Patent Abstract:
Corticotropin releasing factor (CRF) antagonists of formula I:                            
     and their use in treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.

Full Description:
This application claims benefit of Provisional application Ser. No. 60/114,188, filed Dec. 30, 1998. 
    
    
     FIELD OF THE INVENTION 
     This invention relates a treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress, by administration of certain 1H-imidazo[4,5-d]pyridazin-7-ones, 3H-imidazo-[4,5-c]pyridin-4-ones and corresponding thiones. 
     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 feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimerís disease, Parkinsonís disease, Huntingtonís 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 ìanxiolytic-likeî 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 ìanxiogenicî 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 (α-helical CRF 9-41 ) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces ìanxiolytic-likeî 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)]. 
     Several publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application US94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 0778 277 A1. 
     SUMMARY OF THE INVENTION 
     In accordance with one aspect, the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer&#39;s disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer&#39;s disease, Parkinson&#39;s disease and Huntington&#39;s disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn&#39;s disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer&#39;s type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in a mammal. 
     The present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in a mammal. 
     According to another aspect, the present invention provides novel compounds of Formula (1) (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such compounds of Formula (1) and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders. 
     According to yet another aspect of the invention, the 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 
     [1] The present invention comprises novel compounds of Formula (1) (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. This invention comprises compounds of Formula (1):                           
     and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein: 
     X is O or S; 
     A=N or CR 9 ; 
     Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R 4  groups and each Ar is attached via an unsaturated carbon atom; 
     R 1  is independently selected at each occurrence from H, C 1 -C 4 †alkyl, C 2 -C 4 †alkenyl, C 2 -C 4 †alkynyl, halo, CN, C 1 -C 4 †haloalkyl, C 1 -C 12  hydroxyalkyl, C 2 -C 12  alkoxyalkyl, C 2 -C 10  cyanoalkyl, C 3 -C 6  cycloalkyl, C 4 -C 10  cycloalkylalkyl, NR 9 R 10 , C 1 -C 4  alkyl-NR 9 R 10 , NR 9 COR 10 , OR 11 , SH or S(O) n R 12 ; 
     R 2  is selected from: 
     —H, aryl, heteroaryl and heterocyclyl, or 
     —C 1 -C 10 †alkyl, C 2 -C 10 †alkenyl, C 2 -C 10 †alkynyl, C 3 -C 8 †cycloalkyl, C 5 -C 8  cycloalkenyl, C 4 -C 12 †cycloalkylalkyl or C 6 -C 10  cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 6 †alkyl, C 3 -C 6 †cycloalkyl, C 1-6  alkyloxyC 1-6  alkyl, C 2-6  alkenyl, C 3-6  alkynyl, halo, C 1 -C 4 †haloalkyl, cyano, OR 15 , SH, S(O) n R 13 , COR 15 , CO 2 R 15 , OC(O)R 13 , NR 8 COR 15 , N(COR 15 ) 2 , NR 8 CONR 16 R 15 , NR 8 CO 2 R 13 , NR 16 R 15 , CONR 16 R 15 , aryl, heteroaryl and heterocyclyl; 
     R 3  is selected from: 
     —H, aryl, heteroaryl and heterocyclyl, or 
     C 1 -C 4 †lkyl, C 3 -C 6 †alkenyl, C 3 -C 6 †alkynyl, C 3 -C 6 †cycloalkyl, C 4 -C 10  cycloalkylalkyl, each optionally substituted with 1 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, cyano, OR 15 , SH, S(O) n R 13 , COR 15 , CO 2 R 15 , OC(O)R 13 , NR 8 COR 15 , N(COR 15 ) 2 , NR 8 CONR 16 R 15 , NR 8 CO 2 R 13 , NR 16 R 15 , CONR 16 R 15 , aryl, heteroaryl and heterocyclyl; 
     R 4  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, NO 2 , halo, CN, C 1 -C 4 †haloalkyl, NR 6 R 7 , NR 6 COR 7 , NR 6 CO 2 R 7 , COR 7 , OR 7 , CONR 6 R 7 , CO(NOR 9 )R 7 , CO 2 R 7 , or S(O) n R 7 , where each such 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 optionally substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 4  alkyl, NO 2 , halo, CN, NR 6 R 7 , NR 6 COR 7 , NR 6 CO 2 R 7 , COR 7  OR 7 , CONR 6 R 7 , CO 2 R 7 , CO(NOR 9 )R 7 , or S(O) n R 7 ; 
     R 6  and R 7  are independently selected at each occurrence from: 
     —H, 
     —C 1 -C 10  alkyl, C 3 -C 10  alkenyl, C 3 -C 10  alkynyl, C 1 -C 10  haloalkyl with 1-10 halogens, C 2 -C 8  alkoxyalkyl, C 3 -C 6 †cycloalkyl, C 4 -C 12 †cycloalkylalkyl, C 5 -C 10  cycloalkenyl, or C 6 -C 14  cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 6 †alkyl, C 3 -C 6 †cycloalkyl, halo, C 1 -C 4 †aloalkyl, cyano, OR 15 , SH, S(O) n R 13 , COR 15 , CO 2 R 15 , OC(O)R 13 , NR 8 COR 15 , N(COR 15 ) 2 , NR 8 CONR 16 R 15 , NR 8 CO 2 R 13 , NR 16 R 15 , CONR 16 R 15 , aryl, heteroaryl or heterocyclyl, 
     -aryl, aryl(C 1 -C 4  alkyl), heteroaryl, heteroaryl(C 1 -C 4  alkyl), heterocyclyl or heterocyclyl(C 1 -C 4  alkyl); 
     alternatively, NR 6 R 7  is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C 1 -C 4  alkyl groups; 
     R 8  is independently selected at each occurrence from H or C 1 -C 4  alkyl optionally substituted by halogen, C 1 -C 4  alkoxy or C 1 -C 4  halo-alkoxy (1 to 4 halogens); 
     R 9  and R 10  are independently selected at each occurrence from H, C 1 -C 4  alkyl, or C 3 -C 6  cycloalkyl; 
     R 11  is selected from 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 or C 1 -C 4  haloalkyl; 
     R 13  is selected from 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)-, heteroaryl or heteroaryl(C 1 -C 4  alkyl)-; 
     R 15  and R 16  are independently selected at each occurrence from H, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, C 4 -C 16  cycloalkylalkyl, except that for S(O) n R 15 , R 15  cannot be H; 
     aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C 1 -C 6 †alkyl, C 3 -C 6 †cycloalkyl, halo, C 1 -C 4 \haloalkyl, cyano, OR 15 , SH, S(O) n R 15 , COR 15 , CO 2 R 15 , OC(O)R 15 , NR 8 COR 15 , N(COR 15 ) 2 , NR 8 CONR 16 R 15 , NR 8 CO 2 R 15 , NR 16 R 15 , and CONR 16 R 15 ; 
     heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C 1 -C 6 †alkyl, C 3 -C 6 †cycloalkyl, halo, C 1 -C 4 †haloalkyl, cyano, OR 15 , SH, S(O) n R 15 , —COR 15 , CO 2 R 15 , OC(O)R 15 , NR 8 COR 15 , N(COR 15 ) 2 , NR 8 CONR 16 R 15 , NR 8 CO 2 R 15 , NR 16 R 15 , and CONR 16 R 15 ; 
     heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C 1 -C 6 †alkyl, C 3 -C 6 †cycloalkyl, halo, C 1 -C 4 †haloalkyl, cyano, OR 15 , SH, S(O) n R 15 , COR 15 , CO 2 R 15 , OC(O)R 15 , NR 8 COR 15 , N(COR 15 ) 2 , NR 8 CONR 16 R 15 , NR 8 CO 2 R 15 , NR 15 R 16 , and CONR 16 R 15 ; 
     n is independently at each occurrence 0, 1 or 2. 
     [2] Preferred compounds of the above invention also include compounds of Formula (1) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl or pyridyl, each optionally substituted with 1 to 4 R 4  substituents. 
     [3] More preferred compounds of the above invention also include compounds and isomers thereof of formula 1 wherein A is equal to nitrogen (formula 1a), stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.                           
     [4] The present invention also relates to compounds, compositions, and stereoisomeric forms, pharmaceutical salts or pro-drugs thereof wherein, in a compound of formula 1, A is equal to CR 9  (formula 1b):                           
     [5] More preferred compounds of the invention include those compounds of formula 1 wherein X is equal to oxygen. 
     [6] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl or pyridyl and each Ar is optionally substituted with 1 to 3 R 4  substituents. 
     [7] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R 2  is: 
     —C 1 -C 10 †alkyl, C 2 -C 10 †alkenyl, C 2 -C 10 †alkynyl, C 3 -C 8 †cycloalkyl, C 5 -C 8  cycloalkenyl, C 4 -C 12 †cycloalkylalkyl or C 6 -C 10  cycloalkenylalkyl, each optionally substituted with 1 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, cyano, OR 15 , SH, S(O) n R 13 , COR 15 , CO 2 R 15 , OC(O)R 13 , NR 8 COR 15 , N(COR 15 ) 2 , NR 8 CONR 16 R 15 , NR 8 CO 2 R 13 , NR 16 R 15 , CONR 16 R 15 , aryl, heteroaryl and heterocyclyl. 
     [8] More preferred compounds also include those compounds of formula 1 wherein R 1 , R 2  and R 3  are independently selected at each position from zC 1-6  alkyl. 
     [9] The present invention comprises a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer&#39;s disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of Formula (1) with the variables as recited above. 
     The present invention also provides pharmaceutical compositions comprising compounds of Formula (1) with the variables as recited above and a pharmaceutically acceptable carrier. 
     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 “alkyl” includes both branched and straight-chain alkyl having the specified number of carbon atoms. Commonly used abbreviations have the following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. The prefix “n” means a straight chain alkyl. The prefix “c” means a cycloalkyl. The prefix “(S)” means the S enantiomer and the prefix “(R)” means the R enantiomer. Alkenyl” 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, such as ethenyl, propenyl, and the like. “Alkynyl” 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, such as ethynyl, propynyl and the like. “Haloalkyl” is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; “cycloalkyl” is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. “Halo” or “halogen” includes fluoro, chloro, bromo, and iodo. 
     The term “substituted”, 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 substitent 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 “stable compound” or “stable structure” 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 “appropriate amino acid protecting group” means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, “Protective Groups in Organic Synthesis” John Wiley &amp; Sons, New York (1991) and “The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl. 
     The term “pharmaceutically acceptable salts” includes acid or base salts of the compounds of Formulae (1) and (2). 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. 
     “Prodrugs” are considered to be any covalently bonded carriers which release the active parent drug of formula (I) or (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) 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 formulas (I) and (II); and the like. 
     The term “therapeutically effective amount” 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. 
     Syntheses 
     Some compounds of Formula (1) where X=O and A=N, may be prepared from intermediate compounds of Formula (3) using the procedures outlined in Scheme 1. Compounds of Formula (3) may be treated with a halogenating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −80 C. to 250° C. to give products of Formula (4) (where X is halogen). Halogenating agents include, but are not limited to, Br 2 , Cl 2 , I 2 , N-bromosuccinimide, N-iodosuccinimide or N-chlorosuccinimide. Bases may include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from −20° C. to 150° C. The resulting intermediates (4) may then be reacted with alcohols R 2 OH, where R 2  is defined above, in the presence of phosphines R a   3 P (where R a  is lower alkyl, phenyl or substituted phenyl or furyl) and an azodicarboxylate ester R b O 2 CN═NCO 2 R b  (where R b  is lower alkyl) in an inert solvent at temperatures ranging from −80° C. to 150° C. Inert solvents may include, but are not limited to, polyethers (preferably 1,2-dimethoxyethane), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) or aromatic hydrocarbons (preferably benzene or toluene). The choices of phosphine, solvent or azodicarboxylate ester are known to those skilled in the art as described by 0. Mitsunobu (Synthesis, 1 [1981]). Intermediates (5) are treated with a base or an alkali metal in an inert solvent and then reacted with formylating agents YCHO. Y is a halogen, alkoxy, dialkylamino, alkylthio, alkanoyloxy, alkanesulfonyloxy or cyano group. Bases may include, but are not limited to, alkyl lithiums, alkali metal hydrides (preferably sodium hydride), alkaline earth metal halides (e.g. methylmagnesium bromide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) and alkali metal bis(trialkylsilyl)-amides (preferably sodium bis(trimethylsilyl)amide). Inert solvents include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from −80° C. to 100° C.                           
     The resulting aldehydes (6) may be converted to acetals (7) by treatment with an acetal-forming reagent in the presence or absence of an acid in an inert solvent. The dotted line between the R groups means that they may or may not be connected. Acetal-forming reagents may be alcohols ROH, where R is lower alkyl, diols HOR———ROH where R———R is lower alkylene, or orthoesters HC(OR) 3  where R is lower alkyl. Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Preferred temperatures range from ambient temperature to 150° C. 
     Acetals (7) may then be reacted with a base in an inert solvent, followed by treatment with a compound ArCOY (where Y is a halogen, alkoxy, dialkylamino, alkylthio, alkanoyloxy, alkanesulfonyloxy or cyano group) to afford intermediates (8). Bases may include, but are not limited to, alkyl lithiums, alkali metal dialkylamides (preferably lithium di-isopropylamide) or alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide. Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane or aromatic hydrocarbons (preferably benzene or toluene). Intermediates (8) may then be converted to compounds of Formula (9) by treatment with an acetal-cleaving reagent in an inert solvent. Acetal-cleaving reagents may include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, alkanoic acids, alkylsulfonic acids, substituted phenylsulfonic acids, camphorsulfonic acid or haloalkylsulfonic acids. Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). 
     The keto-aldehydes (9) may be converted to esters (10) by treatment with an oxidizing agent in an inert solvent to give a carboxylic acid, followed by treatment with an ester-forming reagent. Oxidizing agents include transition metal oxides, such as CrO 3  or KMnO 4  (with or without a buffering agent such as NaH 2 PO 4 ), pyridinium dichromate or pyridine-SO 3  complex. Inert solvents include water, alkanones (e.g. acetone), aqueous solutions of HCl or H 2 SO 4 , or N,N-dialkylformamides. Ester-forming reagents include but are not limited to alcohols R C OH, where R c  is lower alkyl, or orthoesters HC(OR c ) 3  or combinations of a halogenating reagent and an alcohol R C OH used sequentially or in the same reaction. Halogenating agents include, but are not limited to, POCl 3 , (COCl) 2 , SOCl 2 , N-halosuccinimides, PCl 3 , PCl 5  or PBr3. Inert solvents for the halogenation include, but are not limited to, aromatic hydrocarbons (preferably benzene or toluene), aromatic amines (e.g. pyridine) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0° C. to 150° C. 
     Alternatively, aldehydes (9) may be reacted with a compound MCN, where M is H, alkali metal or tetraalkylammonium moiety, in an inert solvent, treated with an oxidizing agent and reacted with alcohols R c OH where R c  is lower alkyl. Oxidizing include, but are not limited to, transition metal oxides, such as CrO 3  or MnO 2 , pyridine-chromium complexes, such as CrO 3 .C 5 H 5 N, pyridinium dichromate or pyridinium chlorochromate or an oxalylchloride-dimethylsulfoxide-triethylamine reagent system, commonly called the Swern oxidation system (D. Swern et al., J. Organic. Chem., 43, 2480-2482 (1978)). Inert solvents of the oxidation include, but are not limited to, halocarbons of 1 to 6 carbons, preferably dichloromethane or 1,2-dichloroethane, lower alkyl alcohols, preferably ethanol or methanol, or lower alkanoic acids, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or combinations thereof. 
     Esters (10) may then be converted to compounds of Formula (1) where X=O and A=N by one of two methods. Esters (10) may be reacted with hydrazine or its hydrate in an inert solvent, then treated with an alkylating agent in the presence or absence of a base in an inert solvent to provide compounds of Formula (1) where X is O and A=N. Phase transfer catalysts (e.g. tetra-alkylammonium halides or hydroxides) may be optionally employed for the alkylations. Alternatively, esters (10) may be reacted with compounds of Formula R 3 NHNH 2  (where R 3  is defined above) in the presence or absence of a base in an inert solvent. Alkylating agents are compounds of the formula R 3 Z, where Z is halogen, alkanesulfonyloxy (e.g. mesylate), substituted phenylsulfonyloxy (e.g. tosylate) or haloalkanesulfonyloxy (e.g. triflate) groups. Bases may include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, alkyl lithiums, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, water, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) or combinations thereof. Preferred reaction temperatures range from −80° C. to 100° C. 
     Compounds of Formula (1) where A=N and X=O may be converted to compounds of Formula (1) where A=N and X=S according to the procedures outlined in Scheme 2. Compounds of Formula (1) where A=N, X=O and R 3 =H may be converted to compounds of Formula (1) where A=N, X=S and R 3 =H by treatment with a thiocarbonyl-forming reagent in an inert solvent. Thiocarbonyl-forming reagents include but are not limited to, P 2 S 5  or Lawessonis reagent. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0° C. to 160° C. These intermediates may then be converted to compounds of Formula (1) where A=N, X=S and R 3  is not equal to H by treatment with an alkylating agent in the presence or absence of a base in an inert solvent. Alkylating agents are compounds of the formula R 3 Z, where Z is halogen, alkanesulfonyloxy (e.g. mesylate), substituted phenylsulfonyloxy (e.g. tosylate) or haloalkanesulfonyloxy (e.g. triflate) groups. Bases may include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, alkyl lithiums, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from −80° C. to 150° C. Alternatively, Compounds of Formula (1) where A=N, X=O and R 3  is not equal to H may be converted to compounds of Formula (1) where A=N, X=S and R 3  is not equal to H by treatment with a thiocarbonyl-forming reagent in an inert solvent. The reagent and inert solvent are defined above.                           
     Compounds of Formula (1) where A=CR 9  may be prepared from esters (10) by the methods,outlined in Scheme 3. Esters (10) may be treated with phosphonium salts of the formula R d   3 PCH R 9 OR f+  X −  where R d  is phenyl or substituted phenyl or phosphonates (R e O) 2 P(O)CHR 9 OR f  in the presence of a base in an inert solvent to give enol ethers (12). Bases may include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, alkyl lithiums, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide). Inert solvents include, but are not limited to, dialkyl ethers (preferably diethyl ether) or cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane). Intermediates (12) may be hydrolyzed to give intermediates (13) in the presence of an acid in an inert solvent. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Preferred temperatures range from ambient temperature to 150° C. Aldehydes (13) may be treated with amines R 3 NH 2  to generate compounds of Formula (1) where A=CR 8  in the presence or absence of an acid or base in an inert solvent. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Bases may include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, alkyl lithiums, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide). Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred temperatures range from ambient temperature to 150° C.                                                     
     Alternatively, imidazo[4,5-d]pyridazin-7-ones may be obtained from intermediate (4) as shown in Scheme 4. The intermediate (4) may converted to compound of formula (14) using protecting groups but not limited to benzyl, p-MeO-benzyl or benzyloxymethyl groups. Compound 14 may be converted to compound 20 using the conditions previously described for Scheme 1. Compound 10 may then be deprotected to its NH derivative (21) by standard conditions known in literature. Compound 21 may alkylated under mitsunobu conditions described in Scheme 1 or by alkylation using a base and alkyl halides in the presence of a solvent. 
    
