NO315610B1 - Azolotriazines and pyrimidines - Google Patents

Description

The present invention relates to compounds that can be used in the treatment of psychiatric deficiencies and neurological diseases including depression, anxiety-related deficiencies, post-traumatic stress deficiencies, supranuclear palsy and eating disorders as well as the treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disorders and stress, by administering certain [1,5-a]-pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines , [1,5-a]-pyrazolo-pyrimidines and [1,5-a]-1,2,3-triazolo-pyrimidines.

The invention further relates to pharmaceutical preparations containing these compounds.

Finally, the invention relates to the use of compounds as described above, for the production of medicines.

Corticotropin-releasing factor (hereafter CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the posterior pituitary gland [J. Rivier et al., "Proe. Nat. Acad. Sei. (USA)", 80:4851 (1983); W. Vale et al., "Science", 213:1294 (1981)]. In addition to its endocrine role as a pituitary gland, immunohistochemical localization of CRF has shown that the hormone has a wide extrahypothalmic 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 the brain [W. Vale et al., "Ree. 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 to suggest 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 deficits and neurological diseases including depression, anxiety-related deficits and eating disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for an overview see E.B. De Souza, "Hosp. Practice", 23:59 (1988)].

In affective deficiency 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", 226:1432 (1984); CM. 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 reduced 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 adreno-corticotropin (ACTH) response to CRF (administered intravenously), observed in patients with depression [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 further support for the hypothesis that hypersecretion of CRF may be involved in symptoms seen in human depression [R.M. Sapolsky, "Arch. Gen. Psychiatry", 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants may alter CRF levels and thereby modulate the number of CRF receptors in the brain [Grigoriadis et al., "Neuropsychopharmacology", 2:53 (1989)].

A role for CRF in the etiology of anxiety-related deficits has also been postulated. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a number of behavioral anxiety models [D.R. Britton et al., "Life Sci.", 31:363 (1982); C. W. Berridge g AJ. Dunn, "Reg. Peptides", 16:83

(1986)]. Preliminary studies using the putative CRF receptor antagonist α-helical ovine CRF (9-41) in a number of behavioral paradigms show that the antagonist produces "anxiolytic-like" effects qualitatively similar to benzodiazepines [C.W. Berridge and AJ. Dunn, "Horm. Behav", 21:393 (1987), "Brain Research Reviews", 15:71 (1990)]. Neurochemical, endocrine, and receptor binding studies have all shown interactions between CRF and benzodiazepine anxiolytics, providing further evidence for the involvement of CRF in these deficits. Chlordiazepoxide enhances the "anxiogenic" effects of CRF both in 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 (Rol5-1788) which was behaviorally inactive alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner, whereas the benzodiazepine inverse agonist (EG7142) enhanced the effects of CRF [K.T. Britton et al., "Psychopharmacology", 94:306 (1988)].

The mechanisms and sites of action through which standard anxiolytics and antidepressants produce the therapeutic effect have not yet been fully elucidated. However, it is thought that those involved in the suppression of the CRF hypersecretion observed in these are missing. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (α-helical CRF9.41) in a number of behavioral paradigms have shown that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to those of benzodiazepines [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 ed., CRC Press, page 221 (1990)].

Several publications describe corticotropin-releasing factor antagonist compounds and their use in treating psychiatric deficits and neurological diseases. Examples of such publications are DuPont Merck PCT application US 95/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 0778 277 Al.

To the best of our knowledge, [1,5-a]-pyrazoIo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-tria-zines, [ 1,5-a]-pyrazolo-pyrimidines and [1,5-a]-1,2,3-tyrazolo-pyrimidines have not previously been reported as corticotropin-releasing factor antagonist compounds that can be used in the treatment of psychiatric deficiencies and neurological diseases. However, there have been publications describing some of these compounds for other applications.

For example, EP 0 269 859 (Ostuka, 1988) describes pyrazolotriazine compounds of the formula:

where R<1> is OH or alkanoyl, R<2> is H, OH or SH and R<3> is an unsaturated heterocyclic group, naphthyl or substituted phenyl, and indicates that the compounds have xanthine oxidase inhibitory activity and can be used for treatment of gout.

EP 0 594 149 (Ostuke, 1994) describes pyrazolotriazine and pyrazolopyrimidine compounds of the formula:

where A is CH or N, R° and R<3> are H or alkyl, and R<1> and R<2> are H, alkyl, alkoxy, alkylthio, nitro, and so on, indicating that the compounds inhibit androgen and are useful in the treatment of benign prostatic hypertrophy and prostatic carcinoma.

US 3,910,907 (ICI, 1975) describes pyrazolotriazines of the formula:

where R<!>CH3, C2H5 or C6H5, X is H, C6H5, m-CH3 C6H4CN, COOEt, CI, I or Br, Y is H, C6H5,0-CH3C6H4 or p-CH3C6H4 and Z is OH, H, CH3, C2H5, C6H5, n-C3H7, i-C3H7, SH, SCH3, NHC4H9 or N(C2H5)2 and indicates that the compounds are cAMP phosphodiesterase inhibitors that can be used as bronchodilators.

US 3,995,039 describes pyrazolotriazines of the formula:

where R<1> is H or alkyl, R<2> is H or alkyl, R<3> is H, alkyl, alkanoyl, carbamoyl or lower alkylcarbamoyl and R is pyridyl, pyrimidinyl or pyrazinyl and indicates that the compounds are useful as bronchodilators.

US 5,137,887 describes pyrazolotriazines of the formula:

where R is lower alkoxy and states that the compounds are xanthine oxidase inhibitors and can be used for the treatment of gout.

US 4,892,576 describes pyrazolotriazines of the formula:

where X is O or S, Ar is a phenyl, naphthyl, pyridyl or thienyl group, Rg to Rg are H, alkyl, etc., and R9 is H, alkyl, phenyl, etc. The patent states that the compounds are useful as herbicides and as plant growth regulators.

US 5,484,760 and WO 91/10098 describe herbicidal compositions containing, inter alia, a herbicidal compound of the formula: where A may be N, B may be CR 3 , R 3 may be phenyl or substituted phenyl, and so on, R is -N( R4)SO2R5 or -SO2N(R<i)R7 and Ri and R2 together can form

where X, Y and Z are H, alkyl, acyl, and so on and D is O or S.

US 3,910,907 and Senga et al. in "J. Med. Chem.", 1982, 25, 243-249, describes triazolo-triazines cAMP phosphodiesterase inhibitors of the formula:

where Z is H, OH, CH3, C2H5, C6H5, N-C3H7, iso-C3H7, SH, SCH3, NH(n-C4H9) or N(C2H5)2, R is H or CH3 and Ri is CH3 or C2Hs. The reference summarizes eight therapeutic areas where inhibitors of cAMP phosphodiesterase could find application: asthma, diabetes mellitus, women's fertility control, male infertility, psoriasis, thrombosis, anxiety and hypertension.

WO 95/35298 (Otsuka, 1995) describes pyrazolopyrimidines and states that they can be used as analgesics. The compounds are represented by the formula:

where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, R<1> is H, alkyl, and so on, R<2> is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy , R3 is H, alkyl or phenyl, R<4> is H, alkyl, alkoxycarbonyl, phenyl-alkyl, optionally phenylthio-substituted phenyl, or halogen, R<5> and R<6> are H or alkyl.

EP 0 591 528 (Otsuka, 1991) describes the anti-inflammatory use of pyrazolopyrimidines represented by the formula:

where R], R2, R3 and R4 are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl or phenyl, R5 is SRe or NR7R8, Re is pyridyl or optionally substituted phenyl and R7 and R5 are H or optionally substituted phenyl.

Spinger et al. in "J. Med. Chem.", 1976, vol. 19, No. 2,291-296 and Springer US

4,021,556 and 3,920,652 describe pyrazolopyrimidines of the formula:

where R can be phenyl, substituted phenyl or pyridyl, as well as their use for the treatment of gout, based on the ability to inhibit xanthine oxidase.

Joshi et al. describes in "J. Prakt. Chemie", 321,2,1979,341,344, compounds of the formula:

where R<1> is CF3, C2F5 or C6H4F and R<2> is CH3, C2H5, CF3 or CerLjF.

Maquestiau et al. describes in "Bull. Soc. Belg.", vol. 101, No. 2, 1992, pages 131-136 a pyrazolo[1,5-a]pyrimidine of the formula:

Ibrahim et al. describes in "Arch. Pharm, (weinheim) 320,487-491 (1987) pyrazolo[1,5-a]pyrimidines of the formula:

where R is NH 2 or OH and Ar is 4-phenyl-3-cyano-2-aminopyrid-2-yl.

Other references describing azolopyrimidines include EP 0 511528 (Otsuka, 1992), US 4 997 940 (Dow, 1991), EP 0 374 448 (Nissan, 1990), US 4 621 556 (ICN, 1997), EP 0 531 901 ( Fujisawa, 1993), US 4,567,263 (BASF, 1986), EP 0,662,477 (Isagro, 1995), DE 4,243,279 (Bayer, 1994), US 5,397,774 (Upjohn, 1995), EP 0,521,622 ( Upjohn, 1993), WO 94/109017 (Upjohn, 1994), "J. Med. Chem.", 14,610-613 (1981) and "J. Het. Chem.", 22,601 (1985).

According to a feature of the invention, it relates to new compounds, pharmaceutical preparations that can be used in the treatment of affective deficiencies, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immunosuppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa and others eating disorders, drug or alcohol withdrawal symptoms, drug addiction, inflammatory deficiencies, fertility problems, deficiencies whose treatment can be accomplished or alleviated by antagonizing CRF, including but not limited to deficiencies induced or alleviated by CRF, or a deficiency selected from inflammatory deficiencies such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorders; panic, phobias, obsessive-compulsive disorders; post-traumatic stress deficits; sleep deprivation induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single-episode depression, recurrent depression, childhood abuse-induced depression, and postpartum depression; dystemia; bipolar deficits; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndromes, Crohn's disease, spastic colon, diarrhea and post-operative ileus and colonic hypersensitivity associated with psychopathological disorders or stress, eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid disease syndrome; syndrome of insufficient antidiarrheal hormone (ADH); obesity; infertility; head trauma; spinal cord trauma; ischemic neuronal damage (for example, cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hearing-related deficits including hypertension, tachycardia and congestive heart failure; punch; immune dysfunctions including stress-induced immune dysfunctions (for example, stress-induced fever, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation and dysfunctions induced by confinement in chickens, scrapie in sheep or anti-animal interaction-related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer type; multi-infarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (for example, dependence on alcohol, cocaine, heroin, benzodiazepine and other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in mammals.

The invention provides novel compounds that bind to corticotropin-releasing factor receptors and thereby alter the anxiogenic effects of CRF secretion. The compounds of the invention are useful for the treatment of psychiatric deficiencies and neurological diseases, anxiety-related deficiencies, post-traumatic stress deficiencies, supra-nuclear palsy and eating deficiencies as well as the treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disorders and stress in mammals.

According to a further aspect, the invention provides new compounds of formula (1) as described below, which can be used as antagonists of the corticotropin-releasing factor. The compounds of the invention show activity as corticotropin-releasing factor antagonists and appear to suppress CRF hypersecretion. The invention also encompasses pharmaceutical preparations containing such compounds of formula (1) and methods for using such compounds for the suppression of CRF hypersecretion, and/or in the treatment of anxiogenic deficiencies.

According to a further aspect of the invention, the compounds provided (and particularly labeled compounds of the invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.

According to the above, the invention relates to compounds characterized by formula (1):

and isomers thereof, stereoisomeric forms thereof or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein: A is N or CR;

Z CR<2>;

Ar is phenyl or pyridyl, optionally substituted with 1 to 5 R<4> groups and each Ar is

bonded to an unsaturated carbon atom;

R<1> is C 1 -C 4 alkyl;

R<2> is C 1 -C alkyl;

R<3> is selected from:

-OR<7>, halogen, NR<8>COR<7>, NR6R7, NR<6>aR7a or

-C 1-10 alkyl, each optionally substituted with 1 to 3 substituents independently at each occurrence selected from CO 2 R<15> or NR 16 R<15>;

R<4> is independently selected at each occurrence from among:

C1-10alkyl, C3-6cycloalkyl, halo, NR6R7 or OR<7>;

R<6> and R7, R6a and R<7a> independently at each occurrence are selected from:

-H,

-C 1-10 alkyl, C 4-12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently at each occurrence selected from cyano, OR 15 , NR<16>R 1<5> and

phenyl or

alternatively NR<*>R<7> and NR<6a>R<7a> independently are morpholine;

R<8> independently at each occurrence is selected from H or C 1 -C 4 alkyl; and

R15 and R<16> each independently at each occurrence is selected from H or C1-6 alkyl,

provided that when A is CR, Z is CR<2>, R<2> is CMalkyl, R<7> is NR2COR7 and Ar is phenyl, R<7> or R7<a> is not phenyl.

In a preferred embodiment, Ar is phenyl or pyridyl, optionally substituted with 1 to 4 R<4->substituents.

In yet another preferred embodiment, Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R<1> and R<2> are CH3, and R<3> is NR^R<7 >".

In a further preferred embodiment, R<3> is NR<fa>R<7a> or OR<7>.

In yet another preferred embodiment, R<7a> at each occurrence is independently selected from:

-H,

- Cs-C10alkyl or C4-C12cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently at each occurrence selected from cyano, OR15, NR<16>R<15> and phenyl.

Furthermore, in a preferred embodiment, R6a and R<7a> are identical and are:

- C 1 -C 4 alkyl, each optionally substituted with 1 to 3 substituents independently at each occurrence selected from cyano, OR<15>, NR<16>R<15> and phenyl.

In yet another preferred embodiment, R<7a> is selected from:

-Ci-C4alkyl and each such C1-C4alkyl is substituted with 1-3 substituents at each occurrence independently selected from cyano, OR15, NR<I6>R<15> and phenyl.

In yet another preferred embodiment, R6* and R<7a> are independently H or C1-C10alkyl, each C1-C10alkyl being optionally substituted with 1 to 3 substituents independently at each occurrence selected from cyano, OR15, NR<16>R<15 > and hello.

In yet another preferred embodiment, Ar is optionally substituted with 1 to 4 ^-substituents, and R<3> is NR^R<7>" or OR<7>.

In a further preferred embodiment, R<7a> is independently at each occurrence selected from:

-H,

-C 1 -C 10 alkyl and C 4 -C 12 cycloalkylalkyl, each being optionally substituted with 1 to 3 substituents independently at each occurrence selected from cyano, OR 15 , NR<16>R<15> and phenyl.

In a further preferred embodiment, R6a and R<7a> are identical, and are:

-Ci-C4alkyl, each being optionally substituted with 1 to 3 substituents at each occurrence independently selected from cyano, OR<15> NR<16>R<15> and phenyl.

In also a preferred embodiment, R<7a> is selected from:

-C 1 -C 4 alkyl and each such C 1 -C 4 alkyl is substituted with 1-3 substituents at each occurrence independently selected from cyano, OR<15>, NRI 6 R 15 and phenyl.

In yet another preferred embodiment, R<6>" and R<7a> are independently H or C1-C10alkyl, each such C1-C10alkyl being optionally substituted with 1 to 3 substituents independently at each occurrence selected from cyano, OR15, NR< 16>R<1S> and halo.

