 2-Br-4,6-Me.sub.2 -phenyl15 Cl      MeOCH.sub.2 (Et)CH                 NH 4-Br-2,6-Me.sub.2 -phenyl                                   152.816 Cl      MeOCH.sub.2 (Et)CH                 NH 4-MeCO-2,6-Me.sub.2 -phenyl                                   127.116a   Cl      MeOCH.sub.2 (Et)CH                 NH 4-MeCO-2-OMe-6-Me-phenyl                                   179.817 Cl      MeOCH.sub.2 (Et)CH                 NH 2-MeCO-4,6-Me.sub.2 -phenyl18 Cl      MeOCH.sub.2 (Et)CH                 NH 4,6-Me.sub.2 -2-SMe-phenyl19 Cl      MeOCH.sub.2 (Et)CH                 NH 4,6-Me.sub.2 -2-SO.sub.2 Me-phenyl20 Cl      MeOCH.sub.2 (Et)CH                 NH 4-Cl-2-I-6-Me-phenyl                                   121.821 Cl      (MeOCH.sub.2).sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl                                   127.222 Cl      phenyl     NH 2,4,6-Me.sub.3 -phenyl23 CN      MeOCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -phenyl24 CONH.sub.2      MeOCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -phenyl25 COOH    MeOCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -phenyl26 CHO     MeOCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -phenyl27 CH.sub.2 OH      MeOCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -phenyl28 CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,4-Br.sub.2 -phenyl29 CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Br-4-iPr-phenyl30 CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -phenyl30a   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl                                   117.931 CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl32 CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,4-Cl.sub.2 -6-Me-phenyl33 Cl      (MeOCH.sub.2).sub.2 CH                 NH 2,4-Cl.sub.2 -6-Me-phenyl34 Cl      (MeOCH.sub.2).sub.2 CH                 NH 2,4-Br.sub.2 -6-Me-phenyl35 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4,6-Me.sub.3 -phenyl36 Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4,6-Me.sub.3 -phenyl                                   120.036a   Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 4-Br-2-OMe-6-Me-phenyl                                   130.937 Cl      (MeOC.sub.2 H.sub.4).sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl38 Cl      MeOCH.sub.2 (Et)CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl39 Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl40 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl41 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 4-Br-2,6-Me.sub.2 -phenyl42 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl43 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl44 CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl45 CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 4-Br-2,6-Me.sub.2 -phenyl45a   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2-Br-6-F-4-Me-phenyl                                   138.946 CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl46a   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2-Cl-4-OMe-6-Me-phenyl                                   128.347 CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl48 Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl49 Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 4-Br-2,6-Me.sub.2 -phenyl                                   138.650 Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl51 Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl52 Cl      (MeOCH.sub.2).sub.2 CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl53 Cl      (MeOCH.sub.2).sub.2 CH                 NH 4-Br-2,6-Me.sub.2 -phenyl                                   152.154 Cl      (MeOCH.sub.2).sub.2 CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl                                   132.855 Cl      (MeOCH.sub.2).sub.2 CH                 NH 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl56 Cl      MeOCH.sub.2 (Me)CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl57 Cl      MeOCH.sub.2 (Me)CH                 NH 4-Br-2,6-Me.sub.2 -phenyl58 Cl      EtOCH.sub.2 (Et)CH                 NH 4-Br-2,6-Me.sub.2 -phenyl59 Cl      EtOCH.sub.2 (Me)CH                 NH 4-Br-2,6-Me.sub.2 -phenyl60 Cl      MeOCH.sub.2 (Et)CH                 NH 4-Br-2,6-F.sub.2 -phenyl61 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2-Br-4,6-Me.sub.2 -phenyl62 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4-Me.sub.2 -6-SMe-phenyl63 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4-Me.sub.2 -6-SO.sub.2 Me-phenyl64 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 4-NMe.sub.2 -2,6-Me.sub.2 -phenyl65 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4-Cl.sub.2 -6-Me-phenyl66 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 4-Cl-2,6-Me.sub.2 -phenyl67 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,6-Me.sub.2 -4-SMe-phenyl68 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,6-Me.sub.2 -4-OMe-phenyl69 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2, 6-Me.sub.2 -4-SO.sub.2 Me-phenyl70 CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 4-MeC(O)-2,6-Me.sub.2 -phenyl71 CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 4-Br-2,6-Me.sub.2 -phenyl72 CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 4-MeC(O)-2,6-Me.sub.2 -phenyl73 CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,6-Me.sub.2 -4-SMe-phenyl74 CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl75 CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 4-NMe.sub.2 -2,6-Me.sub.2 -phenyl76 CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2-NMe.sub.2 -4,6-Me.sub.2 -phenyl77 Cl      MeOCH.sub.2 (Et)CH                 NH 2,6-Me.sub.2 -4-SMe-phenyl                                   104.978 Cl      MeOCH.sub.2 (Et)CH                 NH 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl79 Cl      MeOCH.sub.2 (Et)CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl                                   116.780 Cl      MeOCH.sub.2 (Et)CH                 NH 4-Br-6-OMe-2-Me-phenyl                                   147.881 Cl      (MeOCH.sub.2).sub.2 CH                 NH 2,6-Me.sub.2 -4-SMe-phenyl                                   158.982 Cl      (MeOCH.sub.2).sub.2 CH                 NH 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl83 Cl      (MeOCH.sub.2).sub.2 CH                 NH 4-Br-6-OMe-2-Me-phenyl                                   175.584 CH.sub.3      Et.sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl                                   10984a   CH.sub.3      Et.sub.2 CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl                                   133.884b   CH.sub.3      Et.sub.2 CH                 NH 2-Cl-4-OMe-6-Me-phenyl                                   121.984c   CH.sub.2 CH.sub.3      Et.sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl                                   79.384d   CH.sub.2 CH.sub.3      Et.sub.2 CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl                                   95.685 Br      Et.sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl                                   MS = 37886 Br      Et.sub.2 CH                 NH 2-Br-4-iPr-phenyl87 Br      Et.sub.2 CH                 