    
     EXAMPLES 
     Analytical data were recorded for the compounds described below using the following general procedures. Proton NMR spectra were recorded on an Varian FT-NMR (300 MHz); chemical shifts were recorded in ppm (δ) from an internal tetramethysilane standard in deuterochloroform or deuterodimethylsulfoxide as specified below. Mass spectra (MS) or high resolution mass spectra (HRMS) were recorded on a Finnegan MAT 8230 spectrometer (using chemi-ionization (CI) with NH 3  as the carrier gas or gas chromatography (GC) as specified below) or a Hewlett Packard 5988A model spectrometer. Melting points were recorded on a Buchi Model 510 melting point apparatus and are uncorrected. Boiling points are uncorrected. All pH determinations during workup were made with indicator paper. 
     Reagents were purchased from commercial sources and, where necessary, purified prior to use according to the general procedures outlined by D. Perrin and W. L. F. Armarego,  Purification of Laboratory Chemicals,  3rd ed., (New York: Pergamon Press, 1988). Chromatography (thin layer (TLC) or preparative) was performed on silica gel using the solvent systems indicated below. For mixed solvent systems, the volume ratios are given. Otherwise, parts and percentages are by weight. 
     The following examples are provided to describe the invention in further detail. These examples, which set forth the best mode presently contemplated for carrying out the invention, are intended to illustrate and not to limit the invention. 
     Example 1 
     4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazin-7-one 
     Part A 
     4,5-dibromo-2-ethyl-1H-imidazole 
     Method A 
     A solution of 2-ethylimidazole (57.6 g, 0.6 moles) in CHCl 3  (700 mL) was cooled to 0-5° C. and then bromine was added (76.8 mL, 1.5 moles) dropwise over 60 min under nitrogen atmosphere. The mixture was stirred at 5° C. for 60 mins and then at room temperature for 2 days. TLC (1:10 MeOH/CH 2 Cl 2 ) revealed disappearence of starting material (Rf=0.25) and showed a new spot (Rf=0.45). The mixture was cooled back to 0° C. and a 2N aq. NaOH solution (750 mL) added dropwise to dissolve the yellow solid separated from the mixture. The aqueous layer was separated and extracted the organic layer with 250 mL of 2N NaOH. The combined aqueous extracts was acidified to pH 8.0 using a concentrated HCl solution. The cream-colored solid separated and it was filtered, washed with water and dried in vacuo at 50° C. to afford 55.0 g of desired product (mp 149-150° C., 36% yield):  1 H NMR (CDCl 3 ): δ1.27-1.3 (t, 3H, CH 3 ), 2.7-2.8 (q, 2H, CH 2 ). Mass spectrum (CI—NH 3 ) m/z: 255.0 (M+H). 
     Method B 
     To a solution of imidazole (2.32 g, 0.0242 moles) in DMF (30.0 mL) was added KHCO 3  (6.1 g, 0.061 moles) and then added bromine (3.12 mL, 0.061 moles) dropwise over 30 mins. at room temp. The mixture was then stirred at 70° C. for 4 hours and then cooled to room temp. TLC (1:10 MeOH/CH 2 Cl 2 ) revealed a new spot (Rf=0.45) along with disappearence of starting material (Rf=0.25). The inorganic materials were filtered, washed the inorganic solids with ethyl acetate and concentrated the filtrate in vacuo to an oil. The oil was treated with water (50.0 mL) and the resulting solid was filtered and dried to afford 4.59 g of a solid ((mp, 149-150° C., 75% yield). 
     Part B 
     4,5-dibromo-2-ethyl-1-(1-ethyl)propyl-1H-imidazole 
     A mixture of part A material (8.3 g, 0.033 moles), triphenylphosphine (9.4 g, 0.036 moles) and molecular sieves (10 g) in THF (100 mL) was cooled to 0 to −5° C. and then 3-pentanol (3.4 g, 0.039 moles) was added under nitrogen atmosphere. The mixture was stirred at 0° C. for 30 mins and then diisopropylazodicarboxylate (7.2 g, 0.033 moles) was added dropwise over 20 min. The mixture was stirred at 0° C. for 2 hours followed by room temperature for 2 days and TLC (1:50 MeOH/CH 2 Cl 2 ) revealed a new spot at Rf=0.5. The reaction mixture was filtered, the collected solid was washed with dichloromethane and the solvent was removed in vacuo to afford yellow liquid. The crude was purified by flash column chromatography using chloroform as eluent to afford 4.9 g (46.5%) of colorless oil.  1 H NMR (CDCl 3 ): δ0.79-0.84 (t, 6H, 2*CH 3 ), 1.3-1.35 (t, 3H, CH 3 ), 1.82-2.18 (m, 4H, 2*CH 2 ), 2.65-2.72 (q, 2H, CH 2 ), 3.95 (m, 1H, CH). Mass spectrum (CI—NH 3 ): m/z 325.0 (M+H). 
     Part C 
     4-bromo-2-ethyl-1-(1-ethyl)propyl-1H-imidazole-5-carboxaldehyde 
     A solution of Part B material (3.7 g, 0.0114 moles) in THF (40.0 mL) was cooled to −78° C. under nitrogen atmosphere and then a 1.6 M n-BuLi solution in hexane (7.4 mL, 0.0119 moles) added dropwise over 30 mins. The mixture was stirred at −78° C. for 1 h and then DMF (2.7 mL, 0.0342 moles) was added dropwise over 15 min. The mixture was stirred at −78° C. for 60 min and quenched with saturated NH 4 Cl (10 mL) at −78° C. TLC (1:50 MeOH/CH 2 Cl 2 ) revealed a new spot at Rf=0.55 along with disappearence of starting material spot at Rf=0.5. The reaction mixture was extracted with diethyl ether (3*25 mL), washed with brine and dried (MgSO 4 ). The solvent was removed in vacuo to afford a yellow oil which was purified by flash column chromatography on silica gel using chloroform as eluent to afford 1.97 g (64% yield) of colorless oil.  1 H NMR (CDCl 3 ): δ0.73-0.83 (t, 6H, 2*CH 3 ), 1.35-1.40 (t, 3H, CH 3 ), 1.59-2.17 (m, 4H, 2*CH 2 ), 2.72-2.80 (q, 2H, CH 2 ), 3.95 (m, 1H, CH), 9.67 (s, 1H, CHO). Mass spectrum (CI—NH 3 ): m/z 275.1 (M+2H). 
     Part D 
     4-bromo-2-ethyl-1-(1-ethyl)propyl-1H-imidazole-5-carboxaldehyde ethylene glycol acetal 
     A mixture of part C material (1.75 g, 0.0064 moles) in benzene (150 mL) was treated with ethylene glycol (1.2 mL, 0.025 moles), pyridine (0.0035 moles) and p-toluenesulfonic acid mono hydrate (0.0035 moles). The reaction mixture was heated at reflux in a 20 mL capacity Dean-Stark trap equipped apparatus for 24 hours and TLC (1:50 MeOH/CH 2 Cl 2 ) revealed a new spot at Rf=0.35 (visible under iodine). The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with 10% sodium bicarbonate, brine and dried (MgSO 4 ). The solvent was evaporated under reduced pressure to furnish yellow oil. The crude was purified by flash column chromatography on silica gel using 25% ethyl acetate/chloroform mixture to afford 1.96 g (97%) white solid (mp 70-71° C.).  1 H NMR (CDCl 3 ): δ0.78-0.89 (t, 6H, 2*CH 3 ), 1.29-1.36 (t, 3H, CH 3 ), 1.77-1.90 (m, 4H, 2*CH 2 ), 2.70-2.73 (q, 2H, CH 2 ), 3.98-4.3 (m, 5H, CH and 2*CH 2 ), 5.86 (s, 1H, CH). Mass spectrum (CI—NH 3 ): 317.1 (M + ). Anal. calcd. for C 13 H 22 Br 1 N 2 O 2 : C, 49.22; H, 6.67; N, 8.83. Found: C, 49.43; H, 6.61; N, 8.78. 
     Part E 
     4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-ethyl)propyl-1H-imidazole-5-carboxaldehyde 
     A solution of part D material (1.08 g, 0.0034 moles) in THF (20.0 mL) was cooled to −78° C. and then a 1.6 M n-BuLi in hexane (2.4 mL, 0.004 moles) was added dropwise over 15 min under nitrogen atmosphere. The mixture was stirred at −78° C. for 2.5 h and then a solution of 2,4-dichlorobenzoyl chloride (0.84 g, 0.004 moles) in THF (5.0 mL) was added over 15 mins. The mixture was stirred at −78° C. for 6 h followed by room temperature overnight and TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.43. The mixture was quenched with saturated NH 4 Cl (10.0 ml ), extracted with ethyl acetate (3*30 mL), washed with brine and dried (MgSO 4 ). The solvent was stripped off in vacuo to afford crude product which was purified by flash column chromatography on a silica gel using 15% EtOAC/hexane to afford 0.61 g (44% yield) of desired product as yellow oil. Mass spectrum (CI—NH 3 ): 411.2 (M + ). The acetal was dissolved in acetone (15.0 mL) and treated with a 3.0 M aqueous HCl solution (30.0 mL) at room temperature. The reaction mixture was stirred for 24 h at this temperature and TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.55. It was then quenched with saturated NaCl (50.0 ml), extracted with ethyl acetate (3*50 mL), washed with brine and dried (MgSO 4 ). The solvent was removed in vacuum to afford yellow liquid and purified the crude by flash column chromatography on a silica gel using 15% EtOAC/hexane to afford 0.28 g (51% yield) of desired product as yellow solid (mp 85-86° C.).  1 H NMR (CDCl 3 ): δ0.785 (m, 6H, 2*CH 3 ), 1.28-1.33 (t, 3H, CH 3 ), 1.90-2.23 (m, 4H, 2*CH 2 ), 2.74-2.82 (q, 2H, CH 2 ), 3.98-4.05 (m, 1H, CH), 7.34-7.37 (d, 1H, aromatic), 7.45-7.46 (d, 1H, aromatic), 7.55-7.58 (d, 1H, aromatic). Mass spectrum (CI—NH 3 ): 367 (M + ). Anal. calcd. for C 18 H 20 Cl 2 N 2 O 2 : C, 58.87; H, 5.50; N, 7.64. Found: C, 58.91; H, 5.60; N, 7.44. 
     Part F 
     Methyl 4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-ethyl) propyl -imidazo-5-carboxylate 
     A mixture of Part E material (0.367 g, 0.001 moles) in methanol (60 mL) was reacted with NaCN (Aldrich, 0.245 g, 0.005 moles, 5 equiv.), AcOH (Baker, 96 mg; 0.0016 moles, 1.6 equiv.) and MnO 2 , activated (Aldrich, 1.24 g, 0.021 moles, 21 equiv.). The resulting mixture was stirred at room temp under nitrogen for 18 h. TLC (1:50 MeOH/CH 2 Cl 2 ) revealed absence of starting material spot at Rf=0.8 and showed a new spot at Rf=0.44. The reaction mixture was filtered through celite, washed with methanol, concentrated in vacuo and the crude was purified by flash column chromatography on a silica gel using 1:100 MeOH/CH 2 Cl 2 as eluent to afford 320 mg (mp 73-74° C., 81%) of white solid after crystallization from hexane. Anal. calcd. for C 19 H 22 Cl 2 N 2 O 3 : C,57.44; H,5.58; N,7.05. Found: C,57.31; H,5.45; N,6.85. 
     Part G 
     Title Compound 
     A mixture of Part F material (0.100 g, 0.00025 moles) in ethanol (10 mL) was treated with anhydrous hydrazine (0.105 g, 0.0033 moles) and refluxed under nitrogen for 48 h. TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.35. The solvent was removed under vacuum and purified the crude by flash column chromatography on a silica gel using 15:85 EtOAc/hexane intially and then methanol to afford 70 mg (74% yield) of the product as white solid after tituration of the oil with diethyl ether (mp 246-247° C.). HRMS calcd. for C 18 H 21 Cl 2 N 4 O 1 : 379.1092. Found: 379.1070 (M+H). 
     Example 2 
     4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-6-(N-methyl)imidazo[4,5-d]pyridazin-7-one 
     A mixture of Part F material of example 1 (0.100 g, 0.00025 moles) in ethanol (10 mL) was treated with anhydrous methylhydrazine (0.150 g, 0.0033 moles) and refluxed under nitrogen for 8 days. TLC (1:50 MeOH/CH 2 Cl 2 ) showed a new spot at Rf=0.55. The solvent was removed under vacuum and purified the crude by flash column chromatography on a silica gel 1:50 MeOH/CH 2 Cl 2  to afford 30 mg (31% yield) of the product as white solid (mp 94-95° C.). HRMS calcd. for C 19 H 23 Cl 2 N 4 O 1 : 393.1249. Found: 393.1250 (M+H). 
     Example 3 
     4-(2,4-dichlorophnyl)-2-ethyl-6-(N-ethyl)-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazin-7-one 
     To a solution of Part G of example 1 (0.1 g, 0.264 mmoles) in benzene (5.0 mL) was added n-tetrabutylammonium bromide (8.5 mg, 0.0264 mmoles), powdered KOH (15.0 mg, 0.264 mmoles) and iodoethane (0.124 g, 0.79 mmoles). The resultant mixture was stirred at room temperature under nitrogen for 20 h. TLC (1:50 MeOH/CH 2 Cl 2 ) showed a new spot at Rf=0.73 along with disappearence of starting material (Rf=0.33). The reaction mixture was diluted with EtOAc (10 mL), washed with brine (10 mL), dried with MgSO 4  and concentrated to a residue. The crude was purified by flash column chromatography on a silica gel using dichloromethane as eluent to afford 58 mg (54% yield) of the product as colorless oil. HRMS calcd. for C 20 H 25 N 4 Cl 2 O 1 :407.1405. Found: 407.1404 (M+H). 
     Example 4 
     4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-6-(N-propyl)-imidazo[4,5-d]pyridazin-7-one 
     The title compound was prepared using Part G of example 1 material and 1-iodopropane and following the conditions outlined in example 3 to afford desired product as colorless oil (56 mg, 51% yield). Anal. calcd. for C 21 H 26 N 4 Cl 2 O 1 : C, 59.86; H, 6.23; N, 13.30. Found: C,59.86; H,6.12; N, 13.13. 
     Example 5 
     6-(N-cyclopropylmethyl)-4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazin-7-one 
     The title compound was prepared using Part G of example 1 material and bromomethylcyclopropane and following the conditions outlined in example 3 to afford desired product as colorless oil (68 mg, 59% yield). HRMS calcd. for C 22 H 27 N 4 Cl 2 O 1 : 433.1562. Found: 433.1563 (M+H). 
     Example 6 
     4-Bis(2,4-trifluoromethylphenyl)-2-ethyl-1-(1-ethyl)propyl-6-(N-methyl)-imidazo[4,5-d]pyridazin-7-one 
     Part A 
     A solution of Part D material of example 1 in THF (30.0 mL) was cooled to −78 C. and then added dropwise 1.6 M n-BuLi in hexane over 15 mins. The mixture was stirred at −78 C. for 2½ h and then added a solution of 2,4-(CF 3 ) 2 —Ph—COCl in 5.0 mL of THF over 15 mins. The mixture was stirred at −78° C. for 6 h and then warm to room temp and stirred overnight. The reaction mixture was quenched with a saturated NH 4 Cl solution (50.0 ml), extracted with ethyl acetate (3*30 mL), the combined organic extracts were washed with brine and the solvent was removed under vacuum to afford an orange yellow liquid (4.3 g). TLC (30:70 EtOAc/hexane) of the crude showed absence of starting material spot (Rf=0.4) along with a new spot at Rf=0.47. The crude was purified by flash column chromatography on a silica gel using 30% EtOAC/hexane to afford 1.53 g (mp 105-106° C., 64% yield) of desired benzoyl derivative as white solid. Mass spec. (CI—NH 3 ): 479.2 (M+H). Anal. calcd. for C 22 H 24 N 2 O 3 F 6 : C, 55.23; H, 5.07; N, 5.87. Found; C, 54.96; H, 5.09; N, 5.72. 