In a further preferred embodiment according to the above is as indicated in formula (50)

selected from the group comprising: a compound of formula (50) wherein R<3> is -NHCH(n-Pr)2, R<4a> is Cl, R<4b> is H, R<4c> is Cl,

R<4d>erHogR<4e>erH;

a compound of formula (50) where R<3> is -N(Et)(n-Bu), R<4a> is Cl, R<4b> is H, R<4c> is Cl,

R<4d>erHogR<4e>erH;

a compound of formula (50) where R<3> is -(n-Pr)(CH2cPr), R<4a> is Cl, R<4b> is H, R<40> is Cl,

R<4d>erHogR<4e>erH;

a compound of formula (50) where R<3> is -N(CH2CH2OMe)2, R<4a> is Cl, R<4b> is H, R<4c> is

CLR^erHogR^erH;

a compound of formula (50) where R<3> is -NHCH(Et)(n-Bu), R<4a> is Cl, R<4b> is H, R<40> is

Cl.R^erHogR^erH;

a compound of formula (50) where R<3> is -NHCH(Et)(CH2OMe), R<4a> is Cl, R<4b> is H, R<4c>

isCl.R^erHogR^erH;

a compound of formula (50) where R3 is -NHCH(CH2OMe)2, R4* is Cl, R<4b> is H, R<46> is

CI, R4" is H and R4* is H;

a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Cl, R<4b> is H, R<4c> is Cl, R<4d> is H

and R 46 is H;

a compound of formula (50) where R<3> is -NHCH(CH2OEt)2, R<4a> is Cl, R<4b> is H, R<4c> is

Cl, R<4d>erHogR<4e>erH;

a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Cl, R<4b> is H, R<4c> is Cl, R4*1

isHogR<4e>isH;

a compound of formula (50) where R<3> is -N(Me)(Ph), R<4a> is CI, R<4b> is H, R<4c> is Cl, Rw

is H and R 40 is H;

a compound of formula (50) where R<3> is -N(n-Pr)2, R<44> is Cl, R<4b> is H, R<4c> is Cl, R<4d> is HogR< 4e>erH;

a compound of formula (50) where R3 is -NHCH(Et)(n-Pr), R<4a> is Cl, R<4b> is H, R<40> is

CLR^erHogR^erH;

a compound of formula (50) where R<3> is -NHCH(CH2OMe)2, R<4a> is Me, R<4b> is H, R<4c>

is Me, R<4d> is H and R4e is Me;

a compound of formula (50) where R<3> is -NHCH(CH2OMe)2, R<4a> is Me, R<4b> is H, R<4c>

is Me, R4d is H and R46 is H;

a compound of formula (50) where R<3> is -N(CH2CH2OMe)2, R<4a> is Me, R<4b> is H, R40 is

Me.R^erHogR^erH;

a compound of formula (50) where R<3> is -NHCH(Et)(CH2OMe), R<4a> is Me, R<4b> is H,

R<4c> is Me, R<4d> is H and R4* is H;

a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Me, R<4b> is H, R<40> is Me,

R4d is H and R46 is H;

a compound of formula (50) where R3 is -OEt, R<43> is Cl, R<4b> is H, R<4c> is Cl, R<4d> is H

and R<46> is H;

a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Me, R<4b> is H, R<40> is Me, R<4*> is

HogR<4e>erH;

a compound of formula (50) where R<3> is -N(CH2CN)2, R<4a> is Me, R<4b> is H, R<40> is Me,

R<4d>erHogR<4e>erH;

a compound of formula (50) where R<3> is -NHCH(Me)(CH2OMe), R<4a> is Me, R<4b> is H,

R<4c> is Me, R<4d> is H and R4* is H;

a compound of formula (50) where R<3> is -OCH(Et)(CH2OMe), R<4a> is Me, R<4b> is H, R<4c>

isMe,R<4d>isHogR<4e>isH;

a compound of formula (50) where R3 is -N(n-Pr)(CH2cPr), R<4a> is Me, R<4b> is H, R<4c> is Me, R<4d> is HogR<4e> isH;

a compound of formula (50) where R<3> is -NHCH(Me)(CH2N(Me)2, R<4a> is Me, R4b is H,

R<4c> is Me, R<4d> is H and R4e is H;

a compound of formula (50) where R<3> is -N(cPr)(CH2CH2CN), R<48> is Me, R<4b> is H, R<4c>

isMe.R^erHogR^erH;

a compound of formula (50) where R<3> is -N(n-Pr)(CH2CH2CN), R<4a> is Me, R<4b> is H,

R4<0> is Me, R<4*> is H and R4e is H;

a compound of formula (50) where R<3> is -N(n-Bu)(CH2CN), R<4a> is Me, R<4b> is H, R4<0> is

Me, R<4d>erHogR<4e>erH;

a compound of formula (50) where R<3> is -NHCH(Et)(CH2OMe), R<4a> is Me, R<4b> is H,

R<4*> is Me, R<4d> is H and R4* is Me;

a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Me, R<4b> is H, R<4c> is Me,

R<4d>erHogR<4e>erMe;

a compound of formula (50) where R<3> is -N(CH2CH2OMe)2, R<4a> is Me, R<4b> is H, R<46> is

M^R^erHogR^erMe;

a compound of formula (50) where R<3> is -NHCH(CH2OMe)2, R<43> is Br, R<4b> is H, R4c is

OMe,R<4d>erHogR<4e>erH;

a compound of formula (50) where R<3> is -NHCH(Et)(CH2OMe), R<4a> is Br, R<4b> is H, R<4c>

isOMe,R<4d>erHogR<4e>erH;

a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Me, R<4b> is H, R<4c> is Me, R<4d> is

H and R4* are Me;

a compound of formula (50) where R<3> is -NHCH(CH2OEt)2, R<4a> is Me, R<4b> is H, R<4c> is

Me.R^erHogR^erH;

a compound of formula (50) where R3 is -NHCH(CH2CH2OMe)2, R<4a> is Me, R<4b> is H,

R<4c> is Me, R<4d> is H and R4e is Me;

a compound of formula (50) where R<3> is morpholino, R<4a> is Me, R<4b> is H, R<4c> is Me, RM

is H and R4* is H;

a compound of formula (50) where R3 is -N(CH2CH2OMe)2, R<4*> is Br, R4b is H, R<4c> is

OMe.R^erHogR^erH;

a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Br, R<4b> is H, R4<*> is OMe,

R^erHogR^erH;

a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Br, R<4b> is H, R<4c> is OMe, R<4d> is

HogR^erH;

a compound of formula (50) where R3 is -NH(c-Pr), R<4a> is Me, R<4b> is H, R<4c> is Me, R<4d>

isHogR<4c>isH;

a compound of formula (50) where R<3> is -NHCH(CH2OMe)2, R<4a> is CN, R<4b> is H, R<4c>

is OMe, R<4d> is H and R46 is H;

a compound of formula (50) where R3 is -N(c-Pr)(CH2CH2CN), R<4a> is Me, R<4b> is H,

R<46> is Me, R<46> is H and R<4e> is Me;

a compound of formula (50) where R3 is -NCH(CH2OMe)2, R<4a> is Me, R<4b> is H, R<40> is

Br, R4<d>erHogR<4e>erH;

a compound of formula (50) where R3 is -NHCH(CH2OMe)(CH2CH2OMe), R<4a> is Me,

R<4b> is H, R<4c> is Br, R<4d> is H and R<4e> is H;

a compound of formula (50) where R3 is -NHCH(CH2OMe)2, R<4a> is Me, R<4b> is H, R<46>

is OMe, R<4d> is Me and R<4e> is H;

a compound of formula (50) where R3 is -N(CH2CH2OMe)2, R<4*> is Me, R<4b> is H, R<46> is

OMe, R4*1 is Me and R46 is H;

a compound of formula (50) where R3 is -NHCH(Et)2, R<4a> is Me, R<4b> is H, R<4c> is OMe,

R4<d>e<r>Me and R<4e>erH;

a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Me, R<4b> is H, R<40> is OMe, R<4d>

is Me and R4e is H;

a compound of formula (50) where R3 is -NHCH(CH2OMe)2, R<4a> is Cl, R<4b> is H, R<4*> is

Me.R^erHogR^erH;

a compound of formula (50) where R<3> is -NHCH(Et)(CH2OMe), R<48> is Cl, R<4b> is H, R<4c>

isMe,R<4d>isHogR<4e>isH;

a compound of formula (50) where R<3> is -NH(CH2CH2OMe)2, R<4a> is Cl, R4b is H, R<4c>

is Me, R<4*1> is H and R46 is H;

a compound of formula (50) where R<3> is -NHCH(CH2CH2OMe), R<4a> is Cl, R<4b> is H,

R<4c> is Me, R<4d> is H and R<4e> is H;

a compound of formula (50) where R<3> is -N(c-Pr)(CH2CH2CN), R<4>" is Me, R<4b> is H,

R<4c> is OMe, R<4d> is Me and R46 is H;

a compound of formula (50) where R3 is -N(c-Pr)(CH2CH2CN), R<4a> is Cl, R<4b> is H, R<*>

isCl,R<4d>isHogR<4e>isH;

a compound of formula (50) where R<3> is -(S)-NHCH(CH2OMe)(CH2CH2OMe), R4a is

Cl, R<4b> is H, R<4*> is Cl, R<4d> is H and R46 is H;

a compound of formula (50) where R3 is -NHCH(CH2OMe)(CH2CH2OMe), R<4a> is Cl,

R<4b> is H, R<40> is Cl, R<4d> is H and R4e is H;

a compound of formula (50) where R<3> is -NHCH(Et)2, R<4>" is Me, R<4b> is H, R<4c> is Br,

R<4d>isHogR<4c>isH;

a compound of formula (50) where R<3> is -NH(CH2CH2OMe)2, R<4a> is Me, R<4b> is H, R<40>

is Br, R4*1 is H and R4* is H;

a compound of formula (50) where R<3> is -NH(CH2OMe)(CH2-iPr), R<4a> is Me, R<4b> is H,

R<40> is Me, R4*1 is H and R4e is H;

a compound of formula (50) where R<3> is -N(CH2CH20Me)2j R<44> is Me, R<4b> is H, R<4c> is

FLR^erHogR^erH;

a compound of formula (50) where R3 is -N(CH2CH2OMe)2, R<4a> is Me, R<4b> is H, R<4c> is

NMe2,R<4d>erHogR<4e>erH;

a compound of formula (50) where R<3> is -NHCH(CH2OMe)(n-Pr), R4a is Me, R<4b> is H,

R<4c> is Me, R<4*1> is H and R46 is H;

a compound of formula (50) wherein R3 is -NCH(CH2OEt)(Et), R<4>" is Me, R<4b> is H, R<4c>

isMe.R^erHogR^erH;

a compound of formula (50) where R<3> is -NHCH(CH2OMe)(CH2CH2OMe), R<4a> is Me,

R<4b> is H, R<40> is NMe, R<4d> is H and R<4e> is H;

a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Me, R<4b> is H, R<4c> is Cl, R<4d> is

HogR^erH;

a compound of formula (50) where R3 is -NHCH(Et)2, R<4a> is Me, R<4b> is H, R<4c> is H,

R<4d>erHogR<4e>erH;

a compound of formula (50) where R3 is -N(CH2CH2OMe)2, R<4a> is Me, R<4b> is H, R<40> is

Cl.R^erHogR^erH;

a compound of formula (50) where R3 is -NHCH(CH2OMe)2, R<4a> is Me, R<4b> is H, R<4c>

is CLR^erHogR^erH;

a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Me, R<4b> is H, R<4*> is Br, R<4d> is

HogR<4e>erH;

a compound of formula (50) where R3 is -N(Et)2, R<4a> is Cl, R<4b> is H, R4c is Me, R<4>" is

HogR4<e>erH;

a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Cl, R4b is H, R40 is Me,

R^erHogR^erH;

a compound of formula (50) where R<3> is -NHCH(Et)2> R<4a> is Me, R<4b> is H, R<40> is

NMe2,R<4d>erHogR<4e>erH;

a compound of formula (50) where R<3> is -(S)-NHCH(CH2OMe)(CH2CH2OMe), R4a is

Me, R<4b> is H, R<4c> is Me, R<4d> is H and R<4*> is H;

a compound of formula (50) where R<3> is -NHCH(CH2OMe)(CH2CH2OMe), R4a is Me,

R<4b> is H, R<40> is Me, R<4d> is H and R<46> is H;

a compound of formula (50) where R<3> is (S)-NHCH(CH2OMe)(CH2CH2OMe), R4a is

Me, R<4b> is H, R<4c> is Cl, R<4d> is H and R<4*> is H;

a compound of formula (50) where R<3> is -NHCH(CH2OMe)(CH2CH2OMe), R<4a> is Me,

R<4b> is H, R<40> is Cl, RM is H and R<4*> is H;

a compound of formula (50) where R<3> is -N(c-Pr)(CH2CH2CN), R4a is Me, R<4b> is H,

R<4c>erCl, R<4d>erHo and R<4e>erH;

a compound of formula (50) where R<3> is -NH(Et)(CH2CN), R<4a> is Me, R<4b> is H, R<4c> is

ClR^erHogR^erH;

a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Me, R<4b> is Me, R<4c> is OMe, R<4d>

is H and R46 is H;

a compound of formula (50) where R<3> is -N(CH2CH2OMe)(CH2CH2OH), R<43> is Cl, R<4b>

is H, R<4c> is Cl, R<4>" is H and R<4e> is H;

a compound of formula (50) where R<3> is -N(CH2CH2OMe)2, R<4*> is Me, R<4b> is Me, R<4*>

isOMe,R<4d>erHogR<4c>erH;

a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Me, R<4b> is Me, R<4c> is

OMe.R^erHogR^erH;

a compound of formula (50) wherein R<3> is -N(CH2c-Pr)(n-Pr), R4a is Me, R<4b> is H, R<40> is Cl.R^erHogR^erH;

a compound of formula (50) where R<3> is -N(c-Pr)(CH2CH2CN), R4a is Me, R<4b> is Me,

R<40> is OMe, R<4d> is H and R4* is H;

a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Cl, R<4b> is H, R<4c> is OMe,

R<4d>isHogR<4c>isH;

a compound of formula (50) where R3 is -N(Et)2, R<4a> is Cl, R<4b> is H, R<4c> is OMe, R4d is

HogR<4e>er<H>;

a compound of formula (50) where R3 is -N(CH2CH2OMe)2, R<4a> is Cl, R<4b> is H, R<4*> is

OMe.R^erHogR^erH;

a compound of formula (50) where R3 is -NHCH(Et)(CH2OMe), R<4a> is Cl, R<4b> is H, R<40>

is OMe, R4d is H and R4* is H;

a compound of formula (50) where R3 is -N(Et)2, R<4a> is Cl, R<4b> is H, R<4c> is CN, R4d is

HogR<4e>erH;

a compound of formula (50) where R<3> is -N(c-Pr)(CH2CH2CN), R<4>" is Cl, R<4b> is H, R<4c>

is OMe, R<4>" is H and R4e is H;

a compound of formula (50) where R3 is -NHCH(CH2OH)2, R<4a> is Cl, R<4b> is H, R<4c> is

Cl, R4d is H and R46 is H; and

a compound of formula (50) where R3 is -N(CH2CH2OMe)2, R<4a> is Me, R4b is H, R<46> is

OMe,R<4d>erHogR<4e>erH.

In yet another embodiment, the compound is 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3 ,5-triazine.

In a further embodiment, the compound is 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1 ,3,5-triazine.

In yet another embodiment, the invention relates to a pharmaceutical preparation which is characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as described above.

As mentioned at the outset, the invention also relates to the use of compounds as described for the production of drugs for the treatment of anxiety, depression and other psychiatric, neurological deficiencies as well as the treatment of immunological, cardiolovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.

As mentioned at the outset, the invention relates to the further use of compounds as described for the production of drugs for the production of drugs for the treatment of affective disorders, anxiety, depression, headaches, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immunosuppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa and other eating disorders, 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 trauma, epilepsy, stroke, ulcer, amyotrophic lateral sclerosis, hypoglycemia or a deficiency can be accomplished or alleviated by antagonizing CRF, including but not limited to deficiencies induced or facilitated by CRF.

Many compounds according to the invention have one or more asymmetric centers or planes. Unless otherwise stated, all chiral (enantiomers and diastereomers) and racemic forms are included within the scope of the invention. Many geometric isomers of definitions, C=N double bonds and the like can also be present in the compounds and all such stable isomers are considered to be covered by the invention. The compounds can be isolated in optically active or racemic form. It is well known in the art how to prepare optically active forms, for example by dissolving racemic forms or by synthesis from optically active starting substances. All chiral (enantiomeric and diastereomeric) and racemic forms and all geometrically isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric 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 meaning: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. The prefix "n" means 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 straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur at any stable point along the chain such as ethenyl, propenyl and the like. "Alkynyl" includes hydrocarbon chains of straight or branched configuration and one or more carbon-carbon triple bonds which may occur at any stable point along the chain, for example ethynyl, propynyl and the like. "Haloalkyl" is intended to include both branched and straight alkyl having the specified number of carbon atoms, substituted with one or more halogen atoms; "Alkoxy" means an alkyl group with the indicated number of carbon atoms attached via an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups including mono-, bi- or polycyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on. "Halo" or "halogen" includes fluorine, chlorine, bromine and iodine.

The term "substituted" as used herein means that one or more hydrogen atoms on the specified atom have been replaced by a choice from the indicated group provided that the normal valence of the specified atom is not exceeded and that the substitution results in a stable compound. When a substituent is keto (that is, =0), 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 sufficiently robust to survive isolation in a reasonable degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

The term "suitable amino acid protecting group" means any group known in the art of organic synthesis for protecting amine or carboxylic acid groups. Such amine protecting groups are those listed by Greene and Wuts in "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1991) as well as in "The Peptides: Analysis, Synthesis, Biology", vol. 3, Academic Press, New York

(1981). Any amine protecting group known in the art may 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 species such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl and 9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate species such as tert-butyloxycarbonyl (Boe), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; (4) cyclic alkyl carbamate species such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl species such as triphenylmethyl and benzyl;

(6) trialkylsilane such as trimethylsilane; and

(7) thiol-containing species such as phenylthiocarbonyl and dithiasuccinoyl.

The term "pharmaceutically acceptable salts" includes acid or base salts of the compounds of formulas (1) and (2). Examples of pharmaceutically acceptable salts include, but are not limited to mineral and organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acid; and such.

Pharmaceutically acceptable salts of the compounds according to the invention can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent, or in a mixture of these; in general, non-aqueous media such as ether, ethyl acetate, ethanol, iso-propanol or acetonitrile are preferred. Lists of suitable salts can be found in "Remington's Pharmaceutical Sciences", 17th ed. Mack Publishing Company, Easton, PA, 1985, page 1418.

"Prodrugs" are intended to mean any covalently bound carriers that release the active parent drug of formula (I) or (TJ) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formulas (I) and (U) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compounds. Prodrugs include those compounds in which hydroxy, amine or sulfhydryl groups are attached to any group which, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino or sulfhydryl group. 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 such.