NEt                    2-Br-4-iPr-phenyl88 Br      Et.sub.2 CH                 NH 2,4-Br.sub.2 -phenyl89 Br      Et.sub.2 CH                 NEt                    2,4-Br.sub.2 -phenyl90 Br      Et.sub.2 CH                 NEt                    2,4,6-Me.sub.3 -phenyl91 Br      Et.sub.2 CH                 NEt                    2,4,6-Me.sub.3 -phenyl92 Br      MeOCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -phenyl93 Br      Et.sub.2 CH                 NH 2-Br-4,6-(MeO).sub.2 -phenyl94 Br      Et.sub.2 CH                 NH 2-CN-4,6-Me.sub.2 -phenyl95 Br      MeOCH.sub.2 (Et)CH                 NH 2-Br-4,6-(MeO).sub.2 -phenyl96 Br      MeOCH.sub.2 (Et)CH                 NH 2-I-4,6-Me.sub.2 -phenyl97 Br      MeOCH.sub.2 (Et)CH                 NH 2,6-Me.sub.2 -4-Br-phenyl98 Br      MeOCH.sub.2 (Et)CH                 NH 2-I-4-Cl-6-Me-phenyl99 Br      (MeOCH.sub.2).sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl100   Br      MeOCH.sub.2 (Et)CH                 NH 2,6-Me2-4-SMe-phenyl101   Br      MeOCH.sub.2 (Et)CH                 NH 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl102   Br      MeOCH.sub.2 (Et)CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl103   Br      MeOCH.sub.2 (Et)CH                 NH 2-Me-4-Br-6-OMe-phenyl104   CH.sub.3      Et.sub.2 CH                 NH 2,4,6-Me.sub.3 -pyrid-3-yl105   CH.sub.3      Et.sub.2 CH                 NH 4,6-Me.sub.2 -pyrid-3-yl106   CH.sub.3      Et.sub.2 CH                 NH 2-Br-6-Me-pyrid-3-yl107   CH.sub.3      Et.sub.2 CH                 NH 2-Br-6-OMe-pyrid-3-yl108   CH.sub.3      Et.sub.2 CH                 NH 2,6-Me.sub.2 -pyrid-3-yl109   CH.sub.3      Et.sub.2 CH                 NH 2-Cl-6-Me-pyrid-3-yl110   CH.sub.3      Et.sub.2 CH                 NH 2-Cl-6-OMe-pyrid-3-yl111   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -pyrid-3-yl112   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 4,6-Me.sub.2 -pyrid-3-yl113   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Br-6-Me-pyrid-3-yl114   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2-Br-6-OMe-pyrid-3-yl115   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,6-Me.sub.2 -pyrid-3-yl116   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2-Cl-6-Me-pyrid-3-yl117   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2-Cl-6-OMe-pyrid-3-yl118   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Br-6-OMe-pyrid-3-yl119   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,6-Me.sub.2 -pyrid-3-yl120   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Cl-6-Me-pyrid-3-yl121   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Cl-6-OMe-pyrid-3-yl120   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,4,6-Me.sub.3 -pyrid-3-yl123   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 4,6-Me.sub.2 -pyrid-3-yl124   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2-Br-6-Me-pyrid-3-yl125   Cl      Et.sub.2 CH                 NH 2-Br-6-OMe-pyrid-3-yl124   Cl      Et.sub.2 CH                 NH 2,6-Me.sub.2 -pyrid-3-yl127   Cl      Et.sub.2 CH                 NH 2-Cl-6-Me-pyrid-3-yl128   Cl      Et.sub.2 CH                 NH 2-Cl-6-OMe-pyrid-3-yl129   Cl      MeOCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -pyrid-3-yl130   Cl      MeOCH.sub.2 (Et)CH                 NH 4,6-Me.sub.2 -pyrid-3-yl131   Cl      MeOCH.sub.2 (Et)CH                 NH 2-Br-6-Me-pyrid-3-yl132   Cl      Et.sub.2 CH                 NH 2,4,6-Me.sub.3 -pyrid-3-yl133   Cl      Et.sub.2 CH                 NH 4,6-Me.sub.2 -pyrid-3-yl134   Cl      Et.sub.2 CH                 NH 2-Br-6-Me-pyrid-3-yl135   Cl      MeOCH.sub.2 (Et)CH                 NH 2-Br-6-OMe-pyrid-3-yl136   Cl      MeOCH.sub.2 (Et)CH                 NH 2,6-Me.sub.2 -pyrid-3-yl137   Cl      MeOCH.sub.2 (Et)CH                 NH 2-Cl-6-Me-pyrid-3-yl138   Cl      MeOCH.sub.2 (Et)CH                 NH 2-Cl-6-OMe-pyrid-3-yl139   Cl      (MeOCH.sub.2).sub.2 CH                 NH 2-Br-6-OMe-pyrid-3-yl140   Cl      (MeOCH.sub.2).sub.2 CH                 NH 2,6-Me.sub.2 -pyrid-3-yl141   Cl      (MeOCH.sub.2).sub.2 CH                 NH 2-Cl-6-Me-pyrid-3-yl142   Cl      (MeOCH.sub.2).sub.2 CH                 NH 2-Cl-6-OMe-pyrid-3-yl143   Cl      (MeOCH.sub.2).sub.2 CH                 NH 2,4,6-Me.sub.3 -pyrid-3-yl144   Cl      (MeOCH.sub.2).sub.2 CH                 NH 4,6-Me.sub.2 -pyrid-3-yl145   Cl      (MeOCH.sub.2).sub.2 CH                 NH 2-Br-6-Me-pyrid-3-yl146   Et.sub.2 CH      CH.sub.3   NH 2,4,6-Me.sub.3 -phenyl147   Et.sub.2 CH      CH.sub.3   NH 2,6-Me.sub.2 -4-Br-phenyl148   Et.sub.2 CH      CH.sub.3   NH 2-Br-4-iPr-phenyl149   MeOCH.sub.2 (Et)CH      CH.sub.3   NH 2,4,6-Me.sub.3 -phenyl150   MeOCH.sub.2 (Et)CH      CH.sub.3   NH 2,6-Me.sub.2 -4-Br-phenyl151   MeOCH.sub.2 (Et)CH      CH.sub.3   NH 2-Cl-4,6-Me.sub.2 -phenyl152   (MeOCH.sub.2).sub.2 CH      CH.sub.3   NH 2,4,6-Me.sub.3 -phenyl153   (MeOCH.sub.2).sub.2 CH      CH.sub.3   NH 2,6-Me.sub.2 -4-Br-phenyl154   (MeOCH.sub.2).sub.2 CH      CH.sub.3   NH 2-Cl-4,6-Me.sub.2 -phenyl155   Et.sub.2 CH      CH.sub.3   NH 2-Br-4,6-(MeO).sub.2 -phenyl156   Et.sub.2 CH      CH.sub.3   NH 2-Cl-4,6-Me.sub.2 -phenyl400   CH.sub.3      Me(Et)CH   NH 2,4,6-Me.sub.3 -phenyl401   CH.sub.3      Me(Et)CH   NH 2-Cl-4,6-Me.sub.2 -phenyl402   CH.sub.3      Me(Et)CH   NH 2,4-Cl.sub.2 -6-Me-phenyl403   CH.sub.3      Me(Et)CH   NH 2,4,6-Cl.sub.3 -phenyl404   CH.sub.3      Me(Et)CH   NH 2-Me-4-MeO-phenyl405   CH.sub.3      Me(Et)CH   NH 2-Cl-4-MeO-phenyl406   CH.sub.3      Me(Et)CH   NH 2,4,6-Me.sub.3 -5-F-phenyl407   CH.sub.3      Me(Et)CH   NH 2,5-Me.sub.2 -4-MeO-phenyl408   CH.sub.3      Me(Et)CH   NH 2,4-Me.sub.2 -6-MeO-phenyl409   CH.sub.3      Me(Et)CH   NH 2,6-Cl.sub.2 -4-Me-phenyl410   CH.sub.3      Me(Et)CH   NH 2,4-Cl.sub.2 -phenyl411   CH.sub.3      Me(Et)CH   NH 2-Cl-4-Me-phenyl412   CH.sub.3      Me(Et)CH   NH 2-Me-4-Cl-phenyl413   CH.sub.3      Me(Et)CH   NH 2-NMe.sub.2 -6-Me-pyrid-5-yl414   CH.sub.3      Me(Et)CH   NH 2-NMe.sub.2 -4-Me-pyrid-5-yl415   CH.sub.3      Me(Et)CH   NH 2-Cl-4-MeO-6-Me-phenyl416   CH.sub.3      Me(Et)CH   NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl417   CH.sub.3      Me(Et)CH   NH 6-Cl-2,3-dihydro-benzofuran-5-yl418   CH.sub.3      Me(Et)CH   NH 6-Me-2,3-dihydro-benzofuran-5-yl419   CH.sub.3      Me(n-Pr)CH NH 2,4,6-Me.sub.3 -phenyl420   CH.sub.3      Me(n-Pr)CH NH 2-Cl-4,6-Me.sub.2 -phenyl421   CH.sub.3      Me(n-Pr)CH NH 2,4-Cl.sub.2 -6-Me-phenyl422   CH.sub.3      Me(n-Pr)CH NH 2,4,6-Cl.sub.3 -phenyl423   CH.sub.3      Me(n-Pr)CH NH 2-Me-4-MeO-phenyl424   CH.sub.3      Me(n-Pr)CH NH 2-Cl-4-MeO-phenyl425   CH.sub.3      Me(n-Pr)CH NH 2,4,6-Me.sub.3 -5-F-phenyl426   CH.sub.3      Me(n-Pr)CH NH 2,5-Me.sub.2 -4-MeO-phenyl427   CH.sub.3      Me(n-Pr)CH NH 2,4-Me.sub.2 -6-MeO-phenyl428   CH.sub.3      Me(n-Pr)CH NH 2,6-Cl.sub.2 -4-Me-phenyl429   CH.sub.3      Me(n-Pr)CH NH 2,4-Cl.sub.2 -phenyl430   CH.sub.3      Me(n-Pr)CH NH 2-Cl-4-Me-phenyl431   CH.sub.3      Me(n-Pr)CH NH 2-Me-4-Cl-phenyl432   CH.sub.3      Me(n-Pr)CH NH 2-NMe.sub.2 -6-Me-pyrid-5-yl433   CH.sub.3      Me(n-Pr)CH NH 2-NMe.sub.2 -4-Me-pyrid-5-yl434   CH.sub.3      Me(n-Pr)CH NH 2-Cl-4-MeO-6-Me-phenyl435   