     Part B 
     A solution of Part A material of example 6 (1.43 g, 2.9 mmoles) in acetone (30.0 mL) was cooled to 15° C. and then added 3M aq. HCl (60.0 mL) over 15 mins. The mixture was stirred below 30° C. for 24 h. TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.63 along with disappearence of starting material (Rf=0.43). The solvent was removed under vacuum, extracted with ethyl acetate (3*50 mL), washed with brine and stripped off the solvent in vacuum to afford yellow liquid. The crude was purified by flash column chromatography on a silica gel using dichloromethane as eluent to afford 1.03 g (82% yield) of desired aldehyde as yellow liquid. Mass spec. (NH 3 —CI): 435 (M+H). Anal. calcd. for C 20 H 20 N 2 O 2 F 6 : C, 55.30; H, 4.64; N, 6.46. Found; C, 55.03; H, 4.45; N, 6.27. 
     Part C 
     A mixture of Part B material of example 6 (0.434 g, 1.0 mmole) in methanol (30 mL) was treated with NaCN (Aldrich, 0.245 g, 5.0 mmoles, 5 equiv.), AcOH (Baker, 96 mg; 1.6 mmoles, 1.6 equiv.) and MnO 2 , activated (Aldrich, 1.24 g, 21.0 mmoles, 21 equiv.). The resulting mixture was stirred at room temp under nitrogen for 24 h. TLC (30:70 EtOAc/hexane) revealed absence of starting material at Rf=0.63 and showed a new spot at Rf=0.55. The reaction mixture was filtered through celite, washed with methanol, concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried and concentrated in vacuo to afford yellow oil. The crude was purified by flash column chromatography on a silica gel using 30:70 EtOAc/hexane as eluent to afford 350 mg (mp 57-58° C., 75%) of pale yellow solid. Mass spec. (NH 3 —CI): 465.3 (M+H). Anal. calcd. for C 21 H 22 N 2 O 3 F 6 : C, 54.31; H, 4.79; N, 6.03. Found: C, 53.92; H, 4.68; N, 5.80. 
     Part D 
     Title Compound 
     A mixture of Part C material of example 6 (0.116 g, 0.250 mmoles) in ethylene glycol (3.0 mL) was treated with anhydrous methylhydrazine (0.15 g, Aldrich, 3.3 mmoles, 13 equiv.) and refluxed under nitrogen for 20 h. TLC (30:70 EtOAc/hexane) revealed both starting material and product had identical Rf values (0.55). The reaction mixture was cooled to room temperature and poured over 25 mL of water, extracted with EtOAc (3*15 mL), washed with brine and dried. The solvent was removed under vacuo and purified the crude by flash column chromatography on a silica gel using 30% EtOAc/hexane to afford an oil which was crystallized from hexane to afford 16 mg (14% yield; mp 139-140° C.) of white solid as desired product. HRMS calcd. for C 21 H 23 N 4 O 1 F 6 : 461.1776. Found: 461.1763 (M+H). 
     Example 7 
     (±)-4-(2,4-dichlorophenyl)-2-ethyl-6-(N-methyl)-1-(1-methyl)butyl-imidazo[4,5-d]pyridazin-7-one 
     Part A 
     To a solution of 4,5-dibromo-2-ethyl-1-(2-pentyl)-1H-imidazole (37.5 g, 0.116 moles, prepared according to the method described in Part B of example 1) in THF (250 mL) was cooled to −78 C. and then a 1.6 M n-BuLi in hexane added dropwise (76.0 mL, 0.122 moles) over 45 mins. The mixture was stirred at −78 C. for 1 h (brown solution) and then added DMF (27.0 g, 0.348 moles) dropwise over 30 mins. The mixture was stirred at −78 C. for 60 mins. The reaction mixture was quenched with saturated ammonium chloride (100 mL) at −78° C. and brought to room temperature. The reaction mixture was extracted with ethyl ether (3*100 mL), washed with brine and dried with anhydrous MgSO 4 . The solvent was evaporated under reduced pressure to afford 31.6 g of crude yellow oil. The crude was purified by flash column chromatography on a silica gel using chloroform as eluent to afford 18.5 g (59% yield) of desired aldehyde as colorless oil. Anal. calcd. for C 11 H 17 N 2 OBr; C, 48.36; H, 6.27; N, 10.25. Found: C, 48.64; H, 6.01; N, 10.00. 
     Part B 
     A mixture of Part A material of example 7 (18.5 g, 0.068 moles) in benzene (250 mL) was treated with ethylene glycol (16.4 g, 0.264 moles), pyridine (2.7 g, 0.034 moles) and p-toluenesulfonic acid monohydrate (6.5 g, 0.034 moles). The reaction mixture was heated at reflux in a 20 mL capacity Dean-Stark trap equipped apparatus for 36 h. TLC (30:70 EtOAc/hexane) revealed a new spot at Rf=0.42 (visible under iodine) along with disappearence of starting material (Rf=0.54). The reaction mixture was cooled to room temperature, diluted with EtOAc (250 mL), washed with 10% sodium bicarbonate (2*250 mL), brine and dried (MgSO 4 ). The solvent was evaporated under reduced pressure to furnish acetal as white solid (20.7 g, mp 69-70° C., 96%). Mass spectrum (CI—NH 3 ): 317.1 (M + ). Anal. calcd. for C 13 H 22 N 2 O 2 Br 1 ; C, 49.22; H, 6.67; N, 8.83. Found: C, 49.38; H, 6.62; N, 8.68. 
     Part C 
     A solution of Part B material of example 7 (2.73 g, 0.01 moles) in THF (30 mL) was cooled to −78° C. and then added dropwise 1.6 M n-BuLi in hexane (7.4 mL) over 15 mins. The mixture was stirred at −78° C. for 2½ h and then added a solution of 2,4-dichlorobenzoyl chloride in 5.0 mL of THF over 15 mins. The mixture was stirred at −78° C. for 6 h and then warm to room temp and stirred overnight. The reaction mixture was quenched with satd. NH 4 Cl (50.0 ml), extracted with ethyl acetate (3*30 mL), washed with brine and stripped off the solvent in vacuum to afford orange yellow liquid (4.3 g). TLC (30:70 EtOAc/hexane) of the crude showed absence of starting material spot (Rf=0.4) and a new spot at Rf=0.47. The crude was purified by flash column chromatography on a silica gel using 30% EtOAC/hexane to afford 2.4 g (mp 129-130° C., 59% yield) of benzoyl derivative as white solid. Mass spec. (CI—NH3): 411 (M + ). Anal. calcd. for C 20 H 24 N 2 O 3 Cl 2 : C, 58.40; H, 5.88; N, 6.81. Found: C, 58.45; H, 5.95; N, 6.68. 
     Part D 
     A solution of Part C material of example 7 (2.3 g, 0.056 moles) in acetone (60 mL) was cooled to 15° C. and then added 3M aq. HCl (120 mL) over 15 mins. The mixture was stirred below 30° C. for 24 h. TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.58 along with disappearence of starting material (Rf=0.43). The solvent was removed under vacuum, extracted with ethyl acetate (3*50 mL), washed with brine and stripped off the solvent in vacuum to afford yellow liquid (2.4 g). The crude was purified by flash column chromatography on a silica gel using dichloromethane as eluent to afford 1.46 g (71% yield) of keto aldehyde derivative as yellow solid (mp 43-44° C.). Mass spec. (NH 3 —CI): 367 (M + ). Anal. calcd. for C 18 H 20 N 2 O 2 Cl 2 : C, 58.87; H, 5.50; N, 7.64. Found: C, 58.96; H, 5.34; N, 7.46. 
     Part E 
     A mixture of Part D material of example 7(1.0 g, 0.0027 moles) in methanol (50 mL) was treated with NaCN (Aldrich, 0.67 g, 0.0136 moles, 5 equiv.), AcOH (Baker, 260 mg; 0.00432 moles, 1.6 equiv.) and MnO 2 , activated (Aldrich, 3.34 g, 0.057 moles, 21 equiv.). The resulting mixture was stirred at room temp under nitrogen for 20 h. TLC (30:70 EtOAc/hexane) revealed absence of starting material at Rf=0.58 and showed a new spot at Rf=0.4. The reaction mixture was filtered through celite, washed with methanol, concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried and concentrated in vacuo to afford 0.98 g of yellow oil. The crude was purified by flash column chromatography on a silica gel using 30:70 EtOAc/hexane as eluent to afford 910 mg (85%) of keto ester derivative as yellow oil. Mass spec.: 397.2 (M + ). Anal. calcd. for C 19 H 22 N 2 O 3 Cl 2 : C, 57.44; H, 5.58; N, 7.05. Found: C, 57.25; H, 5.70; N, 6.80. 
     Part F 
     Title Compound 
     A mixture of Part E material of example 7 (0.100 g, 0.00025 moles) in ethylene glycol (2 mL) was treated with anhydrous methylhydrazine (0.105 g, 0.0033 moles) and refluxed under nitrogen for 4 h. TLC (30:70 EtOAc/hexane) revealed a new spot (Rf=0.44) along with disappearence of starting material (Rf=0.4. The reaction mixture was cooled to room temp and poured over 25 mL of water, extracted with EtOAc (3*15 mL), washed with brine and dried. The solvent was removed under vacuo and purified the crude by flash column chromatography on a silica gel using 15% EtOAc/hexane to afford colorless oil which was crystallized from hexane to afford 42 mg of white solid (43%, mp 89-90° C.). Mass spec. (CI—NH 3 ): 393.2 (M + ). Anal. calcd. for C 19 H 22 N 4 Cl 2 O: C, 58.02; H, 5.65; N, 14.24. Found: C,58.32; H, 5.59; N, 14.14. 
     Example 8 
     (±)-4-(2,4-dichlorophenyl)-2-ethyl-1-(1-methyl)butyl-imidazo[4,5-d]pyridazin-7-one 
     A mixture of Part E material of example 7 (0.460 g, 0.00115 moles) in ethylene glycol (5 mL) was treated with anhydrous hydrazine (0.48 g, 0.0151 moles) and refluxed under nitrogen for 4 h. TLC (30:70 EtOAc/hexane) revealed a new spot (Rf=0.44) along with disappearence of starting material (Rf=0.4). The reaction mixture was cooled to room temp and poured over 25 mL of water, extracted with EtOAc (3*15 mL), washed with brine and dried. The solvent was removed under vacuo and purified the crude by flash column chromatography on a silica gel using 15% EtOAc/hexane to afford colorless oil which was crystallized from hexane to afford 310 mg of white solid (71%, mp 217-18° C.). Mass spec. (CI—NH 3 ):379.2 (M + ). Anal. calcd. for C 18 H 20 N 4 Cl 2 O: C, 57.00; H, 5.33; N, 14.77. Found: C, 57.02; H, 5.35; N, 14.59. 
     Example 9 
     (±)-4-(2,5-dimethyl-4-methoxyphenyl)-2-ethyl-6-(N-methyl)-1-(1-methyl)butyl-imidazo[4,5-d]pyridazin-7-one 
     Part A 
     Synthesis of 2,5-dimethyl-4-methoxybenzoyl chloride 
     To a stirred mixture of 2,5-dimethyl-4-methoxybenzaldehyde (6.7 g, 0.004 moles) in acetone (140 mL) at 60° C. was added KMnO 4  (8.46 g, 0.0054 moles) dissolved in water (250 mL) dropwise over 30 mins. The reaction mixture quickly turned into brown suspended solution. The reaction mixture was further continued for 1 h. The reaction mixture was cooled to room temp., filtered through celite and extracted with diethyl ether. The aq. layer was acidified with con. HCl, filtered the white solid separated, washed with water and dried at 50° C. for 30 mins under vacuum to afford 3.46 g of carboxylic acid as white solid (mp 161-162° C., 48% yield). The carboxylic acid (3.4 g, 0.0189 moles) was dissolved in 75 mL of anhydrous benzene and added few drops of pyridine followed by addition of thionyl chloride (5.0 mL, 0.0689, 3.65 equiv., fw 118.97, d 1.631). The resultant mixture was refluxed at reflux for 20 h. The solvent was removed under vacuum, the solid thus resulted was treated with 5.0 mL of hexane and filtered the undissolved white solid (3.7 9, mp 84-85° C., 98.7%). 
     Part B 
     A solution of Part B material of example 7 (2.73 g, 0.01 moles) in THF was cooled to −78° C. and then added dropwise 1.6 M n-BuLi in hexane (7.4 mL, 0.0115 moles) over 15 mins. The mixture was stirred at −78° C. for 2½ h and then added a solution of 2,5-(Me) 2 -4-OMe—Ph—COCl (2.2 g, 0.012 moles) in 10.0 mL of THF over 15 mins. The mixture was stirred at −78° C. for 6 h and then warm to room temp and stirred overnight. The reaction mixture was quenched with satd. NH 4 Cl (50.0 ml), extracted with ethyl acetate (3*30 mL), washed with brine and stripped off the solvent in vacuum to afford orange yellow liquid. TLC (30:70 EtOAc/hexane) of the crude showed absence of starting material spot (Rf=0.4) along with product spot appeared at Rf=0.38. The crude was purified by flash column chromatography on a silica gel using 15% EtOAC/hexane to afford 1.53 g (mp 160-162° C., 38% yield) of desired benzoyl derivative as pale yellow solid. Mass spec. (CI—NH 3 ): 401.3 (M+H). Anal. calcd. for C 23 H 32 N 2 O 4 : C, 68.97; H, 8.05; N, 6.99. Found; C, 69.05; H, 8.10; N, 6.33. 
     Part C 
     A solution of Part B material of example 9 (1.4 g, 0.0035 moles) in acetone (30 mL) was cooled to 15° C. and then added 3M aq. HCl (60 mL) over 15 mins. The mixture was stirred below 30° C. for 24 h. TLC (30:70 EtOAc/hexane) showed product spot at 0.56. The solvent was removed under vacuum, extracted with ethyl acetate (3*50 mL), washed with brine and stripped off the solvent in vacuum to afford yellow liquid. The crude was purified by flash column chromatography on a silica gel using dichloromethane, followed by 1% MeOH/dichloromethane as eluents to afford 0.48 g (39% yield) of desired product as yellow liquid. HRMS calcd. for C 21 H 29 N 2 O 3 : 357.2178. Found: 357.2169 (M+H). 
     Part D 
     A mixture of Part C material of example 9 (0.357 g, 1.0 mmole) in methanol (30 mL) was treated with NaCN (Aldrich, 0.245 g, 5.0 Mmoles, 5 equiv.), AcOH (Baker, 96 mg; 1.6 mmoles, 1.6 equiv.) and MnO 2 , activated (Aldrich, 1.24 g, 21.0 mmoles, 21 equiv.). The resulting mixture was stirred at room temp under nitrogen for 24 h. TLC (30:70 EtOAc/hexane) revealed absence of starting material at Rf=0.56 and showed a new spot at Rf=0.30. The reaction mixture was filtered through celite, washed with methanol, concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried and concentrated in vacuo to afford yellow oil. The crude was purified by flash column chromatography on a silica gel using 30:70 EtOAc/hexane as eluent to afford 205 mg (53%) of ketoester derivative as pale yellow oil. HRMS calcd. for C 22 H 30 N 2 O 4 : 386.2205. Found: 387.2264 (M+H). 