The term "therapeutically effective amount" of a compound of the invention means an amount effective for antagonizing abnormal levels of CRF or treating the symptoms of affective deficiency, anxiety or depression in a host.

Syntheses

Some compounds of formula (1) can be prepared from intermediates of formula (7) using the procedures outlined in Scheme 1.

The compounds of formula (7) (wherein Y is O) can be treated with a halogenating agent or a sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at a reaction temperature in the range of -80°C to 250°C for thereby giving products of formula (8) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkanesulfonyloxy). Halogenating agents include, but are not limited to, SOCI 2 , POCI 3 , PCI 3 , PCI 5 , POBr 3 , PBr 3 , or PBr 5 . The sulfonyl compounds include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or

-anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride).

alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or

-ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal bis(tiralkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkylamines (preferably N,N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkane nitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydro-

furan or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes with 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). Preferred reaction temperatures are in the range of -20°C to 100°C.

Compounds of formula (8) may be reacted with compounds of formula R<3>H (wherein R<3> is as indicated above except that R<3> is not SH, COR<7>, CO2R<7>, aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at a reaction temperature in the range of -80°C to 250°C to give compounds of formula (1). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxy or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis(trialkylsilyl) amides (preferably sodium bis(trimethylsilyl)amide), trialkylamines (preferably N,N-diisopropyl-N-ethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, 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 with 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). Preferred reaction temperatures are in the range of 0°C to 140°C.

Scheme 2 outlines the procedures for converting intermediates of formula (7) (where Y is S) into certain compounds of formula (1).

Compounds of formula (7) (where Y is S) can be treated with an alkylating agent R,<3>X (where R<13> is as defined above, except that R13 is not aryl or heteroaryl) 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. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(thyralkylsilyl) amides

(preferably sodium bis(trimethylsilyl)amide), trialkylamines (preferably N,N-diiso-propyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, 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 with 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). Preferred reaction temperatures are in the range of -80°C to 100°C.

Compounds of formula (12) (Formula (1) where R3 is SR<13>) can then be reacted with compounds of formula R<3>H to give compounds of formula (1) using the same conditions and reagents as were used for the conversion of compounds of formula (8) into compounds of formula (1) as stated in scheme 1 above. Alternatively, compounds of formula (12) (formula (1) where R 1 is SR 11) can be oxidized to compounds of formula (13) (formula (1) where R<3> is S(0)nR<13>, n is 1 or 2) by treatment with an oxidizing agent in the presence of an inert solvent at temperatures in the range -80°C to 250°C. Oxidizing agents include, but are not limited to, hydrogen peroxide, alkane or aryl peracids (preferably peracetic acid or m-chloro-perbenzoic acid), dioxirane, oxone or sodium periodate. Inert solvents may include, but are not limited to, alkanones (3 to 10 carbon atoms, preferably acetone), water, alkyl alcohols (1 to 6 carbon atoms), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes of 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane) or combinations thereof. The choice of oxidizing agent and solvent is known to those skilled in the art (cf. S. Uemura, "Oxidation of Sulfur, Selenium and Tellurium" in "Comprehensive Organic Synthesis", B.M. Trost, ed., (Elmsford, NY: Pergamon Press, 1991), 7,762- 769). Preferred reaction temperatures are in the range of -20°C to 100°C. Compounds of formula (13) (formula (1) where R<3> is S(0)„R<13>, n is 1 or 2) can then be reacted with compounds of formula R H to give compounds of formula (1) using the same conditions and reagents as were used for the conversion of compounds of formula (8) to compounds of formula (1) as outlined for scheme (1) above. Compounds of formula (1), where R<3> can be -NR<8>COR<7>, -N(COR<7>)2, -NR<8>CONR<6>R7, -NR8C02Rl\ NR< 6>R<7>, -NR<8>SO2R<7>, can be prepared from compounds of formula (7), where Y is NH, by the procedures indicated in scheme 3. The reaction of compounds of formula (7) , where Y is NH, with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with combinations thereof, in the presence or absence of a base, in an inert solvent at reaction temperatures in the range of -80°C to 250°C, can give compounds of formula ( 1), where R<3>can be -NR<8>COR<7>, -N(COR<7>)2, -NR<8>CONR<6>R<7>, -NR<8>CO2R <13>, NR<6>R7, -NR<8>SO2R<7. >Alkylating agents may include, but are not limited to, C 1-10 alkyl halides, tosylates, mesylates or triflates; C 1-10 haloalkyl (1 to 10 halogen atoms) halides, tosylates, mesylates or triflates; C 2-8 alkoxyalkyl halides, tosylates, mesylates or triflates; C3-6 cycloalkyl halides, tosylates, mesylates or triflates; Gmr cycloalkylalkyl halides, tosylates, mesylates or triflates; aryl-(C 1-4 alkyl) halides, tosylates, mesylates or triflates; heteroaryl-(C 1-4 alkyl) halides, tosylates, mesylates or triflates; or heterocyclyl-(C 1-4 alkyl) halides, tosylates, mesylates or triflates. Acylating agents may include, but are not limited to, C1-10-α-alkanoyl halides or anhydrides, C1-10-α-alkanoyl halides or anhydrides, C1-10-haloalkanoyl halides or anhydrides having 1 to 10 halogen atoms, C2.8-alkyl alkanoyl halides or anhydrides, C3-6-cycloalkanoyl halides or anhydrides, C4- i2cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl(Ci-4)alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl(CM)alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides or anhydrides, or heterocyclyl(Ci-4)alkanoyl halides or -anhydrides. Sulfonyl agents include, but are not limited to, C 1-10 alkylsulfonyl halides or anhydrides, C 1-10 haloalkylsulfonyl halides or anhydrides having 1 to 10 halogen atoms, C 2-4 alkoxy alkylsulfonyl halides or anhydrides, C 3-6 cycloalkylsulfonyl halides or anhydrides, C 4-12 cycloalkyl alkylsulfonyl halides or anhydrides . Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl) amides (preferably sodium bis(trimethylsilyl)amide), trialkylamines (preferably di-isopropylethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, 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) or aromatic hydrocarbons ( preferably benzene or toluene). Preferred reaction temperatures are in the range of 0°C to 100°C.

Form 4 summarizes procedures that can be used to prepare intermediate products with formula (7) where Y is O, S and Z is CR<2>.

Compounds of formula ArCt^CN are reacted with compounds of formula R<2>COR<b>, where R is as indicated above and R is halogen, cyano, lower alkoxy (1 to 6 carbon atoms) or lower alkanoyloxy (1 to 6 carbon atoms), in presence of a base in an inert solvent at reaction temperatures in the range from -78°C to 200°C to obtain compounds of formula (3). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms)

(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkylamines (preferably N,N-diisopropyl-N- ethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, preferably acetonitrile), water, 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) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures are in the range of 0°C to 100°C.

Compounds of formula (3) can be reacted with hydrazine hydrate in the presence of an inert solvent at temperatures in the range 0°C to 200°C, preferably 70°C to 150°C, thereby giving compounds of formula (4). Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, 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). Compounds of formula (4) can be reacted with compounds of formula (5) (where R<c> is alkyl (1 to 6 carbon atoms)) in the presence or absence of an acid in the presence of an inert solvent at temperatures in the range 0 °C to 200°C to thereby give compounds of formula

(6). Acids may include, but are not limited to, alkanoic acids with 2 to 10 carbon atoms (preferably acetic acid), haloalkanoic acids (2 to 10 carbon atoms, 1 to 10 halogen atoms, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids with 1 to 10 carbon atoms (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, water, alkane nitriles (1 to 6 carbon atoms, preferably acetonitrile), halocarbons of 1 to 6 carbon atoms and 1 to 6 halogen atoms (preferably dichloromethane or chloroform), alkyl alcohols of 1 to 10 carbon atoms (preferably ethanol), dialkyl ethers (4 to 12 carbon atoms, preferably diethyl ether or diisopropyl ether) or cyclic ethers such as dioxane or tetrahydrofuran. Preferred temperatures are in the range from ambient temperature to 100°C.

Compounds of formula (6) can be converted into intermediates of formula (7) by treatment with compounds C=Y(R<d>)2 (where Y is O or S and Rd is halogen (preferably chlorine), alkoxy (1 to 4 carbon atoms) or alkylthio (1 to 4 carbon atoms)) in the presence or absence of a base in an inert solvent at reaction temperatures from -50°C to 200°C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkali metal carbonates, alkali metal hydroxides, trialkylamines (preferably N,N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, 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 are 0°C to 150°C.

Compounds of formula (1) can also be prepared from compounds of formula (7) where Y is O, S and Z are as indicated above) as outlined in Scheme 6:

Compounds of formula (7) can be reacted with compounds of formula R H in the presence of a dehydrating agent in an inert solvent at reaction temperatures in the range of 0°C to 250°C Dehydrating agents include, but are not limited to P2O5, molecular sieves or inorganic or organic acids. Acids may include, but are not limited to, alkanoic acids of 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbon atoms (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid, or phosphoric acid. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably glyme or diglyme), 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 halocarbons with 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably chloroform). Preferred reaction temperatures are in the range of ambient temperature to 150°C.

Certain compounds with formula (1) (where A is N) can also be prepared by the methods shown in scheme 7:

Intermediates of formula (14), where Z is as indicated above, can be reacted with compounds of the formula R<3>C(OR<e>)3, where Re can be alkyl (1 to 6 carbon atoms) in the presence or absence of a acid in an inert solvent at temperatures in the range 0°C to 250°C. Acids may include, but are not limited to, alkanoic acids of 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbon atoms (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid, or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkane nitriles (1 to 6 carbon atoms, 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 with 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). Preferred reaction temperatures are in the range of 50°C to 150°C.

Intermediates with formula (7) can also be synthesized by the reactions shown in scheme 8.

Compounds of formula (15) (where Y is OH, SH, NR<6>R<7>; Z is as defined above, X is Br, Cl, I, O3SCF3 or B(OR"")2 and R"" is H or alkyl (1 to 6 carbon atoms)) can be reacted with a compound of the formula ArM (where M is halogen, alkali metal, ZnCl, ZnBr, Znl, MgBr, MgCl, Mgl, CeCl2, CeBr2 or copper halides) in the presence or absence of a organometallic catalyst in the presence or absence of a base in an inert solvent at temperatures in the range -100°C to 200°C. Those skilled in the art will recognize that the reagent ArM can be generated in situ. Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd(PPli3)4), palladium halides or alkanoates (such as PdCl2(PPli3)2 or Pd(OAc)2), or nickel complexes (such as NiCl2(PPh3)2). Bases may include, but are not limited to, alkali metal carbonates or trialkylamines (preferably N,N-diisopropyl-N-ethylamine or triethylamine). Inert solvents may include, but are not limited to, 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 water. Preferred reaction temperatures are within the range of -80°C to 100°C. The choice of M and X is known to those skilled in the art (cf. T. Imamoto, "Organocerium Reagents" in "Comprehensive Organic Synthesis", B.M. Trost, ed., (Elmsford, New: Pergamon Press, 1991), 1,231-250; P. Knochel "Organozinc, Organocadmium and Organomercury Reagents" in "Comprehensive Organic Synthesis", B. M. Trost, ed., (Elmsford, NY: Pergamon Press, 1991), 1, 211-230; D. W. Knight, "Coupling Reactions between sp<2 >Carbon Centers" in "Comprehensive Organic Synthesis", B.M. Trost, ed., (Elmsford, NY: Pergamon Press, 1991), 3,481-520).

Compounds of formula (1) can also be prepared using the methods indicated in scheme 9.

Compounds of formula (16), where A, Z, R<1> and R<3> are as indicated above and X is Br, Cl,

I, O3SCF3 or B(OR"")2 and R'"' is H or alkyl (1 to 6 carbon atoms)) can be reacted with a compound of formula ArM (where M is halogen, alkali metal, ZnCl, ZnBr, Znl, MgBr, MgCl, Mgl, CeCh, CeBr2 or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a base in an inert solvent at temperatures in the range of -100°C to +200°C. Those skilled in the art will recognize that the reagents ArM can be generated in situ (see references above in "Comprehensive Organic Synthesis") Organometallic catalysts include but are not limited to palladium phosphine complexes (such as Pd(PPh3)4), palladium halides or alkanoates (such as PdCl2(PPh3)2 or Pd(OAc)2) or nickel complexes (such as NiCl2(PPh3)2). Bases may include, but are not limited to, alkali metal carbonates or trialkylamines (preferably N,N-diisopropyl-N-ethylamine or triethylamine). Inert solvents may include, but are not limited to dialkyl ethers (preferably diethyl ether), cycli ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methyl-pyrrolidin-2-one), dialkylsulfoxides ( preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. Preferred reaction temperatures are in the range -80°C to +100°C.

Intermediates of formula (7) (where Y is O, S, NH, Z is CR<2> and R<1>, R<2> and Ar are as indicated above) can be prepared as shown in Scheme 10.

Compounds of formula (3) can be reacted with compounds of the formulas H2NNH(C=Y)NH2, where Y is O, S or NH, in the presence or absence of a base or an acid in an inert solvent at temperatures from 0°C to +250°C to thereby produce compounds of formula (17). Acids may include, but are not limited to, alkanoic acids of 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbon atoms

(preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids can be used. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium -bis(trimethylsilyl)amide), trialkylamines (preferably N,N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbon atoms), lower alkane nitriles (1 to 6 carbon atoms, 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) or aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes with 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane).

Preferred reaction temperatures are in the range 0°C to +150°C. Compounds of formula (17) can then be reacted with compounds of formula R<3>C(OR<c>)3, where R<c> can be alkyl (1 to 6 carbon atoms) in the presence or absence of an acid in an inert solvent at a temperature in the range 0°C to +250°C. Acids may include, but are not limited to, alkanoic acids of 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbon atoms (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkane nitriles (1 to 6 carbon atoms, 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 with 1

to 10 carbon atoms and I to 10 halogen atoms (preferably dichloromethane). Preferred reaction temperatures are in the range of 50°C to 150°C.

Compounds of the general formula (1), where R<3> can be -NR<8>COR<7>, -N(COR<7>)2, -NR8CONR6R7, -NR<8>C02R<13>, - NR6R<7>, -NR<8>SO2R<7>, can be synthesized as suggested in Scheme 13.

The reaction of compounds of formula (18) where R and R<1> are as indicated above, with compounds of formula (4) in the presence or absence of base in an inert solvent, can give compounds of formula (19) at temperatures from - 50°C to +250°C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bis(tiralkylsilyl)amides ( preferably sodium bis(trimethylsilyl)amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, 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) or aromatic hydrocarbons (preferably benzene or toluene ). Preferred reaction temperatures are in the range of 0°C to 100°C.

Compounds of formula (19) can then be reacted with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with combinations thereof, in the presence or absence of a base in an inert solvent at reaction temperatures in the range -80°C to +250°C, which can give compounds of formula (1), where R3 can be -NR<8>COR<7>, -N(COR<7>)2, -NR<8>CONR<6>R<7>, - NR<8>C02R<13>, -NR<6>R7,

-NR<8>S02R<7>. Alkylating agents may include, but are not limited to, C 1-10 alkyl halides, tosylates, mesylates or triflates; C 1-10 haloalkyl (1 to 10 halogen atoms) halides, tosylates, mesylates or triflates; C3-6cycloalkyl halides, tosylates, mesylates or triflates; C 1 -cycloalkyl alkyl halides, tosylates, mesylates or triflates; aryl(C 1-4 alkyl) halides, tosylates, mesylates or triflates; heteroaryl-(C 1 -C alkyl) halides, tosylates, mesylates or triflates; or heterocyclyl(C 1 -C alkyl) halides, tosylates, mesylates or triflates. Acylating agents may include, but are not limited to, C1-ioalkanoyl halides or anhydrides, Cuiohalogenalkanoyl halides or anhydrides with 1 to 10 halogen atoms, C2.«alkoxyalkanoyl halides or anhydrides, C3^cycloalkanoyl halides or anhydrides, C4.i2. cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl(Ci^)alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl(Ci^)alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides or anhydrides, or heterocyclyl(Ci^)alkanoyl halides or anhydrides . Sulfonyl impurities include, but are not limited to, C1-ioalkylsulfonyl halides or anhydrides, C1-iohaloalkylsulfonyl halides or anhydrides with 1 to 10 halogen atoms, C2.galkoxyalkylsulfonyl halides or anhydrides, C3.6. cycloalkylsulfonyl halides or anhydrides, C4-12cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl(Ci-4alkyl)-, heteroaryl halides or anhydrides, heteroaryl(C1-C alkyl)sulfonyl halides or anhydrides, heterocyclylsulfonyl halides or anhydrides, or heterocyclyl(Ci -4alkyl)-sulfonyl halides or anhydrides. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bis(tiralkylsilyl)amides ( preferably sodium bis(trimethylsilyl)amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, 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) or aromatic hydrocarbons (preferably benzene or toluene ). Preferred reaction temperatures are in the range of 0°C to 100°C.

Compounds of formula (1), where A is CR and R is as indicated above, can be synthesized by methods as indicated in Scheme 14.