CH.sub.3      Me(n-Pr)CH NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl436   CH.sub.3      Me(n-Pr)CH NH 6-Cl-2,3-dihydro-benzofuran-5-yl437   CH.sub.3      Me(n-Pr)CH NH 6-Me-2,3-dihydro-benzofuran-5-yl438   CH.sub.3      Et.sub.2 CH                 NH 2,4-Cl.sub.2 -6-Me-phenyl439   CH.sub.3      Et.sub.2 CH                 NH 2,4,6-Cl.sub.3 -phenyl440   CH.sub.3      Et.sub.2 CH                 NH 2-Me-4-MeO-phenyl441   CH.sub.3      Et.sub.2 CH                 NH 2-Cl-4-MeO-phenyl442   CH.sub.3      Et.sub.2 CH                 NH 2,4,6-Me.sub.3 -5-F-phenyl443   CH.sub.3      Et.sub.2 CH                 NH 2,5-Me.sub.2 -4-MeO-phenyl444   CH.sub.3      Et.sub.2 CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl445   CH.sub.3      Et.sub.2 CH                 NH 2,6-Cl.sub.2 -4-Me-phenyl446   CH.sub.3      Et.sub.2 CH                 NH 2,4-Cl.sub.2 -phenyl447   CH.sub.3      Et.sub.2 CH                 NH 2-Cl-4-Me-phenyl448   CH.sub.3      Et.sub.2 CH                 NH 2-Me-4-Cl-phenyl449   CH.sub.3      Et.sub.2 CH                 NH 2-NMe.sub.2 -6-Me-pyrid-5-yl450   CH.sub.3      Et.sub.2 CH                 NH 2-NMe.sub.2 -4-Me-pyrid-5-yl451   CH.sub.3      Et.sub.2 CH                 NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl452   CH.sub.3      Et.sub.2 CH                 NH 6-Cl-2,3-dihydro-benzofuran-5-yl453   CH.sub.3      Et.sub.2 CH                 NH 6-Me-2,3-dihydro-benzofuran-5-yl454   CH.sub.3      (c-Pr).sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl455   CH.sub.3      (c-Pr).sub.2 CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl456   CH.sub.3      (c-Pr).sub.2 CH                 NH 2,4-Cl.sub.2 -6-Me-phenyl457   CH.sub.3      (c-Pr).sub.2 CH                 NH 2,4,6-Cl.sub.3 -phenyl458   CH.sub.3      (c-Pr).sub.2 CH                 NH 2-Me-4-MeO-phenyl459   CH.sub.3      (c-Pr).sub.2 CH                 NH 2-Cl-4-MeO-phenyl460   CH.sub.3      (c-Pr).sub.2 CH                 NH 2,4,6-Me.sub.3 -5-F-phenyl461   CH.sub.3      (c-Pr).sub.2 CH                 NH 2,5-Me.sub.2 -4-MeO-phenyl462   CH.sub.3      (c-Pr).sub.2 CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl463   CH.sub.3      (c-Pr).sub.2 CH                 NH 2,6-Cl.sub.2 -4-Me-phenyl464   CH.sub.3      (c-Pr).sub.2 CH                 NH 2,4-Cl.sub.2 -phenyl465   CH.sub.3      (c-Pr).sub.2 CH                 NH 2-Cl-4-Me-phenyl466   CH.sub.3      (c-Pr).sub.2 CH                 NH 2-Me-4-Cl-phenyl467   CH.sub.3      (c-Pr).sub.2 CH                 NH 2-NMe.sub.2 -6-Me-pyrid-5-yl468   CH.sub.3      (c-Pr).sub.2 CH                 NH 2-NMe.sub.2 -4-Me-pyrid-5-yl469   CH.sub.3      (c-Pr).sub.2 CH                 NH 2-Cl-4-MeO-6-Me-phenyl470   CH.sub.3      (c-Pr).sub.2 CH                 NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl471   CH.sub.3      (c-Pr).sub.2 CH                 NH 6-Cl-2,3-dihydro-benzofuran-5-yl472   CH.sub.3      (c-Pr).sub.2 CH                 NH 6-Me-2,3-dihydro-benzofuran-5-yl473   CH.sub.3      c-Pr(Me)CH NH 2,4,6-Me.sub.3 -phenyl474   CH.sub.3      c-Pr(Me)CH NH 2-Cl-4,6-Me.sub.2 -phenyl475   CH.sub.3      c-Pr(Me)CH NH 2,4-Cl.sub.2 -6-Me-phenyl476   CH.sub.3      c-Pr(Me)CH NH 2,4,6-Cl.sub.3 -phenyl477   CH.sub.3      c-Pr(Me)CH NH 2-Me-4-MeO-phenyl478   CH.sub.3      c-Pr(Me)CH NH 2-Cl-4-MeO-phenyl479   CH.sub.3      c-Pr(Me)CH NH 2,4,6-Me.sub.3 -5-F-phenyl480   CH.sub.3      c-Pr(Me)CH NH 2,5-Me.sub.2 -4-MeO-phenyl481   CH.sub.3      c-Pr(Me)CH NH 2,4-Me.sub.2 -6-MeO-phenyl482   CH.sub.3      c-Pr(Me)CH NH 2,6-Cl.sub.2 -4-Me-phenyl483   CH.sub.3      c-Pr(Me)CH NH 2,4-Cl.sub.2 -phenyl484   CH.sub.3      c-Pr(Me)CH NH 2-Cl-4-Me-phenyl485   CH.sub.3      c-Pr(Me)CH NH 2-Me-4-Cl-phenyl486   CH.sub.3      c-Pr(Me)CH NH 2-NMe.sub.2 -6-Me-pyrid-5-yl487   CH.sub.3      c-Pr(Me)CH NH 2-NMe.sub.2 -4-Me-pyrid-5-yl488   CH.sub.3      c-Pr(Me)CH NH 2-Cl-4-MeO-6-Me-phenyl489   CH.sub.3      c-Pr(Me)CH NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl490   CH.sub.3      c-Pr(Me)CH NH 6-Cl-2,3-dihydro-benzofuran-5-yl491   CH.sub.3      c-Pr(Me)CH NH 6-Me-2,3-dihydro-benzofuran-5-yl492   CH.sub.3      c-Pr(Et)CH NH 2,4,6-Me.sub.3 -phenyl493   CH.sub.3      c-Pr(Et)CH NH 2-Cl-4,6-Me.sub.2 -phenyl494   CH.sub.3      c-Pr(Et)CH NH 2,4-Cl.sub.2 -6-Me-phenyl495   CH.sub.3      c-Pr(Et)CH NH 2,4,6-Cl.sub.3 -phenyl496   CH.sub.3      c-Pr(Et)CH NH 2-Me-4-MeO-phenyl497   CH.sub.3      c-Pr(Et)CH NH 2-Cl-4-MeO-phenyl498   CH.sub.3      c-Pr(Et)CH NH 2,4,6-Me.sub.3 -5-F-phenyl499   CH.sub.3      c-Pr(Et)CH NH 2,5-Me.sub.2 -4-MeO-phenyl500   CH.sub.3      c-Pr(Et)CH NH 2,4-Me.sub.2 -6-MeO-phenyl501   CH.sub.3      c-Pr(Et)CH NH 2,6-Cl.sub.2 -4-Me-phenyl502   CH.sub.3      c-Pr(Et)CH NH 2,4-Cl.sub.2 -phenyl503   CH.sub.3      c-Pr(Et)CH NH 2-Cl-4-Me-phenyl504   CH.sub.3      c-Pr(Et)CH NH 2-Me-4-Cl-phenyl505   CH.sub.3      c-Pr(Et)CH NH 2-NMe.sub.2 -6-Me-pyrid-5-yl506   CH.sub.3      c-Pr(Et)CH NH 2-NMe.sub.2 -4-Me-pyrid-5-yl507   CH.sub.3      c-Pr(Et)CH NH 2-Cl-4-MeO-6-Me-phenyl508   CH.sub.3      c-Pr(Et)CH NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl509   CH.sub.3      c-Pr(Et)CH NH 6-Cl-2,3-dihydro-benzofuran-5-yl510   CH.sub.3      c-Pr(Et)CH NH 6-Me-2,3-dihydro-benzofuran-5-yl511   CH.sub.3      c-Pr(n-Pr)CH                 NH 2,4,6-Me.sub.3 -phenyl512   CH.sub.3      c-Pr(n-Pr)CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl513   CH.sub.3      c-Pr(n-Pr)CH                 NH 2,4-Cl.sub.2 -6-Me-phenyl514   CH.sub.3      c-Pr(n-Pr)CH                 NH 2,4,6-Cl.sub.3 -phenyl515   CH.sub.3      c-Pr(n-Pr)CH                 NH 2-Me-4-MeO-phenyl516   CH.sub.3      c-Pr(n-Pr)CH                 NH 2-Cl-4-MeO-phenyl517   CH.sub.3      c-Pr(n-Pr)CH                 NH 2,4,6-Me.sub.3 -5-F-phenyl518   CH.sub.3      c-Pr(n-Pr)CH                 NH 2,5-Me.sub.2 -4-MeO-phenyl519   CH.sub.3      c-Pr(n-Pr)CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl520   CH.sub.3      c-Pr(n-Pr)CH                 NH 2,6-Cl.sub.2 -4-Me-phenyl521   CH.sub.3      c-Pr(n-Pr)CH                 NH 2,4-Cl.sub.2 -phenyl522   CH.sub.3      c-Pr(n-Pr)CH                 NH 2-Cl-4-Me-phenyl523   CH.sub.3      c-Pr(n-Pr)CH                 NH 2-Me-4-Cl-phenyl524   CH.sub.3      c-Pr(n-Pr)CH                 NH 2-NMe.sub.2 -6-Me-pyrid-5-yl525   CH.sub.3      c-Pr(n-Pr)CH                 NH 2-NMe.sub.2 -4-Me-pyrid-5-yl526   CH.sub.3      c-Pr(n-Pr)CH                 NH 2-Cl-4-MeO-6-Me-phenyl527   CH.sub.3      c-Pr(n-Pr)CH                 NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl528   CH.sub.3      c-Pr(n-Pr)CH                 NH 6-Cl-2,3-dihydro-benzofuran-5-yl529   CH.sub.3      c-Pr(n-Pr)CH                 NH 6-Me-2,3-dihydro-benzofuran-5-yl530   CH.sub.3      c-Pr(n-Bu)CH                 NH 2,4,6-Me.sub.3 -phenyl531   CH.sub.3      c-Pr(n-Bu)CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl532   CH.sub.3      c-Pr(n-Bu)CH                 NH 2,4-Cl.sub.2 -6-Me-phenyl533   CH.sub.3      c-Pr(n-Bu)CH                 NH 2,4,6-Cl.sub.3 -phenyl534   CH.sub.3      c-Pr(n-Bu)CH                 NH 2-Me-4-MeO-phenyl535   CH.sub.3      c-Pr(n-Bu)CH                 NH 2-Cl-4-MeO-phenyl536   CH.sub.3      c-Pr(n-Bu)CH                 NH 