     Part E 
     A mixture of Part D material of example 9 (0.100 g, 0.000259 moles) in ethylene glycol (3.0 mL) was treated with anhydrous methylhydrazine (0.15 g, Aldrich, 0.0033 moles, 13 equiv.) and refluxed under nitrogen for 14 h. TLC (30:70 EtOAc/hexane) revealed a new spot (Rf=0.40) along with disappearence of starting material (Rf=0.3). The reaction mixture was cooled to room temp and poured over 25 mL of water, extracted with EtOAc (3*15 mL), washed with brine and dried. The solvent was removed under vacuo and purified the crude by flash column chromatography on a silica gel using 30% EtOAc/hexane to afford 43 mg (43% yield) of a solid: HRMS calcd. for C 22 H 31 N 4 O 2 : 383.2447. Found: 383.2433 (M+H). 
     Using the above procedures and modifications known to one skilled in the art of organic synthesis, the following additional examples of Tables 1-4 may be prepared. 
     The examples delineated in Tables 1, 2, 3 and 4 may be prepared by the methods outlined in Examples 1, 2 or 3 or combinations thereof. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example, amorph. is amorphous. 
     Example 544 
     4-(2,4-Dichlorophenyl)-2-ethyl-6-(N-methyl)-imidazo[4,5-d]pyridazin-7-one 
     Part A 
     Synthesis of 1-[(Benzyloxy)methyl]4,5-dibromo-2-ethylimidazole 
     To a mechanically stirred solution of 4,5-dibromo-2-ethylimidazole (25.4 g, 0.1 mole,) in anhydrous DMF (250 mL) was treated with K 2 CO 3  (69.1 g, fw=138.2, 0.5 moles, 5 equiv.) followed by dropwise addition of benzyl chloromethyl ether (18.5 g, 0.11 moles, 93% pure, TCI, fw=156.61) and stirred overnight at room temp under nitrogen for 20 h. TLC (30:70 EtOAc/hexane) revealed absence of starting material imidazole (Rf=0.2) along with formation of product (Rf=0.71). The reaction mixture was filtered, washed the solid with dichloromethane and the combined filterate was evaporated under reduced pressure and purified the crude (47 g) by flash column chromatography (dichloromethane eluent) to afford 31.75 g (85%) of colorless oil. Mass spectrum (m/z=375, M+H). 
     Part B 
     Synthesis of 1-[(Benzyloxy)methyl]-4-bromo-2-ethyl-5-formylimidazole 
     A solution of 1-[(Benzyloxy)methyl]-4,5-dibromo-2-ethylimidazole (28.0 g, 75.0 mmol, Part A of example 544) in THF (300 mL) was cooled to −78° C. under nitrogen atmosphere and then added dropwise 1.6 M n-BuLi in hexane (51.75 mL, 82.5 mmol, Aldrich) over 30 mins. The mixture was stirred at −78° C. for 30 mins and then added DMF (16.5 g, 225 mmol, Aldrich) dropwise over 15 mins. The mixture was stirred at −78° C. for 30 mins. A small portion of the reaction mixture was quenched with satd. NH 4 Cl at −78° C. TLC (30:70 EtOAc/hexane) revealed both starting material and product showed almost identical Rf values (0.71 &amp; 0.70) along with another minor spot at Rf=0.15. However, mass spectrum (CI—NH 3 ) revealed absence of starting material and formation of product (m/z=325, M+2H). The reaction mixture was quenched with satd. ammonium chloride (20 mL) at −78° C. and brought to room temp. The reaction mixture was extracted with ethyl acetate (3×100 mL), washed with brine and dried with anhydrous MgSO 4 . The solvent was evaporated under reduced pressure to afford crude yellow oil. The crude was purified by flah column chromatography on a silica gel using dichloromethane as eluent to afford 22.6 g (93%) of colorless oil. HRMS calcd. for C 14 H 16 N 2 O 2 Br: 323.0395. Found: 323.0394 (M+H). 
     Part C 
     1-[(Benzyloxy)methyl]-4-bromo-2-ethyl-5-formylimidazole ethylene acetal 
     A mixture of 1-[(Benzyloxy)methyl]-4-bromo-2-ethyl-5-formyl-imidazole (22.6 g, 0.0699 moles) in benzene (400 mL) was treated with ethylene glycol (16.9 g, 0.273 moles, fw 62, 3.9 equiv.), pyridine (2.76 g, 0.03495 moles, fw=79.1, 0.5 equiv.) and p-toluenesulfonic acid monohydrate (6.6 g, 0.03495moles, fw=190, 0.5 equiv). The reaction mixture was heated at reflux in a 20 mL capacity Dean-Stark trap equipped apparatus for 24 hours. TLC (30:70 EtOAc/hexane) revealed a new spot at Rf=0.35 (visible under iodine) along with disappearence of starting material (Rf=0.70). The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with 10% sodium bicarbonate, brine and dried (MgSO 4 ). The solvent was evaporated under reduced pressure to furnish yellow oil. The crude was purified by flash column chromatography on silica gel using 25% ethyl acetate/hexane mixture to afford 22.8 g (89%) colorless oil.  1 H NMR (CDCl 3 ): 1.29-1.33 (t, 3H, CH 3 ), 2.71-2.78 (q, 2H, CH 2 ), 3.96 (s, 4H, 2×OCH 2 ), 4.55 (s, 2H, CH 2 ), 5.4 (S, 2H, CH 2 ), 5.88 (S, 1H, CH), 7.27-7.38 (M, 5H, aromatic). HRMS calcd. for C 16 H 20 N 2 O 3 Br 1 : 367.0658. Found: 367.0653 (M+H). 
     Part D 
     1-[(Benzyloxy)methyl]-4-(2,4-dichlorobenzoyl)-2-ethyl-5-formylimidazole ethylene acetal 
     A solution of 1-[(Benzyloxy)methyl]-4-bromo-2-ethyl-5-formylimidazole ethylene acetal (22.5 g, 0.0613 moles, fw=367.25, Part C of Example 544) in THF (200.0 mL) was cooled to −78° C. and then added dropwise 1.6 M n-BuLi in hexane (43.7 mL, 0.071 moles, 1.1 equiv.) over 15 mins under nitrogen atmosphere. The mixture was stirred at −78° C. for 90 mins and then added a solution of 2,4-dichlorobenzoyl chloride (14.3 g, 0.071 moles, 1.1 equiv.) in THF (5.0 mL) over 15 mins. The mixture was stirred at −78° C. for 4 h followed by room temperature overnight. TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.38 along with disappearence of starting material (Rf=0.35). The mixture was quenched with saturated NH 4 Cl (100.0 ml), extracted with ethyl acetate (3×150 mL), washed with brine and dried (MgSO 4 ). The solvent was stripped off in vacuo to afford crude product (yellow oil) which was purified by flash column chromatography on a silica gel using 20% EtOAC/hexane to afford 12.3 g (mp 95-96° C., 43% yield) of desired product as white solid.  1 H NMR (CDCl 3 ): 1.22-1.27 (t, 3H, CH 3 ), 2.74-2.81 (q, 2H, CH 2 ), 3.94-4.03 (m, 4H, 2×OCH 2 ), 4.59 (s, 2H, CH 2 ), 5.54 (s, 2H, CH 2 ), 6.62 (s, 1H, CH), 7.27-7.54 (m, 8H, aromatic). Mass spectrum (CI—NH 3 ): 461 (M + ). Anal. calcd. for C 23 H 22 N 2 O 4 Cl 2 : C, 59.88; H, 4.82; N, 6.07. Found: C, 59.77; H, 4.78; N, 5.93. 
     Part E 
     1-[(Benzyloxy)methyl]-4-(2,4-dichlorobenzoyl)-2-ethyl-5-formylimidazole 
     The above acetal (12.1 g, 0.0263 moles, Part D of Example 544) was dissolved in acetone (200.0 mL) and treated with 3.0 M aqeous HCl (400.0 mL) at room temperature. The reaction mixture was stirred for 24 h at this temperature and TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.55. It was then quenched with saturated NaCl (50.0 ml), extracted with ethyl acetate (3×150 mL), washed with brine and dried (MgSO 4 ). The solvent was removed in vacuum to afford yellow liquid and purified the crude by flash column chromatography on a silica gel using 15% EtOAc/hexane to afford 6.0 g (55% yield) of desired product as colorless oil.  1 H NMR (CDCl 3 ): 1.27-1.32 (t, 3H, CH 3 ), 2.78-2.86 (q, 2H, CH 2 ), 4.62 (s, 2H, CH 2 ), 5.92 (s, 2H, CH 2 ), 7.25-7.55 (m, 8H, aromatic), 10.39 (s, 1H, CHO). Mass spectrum (CI—NH 3 ): 417 (M + ) Anal. calcd. for C 21 H 18 N 2 O 3 Cl 2 : C, 60.44; H, 4.36; N, 6.71. Found: C, 60.43; H, 4.45; N, 6.49. 
     Part F 
     Methyl 1-[(Benzyloxy)methyl]-4-(2,4-dichlorobenzoyl)-2-ethyl-5-imidazole carboxylate 
     A mixture of 2-Et-5-CHO-imidazole derivative (6.0 g, fw=417, 14.34 mmoles, Part E of Example 544) in methanol (120 mL) was treated with NaCN (Aldrich, fw=49, 3.54 g, 12.0 mmoles, 5 equiv.), AcOH (Baker, fw=60, 1.38 g; 22.92 mmoles, 1.6 equiv.) and MnO 2 , activated (Aldrich, fw=86.94, 25.8 g, 301.2 mmoles, 21 equiv.). The resulting mixture was stirred at room temp under nitrogen for 3 h. TLC (30:70 EtOAc/hexane) revealed absence of starting material at Rf=0.55 and showed a new spot at Rf=0.35. The reaction mixture was filtered through celite, washed with methanol, concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried and concentrated in vacuo to afford yellow oil. The crude was purified by flash column chromatography on a silica gel using 30:70 EtOAc/hexane as eluent to afford 4.62 g (72% yield) of colorless oil. HRMS calcd. for C 22 H 21 Cl 2 N 2 O 4 : 447.0878. Found: 447.0870 (M+H). Anal. calcd. for C 22 H 20 Cl 2 N 2 O 4 : C, 59.07; H, 4.52; N, 6.26. Found: C, 58.97; H, 4.65; N, 6.07. 
     Part G 
     1-[(Benzyloxy)methyl]-4-(2,4-dichlorophenyl)-2-ethyl-imidazo[4,5-d]pyridazin-7-one 
     A mixture of imidazole deriv. (3.55 g, fw=447, 0.00794 moles, Part F of Example 544) in ethanol (50 mL) was treated with anhydrous hydrazine (3.3 g, 0.102 moles, 13 equiv) and refluxed under nitrogen for 2 h. TLC (30:70 EtOAc/hexane) revealed absence of starting material (Rf=0.35) and showed a new spot (Rf=0.27). The solvent was removed under vacuo and purified the crude titurating with 1:1 EtOH/hexane to afford 2.2 g (65% yield, mp 174-175° C.) of desired product as white solid. Mass spectrum (APcI): (m/z=429, M + ). Anal. calcd. for C 21 H 18 N 4 Cl 2 O 2 : C, 58.75; H, 4.24; N, 13.05. Found: C, 58.65; H, 4.30; N, 12.86. 
     Part H 
     1-[(Benzyloxy)methyl]-4-(2,4-dichlorophenyl)-2-ethyl-6-(N-methyl)-imidazo[4,5-d]pyridazin-7-one 
     To a solution of the above 6H-imidazo[4,5-d]pyridazin-7-one derivative (2.2 g, 0.005 moles, Part G of Example 544) in benzene (100 mL) was added powdered KOH (0.43 g, 0.0076 moles), n-Bu 4 NBr (161 mg, 0.0005 moles ) and MeI (excess) at room temperature. The reaction mixture appeared white suspension and stirred for 48 h. TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.40 along with disappearence of starting material (Rf=0.27). The reaction mixture was diluted with EtOAc (50 mL), washed with brine (10 mL), dried with MgSO 4  and concentrated to a residue. The crude was purified by flash column chromatography on a silica gel using 25:75 EtOAc/hexane as eluent to afford 1.96 g (86% yield, mp 80-81° C.) of the product as white solid. Anal. calcd. for C 21 H 20 N 4 Cl 2 O 2 : C, 59.60; H, 4.56; N, 12.64. Found: C, 59.61; H, 4.57; N, 12.52. 
     Part I 
     Title Compound 
     A mixture of 1-[(Benzyloxy)methyl]-4-(2,4-dichlorophenyl)-2-ethyl-6-(N-methyl)-imidazo[4,5-d]pyridazin-7-one (2.6 g, fw=443.33, 5.87 mmol, Part H of Example 544) in ethanol (100 mL) was treated with conc. HCl (2.93 mL, 29.3 mmol, 5.0 equiv) and refluxed under nitrogen for 60 mins. TLC (30:70 EtOAc/hexane) revealed disappearence of starting material (Rf=0.40) and a new spot appeared near the origin. The reaction mixture was cooled to room temperature adjusted the pH using NaHCO 3  and the solvent was removed under vacuo and purified the crude by flash column chromatography on a silica gel using 50% EtOAc/hexane to afford 1.85 g (mp 234-235° C., 97% yield) of desired product as white solid. NMR (CDCl 3 ): 1.46-1.52 (t, 3H, CH 3 ), 3.04-3.11 (q, 2H, CH 2 ), 4.04 (s, 3H, N—Me), 7.38-7.41 (d, 2H, aromatic), 7.54-7.57 (m, 3H, aromatic), 13.65 (bs, 1H, NH). Mass spectrum (CI—NH 3 ): m/z=323 (M + ). HRMS calcd. for C 14 H 13 N 4 Cl 2 O 1 : 323.0466. Found: 323.0477 (M+H). Anal. calcd. for C 14 H 12 N 4 Cl 2 O 1 : C, 52.03; H, 3.74. Found: C, 51.92 ; H, 4.07. 
     Example 546 
     1-Butyl-4-(2,4-dichlorophenyl)-2-ethyl-6-(N-methyl)-imidazo[4,5-d]pyridazin-7-one 
     To a solution of imidazopyridazin-7-one deriv. (32.3 mg, fw=323, 0.1 mmol, Part I of example 544) in DMF (2.0 mL) under nitrogen atmosphere was added 60% NaH in oil dispersion (6.0 mg, fw=24, 0.15 mmol, 1.5 equiv.). The mixture was stirred at room temp for 5 mins and then added 1-bromobutane (27.6 mg, fw=184, 0.15 mmol, 1.5 equiv) to reaction mixture and stirred overnight. TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.36 along with disappearence of starting material (Rf=origin). The reaction mixture was diluted with water (5.0 mL), extracted with EtOAc (3*5 mL), washed with brine (10 mL), dried with MgSO 4  and concentrated to a residue. The crude was purified by flash column chromatography on a silica gel using 25:75 EtOAc/hexane as eluent to afford 29.7 mg (78% yield) of the product as colorless oil. HRMS calcd. for C 18 H 21 N 4 O 1 Cl 2 : 379.1092. Found: 379.1086 (M+H). 
     Example 548 
       4 -(2,4-dichlorophenyl)-2-ethyl-1-[1-(ethyl)pentyl)]-6-(N-methyl)-imidazo[4,5-d]pyridazin-7-one 
     To a solution of imidazopyridazin-7-one deriv. (48.3 mg, fw=323, 0.15 mmol, Part I of Example 544) in THF (2.0 mL) under nitrogen atmosphere was added PPh 3  (43.3 mg, fw=262.29, 0.165 mmol, 1.1 equiv.), and 3-heptanol (21.0 mg, Aldrich, 0.18 mmol, fw=116.2, 1.2 equiv.). The mixture was cooled to −20° C. and then added diisopropylazodicarboxylate (33.3 microlit., Aldrich, 0.165 mmol, fw=202, 1.1 equiv.) dropwise using a syringe. The resultant mixture was stirred at −20° C. for 2 h followed by room temperature for 20 h. TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.53 along with trace amount of starting material (Rf=origin). The reaction mixture was concentrated to a residue. The crude was purified by flash column chromatography on a silica gel using 15:85 EtOAc/hexane as eluent to afford 37 mg (58% yield, 110-111° C.) of the product as white solid. HRMS calcd. for C 21 H 27 N 4 O 1 Cl 2 : 421.1562. Found: 421.1555 (M+H). 
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex. 
                 R 3   
                 R 2   
                 Ar 
                 mp (° C.) 
               