Compounds of formula (4) can be treated with compounds of formula (20), where R<1> and R are as indicated above in the presence or absence of base in an inert solvent at a temperature in the range of 0°C to +250°C thereby giving compounds of formula (1) where A is CR and R is as indicated above. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide) alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bis(tiralkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkylamines (preferably di-isopropylethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, 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) or aromatic hydrocarbons (preferably benzene or toluene ). Preferred reaction temperatures are in the range of 0°C to 100°C. Alternatively, compounds of formula (1) where A is CR and R is as indicated above can be synthesized via the intermediates (22) and (23).

Compounds of formula (4) can be treated with compounds of formula (21), where R<1> is as indicated above and Re is alkyl (1 to 6 carbon atoms), in the presence or absence of base in an inert solvent at temperatures in the range 0°C to 250°C, thereby giving compounds of formula (1), where A is CR and R is as indicated above. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bis(thyralkylsilyl) amides ( preferably sodium bis(trimethylsilyl)amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, 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) or aromatic hydrocarbons (preferably benzene or toluene ). Preferred reaction temperatures are in the range of 0°C to 100°C. Compounds of formula (22) can be treated with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures in the range of -80°C to +250°C to thereby give compounds of formula (23 ) (where X is halogen, alkanesulphonyloxy, arylsulphonyloxy or haloalkanesulphonyloxy). Halogenation agents include, but are not limited to SOCl2, POCl3, PC13, PC15, POBr3, PBr3 or PBr5. Sulfonyl impurities include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride), or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal bis(tiralkylsilyl)amides (preferably sodium -bis(trimethylsilyl)amide), trialkylamines (preferably N,N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkane nitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes with 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). Preferred reaction temperatures are in the range -20°C to +100°C.

Compounds of formula (23) may be reacted with compounds of formula R H (wherein R is as defined above, except that R<3> is not SH, COR<7>, CO2R<7>, aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures in the range of -80°C to +250°C to generate compounds of formula (1). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis(tiralkylsilyl) amides (preferably sodium bis(thyrmethylsilyl)-amide), trialkylamines (preferably N,N-diisopropyl-N-ethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4 -dioxane), N,N-dialkylform amides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes with 1 to 10 carbon atoms and 1 to 10 halogen atoms

(preferably dichloromethane). Preferred reaction temperatures are in the range 0°C to +140°C.

Some of the compounds with formula (1) can also be prepared using the methods shown in scheme 15.

A compound of formula (24) (Rc is a lower alkyl group and Ar is as defined above) can be reacted with hydrazine in the presence or absence of an inert solvent to give an intermediate of formula (25) where Ar is as defined above. The conditions used correspond to those used for the production of intermediates with formula (4) from compounds with formula (3) in scheme 4. Compounds with formula (25), where A is N, can be converted into compounds with the formula R'C(= NH)ORe, where R<1> is as indicated above and R* is a lower alkyl group, in the presence or absence of an acid in an inert solvent, followed by reaction with a compound of the formula YisC(Rd)2 (where Y is O or S and Rd is halogen, preferably chlorine), alkoxy (1 to 4 carbon atoms) or alkylthio (1 to 4 carbon atoms)) in the presence or absence of a base in an inert solvent to give compounds of formula (27) ( where A is N and Y is O or S). The conditions for these transformations are the same as those used for the transformations of compounds with formula (4) into compounds with formula (7) in scheme 4.

Alternatively, compounds of formula (25), where A is CR, can be reacted with compounds of the formula R,(C=0)CHR(C=Y)ORc, (where R<1> and R are as indicated above and Rc is a lower alkyl group) to give a compound of formula (27) (where A is CR) using conditions similar to those used to convert compounds of formula (21) to compounds of formula (22) in Scheme 14. Intermediates of formula (27)

(where Y is O) can be treated with halogenation agents or sulfonylation agents in the presence or absence of a base in an inert solvent, followed by reaction with R<3>H or R<2>H in the presence or absence of a base in an inert solvent to give compounds of formula (1) (where Z is CR ).

Those skilled in the art will recognize that different combinations of halogenating agents, sulfonylating agents, R H or R H can be used in different reaction sequence order in scheme 15 to give compounds of formula (1). In some cases, for example, it may be desirable to react compounds with stoichiometric amounts of halogenating agents or sulphonyl agents, react with R<2>H (or R<3>H), then repeat the reaction with halogenating agents or sulphonyl agents and react with R <3>H (or R H) to give compounds of formula (1). The reaction conditions and reagents used for these transformations are similar to those used for the transformation of intermediate products with the formulas (22) to (23) to (1) in scheme 14 (for A equal to CR) or the transformation of the intermediate products with the formulas (7) to (8) to (1) in form 1 (where A is

N).

Alternatively, compounds of formula (27) (where Y is S) can be converted to compounds of formula (1) in Scheme 15. Intermediates of formula (27) can be alkylated with a compound R<f>X (where Rf is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent (then optionally oxidized with an oxidizing agent in an inert solvent) and then reacted with R<3>H in the presence or absence of a base in an inert solvent to give a compound of formula ( 1). Conditions and reagents used are similar to those used when converting intermediate products with formulas (7) to (12) (or to (13)) into compounds with formula (1) in scheme 2.

Compounds of formula (1) can be prepared from compounds of formula (24) using an alternative route as indicated in Scheme 15. Compounds of formula (24) can be converted to compounds of formula (27) via reaction with compounds of the formula NH2NH( C=NH)NH2 in the presence or absence of an acid in an inert solvent, followed by reaction with compounds R'C(ORc)3 (where Rc is lower alkyl and R<1> is as indicated above), using conditions which used for the conversion of compounds with the formulas (3) to (17) to (7) in scheme 10.

EXAMPLES

Analytical data were recorded for the compounds as described above using the following general procedures. Proton NMR spectra were recorded on an IBM-Bruker FT-NMR (300 MHz); chemical shifts were reported in ppm (S) from an internal tetramethylsilane standard in deuterochloroform or deuterodimethylsulfoxide as indicated below. Mass spectra (MS) or high-resolution mass spectra (HRMS) were recorded on a Finnegan MAT 8230 spectrometer (using chemical ionization (CI) with NH3 as 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. The boiling points are uncorrected. All pH determinations during the work-up were carried out with indicator paper.

The reagents were obtained from commercial sources and, if necessary, purified before 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 was carried out on silica gel using solvent systems as indicated below. For mixed solvent systems, the volume ratios are given. If not, parts and percentages are by weight.

The following examples shall describe the invention in greater detail. The examples which indicate the presumed best embodiment for carrying out the invention shall illustrate the invention.

EXAMPLE 1

Preparation of 2,7-dimethyl-8-(2,4-dimethylphenyl)[1,S-a]-pyrazolo-[1,3,5]-triazin-4(3H)-one

(Formula 7, where Y is O, Ri is CH3, Z is C-CH3, Ar is 2,4-dimethylphenyl)

A. 1-cyano-1-{2,4-dimethylphenyl)propan-2-one

To sodium pellets (9.8 g, 0.43 mol) was added portionwise a solution of 2,4-dimethylphenylacetonitrile (48 g, 0.33 mol) in 150 ml of ethyl acetate at ambient temperature. The reaction mixture was heated to reflux temperature and stirred for 16 hours. The resulting suspension was cooled to room temperature and filtered. The collected precipitate was washed with copious amounts of ether and then air dried. The solid was dissolved in water and a 1N HCl solution was added to pH equal to 5-6. The mixture was extracted with 3 x 200 ml ethyl acetate, the combined organic layers were dried over MgSO4 and filtered. The solvent was removed under vacuum and a white solid was obtained (45.7 g, 75% yield).

NMR (CDCl3,300MHz):

CI-MS: 188 (M+H).

B. 5-amino-4-(2,4-dimethylphenyl)-3-methylpyrazole

A mixture of 1-cyano-1-(2,4-dimethylphenyl)propan-2-one (43.8 g, 0.23 mol), hydrazine hydrate (22 mL, 0.46 mol), glacial acetic acid (45 mL, 0 .78 mol) and 500 ml of toluene were stirred under reflux for 18 hours in an apparatus equipped with a Dean-Stark trap. The reaction mixture was cooled to room temperature and the solvent removed under vacuum. The residue was dissolved in 6N HCl and the resulting solution was extracted three times with ether. A concentrated ammonium hydroxide solution was added to the aqueous layer until the pH was equal to 11. The resulting semi-solution was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. The solvent was removed under vacuum to give a pale brown viscous oil (34.6 g, 75% yield): NMR (CDCl 3 , 300 MHz): 7.10 (s, 1H), 7.05 (d, 2H , J=1), 2.37 (s, 3H), 2.10 (s, 3H); CI-MS: 202 (M + H). C. 5-acetamido-4-(2,4-dimethylphenyl)-3-methylpyrazole, acetic acid salt Ethyl acetamidate hydrochloride (60 g, 0.48 mol) was added rapidly to a rapidly stirred mixture of potassium carbonate (69.5 g, 0.50 mol), 120 ml of dichloromethane and 250 ml of water. The layers were separated and the aqueous layer extracted with 2 x 120 ml of dichloromethane. The combined organic layers were dried over MgSO 4 and filtered. The solvent was removed by simple distillation and the residue, a clear pale yellow liquid (35.0 g) was used without further purification.

Glacial acetic acid (9.7 mL, 0.17 mol) was added to a stirred mixture of 5-amino-4-(2,4-dimethylphenyl)-3-methylpyrazole (34 g, 0.17 mol), ethyl acetamidate (22 g , 0.25 mol) and 500 ml of acetonitrile. The resulting reaction mixture was stirred at room temperature for 3 days, after which it was concentrated under vacuum to about 1/3 of the original volume. The resulting suspension was filtered and the collected solid was washed with copious amounts of ether. The white solid was dried under vacuum to give (31.4 g, 61% yield).

NMR (DMSO-de, 300 MHz): 7.00 (s, 1H), 6.90 (dd, 2H, j=7.1), 2.28 (s, 3H), 2.08 (s,

3H), 2.00 (s, 3H), 1.90 (s, 3H), 1.81 (s, 3H);

CI-MS: 243 (M+H).

D. 2,7-Diraethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-[1,3,5]-triazin-4(3H)-one Sodium pellets (23 g, 1 mol ) was added in portions to 500 ml of ethanol with vigorous stirring. After all the sodium was reacted, 5-acetamidino-4-(2,4-dimethylphenyl)-3-methylpyrazole, acetic acid salt (31.2 g, 0.1 mol) and diethyl carbonate (97 mL, 0.8 mol) were added ). The resulting reaction mixture was heated to reflux and stirred for 18 hours. The mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was dissolved in water and a 1N HCl solution was slowly added to pH equal to 5-6. The aqueous layer was extracted three times with ethyl acetate, after which the combined organic layers were dried over MgSO 4 and filtered. Solvent was removed under vacuum and a pale golden solid was obtained (26 g, 98% yield).

NMR (CDCl 3 , 300 MHz): 7.15 (s, 1H), 7.09 (s, 2H), 2.45 (s, 3H), 2.39 (s, 3H), 2.30 (s,

3H);

CI-MS: 269 (M+H).

EXAMPLE 2

Preparation of 5-methylO-(2A6-trimerylphenyl)[1,5-a]-[1,2,3]-triazolo-[1»3,5]-triazin-7(6H)-one

(Formula 7, where Y is O, Ri is CH3, Z is N, Ar is 2,4,6-trimethylphenyl)

A. 1-Phenylmethyl-4-(2,4,6-trimethylphenyl)-5-aminotriazole

A mixture of 2,4,6-trimethylbenzyl cyanide (1.0 g, 6.3 mmol), benzyl azide (0.92 g, 6.9 mmol) and potassium t -butoxide (0.78 g, 6.9 mmol ) in 10 ml tetrahydrofuran was stirred at ambient temperature for 2 XA day. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. The solvent was removed under vacuum and a brown oil was obtained. Trituration of ether and filtration gave a yellow solid (1.12 g, 61% yield).

NMR (CDCl 3 , 300 MHz): 7.60-7.30 (m, 5H), 7.30-7.20 (m, 2H), 5.50 (s, 2H), 3.18 (br

s, 2H), 2.30 (s, 3H), 2.10 (s, 6H);

CI-MS: 293 (M+H).

B. 4-(2,4,6-trimethylphenyl)-5-aminotriazole

Sodium (500 mg, 22 mmol) was added with stirring to a mixture of 30 mL of liquid ammonia and 1-phenylmethyl-4-(2,4,6-trimethylphenyl)-5-aminotriazole (1.1 g, 3.8 mmol ). The reaction mixture was stirred until a dark green color remained. An ammonium chloride solution (ml) was added and the mixture stirred while warming to ambient temperature over 16 hours. The residue was treated with a 1M HCl solution and filtered. The aqueous layer was basified with a concentrated ammonium hydroxide solution (pH = 9) and then extracted three times with ethyl acetate. The combined organic layers were dried over MgSO 4 and filtered. The solvent was removed under vacuum and 520 mg of yellow solid was obtained which was homogeneous by thin layer chromatography (ethyl acetate).

NMR (CDCl 3 , 300 MHz): 6.97 (s, 2H), 3.68-3.50 (br. s, 2H), 2.32 (s, 3H), 2.10 (s, 6H); CI-MS: 203 (M+H).

C. 4-(2,4,6-trimethylphenyl)-5-acetamidinotriazole, acetic acid salt

A mixture of 4-(2,4,6-trimethylphenyl)-5-aminotriazole (400 mg, 1.98 mmol), ethyl acetamidate (261 mg, 3 mmol) and glacial acetic acid (0.1 mL, 1.98 mmol) in 6 ml of acetonitrile was stirred at ambient temperature for 4 hours. The resulting suspension was filtered and the collected solid was washed with copious amounts of water. Drying under vacuum gave a white solid (490 mg, 82% yield).

NMR (DMSO-de, 300 MHz): 7.90-7.70 (br. s, 0.5H), 7.50-7.20 (br. s, 0.5H), 6.90 (s,

2H), 6.90 (s, 2H), 3.50-3.10 (br. s, 3H), 2.30-2.20 (br. s, 3H), 2.05 (d, 1H, J=7), 1.96 (s, 6H), 1.87 (s, 6H);

CI-MS: 244 (M+H).

D. 5-Methyl-3-(2,4,6-trimethylphenyl)[1,5-a]-[1,2,3]-triazoIo-IU,51-triazine-7(4H)-oyl Sodium (368 mg, 16.2 mmol) was added to 10 ml of ethanol at room temperature with stirring. After the sodium had reacted, 4-(2,4,6-trimethylphenyl)-5-acetamide-ino-triazole, acetic acid salt (490 mg, 1.6 mmol) and diethyl carbonate (1.6 mL, 13 mmol) were added. . The reaction mixture was stirred under reflux for 5 hours, after which it was cooled to room temperature. The reaction mixture was diluted with water, a 1N HCl solution was added to pH = 5-6 and the whole was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO 4 and filtered. The solvent was removed under vacuum and a yellow residue was obtained. Trituration with ether and filtration gave a yellow solid (300 mg, 69% yield).

NMR (CDCl 3 , 300 MHz): 6.98 (s, 2H), 2.55 (s, 3H), 2.35 (s, 3H), 2.10 (s, 6H); CI-MS: 270 (M+H).

EXAMPLE 3

Preparation of 4-(di(carbomethoxy)methyl)-2,7-dimethyl-8-(2,4-dimethylphenyl)1,5-a]-pyrazolo-1,3,5-triazine

(Formula 1, where R3 is CH(CHC02CH3)2, R<1> is CH3, Z is C-CH3, Ar is 2,4-dimethylphenyl)

A. 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolotriazine

A mixture of 2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazin-4-one (Example 1.1.38 g, 4, 5 mmol), N,N-dimethylaniline (1 mL, 8 mmol) and 10 mL of phosphorus oxychloride were stirred under reflux for 48 h. Excess phosphorus oxychloride was removed under vacuum. The residue was poured into ice water, stirred rapidly and extracted rapidly three times with ethyl acetate. The combined organic layers were washed with ice water and then dried over MgSO 4 and filtered. The solvent was removed under vacuum and a brown oil was obtained. Flash column chromatography with ethyl acetate.hexanes 1:4 gave a fraction (Rf= 0.5). The solvent was removed under vacuum to give a yellow oil (1.0 g, 68% yield).

NMR (CDCl 3 , 300 MHz): 7.55 (d, 1H, J=1), 7.38 (dd, 1H, J=7,1), 7.30 (d, 1H, J=7),

2.68 (s, 3H), 2.45 (s, 3H);

CI-MS: 327 (M+H).

B. 4-(di(carbomethoxy)methyl-2,7-dimethyl-8-(2,4-dimethylphenyl)[1,S-a]-pyrazolo-1,3,5-triazine

Sodium hydride (60% in oil, 80 mg, 2 mmol) was washed twice with hexanes, decanted after each wash and taken up in 1 ml anhydrous tetrahydrofuran (THF, 1 ml). A solution of diethyl malonate (0.32 g, 2 mmol) in 2 ml of THF was added dropwise over 5 minutes during which time vigorous gas evolution occurred. A solution of 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-]-pyrazolotriazine (0.5 g, 1.75 mmol) in 2 mL of THF was added and the reaction mixture was then stirred under a nitrogen atmosphere for 48 hours. The resulting suspension was poured onto water and extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried over MgSO 4 and filtered. The solvent was removed under vacuum and a brown oil was obtained. Column chromatography with ethyl acetate:hexanes, 1:9, gave, after removal of the solvent under vacuum, a pale yellow solid (Rf = 0.2, 250 mg, 35% yield), mp 50-52°C.