2,4,6-Me.sub.3 -5-F-phenyl537   CH.sub.3      c-Pr(n-Bu)CH                 NH 2,5-Me.sub.2 -4-MeO-phenyl538   CH.sub.3      c-Pr(n-Bu)CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl539   CH.sub.3      c-Pr(n-Bu)CH                 NH 2,6-Cl.sub.2 -4-Me-phenyl540   CH.sub.3      c-Pr(n-Bu)CH                 NH 2,4-Cl.sub.2 -phenyl541   CH.sub.3      c-Pr(n-Bu)CH                 NH 2-Cl-4-Me-phenyl542   CH.sub.3      c-Pr(n-Bu)CH                 NH 2-Me-4-Cl-phenyl543   CH.sub.3      c-Pr(n-Bu)CH                 NH 2-NMe.sub.2 -6-Me-pyrid-5-yl544   CH.sub.3      c-Pr(n-Bu)CH                 NH 2-NMe.sub.2 -4-Me-pyrid-5-yl545   CH.sub.3      c-Pr(n-Bu)CH                 NH 2-Cl-4-MeO-6-Me-phenyl546   CH.sub.3      c-Pr(n-Bu)CH                 NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl547   CH.sub.3      c-Pr(n-Bu)CH                 NH 6-Cl-2,3-dihydro-benzofuran-5-yl548   CH.sub.3      c-Pr(n-Bu)CH                 NH 6-Me-2,3-dihydro-benzofuran-5-yl549   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -phenyl550   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl551   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2,4-Cl.sub.2 -6-Me-phenyl552   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2,4,6-Cl.sub.3 -phenyl553   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2-Me-4-MeO-phenyl554   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2-Cl-4-MeO-phenyl555   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -5-F-phenyl556   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2,5-Me.sub.2 -4-MeO-phenyl557   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl558   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2,6-Cl.sub.2 -4-Me-phenyl559   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2,4-Cl.sub.2 -phenyl560   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2-Cl-4-Me-phenyl561   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2-Me-4-Cl-phenyl562   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2-NMe.sub.2 -6-Me-pyrid-5-yl563   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2-NMe.sub.2 -4-Me-pyrid-5-yl564   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2-Cl-4-MeO-6-Me-phenyl565   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl566   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 6-Cl-2,3-dihydro-benzofuran-5-yl567   CH.sub.3      c-PrCH.sub.2 (Et)CH                 NH 6-Me-2,3-dihydro-benzofuran-5-yl__________________________________________________________________________ 
    
     Compounds that can be synthesized using synthetic Scheme 6 or Scheme 7 are listed in Table 2 
     
                                           TABLE 2__________________________________________________________________________ ##STR11##Ex.No.   R.sup.1 R.sup.3    Y  Ar             mp__________________________________________________________________________200   CH.sub.3      Et.sub.2 CH                 NH 2,4-Br.sub.2 -phenyl201   CH.sub.3      Et.sub.2 CH                 NH 2-Br-4-iPr-phenyl202   CH.sub.3      Et.sub.2 CH                 NEt                    2,4-Br.sub.2 -phenyl203   CH.sub.3      Et.sub.2 CH                 NEt                    2-Br-4-iPr-phenyl204   CH.sub.3      Et.sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl                                   133205   CH.sub.3      Et.sub.2 CH                 NEt                    2,4,6-Me.sub.3 -phenyl206   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -phenyl207   CH.sub.3      Et.sub.2 CH                 NH 2-Br-4,6-(MeO).sub.2 -phenyl208   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Br-4,6-(MeO).sub.2 -phenyl209   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Cl-4,6-(MeO).sub.2 -phenyl210   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,4-Me.sub.2 -6-I-phenyl211   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-CN-4,6-Me.sub.2 -phenyl212   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Br-4,6-Me.sub.2 -phenyl213   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 4-Br-2,6-Me.sub.2 -phenyl214   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 4-MeC(O)-2,6-Me.sub.2 -phenyl215   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-MeC(O)-4,6-Me.sub.2 -phenyl216   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,4-Me.sub.2 -6-SMe-phenyl217   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,4-Me.sub.2 -6-SO.sub.2 Me-phenyl218   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 4-Cl-2-I-6-Me-phenyl219   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl220   CH.sub.3      Et.sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl221   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,4-Cl.sub.2 -6-Me-phenyl222   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,4-Br.sub.2 -6-Me-phenyl223   CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4,6-Me.sub.3 -phenyl224   CH.sub.3      (MeOC.sub.2 H.sub.4).sub.2 CH                 NH 2,4,6-Me.sub.3 -phenyl225   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl226   CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl227   CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2-Br-4,6-Me.sub.2 -phenyl228   CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl229   CH.sub.3      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                 NH 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl230   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl231   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 4-Br-2,6-Me.sub.2 -phenyl232   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl233   CH.sub.3      (MeOCH.sub.2).sub.2 CH                 NH 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl234   CH.sub.3      MeOCH.sub.2 (Me)CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl235   CH.sub.3      MeOCH.sub.2 (Me)CH                 NH 2-Br-4,6-Me.sub.2 -phenyl236   CH.sub.3      EtOCH.sub.2 (Et)CH                 NH 2-Br-4,6-Me.sub.2 -phenyl237   CH.sub.3      EtOCH.sub.2 (Me)CH                 NH 2-Br-4,6-Me.sub.2 -phenyl238   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Br-4,6-F.sub.2 -phenyl239   Et.sub.2 CH      CH.sub.3   NH 2,4,6-Me.sub.3 -phenyl240   Et.sub.2 CH      CH.sub.3   NH 4-Br-2,6-Me.sub.2 -phenyl241   Et.sub.2 CH      CH.sub.3   NH 2-Br-4-iPr-phenyl242   MeOCH.sub.2 (Et)CH      CH.sub.3   NH 2,4,6-Me.sub.3 -phenyl243   MeOCH.sub.2 (Et)CH      CH.sub.3   NH 4-Br-2,6-Me.sub.2 -phenyl244   MeOCH.sub.2 (Et)CH      CH.sub.3   NH 2-Cl-4,6-Me.sub.2 -phenyl245   (MeOCH.sub.2).sub.2 CH      CH.sub.3   NH 2,4,6-Me.sub.3 -phenyl246   (MeOCH.sub.2).sub.2 CH      CH.sub.3   NH 4-Br-2,6-Me.sub.2 -phenyl247   (MeOCH.sub.2).sub.2 CH      CH.sub.3   NH 2-Cl-4,6-Me.sub.2 -phenyl248   Et.sub.2 CH      CH.sub.3   NH 2-Br-4,6-(MeO).sub.2 -phenyl249   Et.sub.2 CH      CH.sub.3   NH 2-Cl-4,6-Me.sub.2 -phenyl250   CH.sub.3      Et.sub.2 CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl251   CH.sub.3      Et.sub.2 CH                 NH 2,4-Cl.sub.2 -6-Me-phenyl252   CH.sub.3      Et.sub.2 CH                 NH 2,4,6-Cl.sub.3 -phenyl253   CH.sub.3      Et.sub.2 CH                 NH 2-Me-4-MeO-phenyl254   CH.sub.3      Et.sub.2 CH                 NH 