               
                   
               
               
                  2 
                 Me 
                 3-pentyl 
                 2,4-Cl 2 —Ph 
                 94-95 
               
               
                  3 
                 Et 
                 3-pentyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                  4 
                 Pr 
                 3-pentyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                  5 
                 CH 2 -c-C 3 H 5   
                 3-pentyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                  6 
                 Me 
                 3-pentyl 
                 2,4-(CF 3 ) 2 —Ph 
                 139-140 
               
               
                  7 
                 Me 
                 2-pentyl 
                 2,4-Cl 2 —Ph 
                 89-90 
               
               
                  9 
                 Me 
                 2-pentyl 
                 2,5-(Me) 2 -4-MeO—Ph 
                 amorph. 
               
               
                  10 
                 Me 
                 CH(Et)CH 2 OH 
                 2,4-Cl 2 —Ph 
               
               
                  12 
                 Me 
                 CH(Et)CH 2 OMe 
                 2,4-Cl 2 —Ph 
               
               
                  13 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2,4-Cl 2 —Ph 
               
               
                  14 
                 Me 
                 2-butyl 
                 2,4-Cl 2 —Ph 
               
               
                  15 
                 Me 
                 cyclobutyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                  16 
                 Me 
                 cyclopentyl 
                 2,4-Cl 2 —Ph 
                 180-181 
               
               
                  17 
                 Me 
                 CH(Me)cyclobutyl 
                 2,4-Cl 2 —Ph 
               
               
                  18 
                 Me 
                 CH(Me)cyclopropyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                  19 
                 Me 
                 CH(Et)cyclobutyl 
                 2,4-Cl 2 —Ph 
               