NMR (CDCl 3 , 300 MHz): 12.35 (br. s, 1H), 7.15-7.00 (m, 3H), 4.40 (q, 2H, J=7), 4.30

(q, 2H, J=7), 2,4,2,35, 2,3, 2,2,2,1 (5s, 12H), 1,4 (t, 3H, J=7), 1, 35-1.25

(m, 3H);

CI-HRMS: Calculated: 411.2032

Found: 411,2023

EXAMPLE 6

Preparation of 4-(1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)-1,5-a]-pyrazolo-1,3,5-triazine

(Formula 1, where R3 is NHCH(CH2OCH3)2, R<1> is CH3, Z is C-CH3, Ar is 2,4-dichlorophenyl)

A. 4-Chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[l,5-a]-pyrazolotriazine A mixture of 2,7-dimethyl-8-(2,4-dimethylphenyl)[l ,5-a]-pyrazolo-1,3,5-triazin-4-one (Example 1.1.38 g, 4.5 mmol), N,N-dimethylaniline (1 mL, 8 mmol) and 10 mL of phosphorus oxychloride was stirred under reflux for 48 hours. Excess phosphorus oxychloride was removed under vacuum. The residue was poured into ice water, stirred briefly and quickly extracted three times with ethyl acetate. The combined organic layers were washed with ice water, then dried over MgSO 4 and filtered. The solvent was removed under vacuum and a brown oil was obtained. Flash column chromatography with ethyl acetate:hexanes, 1:4, gave one fraction (Rf= 0.5). Solvent was removed under vacuum to give a yellow oil (1.0 g, 68% yield).

NMR (CDCb, 300 MHz): 7.55 (d, 1H, J=1), 7.38 (dd, 1H, J=7,1), 7.30 (d, 1H, 3=7),

2.68 (s, 3H), 2.45 (s, 3H);

CI-MS: 327 (M+H).

B. 4-(1^-dimethoxy-2-propylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazine

A mixture of 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazine (part A, 570 mg, 1.74 mmol ), 1,3-dimethoxypropyl-2-aminopropane (25 mg, 2.08 mmol) and 10 mL of ethanol were stirred at ambient temperature for 18 h. The reaction mixture was poured into 25 ml of water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSCu and filtered. The solvent was removed under vacuum. Column chromatography with CH2Cl2:CH3OH, 50:1, gave a fraction. Removal of the solvent in vacuo gave a solid (250 mg, 35% yield) mp 118-120°C.

NMR (CDCl 3 , 300 MHz): 7.50 (s, 1H), 7.28 (dd, 2H, =8.1), 6.75 (d, 1H, J=8), 4.70-4, 58

(m, 1H), 3.70-3.55 (m, 4H), 3.43 (s, 6H), 2.50 (s, 3H), 2.35 (s, 3H);

CI-HRMS: Calculated: 409.1072

Found: 409.1085

Analysis for Ct8H2iCl2N502:

Using the above procedures and modifications known to those skilled in the art, the following additional examples in Tables 1 to 4 can be prepared.

The examples summarized in table 1 can be prepared by the methods outlined in examples 1, 2, 3 or 6. Commonly used abbreviations are: Ph for phenyl, Pr for propyl, Me for methyl, Et for ethyl, Bu for butyl, Ex . is example.

Notes to Table 1:

a) Analysis

b) CI-HRMS:

Calculated: 406.1565

Found: 405.1573 (M + H);

Analysis:

Calculated: C 59.11 H6.20 N 17.23 Cl 17.45

Found: C 59.93 H 6.34 N 16.50 Cl 16.95;

NMR (CDCb, 300 MHz): 0.95 (t, J=8.4H), 1.30-1.40 (m, 4H), 1.50-1.75 (m, 4H),

2.35 (s, 3H), 2.48 (s, 3H), 4.30-4.45 (m, 1H), 6.15 (d, J=8.1H), 7.30 (s, 2H), 7.50 (s, 1H).

c) CI-HRMS:

Calculated: 392.1409

Found: 392.1388 (M + H);

NMR (CDCl3, 300 MHz): 1.00 (t, J=8, 3H), 1.35 (t, J=8, 3H), 1.41 (q, J=8,2H),

1.65-1.85 (m, 2H), 2.30 (s, 3H), 2.40 (s, 3H), 3.85-4.20 (m, 4H), 7.30 (s, 2H), 7.50 (s, 1H).

d) CI-HRMS:

Calculated: 404.1409

Found: 404.1408 (M + H);

NMR (CDCl 3 , 300 MHz): 0.35-0.45 (m, 2H), 0.52-0.62 (m, 2H), 0.98 (t, 8.3H),

1.70-1.90 (m, 2H), 2.30 (s, 3H), 2.40 (s, 3H), 3.85-4.02 (m, 2H), 4.02-4, 20 (m, 2H), 7.30 (s, 2H), 7.50 (s, 1H).

e) CI-HRMS:

Calculated: 424.1307

Found: 424.1307 (M + H);

NMR (CDCl 3 , 300 MHz): 2.28 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.75 (t, J=8.4H),

4.20-4.45 (m, 4H), 7.30 (s, 2H), 7.50 (s, 1H).

f) CI-HRMS:

Calculated: 406.1565

Found: 406.1578 (M + H);

NMR (CDCl 3 , 300 MHz): 0.90 (t, J=8, 3H), 1.00 (t, J=8, 3H), 1.28-1.45 (m, 4H),

1.50-1.80 (m, 4H), 2.35 (s, 3H), 2.50 (s, 3H), 4.20-4.35 (m, 1H), 6.10-6, 23 (m, 1H), 7.30 (s, 2H), 7.50 (s, 1H).

g) CI-HRMS:

Calculated: 394.1201

Found: 394.1209 (M + H);

NMR (CDCl3,300 MHz): 1.02 (t, J=8.3H), 3.40 (s, 3H), 3.50-3.60 (m, 2H), 4.35-4.45 (brs, 1H), 6.50-6.60 (m, 1H), 7.30 (s, 2H), 7.50 (s, 1H).

h) CI-HRMS:

Calculated: 364.1096

Found: 364.1093 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 1.35 (t, J=8, 6H), 2.30 (3, 3H), 2.40 (s, 3H), 3.95-4.15

(m, 4H), 7.30 (s, 2H), 7.50 (d, J=1, 1H).

i) CI-HRMS:

Calculated: 438.1464

Found: 438.1454 (M + H);

NMR (CDCl 3 , 300 MHz): 1.22 (t, J=8, 6H), 2.35 (s, 3H), 2.47 (s, 3H), 3.39 (q, J=8,

4H), 3.65 (dd, J=8,1,2H), 3.73 (dd, J=8,1, 2H), 4.55-4.65 (m, 1H), 6.75 ( d, J=8.1H), 7.30 (d, J=1, 2H), 7.50 (s, 1H).

j) CI-HRMS:

Calculated: 378.1252

Found: 378.1249 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 1.00 (t, J=8, 6H), 1.55-1.70 (m, 2H), 1.70-1.85 (m, 2H),

2.35 (s, 3H), 2.50 (s, 3H), 4.15-4.25 (m, 1H), 6.18 (d, J=8, 1H), 7.30 (s, 2H), 7.50 (s, 1H).

k) CI-HRMS:

Calculated: 398.0939

Found: 398.0922 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 2.05 (s, 3H), 2.50 (s, 3H), 3.78 (s, 3H), 7.20-7.45 (m,

7H), 7.50 (d, J=1, 1H).

1) CI-HRMS:

Calculated: 392.1409

Found: 392.1391 (M + H);

NMR (CDCl 3 , 300 MHz): 0.98 (t, J=8, 6H), 1.70-1.85 (m, 4H), 2.30 (s, 3H), 2.40

(s, 3H), 3.80-4.10 (m, 4H), 7.30 (s, 2H), 7.50 (d, J=1, 1H).

m) CI-HRMS:

Calculated: 392.1409

Found: 392.1415 (M + H);

Analysis:

NMR (CDCl3,300 MHz): 0.90-1.05 (m, 6H), 1.35-1.55 (m, 2H), 1.55-1.85 (m,

4H), 2.35 (s, 3H), 2.48 (s, 3H), 4.20-4.35 (m, 1H), 6.15 (d, J=8.1H), 7.30 (s, 2H), 7.50 (d, J=1, 1H).

n) CI-HRMS:

Calculated: 337.0623

Found: 337.0689 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 1.60 (t, J=8, 3H), 2.40 (s, 3H), 2.55 (s, 3H), 4.0 (q, J=8,

2H), 7.30 (d, J=8,1H), 7.35 (dd, J=8,1,1H), 7.55 (d, J=1, 1H).

o) CI-HRMS:

Calculated: 383.2321

Found: 383.2309 (M + H);

NMR (CDCl 3 , 300 MHz): 2.00 (s, 6H), 2.20 (s, 3H), 2.30 (s, 3H), 2.45 (s, 3H), 3.45

(s, 6H), 3.61 (dd, J=8, 8,2H), 3.70 (dd, J=8, 8, 2H), 4.60-4.70 (m, IH), 6 .70 (d, J=8.1H), 6.94 (s, 2H).

p) CI-HRMS:

Calculated: 370.2243

Found: 370.2246 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 2.18 (s, 3H), 2.30 (s, 3H), 2.45 (s, 3H), 3.45 (s, 6H), 3.60

(dd, J=8.8, 2H), 3.69 (dd, J=8,8,2H), 4.60-4.70 (m, 1H), 6.70 (d, J=8, 1H), 7.05 (d, J=8.1H), 7.07 (d, J=8.1H), 7.10 (s, 1H).

q) CI-HRMS:

Calculated: 384.2400

Found: 384.2393 (M + H);

NMR (CDCU, 300 MHz): 2.16 (s, 3H), 2.25 (s, 3H), 2.35 (s, 3H), 2.39 (s, 3H), 3.40

(s, 6H), 3.77 (t, J=8.4H), 4.20-4.45 (m, 4H), 7.02 (d, J=8.1H), 7.05 (s , 1H), 7.10 (d,J=7.1H).

r) CI-HRMS:

Calculated: 354.2294

Found: 354.2271 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 1.03 (t, J=8, 3H), 1.65-1.88 (m, 2H), 2.17 (s, 3H), 2.30

(s, 3H), 2.35 (s, 3H), 2.45 (s, 3H), 3.40 (s, 3H), 3.50-3.62 (m, 2H), 4.30- 4.45 (m, 1H), 6.51 (d, J=8.1H), 7.04 (d, J=8.1H), 7.10 (d, J=8.1H), 7, 12 (p, 1H).

s) CI-HRMS:

Calculated: 338.2345

Found: 338.2332 (M + H);

Analysis:

NMR (CDCl3,300 MHz): 1.00 (t, J=8, 6H), 1.55-1.70 (m, 2H), 1.70-1.85 (m, 2H),

2.19 (s, 3H), 2.30 (s, 3H), 2.35 (s, 3H), 2.46 (s, 3H), 4.15-4.26 (m, 1H), 6 .17 (d, J=8.1H), 7.06 d, J=8.1H), 7.10 (d, J=1, 1H), 7.13 (s, 1H).'"

t) CI-HRMS:

Calculated: 324.2188

Found: 324.2188 (M + H);

NMR (CDCl 3 , 300 MHz): 1.25 (t, J=8.6H), 2.16 (s, 3H), 2.28 (s, 3H), 2.35 (s, 3H),

2.40 (s, 3H), 3.95-4.20 (m, 4H), 7.05 (dd, J=8, 1.1H), 7.07 (s, 1H), 7.10 ( d,J=l,lH).

u) CI-HRMS:

Calculated: 346.1780

Found: 346.1785 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 2.15 (s, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 2.52 (s, 3H),

5.25-5.35 (m, 4H), 7.08 (s, 2H), 7.15 (s, 1H).

v) CI-HRMS:

Calculated: 340.2137

Found: 340.2137 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 1.40 (d, 3=8, 3H), 2.16 (s, 3H), 2.32 (s, 3H), 2.35 (s, 3H),

2.47 (s, 3H), 3.42 (s, 3H), 3.50-3.60 (m, 2H), 4.50-4.15 (m, 1H), 6.56 (d, J=8.1H), 7.00-7.15 (m, 3H).

w) CI-HRMS:

Calculated: 355.2134

Found: 355.2134 (M + H);

NMR (CDCl 3 , 300 MHz): 1.05 (t, J=8.3H), 1.85-2.00 (m, 2H), 2.17 (s, 3H), 2.36

(s, 6H), 2.50 (s, 3H), 3.41 (s, 3H), 3.45 (dd, J=8, 3.1H), 3.82 (dd, J=8.1 , 1H), 5.70-5.80 (m, 1H), 7.00-7.20 (m, 3H).

x) CI-HRMS:

Calculated: 364.2501

Found: 364.2501 (M + H);

NMR (CDCl 3 , 300 MHz): 0.35-0.43 (m, 2H), 0.50-0.60 (m, 2H), 0.98 (t, J=8, 3H),

1.20-1.30 (m, 1H), 1.72-1.90 (m, 2H), 2.18 (s, 3H), 2.28 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 3.88-4.03 (m, 2H), 4.03-4.20 (m, 2H), 7.00-7.15 (m, 3H) .

y) CI-HRMS:

Calculated: 353.2454

Found: 353.2454 (M + H);

Analysis:

NMR (CDCU, 300 MHz): 1.38 (d, J=8, 3H), 2.18 (s, 3H), 2.30-2.40 (m, 12H), 2.47

(3, 3H), 2.60-2.75 (m, 2H), 4.30-4.50 (m, 1H), 6.60-6.70 (m, 1H), 7.00-7 .15 (m, 3H).

z) CI-HRMS:

Calculated: 361.2140

Found: 361.2128 (M+H);

NMR (CDCl3,300 MHz): 0.75-0.83 (m, 2H), 1.00-1.10 (m, 2H), 2.17 (s, 3H), 2.30

(s, 3H), 2.36 (s, 3H), 2.47 (s, 3H), 2.85 (t, J=8.2H), 3.30-3.40 (m, 1H), 4.40-4.55 (m, 2H), 7.00-7.18 (m, 3H).

aa) CI-HRMS:

Calculated: 363.2297

Found: 363.2311 (M + H);

NMR (CDCl 3 , 300 MHz): 1.01 (t, 3H, J=8), 1.75-1.90 (m, 2H), 2.15 (s, 3H), 2.19

(s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 2.40 (s, 3H), 2.98 (t, 2H, J=8), 3.97- 4.15 (m, 2H), 4.15-4.30 (m, 2H), 7.03 (d, 1H, 1H), 7.08 (d, 1H, J=8), 7.10 ( pp, 1H).

ab) CI-HRMS:

Calculated: 363.2297

Found: 363.2295 (M + H);

NMR (CDCl 3 , 300 MHz): 1.01 (t, 3H, J=8), 1.35-1.55 (m, 2H), 1.75-1.90 (m, 2H),

2.15 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H), 2.46 (s, 3H), 4.10-4.30 (m, 2H), 4 .95-5.10 (br s, 2H), 7.05 (d, 1H, J=8), 7.10 (d, 1H, J=8), 7.15 (s, 1H).

ac) CI-HRMS:

Calculated: 368.2450

Found: 368.2436;

Analysis:

NMR (CDCl 3 , 300 MHz): 1.05 (t, J=8, 3H), 1.70-1.90 (m, 2H), 2.01 (d, J=3, 6H),

2.20 (s, 3H), 2.30 (s, 3H), 2.46, 2.465 (s, s, 3H), 3.42, 3.48 (s, s, 3H), 3.52- 3.63 (m, 2H), 4.35-4.45 (m, 1H), 6.73 (d, J=8.1H), 6.97 (s, 2H).

ad) CI-HRMS:

Calculated: 352.2501

Found: 352.2500 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 1.01 (t, J=8.6H), 1.58-1.70 (m, 2H), 1.70-1.85 (m, 2H),

2.02 (s, 5H), 2.19 (s, 3H), 2.45 (s, 3H), 4.12-4.28 (m, 1H), 6.18 (d, J=8, 1H), 6.95 (s, 2H).

ae) CI-HRMS:

Calculated: 398.2556

Found: 398.2551 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 2.00 (s, 6H), 2.12 (s, 3H), 2.30 (s, 3H), 2.37 (s, 3H), 3.40 (s,

6H), 3.78 (t, J=8.4H), 4.25-4.40 (m, 4H), 6.93 (s, 2H).

af) CI-HRMS:

Calculated: 450.1141

Found: 450.1133 (M + H);

Analysis:

NMR (CDCl3,300 MHz): 2.32 (s, 3H), 2.57 (s, 3H), 3.42 (s, 6H), 3.60 (q, J=8.2H),

3.69 (q, J=8, 2H), 3.82 (s, 3H), 4.60-4.70 (m, 1H), 6.73 (d, J=8, 1H), 6, 93 (dd, J=8.1, 1H), 7.22 (d, J=8, 1H).