2-Cl-4-MeO-phenyl255   CH.sub.3      Et.sub.2 CH                 NH 2,4,6-Me.sub.3 -5-F-phenyl256   CH.sub.3      Et.sub.2 CH                 NH 2,5-Me.sub.2 -4-MeO-phenyl257   CH.sub.3      Et.sub.2 CH                 NH 2,4-Me.sub.2 -6-MeO-phenyl258   CH.sub.3      Et.sub.2 CH                 NH 2,6-Cl.sub.2 -4-Me-phenyl259   CH.sub.3      Et.sub.2 CH                 NH 2,4-Cl.sub.2 -phenyl260   CH.sub.3      Et.sub.2 CH                 NH 2-Cl-4-Me-phenyl261   CH.sub.3      Et.sub.2 CH                 NH 2-Me-4-Cl-phenyl262   CH.sub.3      Et.sub.2 CH                 NH 2-NMe.sub.2 -6-Me-pyrid-5-yl263   CH.sub.3      Et.sub.2 CH                 NH 2-NMe.sub.2 -4-Me-pyrid-5-yl264   CH.sub.3      Et.sub.2 CH                 NH 2-Cl-4-MeO-6-Me-phenyl265   CH.sub.3      Et.sub.2 CH                 NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl266   CH.sub.3      Et.sub.2 CH                 NH 6-Cl-2,3-dihydro-benzofuran-5-yl267   CH.sub.3      Et.sub.2 CH                 NH 6-Me-2,3-dihydro-benzofuran-5-yl268   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Cl-4,6-Me.sub.2 -phenyl269   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,4-Cl.sub.2 -6-Me-phenyl270   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,4,6-Cl.sub.3 -phenyl271   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Me-4-MeO-phenyl272   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Cl-4-MeO-phenyl273   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,4,6-Me.sub.3 -5-F-phenyl274   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,5-Me.sub.2 -4-MeO-phenyl275   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,6-Cl.sub.2 -4-Me-phenyl276   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2,4-Cl.sub.2 -phenyl277   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Cl-4-Me-phenyl278   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Me-4-Cl-phenyl279   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-NMe.sub.2 -6-Me-pyrid-5-yl280   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-NMe.sub.2 -4-Me-pyrid-5-yl281   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Cl-4-MeO-6-Me-phenyl282   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl283   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 6-Cl-2,3-dihydro-benzofuran-5-yl284   CH.sub.3      MeOCH.sub.2 (Et)CH                 NH 6-Me-2,3-dihydro-benzofuran-5-yl__________________________________________________________________________ 
    
     Compounds wherein Y=Oxygen that can be synthesized using synthetic Scheme 3 are listed in Table 3 
     
                                           TABLE 3__________________________________________________________________________ ##STR12##ExNo R.sup.1 R.sup.3    Y Ar             mp/° C.__________________________________________________________________________700   Cl Et.sub.2 CH            O 2-Br-4-iPr-phenyl701   Cl Et.sub.2 CH            O 2,4-Br.sub.2 -phenyl702   Cl Et.sub.2 CH            O 2,4,6-Me.sub.3 -phenyl703   Cl MeOCH.sub.2 (Et)CH            O 2,4,6-Me.sub.3 -phenyl                             116704   Cl Et.sub.2 CH            O 2-Br-4,6-(MeO).sub.2 -phenyl705   Cl Et.sub.2 CH            O 2-CN-4,6-Me.sub.2 -phenyl706   Cl MeOCH.sub.2 (Et)CH            O 2-Br-4,6-(MeO).sub.2 -phenyl707   Cl MeOCH.sub.2 (Et)CH            O 2-Cl-4,6-(MeO).sub.2 -phenyl708   Cl MeOCH.sub.2 (Et)CH            O 2-I-4,6-Me.sub.2 -phenyl709   Cl MeOCH.sub.2 (Et)CH            O 2-CN-4,6-Me.sub.2 -phenyl710   Cl MeOCH.sub.2 (Et)CH            O 2-Br-4,6-Me.sub.2 -phenyl711   Cl MeOCH.sub.2 (Et)CH            O 4-Br-2,6-Me.sub.2 -phenyl712   Cl MeOCH.sub.2 (Et)CH            O 4-MeCO-2,6-Me.sub.2 -phenyl713   Cl MeOCH.sub.2 (Et)CH            O 4-MeCO-2-OMe-6-Me-phenyl714   Cl MeOCH.sub.2 (Et)CH            O 2-MeCO-4,6-Me.sub.2 -phenyl715   Cl MeOCH.sub.2 (Et)CH            O 4,6-Me.sub.2 -2-SMe-phenyl716   Cl MeOCH.sub.2 (Et)CH            O 4,6-Me.sub.2 -2-SO.sub.2 Me-phenyl717   Cl MeOCH.sub.2 (Et)CH            O 4-Cl-2-I-6-Me-phenyl718   Cl (MeOCH.sub.2).sub.2 CH            O 2,4,6-Me.sub.3 -phenyl719   Cl phenyl     O 2,4,6-Me.sub.3 -phenyl720   CH.sub.3 MeOCH.sub.2 (Et)CH            O 2,4-Br.sub.2 -phenyl721   CH.sub.3 MeOCH.sub.2 (Et)CH            O 2-Br-4-iPr-phenyl722   CH.sub.3 MeOCH.sub.2 (Et)CH            O 2,4,6-Me.sub.3 -phenyl723   CH.sub.3 MeOCH.sub.2 (Et)CH            O 2-Cl-4,6-Me.sub.2 -phenyl724   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2,4,6-Me.sub.3 -phenyl725   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2,4-Cl.sub.2 -6-Me-phenyl726   Cl (MeOCH.sub.2).sub.2 CH            O 2,4-Cl.sub.2 -6-Me-phenyl727   Cl (MeOCH.sub.2).sub.2 CH            O 2,4-Br.sub.2 -6-Me-phenyl728   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,4,6-Me.sub.3 -phenyl729   Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,4,6-Me.sub.3 -phenyl730   Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 4-Br-2-OMe-6-Me-phenyl731   Cl (MeOC.sub.2 H.sub.4).sub.2 CH            O 2,4,6-Me.sub.3 -phenyl732   Cl MeOCH.sub.2 (Et)CH            O 2,4-Me.sub.2 -6-MeO-phenyl733   Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,4-Me.sub.2 -6-MeO-phenyl734   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,4-Me.sub.2 -6-MeO-phenyl735   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            0 4-Br-2,6-Me.sub.2 -phenyl736   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2-Cl-4,6-Me.sub.2 -phenyl737   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl738   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2,4-Me.sub.2 -6-MeO-phenyl739   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 4-Br-2,6-Me.sub.2 -phenyl740   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2-Br-6-F-4-Me-phenyl741   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2-Cl-4,6-Me.sub.2 -phenyl742   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2-Cl-4-OMe-6-Me-phenyl743   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl744   Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,4-Me.sub.2 -6-MeO-phenyl745   Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 4-Br-2,6-Me.sub.2 -phenyl746   Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2-Cl-4,6-Me.sub.2 -phenyl747   Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl748   Cl (MeOCH.sub.2).sub.2 CH            O 2,4-Me.sub.2 -6-MeO-phenyl749   Cl (MeOCH.sub.2).sub.2 CH            O 4-Br-2,6-Me.sub.2 -phenyl750   Cl (MeOCH.sub.2).sub.2 CH            O 2-Cl-4,6-Me.sub.2 -phenyl751   Cl (MeOCH.sub.2).sub.2 CH            O 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl752   Cl MeOCH.sub.2 (Me)CH            O 2,4-Me.sub.2 -6-MeO-phenyl753   Cl MeOCH.sub.2 (Me)CH            O 4-Br-2,6-Me.sub.2 -phenyl754   Cl EtOCH.sub.2 (Et)CH            O 4-Br-2,6-Me.sub.2 -phenyl755   Cl EtOCH.sub.2 (Me)CH            O 4-Br-2,6-Me.sub.2 -phenyl756   Cl MeOCH.sub.2 (Et)CH            O 4-Br-2,6-F.sub.2 -phenyl757   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2-Br-4,6-Me.sub.2 -phenyl758   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,4-Me.sub.2 -6-SMe-phenyl759   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,4-Me.sub.2 -6-SO.sub.2 Me-phenyl760   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 