               
                  20 
                 Me 
                 CH(Et)cyclopropyl 
                 2,4-Cl 2 —Ph 
                 117-118 
               
               
                  21 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2,4-Cl 2 —Ph 
               
               
                  22 
                 Me 
                 CH(OH)CH 2 -cyclobutyl 
                 2,4-Cl 2 —Ph 
               
               
                  23 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2,4-Cl 2 —Ph 
               
               
                  24 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2,4-Cl 2 —Ph 
               
               
                  25 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2,4-Cl 2 —Ph 
               
               
                  26 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2,4-Cl 2 —Ph 
               
               
                  27 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2,4-Cl 2 —Ph 
               
               
                  28 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2,4-Cl 2 —Ph 
               
               
                  29 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2,4-Cl 2 —Ph 
               
               
                  30 
                 Me 
                 CH(cyclobutyl) 2   
                 2,4-Cl 2 —Ph 
               
               
                  31 
                 Me 
                 CH(cyclopropyl) 2   
                 2,4-Cl 2 —Ph 
                 140-142 
               
               
                  32 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2,4-Cl 2 —Ph 
               
               
                  33 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2,4-Cl 2 —Ph 
               
               
                  34 
                 Me 
                 CH(CH 2 OMe)Me 
                 2,4-Cl 2 —Ph 
               
               
                  35 
                 Me 
                 CH(CH 2 OMe)Et 
                 2,4-Cl 2 —Ph 
               
               
                  36 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2,4-Cl 2 —Ph 
               
               
                  37 
                 Me 
                 CH(CH 2 OEt)Me 
                 2,4-Cl 2 —Ph 
               
               
                  38 
                 Me 
                 CH(CH 2 OEt)Et 
                 2,4-Cl 2 —Ph 
               
               
                  39 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2,4-Cl 2 —Ph 
               
               
                  40 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2,4-Cl 2 —Ph 
               
               
                  41 
                 Me 
                 CH(CH 2 CH═CHMe)Et 
                 2,4-Cl 2 —Ph 
               
               
                  42 
                 Me 
                 CH(Et)CH 2 OH 
                 2,4,6-Me 3 —Ph 
               
               
                  43 
                 Me 
                 CH(Et)CH 2 OMe 
                 2,4,6-Me 3 —Ph 
               
               
                  44 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2,4,6-Me 3 —Ph 
               
               
                  45 
                 Me 
                 3-pentyl 
                 2,4,6-Me 3 —Ph 
               
               
                  46 
                 Me 
                 2-pentyl 
                 2,4,6-Me 3 —Ph 
               
               
                  47 
                 Me 
                 2-butyl 
                 2,4,6-Me 3 —Ph 
               
               
                  48 
                 Me 
                 cyclobutyl 
                 2,4,6-Me 3 —Ph 
               
               
                  49 
                 Me 
                 cyclopentyl 
                 2,4,6-Me 3 —Ph 
               
               
                  50 
                 Me 
                 CH(Me)cyclobutyl 
                 2,4,6-Me 3 —Ph 
               
               
                  51 
                 Me 
                 CH(Me)cyclopropyl 
                 2,4,6-Me 3 —Ph 
               
               
                  52 
                 Me 
                 CH(OMe)cyclopropyl 
                 2,4,6-Me 3 —Ph 
               
               
                  53 
                 Me 
                 CH(Et)cyclobutyl 
                 2,4,6-Me 3 —Ph 
               
               
                  54 
                 Me 
                 CH(Et)cyclopropyl 
                 2,4,6-Me 3 —Ph 
               
               
                  55 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2,4,6-Me 3 —Ph 
               
               
                  56 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2,4,6-Me 3 —Ph 
               
               
                  57 
                 Me 
                 CH(OMe)CH 2 -cyclopropyl 
                 2,4,6-Me 3 —Ph 
               
               
                  58 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2,4,6-Me 3 —Ph 
               
               
                  59 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2,4,6-Me 3 —Ph 
               
               
                  60 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2,4,6-Me 3 —Ph 
               
               
                  61 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2,4,6-Me 3 —Ph 
               
               
                  62 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2,4,6-Me 3 —Ph 
               
               
                  63 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2,4,6-Me 3 —Ph 
               
               
                  64 
                 Me 
                 CH(cyclobutyl) 2   
                 2,4,6-Me 3 —Ph 
               
               
                  65 
                 Me 
                 CH(cyclopropyl) 2   
                 2,4,6-Me 3 —Ph 
               
               
                  66 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2,4,6-Me 3 —Ph 
               
               
                  67 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2,4,6-Me 3 —Ph 
               
               
                  68 
                 Me 
                 CH(CH 2 OMe)Me 
                 2,4,6-Me 3 —Ph 
               
               
                  69 
                 Me 
                 CH(CH 2 OMe)Et 
                 2,4,6-Me 3 —Ph 
               
               
                  70 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2,4,6-Me 3 —Ph 
               
               
                  71 
                 Me 
                 CH(CH 2 OEt)Me 
                 2,4,6-Me 3 —Ph 
               
               
                  72 
                 Me 
                 CH(CH 2 OEt)Et 
                 2,4,6-Me 3 —Ph 
               
               
                  73 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2,4,6-Me 3 —Ph 
               
               
                  74 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2,4,6-Me 3 —Ph 
               
               
                  75 
                 Me 
                 CH(CH 2 CH═CHMe)Et 
                 2,4,6-Me 3 —Ph 
               
               
                  76 
                 Me 
                 CH(Et)CH 2 OH 
                 2,4-Me 2 —Ph 
               
               
                  77 
                 Me 
                 CH(Et)CH 2 OMe 
                 2,4-Me 2 —Ph 
               
               
                  78 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2,4-Me 2 —Ph 
               
               
                  79 
                 Me 
                 3-pentyl 
                 2,4-Me 2 —Ph 
               
               
                  80 
                 Me 
                 2-pentyl 
                 2,4-Me 2 —Ph 
               
               
                  81 
                 Me 
                 2-butyl 
                 2,4-Me 2 —Ph 
               
               
                  82 
                 Me 
                 cyclobutyl 
                 2,4-Me 2 —Ph 
               
               
                  83 
                 Me 
                 cyclopentyl 
                 2,4-Me 2 —Ph 
               
               
                  84 
                 Me 
                 CH(Me)cyclobutyl 
                 2,4-Me 2 —Ph 
               
               
                  85 
                 Me 
                 CH(OH)cyclobutyl 
                 2,4-Me 2 —Ph 
               
               
                  86 
                 Me 
                 CH(Me)cyclopropyl 
                 2,4-Me 2 —Ph 
               
               
                  87 
                 Me 
                 CH(OH)cyclopropyl 
                 2,4-Me 2 —Ph 
               
               
                  88 
                 Me 
                 CH(Et)cyclobutyl 
                 2,4-Me 2 —Ph 
               
               
                  89 
                 Me 
                 CH(Et)cyclopropyl 
                 2,4-Me 2 —Ph 
               
               
                  90 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2,4-Me 2 —Ph 
               
               
                  91 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2,4-Me 2 —Ph 
               
               
                  92 
                 Me 
                 CH(OMe)CH 2 -cyclopropyl 
                 2,4-Me 2 —Ph 
               
               
                  93 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2,4-Me 2 —Ph 
               
               
                  94 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2,4-Me 2 —Ph 
               
               
                  95 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2,4-Me 2 —Ph 
               
               
                  96 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2,4-Me 2 —Ph 
               
               
                  97 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2,4-Me 2 —Ph 
               
               
                  98 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2,4-Me 2 —Ph 
               
               
                  99 
                 Me 
                 CH(cyclobutyl) 2   
                 2,4-Me 2 —Ph 
               
               
                 100 
                 Me 
                 CH(cyclopropyl) 2   
                 2,4-Me 2 —Ph 
               
               
                 101 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2,4-Me 2 —Ph 
               
               
                 102 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2,4-Me 2 —Ph 
               
               
                 103 
                 Me 
                 CH(CH 2 OMe)Me 
                 2,4-Me 2 —Ph 
               
               
                 104 
                 Me 
                 CH(CH 2 OMe)Et 
                 2,4-Me 2 —Ph 
               
               
                 105 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2,4-Me 2 —Ph 
               
               
                 106 
                 Me 
                 CH(CH 2 OEt)Me 
                 2,4-Me 2 —Ph 
               
               
                 107 
                 Me 
                 CH(CH 2 OEt)Et 
                 2,4-Me 2 —Ph 
               
               
                 108 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2,4-Me 2 —Ph 
               
               
                 109 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2,4-Me 2 —Ph 
               
               
                 110 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2,4-Me 2 —Ph 
               
               
                 111 
                 Me 
                 CH(Et)CH 2 OH 
                 2-Me-4-MeO—Ph 
               
               
                 112 
                 Me 
                 CH(Et)CH 2 OMe 
                 2-Me-4-MeO—Ph 
               
               
                 113 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2-Me-4-MeO—Ph 
               
               
                 114 
                 Me 
                 3-pentyl 
                 2-Me-4-MeO—Ph 
                 125-126 
               
               
                 115 
                 Me 
                 2-pentyl 
                 2-Me-4-MeO—Ph 
                 oil 
               
               
                 116 
                 Me 
                 2-butyl 
                 2-Me-4-MeO—Ph 
               
               
                 117 
                 Me 
                 cyclobutyl 
                 2-Me-4-MeO—Ph 
               
               
                 118 
                 Me 
                 cyclopentyl 
                 2-Me-4-MeO—Ph 
               
               
                 119 
                 Me 
                 CH(Me)cyclobutyl 
                 2-Me-4-MeO—Ph 
               
               
                 120 
                 Me 
                 CH(Me)cyclopropyl 
                 2-Me-4-MeO—Ph 
               
               
                 121 
                 Me 
                 CH(Et)cyclobutyl 
                 2-Me-4-MeO—Ph 
               
               
                 122 
                 Me 
                 CH(Et)cyclopropyl 
                 2-Me-4-MeO—Ph 
               
               
                 123 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2-Me-4-MeO—Ph 
               
               
                 124 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2-Me-4-MeO—Ph 
               
               
                 125 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2-Me-4-MeO—Ph 
               
               
                 126 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2-Me-4-MeO—Ph 
               
               
                 127 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2-Me-4-MeO—Ph 
               
               
                 128 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2-Me-4-MeO—Ph 
               
               
                 129 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2-Me-4-MeO—Ph 
               
               
                 130 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2-Me-4-MeO—Ph 
               
               
                 131 
                 Me 
                 CH(cyclobutyl) 2   
                 2-Me-4-MeO—Ph 
               
               
                 132 
                 Me 
                 CH(cyclopropyl) 2   
                 2-Me-4-MeO—Ph 
               
               
                 133 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2-Me-4-MeO—Ph 
               
               
                 134 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2-Me-4-MeO—Ph 
               
               
                 135 
                 Me 
                 CH(CH 2 OMe)Me 
                 2-Me-4-MeO—Ph 
               
               
                 136 
                 Me 
                 CH(CH 2 OMe)Et 
                 2-Me-4-MeO—Ph 
               
               
                 137 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2-Me-4-MeO—Ph 
               
               
                 138 
                 Me 
                 CH(CH 2 OEt)Me 
                 2-Me-4-MeO—Ph 
               
               
                 139 
                 Me 
                 CH(CH 2 OEt)Et 
                 2-Me-4-MeO—Ph 
               
               
                 140 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2-Me-4-MeO—Ph 
               
               
                 141 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2-Me-4-MeO—Ph 
               
               
                 142 
                 Me 
                 CH(CH 2 CH═CHMe)Et 
                 2-Me-4-MeO—Ph 
               
               
                 143 
                 Me 
                 CH(Et)CH 2 OH 
                 2-Cl-4-MeO—Ph 
               
               
                 144 
                 Me 
                 CH(Et)CH 2 OMe 
                 2-Cl-4-MeO—Ph 
               
               
                 145 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2-Cl-4-MeO—Ph 
               
               
                 146 
                 Me 
                 3-pentyl 
                 2-Cl-4-MeO—Ph 
               
               
                 147 
                 Me 
                 2-pentyl 
                 2-Cl-4-MeO—Ph 
                 112-113 
               
               
                 148 
                 Me 
                 2-butyl 
                 2-Cl-4-MeO—Ph 
               
               
                 149 
                 Me 
                 cyclobutyl 
                 2-Cl-4-MeO—Ph 
               
               
                 150 
                 Me 
                 cyclopentyl 
                 2-Cl-4-MeO—Ph 
               
               
                 151 
                 Me 
                 CH(Me)cyclobutyl 
                 2-Cl-4-MeO—Ph 
               
               
                 152 
                 Me 
                 CH(Me)cyclopropyl 
                 2-Cl-4-MeO—Ph 
               
               
                 153 
                 Me 
                 CH(Et)cyclobutyl 
                 2-Cl-4-MeO—Ph 
               
               
                 154 
                 Me 
                 CH(Et)cyclopropyl 
                 2-Cl-4-MeO—Ph 
               
               
                 155 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2-Cl-4-MeO—Ph 
               
               
                 156 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2-Cl-4-MeO—Ph 
               
               
                 157 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2-Cl-4-MeO—Ph 
               
               
                 158 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2-Cl-4-MeO—Ph 
               
               
                 159 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2-Cl-4-MeO—Ph 
               
               
                 160 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2-Cl-4-MeO—Ph 
               
               
                 161 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2-Cl-4-MeO—Ph 
               
               
                 162 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2-Cl-4-MeO—Ph 
               
               
                 163 
                 Me 
                 CH(cyclobutyl) 2   
                 2-Cl-4-MeO—Ph 
               
               
                 164 
                 Me 
                 CH(cyclopropyl) 2   
                 2-Cl-4-MeO—Ph 
               
               
                 165 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2-Cl-4-MeO—Ph 
               
               
                 166 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2-Cl-4-MeO—Ph 
               
               
                 167 
                 Me 
                 CH(CH 2 OMe)Me 
                 2-Cl-4-MeO—Ph 
               
               
                 168 
                 Me 
                 CH(CH 2 OMe)Et 
                 2-Cl-4-MeO—Ph 
               
               
                 169 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2-Cl-4-MeO—Ph 
               
               
                 170 
                 Me 
                 CH(CH 2 OEt)Me 
                 2-Cl-4-MeO—Ph 
               
               
                 171 
                 Me 
                 CH(CH 2 OEt)Et 
                 2-Cl-4-MeO—Ph 
               
               
                 172 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2-Cl-4-MeO—Ph 
               
               
                 173 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2-Cl-4-MeO—Ph 
               
               
                 174 
                 Me 
                 CH(CH 2 CH═CHMe)Et 
                 2-Cl-4-MeO—Ph 
               
               
                 175 
                 Me 
                 CH(Et)CH 2 OH 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 176 
                 Me 
                 CH(Et)CH 2 OMe 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 177 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 178 
                 Me 
                 3-pentyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 179 
                 Me 
                 2-pentyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 180 
                 Me 
                 2-butyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 181 
                 Me 
                 cyclobutyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 182 
                 Me 
                 cyclopentyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 183 
                 Me 
                 CH(Me)cyclobutyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 184 
                 Me 
                 CH(Me)cyclopropyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 185 
                 Me 
                 CH(Et)cyclobutyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 186 
                 Me 
                 CH(Et)cyclopropyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 187 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 188 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 189 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 190 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 191 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 192 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 193 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 194 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 195 
                 Me 
                 CH(cyclobutyl) 2   
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 196 
                 Me 
                 CH(cyclopropyl) 2   
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 197 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 198 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 199 
                 Me 
                 CH(CH 2 OMe)Me 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 200 
                 Me 
                 CH(CH 2 OMe)Et 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 201 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 202 
                 Me 
                 CH(CH 2 OEt)Me 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 203 
                 Me 
                 CH(CH 2 OEt)Et 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 204 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 205 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 206 
                 Me 
                 CH(CH 2 CH═CHMe)Et 
                 2-Cl-4,5-(MeO) 2 —Ph 
               