ag) CI-HRMS:

Calculated: 434.1192

Found: 434.1169 (M + H);

Analysis:

NMR (CDCl 3 ) 300 MHz): 1.00-1.07 (m, 3H), 1.65-1.85 (m, 2H), 2.35 (s, 3H), 2.46,

2.47 (s, s, 3H), 3.40, 3.45 (s, s, 3H), 3.83 (s, 3H), 4.35-4.45 (m, 1H), 6, 55 (d, J=8.1H), 6.92 (dd, J=8.1.1H), 7.20-7.30 (m, 2H).

ah) CI-HRMS:

Calculated: 337.2266

Found: 337.2251 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 1.35 (t, J=8.6H), 2.01 (s, 6H), 2.15 (s, 3H), 2.30 (s, 3H),

2.38 (s, 3H), 4.07 (q, J=8.4H), 6.93 (s, 2H).

ai) CI-HRMS:

Calculated: 412.2713

Found: 412.2687 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 1.24 (t, J=8.6H), 2.00 (s, 6H), 2.20 (s, 3H), 2.30 (s, 3H),

2.43 (s, 3H), 3.60 (q, J=8,4H), 3.66 (dd, J=8, 3,2H), 3.75 (dd, J=8, 3, 2H ), 4.55-4.65 (m, 1H), 6.75 (d, J=8.1H), 6.95 (s, 2H).

aj) CI-HRMS:

Calculated: 398.2556

Found: 398.2545 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 1.95-2.10 (m, 8H), 2.20 (s, 3H), 2.32 (s, 3H), 2.44 (s,

3H), 3.38 (s, 3H), 3.42 (s, 3H), 3.50-3.70 (m, 4H), 4.58-4.70 (m, 1H), 6.87 (d, J=8.1H), 6.95 (s, 2H).

ak) CI-HRMS:

Calculated: 338,1981

Found: 338.1971 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 2.15 (s, 3H), 2.29 (s, 3H), 2.35 (s, 3H), 2.43 (s, 3H), 3.90

(t, J=8.4), 4.35-4.45 (m, 4H), 7.00-7.15 (m, 3H).

al) CI-HRMS:

Calculated: 464.1297

Found: 464.1297 (M + H);

NMR (CDCl 3 , 300 MHz): 2.28 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.75 (t, J=8.4H),

3.83 (s, 3H), 4.20-4.50 (m, 4H), 6.93 (dd, J=8.1, 1H), 7.20 (s, 1H), 7.24 ( d,J=l,lH).

am) CI-HRMS:

Calculated: 418.1242

Found: 418.1223 (M + H);

NMR (CDCl3,300 MHz): 1.00 (t, d, J=8,1,6H), 1.55-1.75 (m, 4H), 2.34 (s, 3H),

2.49 (s, 3H), 2.84 (s, 3H), 4.15-4.27 (m, 1H), 6.19 (d, J=8.1H), 6.93 (dd, J=8, 1, 1H), 7.21-7.30 (m, 2H).

an) CI-HRMS:

Calculated: 404.1086

Found: 404.1079 (M + H);

NMR (CDCl3,300 MHz): 1.35 (t, J=8.6H), 2.28 (s, 3H), 2.40 (s, 3H), 3.83 & 3H),

3.90-4.08 (ra, 2H), 4.08-4.20 (m, 2H), 6.92 (dd, J=8, 1, 1H), 7.20-7.25 (m , 2H).

ao) CI-HRMS:

Calculated: 308.1875

Found: 308.1872 (M + H);

NMR (CDCl3.300 MHz): 0.75-0.80 (m, 2H), 0.93-1.00 (m, 2H), 2.16 (s, 3H), 2.28

(s, 3H), 2.35 (s, 3H), 2.53 (s, 3H), 3.00-3.10 (m, 1H), 6.50-6.55 (m, 1H), 7.00-7.15 (m, 3H).

ap) CI-HRMS:

Calculated: 397.1988

Found: 397.1984 (M + H);

NMR (CDCl 3 , 300 MHz): 2.43 (s, 3H), 2.50 (s, 3H), 3.43 (s, 3H), 3.61 (dd, J=8, 8,

2H), 3.69 (dd, J=8,8,2H), 3.88 (s, 3H), 4.58-4.70 (m, 1H), 6.75 (d, J=8, 1H), 7.20 (dd, J=8,1,1H), 7.25 (d, J=1, 1H), 7.40 (s, 1H).

aq) CI-HRMS:

Calculated: 375.2297

Found: 375.2286 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 0.79-0.85 (m, 2H), 1.00-1.05 (m, 1H), 2.00 (s, 6H), 2.19

(s, 3H), 2.32 (s, 3H), 2.44 (s, 3H), 2.84 (t, J=8, 2H), 3.30-3.40 (m, 1H), 4.50 (t, J=8.2H), 6.95 (s, 2H).

ar) CI-HRMS:

Calculated: 434.1192

Found: 434.1189 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 2.19 (s, 3H), 2.30 (s, 3H), 2.47 (s, 3H), 3.43 (s, 6H),

3.60 (dd, J=8, 8, 2H), 3.70 (dd, J=8,8, 2H), 4.58-4.70 (m, 1H), 6.71 (d, J =8.1H), 7.08 (d, J=8.1H), 7.37 (dd, J=8.1,1H), 7.45 (d, J=1, 1H).

as) CI-HRMS:

Calculated: 448.1348

Found: 4448.1332 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 1.95-2.10 (m, 2H), 2.20 (s, 3H), 2.30 (s, 3H), 2.47 (s,

3H), 3.38 (s, 3H), 3.41 (s, 3H), 3.50-3.67 (m, 4H), 4.55-4.70 (m, 1H), 6.89 (d, J=8,1H), 7.05 (d, J=8,1H), 7.35 (dd, J=8,1,1H), 7.47 (d, J=1, 1H) .

at) CI-HRMS:

Calculated: 400.2349

Found: 400.2348 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 2.16 (s, 3H), 2.20 (s, 3H), 2.30 (s, 3H), 2.46 (s, 3H), 3.42

(s, 6H), 3.60 (q, J=8, 2H), 3.70 (q, J=8, 2H), 3.85 (s, 3H), 4.59-4.70 (m , 1H), 6.70 (d, J=8.1H), 6.76 (s, 1H), 6.96 (s, 1H).

au) CI-HRMS:

Calculated: 414.2505

Found: 414.2493 (M + H);

NMR (CDCl 3 , 300 MHz): 2.15 (s, 3H), 2.19 (s, 3H), 2.25 (s, 3H), 2.40 (s, 3H), 3.40

(s, 6H), 3.76 (t, J=8.4H), 3.84 (s, 3H), 4.20-4.45 (m, 4H), 6.77 (s, 1H), 6.93 (p, 1H).

of) CI-HRMS:

Calculated: 368.2450

Found: 368.2447 (M + H);

NMR (CDCl 3 , 300 MHz): 1.00 (t, J=8, 6H), 1.55-1.85 (m, 4H), 2.19 (s, 3H), 2.20

(s, 3H), 2.30 (s, 3H), 2.47 (s, 3H), 3.88 (s, 3H), 4.10-4.30 (m, 1H), 6.15 ( d, J=8.1H), 6.78 (s, 1H), 6.98 (s, 1H).

aw) CI-HRMS:

Calculated: 353.2216

Found: 353.2197 (M + H);

NMR (CDCl 3 , 300 MHz): 1.35 (t, J=8, 6H), 2.17 (s, 3H), 2.19 (s, 3H), 2.28 (s, 3H),

2.40 (s, 3H), 3.85 (s, 3H), 3.90-4.20 (m, 4H), 6.78 (s, 1H), 6.95 (s, 1H).

ax) CI-HRMS:

Calculated: 390.1697

Found: 390.1688 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 2.35 (s, 3H), 2.37 (s, 3H), 2.48 (s, 3H), 3.42 (s, 6H), 3.60

(dd, J=8, 8.2H), 3.68 (dd, J=8, 8.2H), 4.59-4.72 (m, 1H), 6.72 (d, J=8, 1H), 7.12 (d, J=8.1H), 7.23 (d, J=8.1H), 7.32 (s, 1H).

ay) CI-HRMS:

Calculated: 374.1748

Found: 374.1735 (M + H);

Analysis:

NMR (CDCl3,300 MHz): 1.01 (t, J=8.3H), 1.62-1.88 (m, 4H), 2.35 (s, 3H), 2.37

(s, 3H), 2.48 (d, J=l, 3H), 3.40, 3.45 (s, s, 3H), 3.50-3.64 (m, 2H), 4.38 -4.47 (m, 1H), 6.53 (d, J=8.1H), 7.12 (d, J=8.1H), 7.07 (d, J=8.1H), 7 ,12 (p, 1H).

az) CI-HRMS:

Calculated: 404.1853

Found: 404.1839 (M + H);

NMR (CDCl 3 , 300 MHz): 2.29 (s, 3H), 2.38 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.76

(t, J=8.4H), 4.20-4.45 (m, 4H), 7.11 (d, J=8.1H), 7.22 (d, J=8, 1H), 7 ,31 (p, 1H).

ba) CI-HRMS:

Calculated: 404.1853

Found: 404.1859 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 1.95-2.08 (m, 2H), 2.35 (s, 3H), 2.38 (s, 3H), 2.46 (s,

3H), 3.38 (s, 3H), 3.41 (s, 3H), 3.50-3.65 (m, 4H), 4.56-4.70 (m, 1H), 6.85 (d, J=8.1H), 7.12 (d, J=8.1H), 7.45 (d, J=8.1H), 7.32 (s, 1H).

bb) CI-HRMS:

Calculated: 391.2246

Found: 391.2258 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 0.76-0.84 (m, 2H), 0.84-0.91 (m, 2H), 1.00-1.08 (m,

2H), 2.15 (s, 3H), 2.20 (s, 3H), 2.29 (s, 3H), 2.45 (s, 3H), 2.85 (t, J=8, 2H ), 3.28-3.30 (m, 1H), 3.85 (s, 3H), 6.78 (s, 1H), 6.95 (s, 1H).

bc) CI-HRMS:

Calculated: 386.2192

Found: 386.2181 (M + H);

Analysis:

NMR (CDCl3,300 MHz): 7.1 (d, 1H, J=8), 6.9 (d, 1H, J=1), 6.8 (dd, 1H, J=8,1),

6.7 (br.d, 1H, J=8), 4.7-4.6 (m, 1H), 3.85 (s, 3H), 3.70-3.55 (m, 4H), 3.45 (s, 6H), 2.5 (s, 3H), 2.3 (s, 3H), 2.15 (s, 3H).

bd) CI-HRMS:

Calculated: 400.2349

Found: 400.2336 (M + H);

NMR (CDCl 3 , 300 MHz): 7.1 (d, 1H, 5=1), 6.85 (d, 1H, J=1), 6.75 (dd, 1H, J=7,1),

4.45-4.25 (br.s, 4H), 3.75 (t, 4H, J=7), 3.4 (s, 6H), 2.4 (s, 3H), 2.25 ( s, 3H), 2.15(s, 3H).

be) CI-HRMS:

Calculated: 370.2243

Found: 370.2247 (M + H);

Analysis:

NMR (CDCl3,300 MHz): 7.1 (d, 1H, J=8), 6.85 (d, 1H, J=1), 6.8 (dd, 1H, J=8,1),

6.5 (br.d, 1H, J=l), 4.5-4.3 (m, 1H), 3.85 (s, 3H), 3.65-3.5 (m, 2H), 3.4 (s, 2H), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.9-1.7 (m, 2H), 1 .05 (t, 3H, J=7).

bf) CI-HRMS:

Calculated: 379.2246

Found: 379.2248 (M + H);

NMR (CDCl3,300 MHz): 7.1 (d, 1H, J=8), 6.85 (d, 1H, 3=1), 6.8 (dd, 1H, J=8,1),

4.3-4.0 (m, 4H), 3.85 (s, 3H), 3.0 (t, 2H, J=7), 2.45 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.9-1.8 (m, 2H), 1.0 (t, 3H, J=7).

bg) CI-HRMS:

Calculated: 340.2137

Found: 340.2122 (M + H);

NMR (CDCl 3 , 300 MHz): 7.1 (d, 1H, J=8), 6.85 (d, 1H, J=1), 6.75 (dd, 1H, J=8,1),

4.2-4.0 (br.m, 4H), 3.85 (s, 3H), 2.4 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H) , 1.35 (t, 6H, J=7).

bh) CI-HRMS:

Calculated: 313.1665

Found: 313.6664 (M + H).

bi) CI-HRMS:

Calculated: 400.2349

Found: 400.2346 (M + H);

NMR (CDCl 3 , 300 MHz): 7.1 (d, 1H, 5=7), 6.9-6.75 (m, 3H), 4.7-4.55 (m, 1H), 3.8

(s, 3H), 3.7-3.5 (m, 4H), 3.45 (s, 3H), 3.35 (s, 3H), 2.5 (s, 3H), 2.3 ( s, 3H), 2.2 (s, 3H), 2.1-1.95 (m, 2H).

bj) CI-HRMS:

Calcd: 377.2090 Found: 377.2092 (M + H);

Analysis:

NMR (CDCl 3 , 300 MHz): 7.1 (d, 1H, J=8), 6.9 (d, 1H, J=1), 6.8 (dd, 1H, J=8,1),

4.55-4.4 (m, 2H), 3.85 (s, 3H), 3.4-3.3 (m, 1H), 2.85 (t, 2H, 5=7), 2, 5 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.1-1.0 (m, 2H), 0.85-0.75 (m, 2H) .

bk) CI-HRMS:

Calcd: 413.2427 Found: 413.2416 (M + H);

NMR (CDCl 3 , 300 MHz): 7.1 (d, 1H, J=8), 6.85 (d, 1H, J=1), 6.75 (dd, 1H, J=8,1),

4.6 (m, 1H), 3.85 (s, 3H), 3.75-3.6 (m, 4H), 3.6 (q, 4H, J=7), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.25 (t, 6H, J=7).

bl) CI-HRMS:

Calcd: 420.1802 Found: 420.1825 (M+H).

bm) CI-HRMS:

Calculated: 390.1697 Found: 390.1707 (M + H).

bn) CI-HRMS:

Calculated: 397.1465 Found: 397.1462 (M + H).

bo) CI-HRMS:

Calcd: 360.1513 Found: 360.1514 (M+H).

bp) CI-HRMS:

Calcd: 374.1748 Found: 374.1737 (M + H).

bq) CI-HRMS:

Calculated: 479.1155 Found: 479.1154 (M + H).

br) CI-HRMS:

Calcd: 463.1219 Found: 463.1211 (M + H);

Analysis:

bs) CI-HRMS:

Calculated: 433.1113

Found: 433.1114 (M, <79>Br).

bt) NH3-CI MS:

Calculated: 406

Found: 406 (M + H)<+>;

NMR (CDCl 3 , 300 MHz): δ 7.28 (d, J=10Hz, 1H), 7.03 (d, J=8Hz, 1H), 6.96 (s,

1H), 6.7 (d, J=9.1H), 4.63 (m, 1H), 3.79 (s, 3H), 3.6 (m, 4H), 3.42 s, 6H) , 2.47 (p, 3H), 2.32 (p, 3H).

EXAMPLE 431

Preparation of 2,4,7-dimethyl-8-(4-methoxy-2-methylphenyl)[1,5-a]-pyrazolo-1,3,5-triazine

(Formula 1, where R<3> is CH3, R<1> is CH3, Z is C-CH3, Ar is 2,4-dimethylphenyl)

5-Acetamidino-4-(4-methoxy-2-methylphenyl)-3-methylpyrazole, acetic acid salt (602 mg, 2 mmol) was mixed with 10 mL saturated NaHCO3 solution. The aqueous mixture was extracted with EtOAc three times. The combined organic layers were dried over MgSO 4 , filtered and concentrated in vacuo. The residue was taken up in 10 mL of toluene and triethyl orthoacetate (0.26 g, 3 mmol) was added to the suspension. The reaction mixture was heated to reflux under a nitrogen atmosphere and stirred for 16 hours. After cooling to ambient temperature, the reaction mixture was concentrated under vacuum and an oily solid was obtained. Column chromatography with CHCl3:MeOH, 9:1, gave, after removal of the solvent under vacuum, a yellow, viscous oil (Rf = 0.6, 210 mg, 37% yield: NMR (CDCl3,300 MHz): 7.15 ( d, 1H, J=8), 6.9 (d, 1H, J=l), 6.85 (dd, 1H, J=8,l), 3.85

(s, 3H), 2.95 (s, 3H), 2.65 (s, 3H), 2.4 (s, 3H), 2.15 (s, 3H);

CI-HRMS:

Calculated: 283.1559

Found: 283.1554 (M + H).