4-NMe.sub.2 -2,6-Me.sub.2 -phenyl761   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,4-Cl.sub.2 -6-Me-phenyl762   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 4-Cl-2,6-Me.sub.2 -phenyl763   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,6-Me.sub.2 -4-SMe-phenyl764   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,6-Me.sub.2 -4-OMe-phenyl765   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl766   CH.sub.3 MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH            O 4-MeC(O)-2,6-Me.sub.2 -phenyl767   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 4-Br-2,6-Me.sub.2 -phenyl768   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 4-MeC(O)-2,6-Me.sub.2 -phenyl769   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2,6-Me.sub.2 -4-SMe-phenyl770   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl771   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 4-NMe.sub.2 -2,6-Me.sub.2 -phenyl772   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2-NMe.sub.2 -4,6-Me.sub.2 -phenyl773   Cl MeOCH.sub.2 (Et)CH            O 2,6-Me.sub.2 -4-SMe-phenyl774   Cl MeOCH.sub.2 (Et)CH            O 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl775   Cl MeOCH.sub.2 (Et)CH            O 2-Cl-4,6-Me.sub.2 -phenyl776   Cl MeOCH.sub.2 (Et)CH            O 4-Br-6-OMe-2-Me-phenyl777   Cl (MeOCH.sub.2).sub.2 CH            O 2,6-Me.sub.2 -4-SMe-phenyl778   Cl (MeOCH.sub.2).sub.2 CH            O 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl779   Cl (MeOCH.sub.2).sub.2 CH            O 4-Br-6-OMe-2-Me-phenyl780   CH.sub.3 Et.sub.2 CH            O 2,4,6-Me.sub.3 -phenyl781   CH.sub.3 Et.sub.2 CH            O 2-Cl-4,6-Me.sub.2 -phenyl782   CH.sub.3 Et.sub.2 CH            O 2-Cl-4-OMe-6-Me-phenyl783   CH.sub.3 Et.sub.2 CH            O 2,4,6-Me.sub.3 -pyrid-3-yl784   CH.sub.3 Et.sub.2 CH            O 4,6-Me.sub.2 -pyrid-3-yl785   CH.sub.3 Et.sub.2 CH            O 2-Br-6-Me-pyrid-3-yl786   CH.sub.3 Et.sub.2 CH            O 2-Br-6-OMe-pyrid-3-yl787   CH.sub.3 Et.sub.2 CH            O 2,6-Me.sub.2 -pyrid-3-yl788   CH.sub.3 Et.sub.2 CH            O 2-Cl-6-Me-pyrid-3-yl789   CH.sub.3 Et.sub.2 CH            O 2-Cl-6-OMe-pyrid-3-yl790   CH.sub.3 MeOCH.sub.2 (Et)CH            O 2,4,6-Me.sub.3 -pyrid-3-yl791   CH.sub.3 MeOCH.sub.2 (Et)CH            O 4,6-Me.sub.2 -pyrid-3-yl792   CH.sub.3 MeOCH.sub.2 (Et)CH            O 2-Br-6-Me-pyrid-3-yl793   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2-Br-6-OMe-pyrid-3-yl794   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2,6-Me.sub.2 -pyrid-3-yl795   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2-Cl-6-Me-pyrid-3-yl796   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2-Cl-6-OMe-pyrid-3-yl797   CH.sub.3 MeOCH.sub.2 (Et)CH            O 2-Br-6-OMe-pyrid-3-yl798   CH.sub.3 MeOCH.sub.2 (Et)CH            O 2,6-Me.sub.2 -pyrid-3-yl799   CH.sub.3 MeOCH.sub.2 (Et)CH            O 2-Cl-6-Me-pyrid-3-yl800   CH.sub.3 MeOCH.sub.2 (Et)CH            O 2-Cl-6-OMe-pyrid-3-yl801   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2,4,6-Me.sub.3 -pyrid-3-yl802   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 4,6-Me.sub.2 -pyrid-3-yl803   CH.sub.3 (MeOCH.sub.2).sub.2 CH            O 2-Br-6-Me-pyrid-3-yl804   Cl Et.sub.2 CH            O 2-Br-6-OMe-pyrid-3-yl805   Cl Et.sub.2 CH            O 2,6-Me.sub.2 -pyrid-3-yl806   Cl Et.sub.2 CH            O 2-Cl-6-Me-pyrid-3-yl807   Cl Et.sub.2 CH            O 2-Cl-6-OMe-pyrid-3-yl808   Cl MeOCH.sub.2 (Et)CH            O 2,4,6-Me.sub.3 -pyrid-3-yl809   Cl MeOCH.sub.2 (Et)CH            O 4,6-Me.sub.2 -pyrid-3-yl810   Cl MeOCH.sub.2 (Et)CH            O 2-Br-6-Me-pyrid-3-yl811   Cl Et.sub.2 CH            O 2,4,6-Me.sub.3 -pyrid-3-yl812   Cl Et.sub.2 CH            O 4,6-Me.sub.2 -pyrid-3-yl813   Cl Et.sub.2 CH            O 2-Br-6-Me-pyrid-3-yl814   Cl MeOCH.sub.2 (Et)CH            O 2-Br-6-OMe-pyrid-3-yl815   Cl MeOCH.sub.2 (Et)CH            O 2,6-Me.sub.2 -pyrid-3-yl816   Cl MeOCH.sub.2 (Et)CH            O 2-Cl-6-Me-pyrid-3-yl817   Cl MeOCH.sub.2 (Et)CH            O 2-Cl-6-OMe-pyrid-3-yl818   Cl (MeOCH.sub.2).sub.2 CH            O 2-Br-6-OMe-pyrid-3-yl819   Cl (MeOCH.sub.2).sub.2 CH            O 2,6-Me.sub.2 -pyrid-3-yl820   Cl (MeOCH.sub.2).sub.2 CH            O 2-Cl-6-Me-pyrid-3-yl821   Cl (MeOCH.sub.2).sub.2 CH            O 2-Cl-6-OMe-pyrid-3-yl822   Cl (MeOCH.sub.2).sub.2 CH            O 2,4,6-Me.sub.3 -pyrid-3-yl823   Cl (MeOCH.sub.2).sub.2 CH            O 4,6-Me.sub.2 -pyrid-3-yl824   Cl (MeOCH.sub.2).sub.2 CH            O 2-Br-6-Me-pyrid-3-yl825   CH.sub.3 Me(Et)CH   O 2,4,6-Me.sub.3 -phenyl826   CH.sub.3 Me(Et)CH   O 2-Cl-4,6-Me.sub.2 -phenyl827   CH.sub.3 Me(Et)CH   O 2,4-Cl.sub.2 -6-Me-phenyl828   CH.sub.3 Me(Et)CH   O 2,4,6-Cl.sub.3 -phenyl829   CH.sub.3 Me(Et)CH   O 2-Me-4-MeO-phenyl830   CH.sub.3 Me(Et)CH   O 2-Cl-4-MeO-phenyl831   CH.sub.3 Me(Et)CH   O 2,4,6-Me.sub.3 -5-F-phenyl832   CH.sub.3 Me(Et)CH   O 2,5-Me.sub.2 -4-MeO-phenyl833   CH.sub.3 Me(Et)CH   O 2,4-Me.sub.2 -6-MeO-phenyl834   CH.sub.3 Me(Et)CH   O 2,6-Cl.sub.2 -4-Me-phenyl835   CH.sub.3 Me(Et)CH   O 2,4-Cl.sub.2 -phenyl836   CH.sub.3 Me(Et)CH   O 2-Cl-4-Me-phenyl837   CH.sub.3 Me(Et)CH   O 2-Me-4-Cl-phenyl838   CH.sub.3 Me(Et)CH   O 2-NMe.sub.2 -6-Me-pyrid-5-yl839   CH.sub.3 Me(Et)CH   O 2-NMe.sub.2 -4-Me-pyrid-5-yl840   CH.sub.3 Me(Et)CH   O 2-Cl-4-MeO-6-Me-phenyl841   CH.sub.3 Me(Et)CH   O 2-Cl-4,6-Me.sub.2 -5-F-phenyl842   CH.sub.3 Me(Et)CH   O 6-Cl-2,3-dihydro-benzofuran-5-yl843   CH.sub.3 Me(Et)CH   O 6-Me-2,3-dihydro-benzofuran-5-yl844   CH.sub.3 Me(n-Pr)CH O 2,4,6-Me.sub.3 -phenyl845   CH.sub.3 Me(n-Pr)CH O 2-Cl-4,6-Me.sub.2 -phenyl846   CH.sub.3 Me(n-Pr)CH O 2,4-Cl.sub.2 -6-Me-phenyl847   CH.sub.3 Me(n-Pr)CH O 2,4,6-Cl.sub.3 -phenyl848   CH.sub.3 Me(n-Pr)CH O 2-Me-4-MeO-phenyl849   CH.sub.3 Me(n-Pr)CH O 2-Cl-4-MeO-phenyl850   CH.sub.3 Me(n-Pr)CH O 2,4,6-Me.sub.3 -5-F-phenyl851   CH.sub.3 Me(n-Pr)CH O 2,5-Me.sub.2 -4-MeO-phenyl852   CH.sub.3 Me(n-Pr)CH O 2,4-Me.sub.2 -6-MeO-phenyl853   CH.sub.3 Me(n-Pr)CH O 2,6-Cl.sub.2 -4-Me-phenyl854   CH.sub.3 Me(n-Pr)CH O 2,4-Cl.sub.2 -phenyl855   CH.sub.3 Me(n-Pr)CH O 2-Cl-4-Me-phenyl856   CH.sub.3 Me(n-Pr)CH O 2-Me-4-Cl-phenyl857   CH.sub.3 Me(n-Pr)CH O 2-NMe.sub.2 -6-Me-pyrid-5-yl858   CH.sub.3 Me(n-Pr)CH O 2-NMe.sub.2 -4-Me-pyrid-5-yl859   CH.sub.3 Me(n-Pr)CH O 2-Cl-4-MeO-6-Me-phenyl860   CH.sub.3 Me(n-Pr)CH O 2-Cl-4,6-Me.sub.2 -5-F-phenyl861   CH.sub.3 Me(n-Pr)CH O 6-Cl-2,3-dihydro-benzofuran-5-yl862   CH.sub.3 Me(n-Pr)CH O 6-Me-2,3-dihydro-benzofuran-5-yl863   CH.sub.3 c-Pr.sub.2 CH            O 2,4,6-Me.sub.3 -phenyl864   CH.sub.3 c-Pr.sub.2 CH            O 2-Cl-4,6-Me.sub.2 -phenyl865   CH.sub.3 c-Pr.sub.2 CH            O 2,4-Cl.sub.2 -6-Me-phenyl866   CH.sub.3 c-Pr.sub.2 CH            O 2,4,6-Cl.sub.3 -phenyl867   CH.sub.3 c-Pr.sub.2 CH            O 2-Me-4-MeO-phenyl868   CH.sub.3 c-Pr.sub.2 CH            O 2-Cl-4-MeO-phenyl869   CH.sub.3 c-Pr.sub.2 CH            O 2,4,6-Me.sub.3 -5-F-phenyl870   CH.sub.3 c-Pr.sub.2 CH            O 2,5-Me.sub.2 -4-MeO-phenyl871   CH.sub.3 c-Pr.sub.2 CH            O 2,4-Me.sub.2 -6-MeO-phenyl872   CH.sub.3 c-Pr.sub.2 CH            O 2,6-Cl.sub.2 -4-Me-phenyl873   