               
                 207 
                 Me 
                 CH(Et)CH 2 OH 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 208 
                 Me 
                 CH(Et)CH 2 OMe 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 209 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 210 
                 Me 
                 3-pentyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 211 
                 Me 
                 2-pentyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 212 
                 Me 
                 2-butyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 213 
                 Me 
                 cyclobutyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 214 
                 Me 
                 cyclopentyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 215 
                 Me 
                 CH(Me)cyclobutyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 216 
                 Me 
                 CH(Me)cyclopropyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 217 
                 Me 
                 CH(Et)cyclobutyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 218 
                 Me 
                 CH(Et)cyclopropyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 219 
                 Me 
                 CH(OEt)cyclobutyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 220 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 221 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 222 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 223 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 224 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 225 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 226 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 227 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 228 
                 Me 
                 CH(cyclobutyl) 2   
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 229 
                 Me 
                 CH(cyclopropyl) 2   
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 230 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 231 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 232 
                 Me 
                 CH(CH 2 OMe)Me 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 233 
                 Me 
                 CH(CH 2 OMe)Et 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 234 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 234 
                 Me 
                 CH(CH 2 OEt)Me 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 235 
                 Me 
                 CH(CH 2 OEt)Et 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 236 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 237 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 238 
                 Me 
                 CH(CH 2 CH═CHMe)Et 
                 2-Cl-4-MeO-5-F—Ph 
               
               
                 239 
                 Me 
                 CH(Et)CH 2 OH 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 240 
                 Me 
                 CH(Et)CH 2 OMe 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 241 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 242 
                 Me 
                 3-pentyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 243 
                 Me 
                 2-pentyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 244 
                 Me 
                 2-butyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 245 
                 Me 
                 cyclobutyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 246 
                 Me 
                 cyclopentyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 247 
                 Me 
                 CH(Me)cyclobutyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 248 
                 Me 
                 CH(Me)cyclopropyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 249 
                 Me 
                 CH(OMe)cyclopropyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 250 
                 Me 
                 CH(Et)cyclobutyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 251 
                 Me 
                 CH(Et)cyclopropyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 252 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 253 
                 Me 
                 CH(OMe)CH 2 -cyclobutyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 254 
                 Me 
                 CH(OH)CH 2 -cyclobutyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 255 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 256 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 257 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 258 
                 Me 
                 CH(OMe)CH 2 -cyclobutyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 259 
                 Me 
                 CH(OMe)CH 2 -cyclopropyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 260 
                 Me 
                 CH(OEt)CH 2 -cyclobutyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 261 
                 Me 
                 CH(OEt)CH 2 -cyclopropyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 262 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 263 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 264 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 265 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 266 
                 Me 
                 CH(cyclobutyl) 2   
                 2-Me-4-MeO-5-F—Ph 
               
               
                 267 
                 Me 
                 CH(cyclopropyl) 2   
                 2-Me-4-MeO-5-F—Ph 
               
               
                 268 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2-Me-4-MeO-5-F—Ph 
               
               
                 269 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2-Me-4-MeO-5-F—Ph 
               
               
                 270 
                 Me 
                 CH(CH 2 OMe)Me 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 271 
                 Me 
                 CH(CH 2 OMe)Et 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 272 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 273 
                 Me 
                 CH(CH 2 OEt)Me 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 274 
                 Me 
                 CH(CH 2 OEt)Et 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 275 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 276 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 277 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2-Me-4-MeO-5-F—Ph 
               
               
                 278 
                 Me 
                 CH(Et)CH 2 OH 
                 2,5-(Me)2-4-MeO—Ph 
               
               
                 279 
                 Me 
                 CH(Et)CH 2 OMe 
                 2,5-(Me)2-4-MeO—Ph 
               
               
                 280 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2,5-(Me)2-4-MeO—Ph 
               
               
                 281 
                 Me 
                 3-pentyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 282 
                 Me 
                 2-butyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 283 
                 Me 
                 cyclobutyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 284 
                 Me 
                 cyclopentyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 285 
                 Me 
                 CH(Me)cyclobutyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 286 
                 Me 
                 CH(Me)cyclopropyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 287 
                 Me 
                 CH(Et)cyclobutyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 288 
                 Me 
                 CH(Et)cyclopropyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 289 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 290 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 291 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 292 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 293 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 294 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 295 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 296 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 297 
                 Me 
                 CH(cyclobutyl) 2   
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 298 
                 Me 
                 CH(cyclopropyl) 2   
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 299 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 300 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 301 
                 Me 
                 CH(CH 2 OMe)Me 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 302 
                 Me 
                 CH(CH 2 OMe)Et 
                 2,5-(Me) 2 -4-MeC—Ph 
               
               
                 303 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 304 
                 Me 
                 CH(CH 2 OEt)Me 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 305 
                 Me 
                 CH(CH 2 OEt)Et 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 306 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 307 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 308 
                 Me 
                 CH(CH 2 CH═CHMe)Et 
                 2,5-(Me) 2 -4-MeO—Ph 
               
               
                 309 
                 Me 
                 CH(Et)CH 2 OH 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 310 
                 Me 
                 CH(Et)CH 2 OMe 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 311 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 312 
                 Me 
                 3-pentyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 313 
                 Me 
                 2-pentyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 314 
                 Me 
                 2-butyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 315 
                 Me 
                 cyclobutyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 316 
                 Me 
                 cyclopentyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 317 
                 Me 
                 CH(Me)cyclobutyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 318 
                 Me 
                 CH(Me)cyclopropyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 319 
                 Me 
                 CH(Et)cyclobutyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 320 
                 Me 
                 CH(Et)cyclopropyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 321 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 322 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 323 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 324 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 325 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 326 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 327 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 328 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 329 
                 Me 
                 CH(cyclobutyl) 2   
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 330 
                 Me 
                 CH(cyclopropyl) 2   
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 331 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 332 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 333 
                 Me 
                 CH(CH 2 OMe)Me 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 334 
                 Me 
                 CH(CH 2 OMe)Et 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 335 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 336 
                 Me 
                 CH(CH 2 OEt)Me 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 337 
                 Me 
                 CH(CH 2 OEt)Et 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 338 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 339 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 340 
                 Me 
                 CH(CH 2 CH═CHMe)Et 
                 2-Me-6-Me 2 N—pyrid-3-yl 
               
               
                 341 
                 Me 
                 CH(Et)CH 2 OH 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 342 
                 Me 
                 CH(Et)CH 2 OMe 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 343 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 344 
                 Me 
                 3-pentyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 345 
                 Me 
                 2-pentyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 346 
                 Me 
                 2-butyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 347 
                 Me 
                 cyclobutyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 348 
                 Me 
                 cyclopentyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 349 
                 Me 
                 CH(Me)cyclobutyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 350 
                 Me 
                 CH(Me)cyclopropyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 351 
                 Me 
                 CH(Et)cyclobutyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 352 
                 Me 
                 CH(Et)cyclopropyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 353 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 354 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 355 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 356 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 357 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 358 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 359 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 360 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 361 
                 Me 
                 CH(cyclobutyl) 2   
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 362 
                 Me 
                 CH(cyclopropyl) 2   
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 363 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 364 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 365 
                 Me 
                 CH(CH 2 OMe)Me 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 366 
                 Me 
                 CH(CH 2 OMe)Et 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 367 
                 Me 
                 CH(CH 2 OMe)Pr 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 368 
                 Me 
                 CH(CH 2 OEt)Me 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 369 
                 Me 
                 CH(CH 2 OEt)Et 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 370 
                 Me 
                 CH(CH 2 OEt)Pr 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 371 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 372 
                 Me 
                 CH(CH 2 CH═CHMe)Et 
                 4-Me-2-Me 2 N—pyrid-5-yl 
               
               
                 373 
                 Me 
                 CH(Et)CH 2 OH 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 374 
                 Me 
                 CH(Et)CH 2 OMe 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 375 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 376 
                 Me 
                 3-pentyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 377 
                 Me 
                 2-pentyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 378 
                 Me 
                 2-butyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 379 
                 Me 
                 cyclobutyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 380 
                 Me 
                 cyclopentyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 381 
                 Me 
                 CH(Me)cyclobutyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 382 
                 Me 
                 CH(Me)cyclopropyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 383 
                 Me 
                 CH(Et)cyclobutyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 384 
                 Me 
                 CH(Et)cyclopropyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 385 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 386 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 387 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 388 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 389 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 390 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 391 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 392 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 393 
                 Me 
                 CH(cyclobutyl) 2   
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 394 
                 Me 
                 CH(cyclopropyl) 2   
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 395 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 396 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 397 
                 Me 
                 CH(CH 2 OMe)Me 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 398 
                 Me 
                 CH(CH 2 OMe)Et 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 399 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 400 
                 Me 
                 CH(CH 2 OEt)Me 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 401 
                 Me 
                 CH(CH 2 OEt)Et 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 402 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 403 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 404 
                 Me 
                 CH(CH 2 CH═CHMe)Et 
                 2-Me-6-MeO—pyrid-3-yl 
               
               
                 405 
                 Me 
                 CH(Et)CH 2 OH 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 406 
                 Me 
                 CH(Et)CH 2 OMe 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 407 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 408 
                 Me 
                 3-pentyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 409 
                 Me 
                 2-pentyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 410 
                 Me 
                 2-butyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 411 
                 Me 
                 cyclobutyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 412 
                 Me 
                 cyclopentyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 413 
                 Me 
                 CH(Me)cyclobutyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 414 
                 Me 
                 CH(Me)cyclopropyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 415 
                 Me 
                 CH(Et)cyclobutyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 416 
                 Me 
                 CH(Et)cyclopropyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 417 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 418 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 419 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 420 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 421 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 422 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 423 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 424 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 425 
                 Me 
                 CH(cyclobutyl) 2   
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 426 
                 Me 
                 CH(cyclopropyl) 2   
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 427 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 428 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 429 
                 Me 
                 CH(CH 2 OMe)Me 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 430 
                 Me 
                 CH(CH 2 OMe)Et 
                 4-Me-2-MeO—pyrid-5 yl 
               
               
                 431 
                 Me 
                 CH(CH 2 OMe)Pr 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 432 
                 Me 
                 CH(CH 2 OEt)Me 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 433 
                 Me 
                 CH(CH 2 OEt)Et 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 434 
                 Me 
                 CH(CH 2 OEt)Pr 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 435 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 436 
                 Me 
                 CH(CH 2 CH═CHMe)Et 
                 4-Me-2-MeO—pyrid-5-yl 
               
               
                 536 
                 H 
                 2-pentyl 
                 2,4-Cl 2 -5-F—Ph 
                 159-160 
               
               
                 537 
                 Me 
                 2-pentyl 
                 2,4-Cl 2 -5-F—Ph 
                 120-121 
               
               
                 538 
                 Me 
                 (R)-2-butyl 
                 2,4-Cl 2 —Ph 
                 105-107 
               
               
                 539 
                 Me 
                 (S)-2-butyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 540 
                 Me 
                 2-pentyl 
                 4-Br-2-Cl—Ph 
                 97-98 
               
               
                 541 
                 Me 
                 2-pentyl 
                 Ph 
                 oil 
               
               
                 542 
                 Me 
                 2-pentyl 
                 4-OMe—Ph 
                 oil 
               
               
                 543 
                 Me 
                 CH 2 OCH 2 Ph 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 544 
                 Me 
                 H 
                 2,4-Cl 2 —Ph 
                 234-235 
               
               
                 545 
                 H 
                 CH 2 OCH 2 Ph 
                 2,4-Cl 2 —Ph 
                 174-175 
               
               
                 546 
                 Me 
                 n-butyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 547 
                 Me 
                 CH 2 CH 2 OMe 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 548 
                 Me 
                 3-heptyl 
                 2,4-Cl 2 —Ph 
                 110-111 
               
               
                 549 
                 Me 
                 (S)-2-pentyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 550 
                 Me 
                 (R)-2-pentyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 551 
                 Me 
                 CH(Et)CH 2 C≡CH 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 552 
                 Me 
                 2-hexyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 553 
                 Me 
                 3-hexyl 
                 2,4-Cl 2 —Ph 
                 135-136 
               
               
                 554 
                 Me 
                 CH(Et)CH 2 CH 2 CH═CH 2   
                 2,4-Cl 2 —Ph 
                 106-107 
               
               
                 555 
                 Me 
                 CH(CH 2 CH═CH 2 ) 2   
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 556 
                 Me 
                 CH(Me)CH 2 OCH 3   
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 557 
                 Me 
                 CH(n-C 3 H 7 )-cyclopropyl 
                 2,4-Cl 2 —Ph 
                 139-140 
               
               
                 558 
                 Me 
                 CH(Ph)-cyclopropyl 
                 2,4-Cl 2 —Ph 
                 172-173 
               
               
                 559 
                 Me 
                 CH(4-OMe—Ph)-cyclopropyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 560 
                 Me 
                 CH(4-Me—Ph)-cyclopropyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 561 
                 Me 
                 CH(4-F—Ph)-cyclopropyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 562 
                 Me 
                 CH 2 CH(CH 3 ) 2   
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 563 
                 Me 
                 CH 2 C(═CH 2 )Me 
                 2,4-Cl 2 —Ph 
                 126-127 
               
               
                 564 
                 Me 
                 CH 2 CH 2 CH(CH 3 ) 2   
                 2,4-Cl 2 —Ph 
                 105-106 
               
               
                 565 
                 Me 
                 CH 2 CH 2 CH═CH 2   
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 566 
                 Me 
                 CH 2 C≡CMe 
                 2,4-Cl 2 —Ph 
                 148-149 
               