EXAMPLE 432

7-hydroxy-5-methyl-3-(2-chloro-4-merylphenyt)pyrazolo[1,5-a]pyridinidine

(Formula 1 where A is CH, R<1> is Me, R<3> is OH, Z is C-Me, Ar is 2-chloro-4-methylphenyl)

5-Amino-4-(2-chloro-4-methylphenyl)-3-methylpyrazole (1.86 g, 8.4 mmol) was dissolved in 30 mL of glacial acetic acid with stirring. Ethyl acetoacetate (1.18 mL, 9.2 mmol) was then added dropwise to the resulting solution. The reaction mixture was then heated to reflux temperature and stirred for 16 hours and then cooled to room temperature. 100 ml of ether was added and that

resulting precipitate was collected by filtration. Drying under vacuum gave a white solid (1.0 g, 42% yield).

NMR (CDCl 3 , 300 MHz): 8.70 (br.s, 1H), 7.29 (s, 1H), 7.21-7.09 (m, 2H), 5.62 (s, 1H),

2.35 (s, 6H), 2.29 (s, 3H);

CI-MS: 288 (M+H).

EXAMPLE 433

7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyridimidine

(Formula 1 where A is CH, R<1> is Me, R<3> is Cl, Z is C-Me, Ar is 2-chloro-4-methylphenyl)

A mixture of 7-hydroxy-5-methyl-3-(2-chloro-4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (1.0 g, 3.5 mmol), phosphorus oxychloride (2.7 g , 1.64 mL, 17.4 mmol), N,N-diethylaniline (0.63 g, 0.7 mL, 4.2 mmol) and 20 mL of toluene were stirred under reflux for 3 h and then cooled to ambient temperature. The volatiles were removed under vacuum. Flash chromatography with EtOAc:hexane, 1:2, on the residue gave 7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (900 mg, 84% yield) as a yellow oil.

NMR (CDCl 3 , 300 MHz): 7.35 (s, 1H), 7.28-7.26 (m, 1H), 7.16 (d, 1H, J=7), 6.80 (s,

1H), 2.55 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H);

CI-MS: 306 (M+H).

EXAMPLE 434

7-(pentyl-3-amino)-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,S-a]pyrimidine (Formula 1, where A is CH, R1 is Me, R3 is pentyl- 3-amino, Z is C-Me, Ar is 2-chloro-4-methyl phenyl)

A solution of 3-pentylamine (394 mg, 6.5 mmol) and 7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine (200 mg, 0, 65 mmol) in 10 ml of dimethylsulfoxide

(DMSO) was stirred at 150°C for 2 hours and then cooled to room temperature. The reaction mixture was then poured into 100 ml of water and mixed. Three extractions with dichloromethane, washing the combined organic layers with brine, drying over MgSO4, filtration and removal of the solvent in vacuo gave a yellow solid. Flash chromatography with EtOAc:hexanes, 1:4 gave a white solid (8140 mg, 60% yield) mp 139-141°C.

NMR (CDCl 3 , 300 MHz): 7.32 (s, 1H), 7.27 (d, 1, J=8), 7.12 (d, 1H, J=7), 6.02 (d, 1H ,

J=9), 5.78 (s, 1H), 3.50-3.39 (m, 1H), 2.45 (s, 3H), 2.36 (s, 6H), 1.82-1 .60 (m, 4H), 1.01 (t, 6H, J=8);

Analysis for C20H25CIN4:

The examples summarized in table 2 can be prepared by the methods outlined in examples IA, IB, 432, 433 and 434. Commonly used abbreviations are: Ph for phenyl, Pr for propyl, Me for methyl, Et for ethyl, Bu for butyl, Ex . for example, EtOAc for ethyl acetate.

Notes to table 2:

b) CI-HRMS:

Calculated: 423.1355

Found: 423.1337 (M + H).

c) Analysis:

d) Analysis: e) Analysis: f) Analysis:

h) CI-HRMS:

Calculated: 337.2388

Found: 337.2392 (M + H).

i) Analysis:

j) Analysis: k) Analysis:

1) CI-HRMS:

Calcd: 403.1899 Found: 403.1901 (M +H).

m) Analysis:

n) Analysis: o) Analysis: p) Analysis: q) Analysis:

r) CI-HRMS:

Calculated: 353.2333 Found: 353.2341 (M + H).

s) Analysis:

t) Analysis:

u) CI-HRMS:

Calculated: 399.2398 Found: 399.2396 (M + H).

v) CI-HRMS:

Calculated: 399.2398 Found: 399.2396 (M + H).

w) CI-HRMS:

Calculated: 383.2450 Found: 383.2447 (M + H).

x) CI-HRMS:

Calcd: 403.1887 Found: 403.1901 (M+H).

y) CI-HRMS:

Calcd: 293.1919 Found: 295.1923 (M+H).

z) Analysis:

aa) Analysis:

ab) CI-HRMS:

Calculated: 337.2017 Found: 337.2028 (M + H).

ac) CI-HRMS:

Calculated: 403.1893 Found: 403.1901 (M + H). ad) Analysis: ae) Analysis: ag) Analysis: ah) Analysis: ai) Analysis:

aj) CI-HRMS:

Calculated: 369.2278 Found: 369.2291 (M + H). ak) Analysis:

The examples summarized in table 3 can be prepared by the methods outlined in examples 1,2,3 or 6. Commonly used abbreviations are: Ph for phenyl, Pr for propyl, Me for methyl, Et for ethyl, Bu for butyl, Ex . for example.

Notes to table 3:

a) CI-HRMS:

Calculated: 367.2610

Found: 367.2607 (M + H).

b) CI-HRMS:

Calculated: 384.2400

Found: 384.2393 (M + H).

c) CI-HRMS:

Calculated: 404.1853

Found: 404.1844 (M + H).

d) CI-HRMS:

Calculated: 381.1594

Found: 381.1596 (M + H);

Analysis:

e) CI-HRMS:

Calculated: 369.1594

Found: 369.1576 (M + H).

f) CI-HRMS:

Calculated: 354.2216

Found: 354.2211 (M + H).

g) CI-HRMS:

Calculated: 410.1072

Found: 410.1075 (M + H).

h) CI-HRMS:

Calculated: 414.2427

Found: 414.2427 (M + H).

i) CI-HRMS:

Calculated: 368.2372 Found: 368.2372 (M + H).

j) CI-HRMS:

Calcd: 384.1955 Found: 384.1947 (M + H).

k) CI-HRMS:

Calculated: 391.2168 Found: 391.2160 (M + H).

1) CI-HRMS:

Calculated: 335.1984

Found: 335.1961 (M + H).

m) CI-HRMS:

Calculated: 382.0759

Found: 382.0765 (M + H).

n) NH3-CIMS:

Calculated: 360

Found: 360(M + H)<+>.

o) NH3-CIMS:

Calculated: 374

Found: 374(M + H)<+>;

NMR (CDCl3,300 MHz): δ 7.29 (d, J=8.4Hz, 1H), 7.04 (dd, J=1.8, 8Hz, 1H), 6.96

(d, J=1.8 Hz, 1H), 6.15 (d, J=10.1H), 4.19 (m, 1H), 3.81 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H), 1.65 (m, 4H), 0.99 (t, J=7.32Hz, 6H).

p) NH3-CIMS:

Calculated: 390

Found: 390 (M + H)<+>;

NMR (CDCl3,300 MHz): δ 7.28 (d, J=8Hz, 1H), 7.03 (d, J=8Hz, 1H), 6.96 (s, 1H),

6.52 (d, J=9Hz, 1H), 4.36 (m, 1H), 3.8 (s, 3H), 3.55 (m, 2H), 3.39 (s, 3H), 2 .47 (s, 3H), 2.32 (s, 3H), 1.76 (m, 2H), 1.01 (t, J=7.32Hz, 3H).

q) CI-HRMS:

Calculated: 354.2294

Found: 354.2279 (M + H)<+.>

r) CI-HRMS:

Calculated: 340.2137

Found: 340.2138 (M + H)<+>.

s) CI-HRMS:

Calculated: 436.1307

Found: 436.1296 (M + H)<+>.

The examples listed in table 4 can be prepared by the methods outlined in examples IA, IB, 432, 433 and 434. Commonly used abbreviations are: Ph for phenyl, Pr for propyl, Me for methyl, Et for ethyl, Bu for butyl, Ex . for example, EtOAc for ethyl acetate.

The examples in table 6 can be prepared by the methods illustrated in examples IA, IB, 2,3,6,431,432,433 and 434 or by suitable combinations thereof. Commonly used abbreviations are: Ph for phenyl, Pr for propyl, Me for methyl, Et for ethyl, Bu for butyl, Ex. for example.

Applicability

CRF-R1 Receptor Binding Assay for Assessment of Biological Activity The following is a description of the isolation of cell membranes containing cloned human CRF-R1 receptors for use in the standard binding assay as well as a description of the assay itself.

Messenger RNA was isolated from human hippocampus. mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to

stop codons. The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from which the insert was retrieved using XhoI + XbaI and cloned into the XhoI + XbaI sites of vector pm3ar (containing a CMV promoter, SV40 'f- the splice and early poly-A signals, an Epstein-Barr viral origin of replication and a hygromycin-selectable marker). The resulting expression vector, named phchCRFR, was transfected into 293EBNA cells and cells retaining the episome were selected in the presence of 400 µM hygromycin. Cells that survived 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay as described below. Individual aliquots containing about 1 x 10 Q of the suspended cells were then centrifuged to form a pellet and then deep frozen.

For the binding assay, a frozen pellet as described above containing 293EBNA cells transfected with hCRFR1 receptors was homogenized in 10 ml of ice-cold tissue buffer (50 mM HEPES buffer, pH 7.0, containing 10 mM MgCl2, 2 mM EGTA, 1 µg/l aprotitin, 1 ug/ml leupeptin and 1 ug/ml pepstatin). The homogenate is centrifuged at 40,000 x G for 12 minutes and the resulting pellet is rehomogenized in 10 ml of tissue buffer. After further centrifugation at 40,000 x G for 12 minutes, the pellet was resuspended to a protein concentration of 360 µg/ml for use in the assay.

Binding analyzes were carried out in 96-well plates, where each well had a capacity of 300 ul. To each well was added 50 µl of test drug dilutions (the final concentration of the drugs was in the range 10<*10> to 10"5 M), 100 µl of l25I-ovine-CRF (<!25>I-o-CRF) (final concentration 150 pM ) and 150 µl of the cell homogenate described above. Plates were then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (pre-moistened with 0.3% polyethyleneimine) using a suitable cell harvester. The filters are rinsed twice with an ice-cold analysis buffer before removal of individual filters and assessment for radioactivity on a y-counter.

Curves of inhibition of <I25>I-o-CRF binding to the cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND (P.J. Munson and D. Rodbart, "Anal. Biochem.", 107:220 (1980)), which gives K; values for inhibition which are then used to assess biological activity.

A compound is considered to be active if it has a Kj value of less than approx.

10,000 nM for inhibition of CRF.

Inhibition of CRF-stimulated adenylate cyclase activity

Inhibition of CRF-stimulated andeneylate cyclase activity can be carried out as described by G. Battaglia et al., "Synapse", 1:572 (1987). Briefly, assays are carried out at 37°C for 10 minutes in 200 ml buffer containing 100 mM Tris-HCl (pH 7.4 at 37°C), 10 mM MgCl2, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (BMX), 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 (approx. 40-60 mg protein). The reactions are initiated by the addition of 1 mM ATP[<32>P]ATP (around 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. To monitor recovery of cAMP, 1 µl of [<3>H]cAMP (around 40,000 dpm) is added to each tube for separation. The separation of [32P]cAMP from [<3Z>P]ATP is carried out by sequential elution over Dowex and aluminum oxide columns.

In vivo biological analysis

The in-vivo activity of the compounds according to the invention can be estimated using one of the biological assays available and accepted in the art. Illustrative of these tests are the "Acoustic Startle Assay", the "Stair Climbing Test" and the "Chronic Administration Assay". These and other models which can be used for testing compounds according to the invention are outlined by C.W. Berridge and A.J. Dunn in "Brain Research Reviews", 15:71 (1990). Compounds can be tested in any species of rodent or small animal.

Compounds according to the invention can be used in the treatment of imbalances associated with abnormal levels of corticotropin-releasing factor in patients suffering from depression, affective deficits and/or anxiety.

The compounds of the invention can be administered to treat these abnormalities in a manner that provides contact between the active ingredient and the agent's site of action in a mammal's body. The compounds may be administered by any conventional means available for use in pharmaceuticals, either as individual therapeutic agents or in combination thereof. They may 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 use and known factors such as the pharmacodynamic nature of the particular agent, its mode and route of administration; recipient's age, weight and health; nature and degree of symptoms; type of existing treatment; treatment frequency; and desired effect. For use in the treatment of said diseases or conditions, the compounds according to the invention can be administered daily orally in a dosage of active ingredient of 0.002 to 200 mg/kg body weight. Typically, a dose of 0.01 to 10 mg/kg in divided doses 1 to 4 times daily, or in delayed release formulations, will be effective in achieving the desired pharmacological effect.

Dosage forms (preparations) that are suitable for administration contain from around 1 mg to 100 mg of active ingredient per unit. In these pharmaceutical preparations, the active ingredient will usually be present in an amount of around 0.5 to 95% by weight, calculated on the total weight of the preparation.

The active ingredient can be administered orally in solid dosage form, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups and/or suspensions. The compounds of the invention can also be administered parenterally in sterile, liquid dosage formulations.

Gelatin capsules can be used containing the active ingredient and a suitable carrier such as, but not limited to, lactose, starch, magnesium stearate, steric acid or cellulose derivatives. Corresponding diluents can be used to produce compressed

pills. Both tablets and capsules can be produced as products with delayed release

in administration to provide continuous release of medication over a certain period of time. Pressed

tablets can be coated with sugar or with a film to mask any unpleasant taste or be used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablets in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain coloring or flavoring agents to increase acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glu-cose) and related sugar solutions, and glycols such as propylene glycol or polyethylene-

in glycol, suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizers and, if necessary, lubricants. Antioxidants such as sodium bisulphite, sodium sulphite or ascorbic acid, either alone or in combination, are

suitable stabilizers. Citric acid and its salts as well as EDTA are also used. IN

in addition, parenteral solutions containing preservatives such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Suitable pharmaceutical carriers are described in "Remington's Pharmacuetical Sciences", A.

Osol, a standard reference in this area.

in

Usable pharmaceutical dosage forms for administering the compounds according to the invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standard two-part hard gelatin capsules with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate in each capsule.

Soft gelatin capsules

A mixture of active ingredient in an edible oil such as soybean oil, cottonseed oil or

olive oil, prepared and injected using a positive displacement, was pumped into

; gelatin to form soft gelatin capsules containing 100 mg of active ingredient. The capsules were then washed and dried.

Pills

A large number of tablets are prepared by conventional procedures so that unit dose-

in none was 100 mg of 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 of lactose. Suitable coatings can be added to increase palatability or delay adsorption.

The compounds according to the invention can also be used as reagents or standards in the biochemical study of neurological functions, dysfunctions and diseases.

Although the invention has been described and explained using certain preferred embodiments, other embodiments will be obvious to those skilled in the art. The invention is therefore

not limited to the particular embodiments described and exemplified, but

i can be modified or varied without going beyond the spirit and scope of the invention as defined in the attached claims.