CH.sub.3 c-Pr.sub.2 CH            O 2,4-Cl.sub.2 -phenyl874   CH.sub.3 c-Pr.sub.2 CH            O 2-Cl-4-Me-phenyl875   CH.sub.3 c-Pr.sub.2 CH            O 2-Me-4-Cl-phenyl876   CH.sub.3 c-Pr.sub.2 CH            O 2-NMe.sub.2 -6-Me-pyrid-5-yl877   CH.sub.3 c-Pr.sub.2 CH            O 2-NMe.sub.2 -4-Me-pyrid-5-yl878   CH.sub.3 c-Pr.sub.2 CH            O 2-Cl-4-MeO-6-Me-phenyl879   CH.sub.3 c-Pr.sub.2 CH            O 2-Cl-4,6-Me.sub.2 -5-F-phenyl880   CH.sub.3 c-Pr.sub.2 CH            O 6-Cl-2,3-dihydro-benzofuran-5-yl881   CH.sub.3 c-Pr.sub.2 CH            O 6-Me-2,3-dihydro-benzofuran-5-yl882   CH.sub.3 c-Pr(Me)CH O 2,4,6-Me.sub.3 -phenyl883   CH.sub.3 c-Pr(Me)CH O 2-Cl-4,6-Me.sub.2 -phenyl884   CH.sub.3 c-Pr(Me)CH O 2,4-Cl.sub.2 -6-Me-phenyl885   CH.sub.3 c-Pr(Me)CH O 2,4,6-Cl.sub.3 -phenyl886   CH.sub.3 c-Pr(Me)CH O 2-Me-4-MeO-phenyl887   CH.sub.3 c-Pr(Me)CH O 2-Cl-4-MeO-phenyl888   CH.sub.3 c-Pr(Me)CH O 2,4,6-Me.sub.3 -5-F-phenyl889   CH.sub.3 c-Pr(Me)CH O 2,5-Me.sub.2 -4-MeO-phenyl890   CH.sub.3 c-Pr(Me)CH O 2,4-Me.sub.2 -6-MeO-phenyl891   CH.sub.3 c-Pr(Me)CH O 2,6-Cl.sub.2 -4-Me-phenyl892   CH.sub.3 c-Pr(Me)CH O 2,4-Cl.sub.2 -phenyl893   CH.sub.3 c-Pr(Me)CH O 2-Cl-4-Me-phenyl894   CH.sub.3 c-Pr(Me)CH O 2-Me-4-Cl-phenyl895   CH.sub.3 c-Pr(Me)CH O 2-NMe.sub.2 -6-Me-pyrid-5-yl896   CH.sub.3 c-Pr(Me)CH O 2-NMe.sub.2 -4-Me-pyrid-5-yl897   CH.sub.3 c-Pr(Me)CH O 2-Cl-4-MeO-6-Me-phenyl898   CH.sub.3 c-Pr(Me)CH O 2-Cl-4,6-Me.sub.2 -5-F-phenyl899   CH.sub.3 c-Pr(Me)CH O 6-Cl-2,3-dihydro-benzofuran-5-yl900   CH.sub.3 c-Pr(Me)CH O 6-Me-2,3-dihydro-benzofuran-5-yl901   CH.sub.3 c-Pr(Et)CH O 2,4,6-Me.sub.3 -phenyl902   CH.sub.3 c-Pr(Et)CH O 2-Cl-4,6-Me.sub.2 -phenyl903   CH.sub.3 c-Pr(Et)CH O 2,4-Cl.sub.2 -6-Me-phenyl904   CH.sub.3 c-Pr(Et)CH O 2,4,6-Cl.sub.3 -phenyl905   CH.sub.3 c-Pr(Et)CH O 2-Me-4-MeO-phenyl906   CH.sub.3 c-Pr(Et)CH O 2-Cl-4-MeO-phenyl907   CH.sub.3 c-Pr(Et)CH O 2,4,6-Me.sub.3 -5-F-phenyl908   CH.sub.3 c-Pr(Et)CH O 2,5-Me.sub.2 -4-MeO-phenyl909   CH.sub.3 c-Pr(Et)CH O 2,4-Me.sub.2 -6-MeO-phenyl910   CH.sub.3 c-Pr(Et)CH O 2,6-Cl.sub.2 -4-Me-phenyl911   CH.sub.3 c-Pr(Et)CH O 2,4-Cl.sub.2 -phenyl912   CH.sub.3 c-Pr(Et)CH O 2-Cl-4-Me-phenyl913   CH.sub.3 c-Pr(Et)CH O 2-Me-4-Cl-phenyl914   CH.sub.3 c-Pr(Et)CH O 2-NMe.sub.2 -6-Me-pyrid-5-yl915   CH.sub.3 c-Pr(Et)CH O 2-NMe.sub.2 -4-Me-pyrid-5-yl916   CH.sub.3 c-Pr(Et)CH O 2-Cl-4-MeO-6-Me-phenyl917   CH.sub.3 c-Pr(Et)CH O 2-Cl-4,6-Me.sub.2 -5-F-phenyl918   CH.sub.3 c-Pr(Et)CH O 6-Cl-2,3-dihydro-benzofuran-5-yl919   CH.sub.3 c-Pr(Et)CH O 6-Me-2,3-dihydro-benzofuran-5-yl920   CH.sub.3 c-Pr(n-Pr)CH            O 2,4,6-Me.sub.3 -phenyl921   CH.sub.3 c-Pr(n-Pr)CH            O 2-Cl-4,6-Me.sub.2 -phenyl922   CH.sub.3 c-Pr(n-Pr)CH            O 2,4-Cl.sub.2 -6-Me-phenyl923   CH.sub.3 c-Pr(n-Pr)CH            O 2,4,6-Cl.sub.3 -phenyl924   CH.sub.3 c-Pr(n-Pr)CH            O 2-Me-4-MeO-phenyl925   CH.sub.3 c-Pr(n-Pr)CH            O 2-Cl-4-MeO-phenyl926   CH.sub.3 c-Pr(n-Pr)CH            O 2,4,6-Me.sub.3 -5-F-phenyl927   CH.sub.3 c-Pr(n-Pr)CH            O 2,5-Me.sub.2 -4-MeO-phenyl928   CH.sub.3 c-Pr(n-Pr)CH            O 2,4-Me.sub.2 -6-MeO-phenyl929   CH.sub.3 c-Pr(n-Pr)CH            O 2,6-Cl.sub.2 -4-Me-phenyl930   CH.sub.3 c-Pr(n-Pr)CH            O 2,4-Cl.sub.2 -phenyl931   CH.sub.3 c-Pr(n-Pr)CH            O 2-Cl-4-Me-phenyl932   CH.sub.3 c-Pr(n-Pr)CH            O 2-Me-4-Cl-phenyl933   CH.sub.3 c-Pr(n-Pr)CH            O 2-NMe.sub.2 -6-Me-pyrid-5-yl934   CH.sub.3 c-Pr(n-Pr)CH            O 2-NMe.sub.2 -4-Me-pyrid-5-yl935   CH.sub.3 c-Pr(n-Pr)CH            O 2-Cl-4-MeO-6-Me-phenyl936   CH.sub.3 c-Pr(n-Pr)CH            O 2-Cl-4,6-Me.sub.2 -5-F-phenyl937   CH.sub.3 c-Pr(n-Pr)CH            O 6-Cl-2,3-dihydro-benzofuran-5-yl938   CH.sub.3 c-Pr(n-Pr)CH            O 6-Me-2,3-dihydro-benzofuran-5-yl939   CH.sub.3 c-Pr(n-Bu)CH            O 2,4,6-Me.sub.3 -phenyl940   CH.sub.3 c-Pr(n-Bu)CH            O 2-Cl-4,6-Me.sub.2 -phenyl941   CH.sub.3 c-Pr(n-Bu)CH            O 2,4-Cl.sub.2 -6-Me-phenyl942   CH.sub.3 c-Pr(n-Bu)CH            O 2,4,6-Cl.sub.3 -phenyl943   CH.sub.3 c-Pr(n-Bu)CH            O 2-Me-4-MeO-phenyl944   CH.sub.3 c-Pr(n-Bu)CH            O 2-Cl-4-MeO-phenyl945   CH.sub.3 c-Pr(n-Bu)CH            O 2,4,6-Me.sub.3 -5-F-phenyl946   CH.sub.3 c-Pr(n-Bu)CH            O 2,5-Me.sub.2 -4-MeO-phenyl947   CH.sub.3 c-Pr(n-Bu)CH            O 2,4-Me.sub.2 -6-MeO-phenyl948   CH.sub.3 c-Pr(n-Bu)CH            O 2,6-Cl.sub.2 -4-Me-phenyl949   CH.sub.3 c-Pr(n-Bu)CH            O 2,4-Cl.sub.2 -phenyl950   CH.sub.3 c-Pr(n-Bu)CH            O 2-Cl-4-Me-phenyl951   CH.sub.3 c-Pr(n-Bu)CH            O 2-Me-4-Cl-phenyl952   CH.sub.3 c-Pr(n-Bu)CH            O 2-NMe.sub.2 -6-Me-pyrid-5-yl953   CH.sub.3 c-Pr(n-Bu)CH            O 2-NMe.sub.2 -4-Me-pyrid-5-yl954   CH.sub.3 c-Pr(n-Bu)CH            O 2-Cl-4-MeO-6-Me-phenyl955   CH.sub.3 c-Pr(n-Bu)CH            O 2-Cl-4,6-Me.sub.2 -5-F-phenyl956   CH.sub.3 c-Pr(n-Bu)CH            O 6-Cl-2,3-dihydro-benzofuran-5-yl957   CH.sub.3 c-Pr(n-Bu)CH            O 6-Me-2,3-dihydro-benzofuran-5-yl958   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2,4,6-Me.sub.3 -phenyl959   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2-Cl-4,6-Me.sub.2 -phenyl960   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2,4-Cl.sub.2 -6-Me-phenyl961   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2,4,6-Cl.sub.3 -phenyl962   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2-Me-4-MeO-phenyl963   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2-Cl-4-MeO-phenyl964   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2,4,6-Me.sub.3 -5-F-phenyl965   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2,5-Me.sub.2 -4-MeO-phenyl966   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2,4-Me.sub.2 -6-MeO-phenyl967   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2,6-Cl.sub.2 -4-Me-phenyl968   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2,4-Cl.sub.2 -phenyl969   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2-Cl-4-Me-phenyl970   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2-Me-4-Cl-phenyl971   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2-NMe.sub.2 -6-Me-pyrid-5-yl972   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2-NMe.sub.2 -4-Me-pyrid-5-yl973   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2-Cl-4-MeO-6-Me-phenyl974   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 2-Cl-4,6-Me.sub.2 -5-F-phenyl975   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 6-Cl-2,3-dihydro-benzofuran-5-yl976   CH.sub.3 c-PrCH.sub.2 (Et)CH            O 6-Me-2,3-dihydro-benzofuran-5-yl977   CH.sub.3 Et.sub.2 CH            O 2,4-Cl.sub.2 -6-Me-phenyl978   CH.sub.3 Et.sub.2 CH            O 2,4,6-Cl.sub.3 -phenyl979   CH.sub.3 Et.sub.2 CH            O 2-Me-4-MeO-phenyl980   CH.sub.3 Et.sub.2 CH            O 2-Cl-4-MeO-phenyl981   CH.sub.3 Et.sub.2 CH            O 2,4,6-Me.sub.3 -5-F-phenyl982   CH.sub.3 Et.sub.2 CH            O 2,5-Me.sub.2 -4-MeO-phenyl983   CH.sub.3 Et.sub.2 CH            O 2,4-Me.sub.2 -6-MeO-phenyl984   CH.sub.3 Et.sub.2 CH            O 2,6-Cl.sub.2 -4-Me-phenyl985   CH.sub.3 Et.sub.2 CH            O 2,4-Cl.sub.2 -phenyl986   CH.sub.3 Et.sub.2 CH            O 2-Cl-4-Me-phenyl987   CH.sub.3 Et.sub.2 CH            O 2-Me-4-Cl-phenyl988   CH.sub.3 Et.sub.2 CH            O 2-NMe.sub.2 -6-Me-pyrid-5-yl989   CH.sub.3 Et.sub.2 CH            O 2-NMe.sub.2 -4-Me-pyrid-5-yl990   CH.sub.3 Et.sub.2 CH            O 2-Cl-4,6-Me.sub.2 -5-F-phenyl991   CH.sub.3 Et.sub.2 CH            O 6-Cl-2,3-dihydro-benzofuran-5-yl992   CH.sub.3 Et.sub.2 CH            O 6-Me-2,3-dihydro-benzofuran-5-yl__________________________________________________________________________ 
    