               
                 567 
                 Me 
                 (R)-CH 2 CH(Me)CH 2 CH 3   
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 568 
                 Me 
                 (S)-CH 2 CH(Me)CH 2 CH 3   
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 569 
                 Me 
                 CH 2 COCH 2 CH 3   
                 2,4-Cl 2 —Ph 
                 104-105 
               
               
                 570 
                 Me 
                 CH 2 CH(CH 2 CH 3 ) 2   
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 571 
                 Me 
                 n-pentyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 572 
                 Me 
                 CH 2 (CH 2 ) 2 CH═CH 2   
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 573 
                 Me 
                 CH 2 CH═CHCH 2 CH 3   
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 574 
                 Me 
                 CH 2 (2-Cl—Ph) 
                 2,4-Cl 2 —Ph 
                 163-165 
               
               
                 575 
                 Me 
                 CH 2 (3-Cl—Ph) 
                 2,4-Cl 2 —Ph 
                 82-84 
               
               
                 576 
                 Me 
                 CH 2 (4-Cl—Ph) 
                 2,4-Cl 2 —Ph 
                 149-150 
               
               
                 577 
                 Me 
                 CH 2 (2,4-Cl 2 —Ph) 
                 2,4-Cl 2 —Ph 
                 85-87 
               
               
                 578 
                 Me 
                 CH 2 (2,4-F 2 —Ph) 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 579 
                 Me 
                 CH(Me)Ph 
                 2,4-Cl 2 —Ph 
                 179-180 
               
               
                 580 
                 Me 
                 CH 2 CH 2 Ph 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 581 
                 Me 
                 CH 2 -cyclobutyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 582 
                 Me 
                 2-pentyl 
                 2-4-CF 3 —Ph 
                 oil 
               
               
                 583 
                 Me 
                 2-pentyl 
                 2-Cl-4-F—Ph 
                 oil 
               
               
                 584 
                 Me 
                 2-pentyl 
                 2,4-Cl 2 —Ph 
                 oil 
               
               
                 585 
                 Me 
                 2-pentyl 
                 2,6-(OMe) 2 —pyrid-5-yl 
                 oil 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex. 
                 R 3   
                 R 2   
                 Ar 
                 mp(° C.) 
               
               
                   
               
               
                 437 
                 Me 
                 CH(Et)CH 2 OH 
                 2,4-Cl 2 -Ph 
                   
               
               
                 438 
                 Me 
                 CH(Et)CH 2 OMe 
                 2,4-Cl 2 -Ph 
               
               
                 439 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2,4-Cl 2 -Ph 
               
               
                 440 
                 Me 
                 3-pentyl 
                 2,4-Cl 2 -Ph 
               
               
                 441 
                 Me 
                 2-pentyl 
                 2,4-Cl 2 -Ph 
               
               
                 442 
                 Me 
                 2-butyl 
                 2,4-Cl 2 -Ph 
               
               
                 443 
                 Me 
                 cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 444 
                 Me 
                 cyclopentyl 
                 2,4-Cl 2 -Ph 
               
               
                 445 
                 Me 
                 CH(Me)cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 446 
                 Me 
                 CH(Me)cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 447 
                 Me 
                 CH(Et)cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 448 
                 Me 
                 CH(Et)cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 449 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 450 
                 Me 
                 CH(OH)CH 2 -cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 451 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 452 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 453 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 454 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 455 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 456 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 457 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 458 
                 Me 
                 CH(cyclobutyl) 2   
                 2,4-Cl 2 -Ph 
               
               
                 459 
                 Me 
                 CH(cyclopropyl) 2   
                 2,4-Cl 2 -Ph 
               
               
                 460 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2,4-Cl 2 -Ph 
               
               
                 461 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2,4-Cl 2 -Ph 
               
               
                 462 
                 Me 
                 CH(CH 2 OMe)Me 
                 2,4-Cl 2 -Ph 
               
               
                 463 
                 Me 
                 CH(CH 2 OMe)Et 
                 2,4-Cl 2 -Ph 
               
               
                 464 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2,4-Cl 2 -Ph 
               
               
                 465 
                 Me 
                 CH(CH 2 OEt)Me 
                 2,4-Cl 2 -Ph 
               
               
                 466 
                 Me 
                 CH(CH 2 OEt)Et 
                 2,4-Cl 2 -Ph 
               
               
                 467 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2,4-Cl 2 -Ph 
               
               
                 468 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2,4-Cl 2 -Ph 
               
               
                 469 
                 Me 
                 CH(CH 2 CH═CHMe)Et 
                 2,4-Cl 2 -Ph 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex. 
                 R 3   
                 R 2   
                 Ar 
                 mp(° C.) 
               
               
                   
               
               
                 470 
                 Me 
                 CH(Et)CH 2 OH 
                 2,4-Cl 2 -Ph 
                   
               
               
                 471 
                 Me 
                 CH(Et)CH 2 OMe 
                 2,4-Cl 2 -Ph 
               
               
                 472 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2,4-Cl 2 -Ph 
               
               
                 473 
                 Me 
                 3-pentyl 
                 2,4-Cl 2 -Ph 
               
               
                 474 
                 Me 
                 2-pentyl 
                 2,4-Cl 2 -Ph 
               
               
                 475 
                 Me 
                 2-butyl 
                 2,4-Cl 2 -Ph 
               
               
                 476 
                 Me 
                 cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 477 
                 Me 
                 cyclopentyl 
                 2,4-Cl 2 -Ph 
               
               
                 478 
                 Me 
                 CH(Me)cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 479 
                 Me 
                 CH(Me)cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 480 
                 Me 
                 CH(Et)cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 481 
                 Me 
                 CH(Et)cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 482 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 483 
                 Me 
                 CH(OH)CH 2 -cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 484 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 485 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 486 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 487 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 488 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 489 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 490 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 491 
                 Me 
                 CH(cyclobutyl) 2   
                 2,4-Cl 2 -Ph 
               
               
                 492 
                 Me 
                 CH(cyclopropyl) 2   
                 2,4-Cl 2 -Ph 
               
               
                 493 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2,4-Cl 2 -Ph 
               
               
                 494 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2,4-Cl 2 -Ph 
               
               
                 495 
                 Me 
                 CH(CH 2 OMe)Me 
                 2,4-Cl 2 -Ph 
               
               
                 496 
                 Me 
                 CH(CH 2 OMe)Et 
                 2,4-Cl 2 -Ph 
               
               
                 497 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2,4-Cl 2 -Ph 
               
               
                 498 
                 Me 
                 CH(CH 2 OEt)Me 
                 2,4-Cl 2 -Ph 
               
               
                 499 
                 Me 
                 CH(CH 2 OEt)Et 
                 2,4-Cl 2 -Ph 
               
               
                 500 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2,4-Cl 2 -Ph 
               
               
                 501 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2,4-Cl 2 -Ph 
               
               
                 502 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2,4-Cl 2 -Ph 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex. 
                 R 3   
                 R 2   
                 Ar 
                 mp(° C.) 
               
               
                   
               
               
                 503 
                 Me 
                 CH(Et)CH 2 OH 
                 2,4-Cl 2 -Ph 
                   
               
               
                 504 
                 Me 
                 CH(Et)CH 2 OMe 
                 2,4-Cl 2 -Ph 
               
               
                 505 
                 Me 
                 CH(Et)CH 2 CH 2 OMe 
                 2,4-Cl 2 -Ph 
               
               
                 506 
                 Me 
                 3-pentyl 
                 2,4-Cl 2 -Ph 
               
               
                 507 
                 Me 
                 2-pentyl 
                 2,4-Cl 2 -Ph 
               
               
                 508 
                 Me 
                 2-butyl 
                 2,4-Cl 2 -Ph 
               
               
                 509 
                 Me 
                 cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 510 
                 Me 
                 cyclopentyl 
                 2,4-Cl 2 -Ph 
               
               
                 511 
                 Me 
                 CH(Me)cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 512 
                 Me 
                 CH(Me)cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 513 
                 Me 
                 CH(Et)cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 514 
                 Me 
                 CH(Et)cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 515 
                 Me 
                 CH(Me)CH 2 -cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 516 
                 Me 
                 CH(OH)CH 2 -cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 517 
                 Me 
                 CH(Me)CH 2 -cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 518 
                 Me 
                 CH(Et)CH 2 -cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 519 
                 Me 
                 CH(Et)CH 2 -cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 520 
                 Me 
                 CH(CH 2 OMe)cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 521 
                 Me 
                 CH(CH 2 OMe)cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 522 
                 Me 
                 CH(CH 2 OEt)cyclobutyl 
                 2,4-Cl 2 -Ph 
               
               
                 523 
                 Me 
                 CH(CH 2 OEt)cyclopropyl 
                 2,4-Cl 2 -Ph 
               
               
                 524 
                 Me 
                 CH(cyclobutyl) 2   
                 2,4-Cl 2 -Ph 
               
               
                 525 
                 Me 
                 CH(cyclopropyl) 2   
                 2,4-Cl 2 -Ph 
               
               
                 526 
                 Me 
                 CH(Et)CH 2 CONMe 2   
                 2,4-Cl 2 -Ph 
               
               
                 527 
                 Me 
                 CH(Et)CH 2 CH 2 NMe 2   
                 2,4-Cl 2 -Ph 
               
               
                 528 
                 Me 
                 CH(CH 2 OMe)Me 
                 2,4-Cl 2 -Ph 
               
               
                 529 
                 Me 
                 CH(CH 2 OMe)Et 
                 2,4-Cl 2 -Ph 
               
               
                 530 
                 Me 
                 CH(CH 2 OMe)Pr 
                 2,4-Cl 2 -Ph 
               
               
                 531 
                 Me 
                 CH(CH 2 OEt)Me 
                 2,4-Cl 2 -Ph 
               
               
                 532 
                 Me 
                 CH(CH 2 OEt)Et 
                 2,4-Cl 2 -Ph 
               
               
                 533 
                 Me 
                 CH(CH 2 OEt)Pr 
                 2,4-Cl 2 -Ph 
               
               
                 534 
                 Me 
                 CH(CH 2 C≡CMe)Et 
                 2,4-Cl 2 -Ph 
               
               
                 535 
                 Me 
                 CH(CH 2 CH≡CHMe)Et 
                 2,4-Cl 2 -Ph 
               
               
                   
               
             
          
         
       
     
     Examples shown above in Tables 1-4 wherein R 3  is H, C 2 H 5 , C 3 H 7  or C 1-6 alkylC 3-6  cycloalkyl are also readily prepared according to the procedures disclosed herein. 
     CRF Receptor Binding Assay for the Evaluation of Biological Activity 
     Radioligand Binding Experiments 
     Compounds of the invention were tested for in vitro activity as CRF receptor antagonists. The tests described below demonstrated that the examples tested had K i s of 10,000 nM or less and are thus useful as CRF receptor antagonists. Preferred antagonists have or will have a K i  of 1,000 nM or less. Radioligand binding experiments were performed with membranes from rat frontal cortex to determine binding affinities (K i &#39;s) of test compounds for the rat CRH 1  receptor using a modified version of methods described earlier (see E. B. DeSouza, J. Neurosci, 7:88, 1987). Rat cortex was homogenized in tissue buffer (containing 50 mM HEPES, 10 mM MgCl 2 , 2 mM EGTA, and 1 μg/ml each of aprotonin, leupeptin, and pepstatin, pH 7.0 @ 23° C.) using a Brinkman Polytron (PT-10, setting 6 for 10 sec). The homogenate was centrifuged at 48,000×g for 12 min and the resulting pellet was washed by two sequential re-suspension and centrifugation steps. The final pellet was suspended to tissue buffer to a working concentration of 0.1 mg/ml protein. Protein determinations were made using the bicinchoninic acid (BCA) assay (Pierce, Rockford, Ill.) with bovine serum albumin as the standard. 
     All test compounds were prepared in assay buffer, which was identical to the tissue buffer except for the inclusion of 0.15 mM bacitracin and 0.1% w/v ovalbumin. Binding assay were conducted in disposable polypropylene 96-well plates (Costar Corp., Cambridge, Mass.) and initiated by the addition of 100 μl membrane homogenate (containing 40-60 μg protein) to 200 μl of assay buffer containing radioligands (150 pM, final concentration, [ 125 I] tyr o  ovine CRH; New England Nuclear, MA) and competing test compounds. Specific binding was determined in the presence of 10 μM α-helical CRH. Competition experiments were conducted using 12 concentrations of ligand (ranging from 1×10 −11  to 1×10 −5  M). The reactions mixtures were incubated to equilibrium for 2 hr at 23° C. and terminated by rapid filtration using a cell harvester (Inotech Biosystems Inc., Lansing Mich.) over GFF glass-fibers (pre-soaked in 0.3% v/v polyethyleneimine). Filters were rapidly washed 3× with 0.3 ml cold wash buffer (PBS, pH 7.0, containing 0.01% Triton X-100), dried, and counted in a gamma counter at 80% efficiency. 
     Binding affinities (K i &#39;s) of ligands for the CRH 1  receptor were calculated using the iterative nonlinear regression curve-fitting programs (LIGAND) of Munson and Rodbard (Anal. Biochem. 1980, 107, 220-239) or Prism (GraphPad Prism, San Diego, Calif.). Data were best-fit by the one-site/state competition equation. 
     Inhibition of CRF-Stimulated Adenylate Cyclase Activity 
     Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G. Battaglia et al.  Synapse  1:572 (1987). Briefly, assays are 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′-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10 −9  to 10 −6m ) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions are 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) is added to each tube prior to separation. The separation of [ 32 P]cAMP from [ 32 P]ATP is performed by sequential elution over Dowex and alumina columns. 
     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. 
     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 “Remington&#39;s Pharmaceutical Sciences”, 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. 
     Although the present invention has been described and exemplified in terms of certain preferred embodiments, other embodiments will be apparent to those skilled in the art. The invention is, therefore, not limited to the particular embodiments described and exemplified, but is capable of modification or variation without departing from the spirit of the invention, the full scope of which is delineated by the appended claims.

Technology Classification (CPC): 2