Claims (20)

1. Compounds characterized by formula (1): and isomers thereof, stereoisomeric forms thereof or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein: A is N or CR; Z CR<2>; Ar is phenyl or pyridyl, optionally substituted with 1 to 5 R<4> groups and each Ar is bonded to an unsaturated carbon atom; R<1> is C 1 -C 4 alkyl; R<2> is C 1 -C alkyl; R<3> is selected from: -OR<7>, halogen, NR<8>COR<7>, NR<6>R<7>, NR<6a>R<7a> or -C 1-10 alkyl, each optionally substituted with 1 to 3 substituents independently at each occurrence selected from CO2R<15> or NR16R<15>; R<4> is independently selected at each occurrence from: CMOalkyl, C3-6cycloalkyl, halo, NR6R7 or OR<7>; R6 and R7, R<68> and R<7a> independently at each occurrence are selected from: -H, -Ct.toalkyl, C.sub.1-cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently at each occurrence selected from cyano, OR15, NR<16>R1<5> and phenyl or alternatively NR^<7> and NR<6a>R<7a> independently are morpholine; R Q independently at each occurrence is selected from H or C-1 alkyl; and R<1>5 and R1<6> each independently at each occurrence is selected from H or C1-6 alkyl, provided that when A is CR, Z is CR<2>, R<2> is C 1-6 alkyl, R<7> is NR<2>COR<7> and Ar is phenyl, R<7>or R<7a> is not phenyl. 2. Compound according to claim 1, characterized in that Ar is phenyl or pyridyl optionally substituted with 1 to 4 R<4->substituents. 3. Compound according to claim 2, characterized in that Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R<1> and R<2> are CH3, and R<3> is NR6* R7a. 4. Pharmaceutical preparation, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to one of claims 1, 2 or 3. 5. Compound according to claim 1, characterized in that R3 is NR^R<7>" or OR<7>. 6. Compound according to claim 5, characterized in that R7a at each occurrence is independently selected from: -H, - Cs-C10alkyl or C4-C12cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently at each occurrence selected from cyano, OR<15>, NR16R15 and phenyl. 7. Compound according to claim 5, characterized in that R6a and R7<a> are identical and are: - Ci-C4 alkyl, each optionally substituted with 1 to 3 substituents independently at each occurrence selected from cyano, OR<!5>, NR<,6>R <15> and phenyl. 8. Compound according to claim 5, characterized in that R7a is selected from among: -Ci-C4alkyl and each such Ci-C4alkyl is substituted with 1-3 substituents at each occurrence independently selected from cyano, OR15, NR<,6>R<15> and <f >enyl. 9. Compound according to claim 5, characterized in that R<6a> and R<7a> are independently H or Ci-Cioalkyl, each Ci-Cioalkyl optionally being substituted with 1 to 3 substituents independently at each occurrence selected from cyano, OR15, NR< I6>R<15> and halo. 10. Compound according to claim 1, characterized in that Ar is optionally substituted with 1 to 4 R<4->substituents, and R<3> is NR^R<78> or OR<7>. 11. Compound according to claim 10, characterized in that R<7a >in each occurrence is independently selected from: -H, -C5-C10alkyl and C4-C12cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently at each occurrence selected from cyano, OR'<5>, NR16R15 and phenyl. 12. Compound according to claim 10, characterized in that R6a and R<7a> are identical, and are: -Ci-C4alkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from cyano, OR<15> NR<16>R15 and phenyl. 13. Compound according to claim 10, characterized by atatR<7a>is selected from: -C|-C4alkyl and each such C1-C4alkyl is substituted with 1-3 substituents at each occurrence independently selected from cyano, OR<15>, NR,<6R15 > and phenyl. 14. Compound according to claim 10, characterized in that R6a and R<7a> are independently H or C1-C10alkyl, each such C1-C10alkyl being optionally substituted with 1 to 3 substituents independently at each occurrence selected from cyano, OR<15>, NR1 V5 and hello. 15. Compound according to claim 1, characterized* by formula (50) selected from the group comprising: a compound of formula (50) wherein R3 is -NHCH(n-Pr)2, R<43> is Cl, R<4b> is H, R<40> is Cl, R4derHogR4eer H; a compound of formula (50) where R3 is -N(Et)(n-Bu), R<4a> is Cl, R<4b> is H, R<4c> is Cl, R<4d>erHogR<4e>erH; a compound of formula (50) where R<3> is -(n-Pr)(CH2cPr), R<4a> is Cl, R<4b> is H, R<40> is Cl, R<4d>erHogR<4e>erH; a compound of formula (50) where R<3> is -N(CH2CH2OMe)2, R<48> is Cl, R<4b> is H, R<4c> is Cl, R<4d>erHogR<4B>erH; a compound of formula (50) where R<3> is -NHCH(Et)(n-Bu), R<4*> is Cl, R4b is H, R<4c> is Cl, R<4>" is H and R4e is H; a compound of formula (50) wherein R<3> is -NHCH(Et)(CH2OMe), R<4a> is Cl, R<4b> is H, R<4c> isCl, R<4d>isHogR<4c>isH; a compound of formula (50) where R<3> is -NHCH(CH2OMe)2, R<4a> is Cl, R<4b> is H, R<40> is Cl.R^erHogR^erH; a compound of formula (50) where R3 is -N(Et)2, R<4>" is Cl, R<4b> is H, R<40> is Cl, RM is H and R<4*> is H; a compound of formula (50) where R<3> is -NHCH(CH2OEt)2, R<4a> is Cl, R<4b> is H, R<40> is Cl, R<46> is H and R46 is H; a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Cl, R<4b> is H, R<4c> is Cl, R<4d > is H and R46 is H; a compound of formula (50) where R<3> is -N(Me)(Ph), R<4a> is Cl, R<4b> is H, R<40> is Cl, R<4d > isHogR<4e>isH; a compound of formula (50) where R<3> is -N(n-Pr)2, R<4a> is Cl, R<4b> is H, R<4c> is Cl, R<4d> is HogR^erH; a compound of formula (50) where R<3> is -NHCH(Et)(n-Pr), R<4a> is Cl, R<4b> is H, R<40> is Cl, R<4d>erHogR<4e>erH; a compound of formula (50) where R<3> is -NHCH(CH2OMe)2, R<4a> is Me, R<4b> is H, R<4>" is Me, R<4d>is HogR<4e>isMe; a compound of formula (50) where R<3> is -NHCH(CH2OMe)2, R<4a> is Me, R<4b> is H, R<4c > isMe,R<4d>isHogR<4e>isH; a compound of formula (50) where R3 is -N(CH2CH2OMe)2, R<4a> is Me, R<4b> is H, R<*0> is McR^erHogR^erH; a compound of formula (50) where R3 is -NHCH(Et)(CH2OMe), R4a is Me, R<4b> is H, R^erMe.R^erHogR^erH; a compound of formula (50) where R3 is -NHCH(Et)2, R<4a> is Me, R<4b> is H, R<4c> is Me, R^erHogR^erH; a compound of formula (50) where R3 is -OEt, R<43> is Cl, R<4b> is H, R<4c> is Cl, R<4d> is H and R^ is H; a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Me, R<4b> is H, R<4c> is Me, R<4*> is HogR<4e>erH; a compound of formula (50) where R3 is -N(CH2CN)2, R<4a> is Me, R4b is H, R<40> is Me, R<4d>erHogR<4e>erH; a compound of formula (50) where R<3> is -NHCH(Me)(CH2OMe), R<48> is Me, R<4b> is H, R<40> is Me, R<4>" is H and R4c is H; a compound of formula (50) where R3 is -OCH(Et)(CH2OMe), R4a is Me, R4b is H, R<4c > isMe,R<4d>isHogR<4e>isH; a compound of formula (50) where R3 is -N(n-Pr)(CH2cPr), R<4a> is Me, R<4b> is H, R<46> is McR^erHogR^erH; a compound of formula (50) where R<3> is -NHCH(Me)(CH2N(Me)2, R<43> is Me, R<4b> is H, R<4c> is Me, R<4d> is H and R<46> is H; a compound of formula (50) where R<3> is -N(cPr)(CH2CH2CN), R<4a> is Me, R4b is H, R<4c > isMe,R<4d>isHogR<4c>isH; a compound of formula (50) where R<3> is -N(n-Pr)(CH2CH2CN), R<4a> is Me, R<4b> is H, R4c is Me, R4d is H and R4c is H; a compound of formula (50) where R3 is -N(n-Bu)(CH2CN), R<4a> is Me, R<4b> is H, R<4c> is Me, R<4d>erHogR<4e>erH; a compound of formula (50) where R3 is -NHCH(Et)(CH2OMe), R<4a> is Me, R<4b> is H, R<40> is Me, R4*1 is H and R<4e> is Me; a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Me, R<4b> is H, R<4c> is Me, R^erHogR^erMe; a compound of formula (50) where R<3> is -N(CH2CH2OMe)2, R<4a> is Me, R<4b> is H, R<40> is McR^erHogR^erMe; a compound of formula (50) where R3 is -NHCH(CH2OMe)2, R<48> is Br, R<4b> is H, R<4c> is OMe.R^erHogR^erH; a compound of formula (50) where R<3> is -NHCH(Et)(CH2OMe), R<4a> is Br, R<4b> is H, R<46 > is OMe, R<4*1> is H and R4* is H; a compound of formula (50) where R<3> is -N(Et)2, R<43> is Me, R<4b> is H, R<4c> is Me, R<4d> is HogR4eer Me; a compound of formula (50) where R3 is -NHCH(CH2OEt)2, R<4a> is Me, R<4b> is H, R40 is Me.R^erHogR^erH; a compound of formula (50) where R<3> is -NHCH(CH2CH2OMe)2, R<4>" is Me, R4b is H, R4<0> is Me, R<4d> is H and R<4*> is Me; a compound of formula (50) where R3 is morpholino, R<4a> is Me, R4b is H, R<4c> is Me, Ru isHogR<4e>isH; a compound of formula (50) where R3 is -N(CH2CH2OMe)2, R<4a> is Br, R<4b> is H, R<4c> is OMcR^erHogR^erH; a compound of formula (50) where R<3> is -NHCH(Et)2, R<43> is Br, R<4b> is H, R<4c> is OMe, R^erHogR^erH; a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Br, R<4b> is H, R<40> is OMe, R4d is HogR<4c>erH; a compound of formula (50) where R3 is -NH(c-Pr), R<4a> is Me, R<4b> is H, R<4c> is Me, R<4d > is H and R4* is H; a compound of formula (50) where R<3> is -NHCH(CH2OMe)2, R<4a> is CN, R<4b> is H, R<40 > is OMe, R<4d> is H and R4e is H; a compound of formula (50) where R<3> is -N(c-Pr)(CH2CH2CN), R<4>" is Me, R<4b> is H, R<4c> is Me, R4<*> is H and R4* is Me; a compound of formula (50) where R<3> is -NCH(CH2OMe)2, R<4a> is Me, R<4b> is H, R<46> is Br,R4derHogR4eer H; a compound of formula (50) where R3 is -NHCH(CH2OMe)(CH2CH2OMe), R4* is Me, R<4b> is H, R<4c> is Br, R<4d> is H and R4e is H; a compound of formula (50) where R<3> is -NHCH(CH2OMe)2, R<4a> is Me, R<4b> is H, R<4c > is OMe, R<4*5> is Me and R4e is H; a compound of formula (50) where R<3> is -N(CH2CH2OMe)2, R<4a> is Me, R<4b> is H, R4*5 is OMe, R<4d> is Me and R4* is H; a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Me, R<4b> is H, R<40> is OMe, R4derMe and R4eerH; a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Me, R<4b> is H, R<4*> is OMe, R<4* > is Me and R4eerH; a compound of formula (50) where R3 is -NHCH(CH2OMe)2, R<4a> is Cl, R<4b> is H, R<45> is Me, R<4d>erHogR<4e>erH; a compound of formula (50) where R<3> is -NHCH(Et)(CH2OMe), R<4a> is Cl, R<4b> is H, R<4c > isM^R^erHogR^erH; a compound of formula (50) where R<3> is -NH(CH2CH2OMe)2, R<4a> is CI, R4b is H, R<4c> isMe,R<4d>isHogR<4e>isH; a compound of formula (50) where R<3> is -NHCH(CH2CH2OMe), R<4a> is Cl, R<4b> is H, R<4c> is Me, R<4*1> is H and R<4e> is H; a compound of formula (50) where R<3> is -N(c-Pr)(CH2CH2CN), R<4a> is Me, R<4b> is H, R<41> is OMe, R<4d> is Me and R4e is H; a compound of formula (50) where R<3> is -N(c-Pr)(CH2CH2CN), R<4a> is Cl, R<4b> is H, R<4c > isCLR^isHogR^isH; a compound of formula (50) where R<3> is -(S)-NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R<4b> is H, R<4*5> is Cl, R<4d> is H and R4* is H; a compound of formula (50) where R<3> is -NHCH(CH2OMe)(CH2CH2OMe), R4a is <C>1, R<4b> is H, R<40> is Cl, R<4d> is H and R4e is H; a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Me, R<4b> is H, R<4c> is Br, R^erHogR^erH; a compound of formula (50) where R<3> is -NH(CH2CH2OMe)2, R<4a> is Me, R<4b> is H, R<4c > is Br, R<4d> is H and R<46> is H; a compound of formula (50) where R3 is -NH(CH2OMe)(CH2-iPr), R41 is Me, R4b is H, R<46> is Me, R<4d> is H and R<4c> is H; a compound of formula (50) where R<3> is -N(CH2CH2OMe)2, R<4*> is Me, R<4b> is H, R<40> is H.R^erHogR^erH; a compound of formula (50) where R<3> is -N(CH2CH2OMe)2, R<4a> is Me, R<4b> is H, R<4c> is NMe2,R<4d>erHogR<4e>erH; a compound of formula (50) where R<3> is -NHCH(CH2OMe)(n-Pr), R4a is Me, R<4b> is H, R<40> is Me, R<4d> is H and R<4*> is H; a compound of formula (50) where R<3> is -NCH(CH2OEt)(Et), R<4a> is Me, R<4b> is H, R<4c > isM^R^erHogR^erH; a compound of formula (50) where R<3> is -NHCH(CH2OMe)(CH2CH2OMe), R<4a> is Me, R<4b> is H, R<40> is NMe, R<4d> is H and R46 is H; a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Me, R<4b> is H, R<4c> is Cl, R<4d> is HogR^erH; a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Me, R<4b> is H, R<4c> is H, R^erHogR^erH; a compound of formula (50) where R<3> is -N(CH2CH2OMe)2, R<41> is Me, R4<b> is H, R<46> is Cl.R^erHogR^erH; a compound of formula (50) where R<3> is -NHCH(CH2OMe)2, R<43> is Me, R<4b> is H, R<4c > isCl.R^erHogR^erH; a compound of formula (50) where R3 is -N(Et)2, R<4a> is Me, R4b is H, R<40> is Br, R<4d> is HogR^erH; a compound of formula (50) where R3 is -N(Et)2, R<4a> is Cl, R<4b> is H, R<40> is Me, R<4d> is HogR<4e>erH; a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Cl, R<4b> is H, R<4c> is Me, R<4d>isHogR<4c>isH; a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Me, R<4b> is H, R<40> is NMe^R^erHogR^erH; a compound of formula (50) wherein R3 is -(S)-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R<4b> is H, R<40> is Me, R<4d> is H and R<46> is H; a compound of formula (50) where R3 is -NHCH(CH2OMe)(CH2CH2OMe), R<4a> is Me, R<4b> is H, R40 is Me, R4*5 is H and R4e is H; a compound of formula (50) where R<3> is (S)-NHCH(CH2OMe)(CH2CH2OMe), R<4a> is Me, R<4b> is H, R<4c> is Cl, R<4d> is H and R<4c> is H; a compound of formula (50) where R3 is -NHCH(CH2OMe)(CH2CH2OMe), R<4a> is Me, R<4b> is H, R<4c> is Cl, R4*1 is H and R46 is H; a compound of formula (50) where R<3> is -N(c-Pr)(CH2CH2CN), R<4a> is Me, R<4b> is H, R<4c> is Cl, R4*1 is H and R4e is H; a compound of formula (50) where R<3> is -NH(Et)(CH2CN), R<4a> is Me, R<4b> is H, R<4c> is Cl, R<4d>erHogR<4e>erH; a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Me, R4b is Me, R<4c> is OMe, R<4d > isHogR<4c>isH; a compound of formula (50) where R<3> is -N(CH2CH2OMe)(CH2CH2OH), R<4a> is Cl, R<4b > is H, R<4c> is Cl, R<4d> is H and R46 is H; a compound of formula (50) where R<3> is -N(CH2CH2OMe)2, R<4a> is Me, R<4b> is Me, R<4* > is OMe, R<4d> is H and R<4c> is H; a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Me, R<4b> is Me, R<4c> is OMe,R<4d>erHogR<4c>erH; a compound of formula (50) where R3 is -N(CH2c-Pr)(n-Pr), R<4a> is Me, R<4b> is H, R<40> is Cl, R<4d>erHogR<4e>erH; a compound of formula (50) where R<3> is -N(c-Pr)(CH2CH2CN), R<4a> is Me, R<4b> is Me, R<4c> is OMe, R<4d> is H and R<4*> is H; a compound of formula (50) where R<3> is -NHCH(Et)2, R<4a> is Cl, R<4b> is H, R<4c> is OMe, R^erHogR^erH; a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Cl, R<4b> is H, R<4c> is OMe, R<4d> is HogR<4e>erH; a compound of formula (50) where R<3> is -N(CH2CH2OMe)2, R<4a> is Cl, R<4b> is H, R<4c> is OMe, R4*1 is H and R<4*> is H; a compound of formula (50) where R<3> is -NHCH(Et)(CH2OMe), R<4*> is Cl, R<4b> is H, R4*1 is OMe, R4*1 is H and R4* is H; a compound of formula (50) where R<3> is -N(Et)2, R<4a> is Cl, R<4b> is H, R<4c> is CN, R* 6 is HogR^erH; a compound of formula (50) where R<3> is -N(c-Pr)(CH2CH2CN), R<4>" is Cl, R<4b> is H, R<4c > is OMe, R<4d> is H and R4e is H; a compound of formula (50) where R<3> is -NHCH(CH2OH)2, R4<a> is Cl, R<4b> is H, R<40> is CLR^erHogR^erH; and a compound of formula (50) wherein R<3> is -N(CH2CH2OMe)2, R<4*> is Me, R<4b> is H, R<4c> is OMe.R^erHogR^erH. 16. Compound according to claim 1, characterized in that it is 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo -1,3,5-triazine. 17. Compound according to claim 1, characterized in that it is 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a] -pyrazolo-1,3,5-triazine. 18. Pharmaceutical preparation, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claims 1 to 17. 19. Use of compounds according to claims 1 to 17, for the preparation of drugs for the treatment of anxiety, depression and other psychiatric, neurological deficiencies as well as the treatment of immunological, cardiolovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress. 20. Use of compounds according to claims 1 to 17, for the preparation of medicaments for the treatment of affective deficiencies, anxiety, depression, headaches, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immunosuppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa and other eating disorders, 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 trauma, epilepsy, stroke, ulcer, amyo tro fish lateral sclerosis, hypoglycemia or a deficiency can be accomplished or alleviated by antagonizing CRF, including but not limited to deficiencies induced or facilitated by CRF.