     Additional compounds, wherein Y=oxygen that can be synthesized using synthetic Scheme 6 or Scheme 7 are listed Table 4 
     
                       TABLE 4______________________________________ ##STR13##Ex.No.  R.sup.1 R.sup.3 Y    Ar               mp______________________________________1000 CH.sub.3        Et.sub.2 CH                O    2,4,6-Me.sub.3 -phenyl1001 CH.sub.3        Et.sub.2 CH                O    2-Cl-4,6-Me.sub.2 -phenyl1002 CH.sub.3        Et.sub.2 CH                O    2,4-Cl.sub.2 -6-Me-phenyl1003 CH.sub.3        Et.sub.2 CH                O    2,4,6-Cl.sub.3 -phenyl1004 CH.sub.3        Et.sub.2 CH                O    2-Me-4-MeO-phenyl1005 CH.sub.3        Et.sub.2 CH                O    2-Cl-4-MeO-phenyl1006 CH.sub.3        Et.sub.2 CH                O    2,4,6-Me.sub.3 -5-F-phenyl1007 CH.sub.3        Et.sub.2 CH                O    2,5-Me.sub.2 -4-MeO-phenyl1008 CH.sub.3        Et.sub.2 CH                O    2,4-Me.sub.2 -6-MeO-phenyl1009 CH.sub.3        Et.sub.2 CH                O    2,6-Cl.sub.2 -4-Me-phenyl1010 CH.sub.3        Et.sub.2 CH                O    2,4-Cl.sub.2 -phenyl1011 CH.sub.3        Et.sub.2 CH                O    2-Cl-4-Me-phenyl1012 CH.sub.3        Et.sub.2 CH                O    2-Me-4-Cl-phenyl1013 CH.sub.3        Et.sub.2 CH                O    2-NMe.sub.2 -6-Me-pyrid-5-yl1014 CH.sub.3        Et.sub.2 CH                O    2-NMe.sub.2 -4-Me-pyrid-5-yl1015 CH.sub.3        Et.sub.2 CH                O    2-Cl-4-MeO-6-Me-phenyl1016 CH.sub.3        Et.sub.2 CH                O    2-Cl-4,6-Me.sub.2 -5-F-phenyl1017 CH.sub.3        Et.sub.2 CH                O    6-Cl-2,3-dihydro-benzofuran-5-yl1018 CH.sub.3        Et.sub.2 CH                O    6-Me-2,3-dihydro-benzofuran-5-yl______________________________________ 
    
     Utility 
     CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity 
     The following is a description of the isolation of cell membranes containing cloned human CRF-R1 receptors for use in the standard binding assay as well as a description of the assay itself. 
     Messenger RNA was isolated from human hippocampus. The mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to stop codons The resulting PCR fragment was cloned into the EcoRV site of PGEMV, from whence the insert was reclaimed using XhoI+XbaI and cloned into the XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the SV40 `t` splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 mM hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay described below. Individual aliquots containing approximately 1×10 8  of the suspended cells were then centrifuged to form a pellet and frozen. 
     For the binding assay a frozen pellet described above containing 293EBNA cells transfected with hCRFR1 receptors is homogenized in 10 ml of ice cold tissue buffer (50 mM HEPES buffer pH 7.0, containing 10 mM MgCl 2 , 2 mM EGTA, 1 mg/l aprotinin, 1 mg/ml leupeptin and 1 mg/ml pepstatin). The homogenate is centrifuged at 40,000×g for 12 min and the resulting pellet rehomogenized in 10 ml of tissue buffer. After another centrifugation at 40,000×g for 12 min, the pellet is resuspended to a protein concentration of 360 mg/ml to be used in the assay. 
     Binding assays are performed in 96 well plates; each well having a 300 ml capacity. To each well is added 50 ml of test drug dilutions (final concentration of drugs range from 10 -10  -10 -5  M), 100 ml of  125  I-ovine-CRF ( 125  I-o-CRF) (final concentration 150 pM) and 150 ml of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter. 
     Curves of the inhibition of  125  I-o-CRF binding to cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND [P. J. Munson and D. Rodbard, Anal. Biochem. 107:220 (1980)], which provides Ki values for inhibition which are then used to assess biological activity. 
     A compound is considered to be active if it has a K i  value of less than about 10000 nM for the inhibition of CRF. Compounds with a K i  less than 100 nM for the inhibition of CRF are desirable. A number of compounds of the invention have been made and tested in the above assay and shown to have K i  values less than 100 nM thus confirming the utility of the invention. 
     Inhibition of CRF-Stimulated Adenylate Cyclase Activity 
     Inhibition of CRF--Stimulated adenylate cyclase activity was performed as described by G. Battaglia et al. Synapse 1:572 (1987). Briefly, assays were carried out at 37° C. for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl 2 , 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5&#39;-triphosphate, 100 nM OCRF, antagonist peptides (concentration range 10 -9  to  10   -6  m) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions were initiated by the addition of 1 mM ATP/[ 32  P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 μl of [ 3  H]cAMP (approximately 40,000 dpm) was added to each tube prior to separation. The separation of [ 32  P]cAMP from [ 32  P]ATP was performed by sequential elution over Dowex and alumina columns. Recovery was consistently greater than 80%. 
     A compound of this invention was tested in this assay and found to be active; IC 50  &lt;10000 nM. 
     In vivo Biological Assay 
     The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990) 
     Compounds may be tested in any species of rodent or small mammal. Disclosure of the assays herein is not intended to limit the enablement of the invention. 
     Compounds of this invention have utility in the treatment of inbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders, and/or anxiety. 
     Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent&#39;s site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. 
     The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient&#39;s age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect. 
     Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition. 
     The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations. 
     Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract. 
     Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance. 
     In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. 
     Suitable pharmaceutical carriers are described in &#34;Remington&#39;s Pharmaceutical Sciences&#34;, A. Osol, a standard reference in the field. 
     Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: 
     Capsules 
     A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate. 
     Soft Gelatin Capsules 
     A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried. 
     Tablets 
     A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption. 
     The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.